HHS Publication FDA 83-4159 Investigational Device Exemptions Regulatory Requirements for Medical Devices Prepared by Office of Small Manufacturers Assistance Office of Medical Devices January 1983 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Food and Drug Administration \ National Center for Devices and Radiological Health - Rockville, Maryland 20857 Rise lc I'9%73 FOREWORD PUR L In October 1982, FDA established the National Center for Devices and Radiological Health (NCDRH) by merging the Bureau of Medical Devices (now the Office of Medical Devices) and the Bureau of Radiological Health (now the Office of Radiological Health). Both Offices develop and implement national programs to protect the public health. The Office of Medical Devices is concerned with assuring the safety, effectiveness, and proper labeling of medical devices, while the Office of Radiological Health works to control unnecessary human exposure to potentially hazardous ionizing and nonionizing radiation and to ensure the safe, efficacious use of such radiation. The Center publishes the results of its work in scientific journals and in its own technical reports. These reports provide a mechanism for disseminating results of NCDRH and contractor projects. They are sold by the Government Printing Office and/or the National Technical Information Service. The Office of Radiological Health also makes its technical reports available to the World Health Organization under a memorandum of agreement between WHO and the Department of Health and Human Services. Three WHO collaborating Centers, established under the Bureau of Radiological Health, continue to function under NCDRH: WHO Collaborating Center for Standardization of Protection Against Nonionizing Radiations; WHO Collaborating Center for Training and General Tasks in Radiation Medicine; and WHO Collaborating Center for Nuclear Medicine. We welcome your comments and requests for further information. (v7. John C. Villforth Director National Center for Devices and Radiological Health iii PREFACE To encourage the discovery and development of useful medical devices, the drafters of the 1976 Amendments created a key exemption from premarket notification, premarket approval, and other controls in the Act. This exemption, known as the Investigational Device Exemption (IDE), permits devices to be shipped in interstate commerce for clinical investigation to determine their safety and effectiveness. The exemption requires safeguards for humans who are subjects of investigations; maintenance of sound ethical standards; and procedures to assure development of reliable scientific data. The IDE regulation is flexible in that it allows for two levels of control. It considers the degree of risk involved to the patient and leaves to local specialists the decision on whether or not a new device presents a "significant risk." If those specialists, meeting as an Institutional Review Board, decide that a device to be clinically studied does not represent a significant risk to users, the device sponsor may conduct patient studies without FDA approval. The term "medical device" describes a large and diverse set of products. Regulation of these products is a challenging and complicated process, not only because of sheer volume and variety, but also because of their increasing importance in the delivery of patient health care. The Medical Device Amendments of May 28, 1976 mandated the establishment of . . "an identifiable office to provide technical and other non-financial assistance to small manufacturers of medical devices to assist them in complying with the requirements of the Federal Food, Drug, and Cosmetic Act." The Office of Small Manufacturers Assistance (OSMA) was established to meet these requirements. In addition to providing individual guidance and workshops, OSMA distributes a wide variety of printed materials, such as regulations, guidelines, policy statements, question-and-answer booklets, the SMA Memo, and other FDA documents that help manufacturers understand the substance and impact of requirements, as well as the simplest or most effective ways to meet them. This publication deals with the procedures, rules, and safeguards that must be observed by those participating in the clinical testing of new devices. Included in the text are copies of applicable regulations, together with overviews, tables, and other explanatory matter. Many persons in the Office of Medical Devices provided materials as well as suggestions and support in the preparation of these materials. OSMA acknowledges their valuable contributions with thanks. OSMA is ready to answer your requests for information and guidance. The basic view provided here should help you to get oriented and to focus on further specific questions you wish to ask. It is OSMA's mission to assist you and to identify ways of complying with FDA requirements. Feel free to visit, write, or call us collect at (301) 427-7184. If your questions are highly technical, you will be referred to the appropriate device evaluation expert, or you may call the Device Evaluation Office at (301) 427-7230. H77 H. Neal Dunning, Ph.D. Director Office of Small Manufacturers Assistance iv CONTENTS ADSIPECL « « © + % » + x 5 & +. 5 4 % & % ¥ 5 8 F 4 6" bE Ese ws Introductory Outline. . . . . . . « « ¢ & vv tt tt ve ee eee IDE Applicability . . «. « « « tt 0 th ee ee ee ee ee eee Tables: Responsibilities of Sponsors, Investigators, and IRBs inRecordsand Reports. - . . « « v ¢ « ¢ « ¢ o « « « « « « o « & Procedures for Investigational Device Exemptions ( Preamble, FR 1/18/81 and Final Rule 21 CFR 812 revised as of April 1, 1981). . . . . . . . Protection of Human Subjects; Informed Consent; Standards for Institutional Review Boards for Clinical Investigations; and Clinical Investigations Which May Be Reviewed Through Expedited Review Procedure (FR 1/27/81, pp. 8042-8980) , . . . . . . . .. Questions and Answers on the IDE Regulation. . . . . . . . . . . . .. Extract from an Unofficial Sample Format: Application for an Investi- gational Device Exemption for a Significant Risk Device , . . . . . . Summary of the Good Laboratory Practice Regulations (FR 12/22/78, pp. 59986-60025) . . . . . . . + +. vv ov oo . . Page iii iv vi 14 ABSTRACT Prepared by the Office of Small Manufacturers Assistance, Office of Medical Devices, NCDRH. Investigational Device Exemptions - Regulatory Requirements for Medical Devices. HHS Publication FDA 83-4159 (January 1983) (pp. 114). This publication covers regulatory requirements for investigational device exemptions, which are granted for purposes of conducting clinical studies. Exemption from certain regulatory controls requires safeguards for human subjects of investigations; maintenance of sound ethical standards; and procedures to assure development of sound scientific data. On October 8, 1982, the Bureau of Radiological Health and the Bureau of Medical Devices were merged into a single organization, the National Center for Devices and Radiological Health. The two former bureaus are now designated as the Office of Radiological Health and the Office of Medical De- vices. Original publication of this reprint predates the merger, but titles, addresses, and phone numbers referred to in the text are current as of the reprint publication date. vi INVESTIGATIONAL DEVICE EXEMPTIONS INTRODUCTORY OUTLINE Section 520(g) of the Act authorizes the FDA to grant an investigational device exemption (IDE) in cases where studies undertaken to develop safety and effectiveness data for medical devices involve the use of human subjects. Persons who may become involved in research. with human subjects should be familiar ‘with the following definitions, as stated in Parts 812 and 56: Institutional Review Board (IRB) means any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of biomedical research involving human subjects. The IRB should be established, oper- ated,and function in conformance with Part 56. The term has the same meaning as "institutional review committee" in Section 520(g). Investigator means an individual who actually conducts an investigation and under whose immediate direc- tion the investigational device is administered, dispensed or used. Monitor when used as a noun, means an individual designated by a sponsor or contract research organization to oversee the progress of an investigation. The monitor may be an employee of a sponsor or a consultant to the sponsor, or an employee of or consultant to a contract research organization. "Monitor," when used as a verb, means to oversee an investigation. « Sponsor means a person who initiates, but who does not actually conduct the investigation: that is, the investi- gational device is administered, dispensed, or used under the immediate direction of another individual. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators. o Sponsor-investigator means an individual who both initiates and actually conducts, alone or with others, an investigation, that is, under whose immediate direction the investigational device is administered, dispensed or used. The term does not include any person other than an individual. The obligations of a sponsor-investigator under this part include those of an investigator and those of a sponsor. « Implant means a device that is placed into a surgically or naturally formed cavity of the human body if it is intended to remain there for a period of 30 days or more. In order to protect public health, FDA may determine that devices placed in subjects for shorter periods are also implants. Persons applying for investigational device exemptions are required to submit information demonstrating that: o the testing of the device will be supervised by an institutional review board (IRB) » appropriate informed consent will be provided, and o certain records and reports will be maintained. For the purposes of investigation, the IDE regulation distinguishes between significant and nonsignificant risk devices. Procedures for obtaining an IDE differ accordingly. IDE REQUIREMENTS AND TERMINOLOGY: WHAT REQUIREMENTS APPLY? All Clinical Investigations of Devices r 1 Investigations Investigations Subject to Exempt From IDE Regulation IDE Regulation Investigations Investigations of Significant of Non-Significant Risk Devices Risk Devices Must Meet Must Meet Full Requirements Abbreviated Requirements Significant vs. Nonsignificant Risk Devices A significant risk device is one that presents a potential for serious risk to the health, safety, or welfare of a subject and is: + an implant, or . used in supporting or sustaining human life, or « substantially important in diagnosing, curing, mitigating or treating disease or in preventing impairment of human health. Before initiating human studies, sponsors must apply these criteria in order to determine whether their devices fit the definition of significant risk. The institutional review board (IRB) reviewing the investigational plan should also determine whether the device presents a significant or nonsignificant risk. Examples of significant risk devices are pacemakers, intrauterine devices (IUDs), and hemodialysis systems. Nonsignificant risk devices are those that do not pose a serious risk to human subjects. Requirements for Investigation of Nonsignificant Risk Devices Sponsors of studies involving nonsignificant risk devices do not have to submit IDE applications to FDA. Unless notified otherwise by FDA, TRB approval of an investigation for a nonsignificant risk device is considered to be FDA-ap- proved if the device is not a banned device and the Sponsor: oT » obtains IRB approval after presenting the IRB with a brief explanation of why the device does not pose significant risk « labels the device in accordance with the IDE regulation o maintains IRB approval throughout the investigation « ensures that investigators obtain and document informed consent under Part 50 for each subject under their care unless, in accordance with §56.109(c¢), documentation is waived by an IRB » complies with IDE requirements for monitoring inves- tigations, maintaining records, and making reports o ensures that participating investigators maintain all required records and make all required reports, and « complies with prohibitions on promotion, test market- ing, and commercialization of investigational devices. Investigators of nonsignificant risk devices are required to maintain certain records and make reports, as specified by the IDE regulation. If IRBs disagree with sponsors and believe that an investigational device poses a significant risk, sponsors are required to notify FDA and submit an application for the investigation of the device. Requirements for Investigation of Significant Risk Devices A sponsor of a significant risk device must obtain approval from both FDA and an IRB before beginning an investigation. Under the requirements of the Investigational Device Exemption (IDE) regulation (21 CFR 812), sponsors are: « required to have an approved IDE in order to conduct clinical investigations on the safety and effectiveness of significant risk devices, and « exempted during the period of their investigations from having to comply with certain sections of the Federal Food, Drug, and Cosmetic Act — e.g., misbranding, registration, listing, premarket notification, premarket approval, good manufacturing practices, performance standards, restricted device, banned device, and color additive requirements. To obtain IDE approval for a significant risk device investigation, a sponsor « develop an investigational plan and assemble reports of prior investigations « select qualified investigators, provide them with all necessary information on the plan and on reports of prior investigations, and obtain signed agreements from them « submit the investigational plan and reports of prior investigations to the IRB for review and approval, and « submit an adequately documented IDE application to FDA for review and assure that FDA and any reviewing IRB are promptly informed of significant new informa- tion about the investigation. Content of Applications There is no preprinted form for IDE applications, but 21 CRF 812.20(b) details the kinds of information that they must contain, including the following items: 1. Name and address of sponsor 2. Complete reports of prior investigation, including: o results of all prior clinical, animal, and laboratory testing 3. 10. 11. 12. o bibliography of relevant publications, whether adverse or supportive e summary of relevant unpublished information, whether adverse or supportive, and o statement of extent of compliance with the Good Laboratory Practices regulation Complete investigational plan, or an accurate summary, in the following order: « name and intended use of the device and objectives and duration of the investigation o written protocol describing the methodology and scien- tific soundness of the investigation e risk analysis o description of the device, important components, and principles- of operation e monitoring procedures and names and addresses of monitors Description of methods, facilities, and controls used for manufacture, processing, packing, storage, and installation of the device Example of the agreement to be signed by investigators and a list of investigator names and addresses and the IRBs with which they are associated Certification that all investigators have signed the agreement List of name, address and chairperson of each IRB that reviews the investigation and certification of IRB approval or disapproval Name and address of any institution (other than those above) at which a part of the investigation may be conducted The amount, if any, charged for the device and an explanation of why sale does not constitute commercialization Environmental analysis (if requested by FDA) All labeling for the device Samples of all informed consent forms and all related informational materials. If a sponsor or investigator proposes a change in the investigational plan, the sponsor 1s required: — e to submit a supplemental IDE application to FDA, and « to defer beginning that part of an investigation for which the supplemental application is submitted until an IRB and FDA have both approved the supplemental application. The Bureau of Medical Devices offers general literature and guidance on pre- paring applications.” Sponsors filing applications should: - e« submit three copies of the signed IDE application, together with accompanying materials (Three copies of supplemental applications and other IDE correspondence must also be submitted.) o clearly identify the submission with whichever phrase applies (e.g., "IDE Application,» "Supplemental IDE Application," "Correspondence Concerning an IDE Ap- plication"), and eo mail or hand carry submissions to: Food and Drug Administration, Bureau of Medical Devices, Document Control Center, HFK-20, 8757 Georgia Avenue, Silver Spring, MD 20910. FDA Review; « FDA reviews each IDE application. Sponsors are notified in writing of the date FDA receives their applications. Within 30 days, FDA will approve, approve with modifications and minor corrections, or disapprove an IDE application. In cases of disapproval, a sponsor has the opportunity to request a hearing. Investigations may begin: « after IRB approval has been obtained and o at the expiration of 30 days after FDA receives the application, unless FDA notifies the sponsor to the contrary. Sponsors who wish to conduct investigations of banned devices shall not begin an investigation before obtaining written FDA approval. There is no time limit for FDA review of a banned device investigation. Responsibilities of Sponsors, Investigators and IRBs The IDE regulation specifies basic requirements for conducting investigations and identifies the responsibilities of participants. Sponsors are required to: « ensure that both FDA and an IRB have approved the application (or supplemental application) before be- ginning an investigation (or part of an investigation) « ensure proper monitoring of the investigation directly or through qualified monitors, including immediate eval- uation of unanticipated adverse device effects and term- ination of investigations that present unreasonable risks to subject « ship the devices only to qualified investigators e ensure that IRBs and FDA are informed of all new information « secure IRB and FDA approval for resumption of termi- nated investigations « maintain accurate and current records on investigations e prepare and submit required reports « avoid commercialization or test marketing of the device under investigation . ensure that the investigation is not unduly prolonged, and « permit FDA inspections. IRBs must comply with all applicable requirements of Part 56 and the IDE reg- ulation in reviewing and approving investigations. IRBs are required to: « be composed of qualified members as specified in the regulation « adopt and follow written review procedures . ensure that IRB business is conducted with a majority of members present and that members with conflicts of interest do not participate in the review of investigations o review all research activities « evaluate risks and benefits to subjects, knowledge to be gained, and the adequacy of informed consent « review proposed investigations in a timely manner « notify investigators and sponsors, if appropriate, of IRB decisions and the basis for them . maintain certain records in accordance with Part 56, and « permit authorized FDA employees to inspect records. Investigators are required to: « conduct investigations according to signed agreements, the investigational plan, applicable FDA regulations, and any other conditions of approval imposed by an IRB or FDA . ensure informed consent is properly obtained and docu- mented in accordance with Part 50 o evaluate and report any unanticipated adverse device effects e supervise the use of devices « maintain records relating to investigations eo prepare and submit reports e return to sponsors all remaining supplies of devices, or dispose of them as directed, when an investigation is completed or terminated, and « permit FDA inspections. Persons who import investigational devices are: e subject to the IDE regulation « considered to be the agent of the foreign importer, and e required to act as sponsor of the investigation or ensure that another person act as the foreign exporter's agent and sponsor. Before exporting investigational devices, sponsors or manufacturers of devices must notify FDA, as required by 801(d) of the Act. FDA will determine if the export of the device is contrary to the public health and will approve or disapprove the export. Inspectional Authority « FDA has authority to inspect facilities at which inves- tigational devices are manufactured, processed, held or used. « sponsors, IRBs and investigators are required to permit authorized FDA employees reasonable access at reason- able times to inspect and copy records on an investiga- tion. Bureau guidance is available to interested persons and sponsors who are unsure of whether an IDE application may be required or who may need other informa- tion and literature. 10 For assistance, contact: Michael J. Andrews, Ph.D. Bureau of Medical Devices, HFK-403 Food and Drug Administration 8757 Georgia Avenue Silver Spring, Maryland 20910 (301) 427-8162 or Office of Small Manufacturers Assistance, HFK-60 (same address) (301) 427-7184 11 IDE APPLICABILITY After July 16, 1980, all device clinical investiga- tions must have an approved IDE unless exempted. Except for ‘‘transitional devices, the following devices are exempt from the regulation: 1. preamendments devices, i.e., devices in commercial distribu- tion before the Medical Device Amendments of May 28, 1976, and substantially equivalent devices if used or investigated in accord with the labeling in effect at that time. This exemption expires at the time premarket approval applications (PMAs) are required or an FDA mandatory standard takes effect; 2. diagnostic devices that comply with all the applicable re- quirements of 21 CFR 809.10(g) and if the testing: (i) is nonin- vasive; (ii) does not require an invasive sampling procedure that presents significant risk; (iii) does not by design or inten- tion introduce energy into a subject; and (iv) is not used as a diagnostic procedure without confirmation by another medi- cally established diagnostic product or procedure; 3. devices undergoing consumer preference testing, testing of a modification, or testing or a combination of devices in com- mercial distribution, if the testing is not to determine safety or effectiveness; 4. devices intended solely for veterinary use or for research with laboratory animals and that are so designated in the labeling; and 5. custom devices unless used to determine safety or effec- tiveness for commercial distribution. * Transitional devices are those for which Notices of Claimed Investigational Exemption for a New Drug (INDs) were required. For transitional devices with INDs--other than exempt diagnostic devices--an approved IDE is required by October 14, 1980. Other transitional devices must have an IDE in order to be investigated. 13 Table | Responsibilities for Maintaining Records Maintained by Records Investigator Sponsor -- All Correspondence Pertaining to the Investigation Vv v > - - Shipment, Receipt, Disposition v v @ - - Device Administration and Use Vv en 548 | -- Subject Case Histories v — SZ |-- Informed Consent vv — La - - Protocols and Reason for Deviations from Protocol v —_ & - - Adverse Device Effects and Complaints v v @% - - Signed Investigator Agreements — v - - Membership/Employment/Conflicts of Interest _ Ny - - Minutes of Meetings = —_ e -- Name and Intended Use of Device _ v S& | -- Brief Explanation of Why Device Does Not Involve ES Significant Risk a= Vv za -- Name and Addresses of Investigator(s) and IRBs — v 2 % | -- Degree GMPs Followed Rig Vv gx |-- Informed Consent Vv i z - - Adverse Device Effects and Complaints ws Z Records Maintained by IRB - - Research Proposals Reviewed - - Sample Consent Documents - - Investigator Progress Reports - - Reports of Subject Injuries - - Meeting Minutes Attendance Actions Taken Votes Basis for Changes or Disapproval Summary of Controverted Issues - - Records of Continuing Reviews - - Correspondence - - Membership - - Written Procedures - - Record Retention - - Statements of Significant New Findings 14 Table iI Responsibliities For Preparing and Submitting Reports For Nonsignificant Risk Devices ———— REPORT PREPARED BY— TYPE OF REPORT INVESTIGATORS SPCNSDns Unanticipated Adverse Effect Evaluation Sponsors and IRBs FDA, Investigators and IRBs Withdrawal of IRB Approval Sponsors FDA, Investigators and IRBs Progress Report N/A IRBs Final Report N/A IRBs Inability to Obtain Informed Consent Sponsors and IRBs FDA Withdrawal of FDA Approval N/A IRBs and Investigators Recall and Device Disposition N/A FDA and IRBs Significant Risk Determinations N/A FDA Table 111 Responsibilities For Preparing and Submitting Reports For Significant Risk Devices REPORT PREPARED BY ———— TYPE OF REPORT INVESTIGATORS SPONSonS Unanticipated Adverse Effect Evaluation Sponsors and IRBs FDA, Investigators and IRBs Withdrawal of IRB Approval Sponsors FDA, Investigators and IRBs Progress Report Sponsors, Monitors and IRBs FDA and IRBs Final Report Sponsors and IRBs FDA, Investigators and IRBs Emergencies (Protocol Deviations) Sponsors and IRBs FDA Inability to Obtain Informed Consent Sponsors and IRBs FDA Withdrawal of FDA Approval N/A IRBs and Investigators Current Investigator List N/A FDA Recall and Device Disposition N/A FDA and IRBs Records Maintenance Transfer FDA FDA Significant Risk Determinations N/A FDA 15 A ——————— Friday January 18, 1980 Part Il Department of Health, Education, and Welfare Food and Drug Administration Medical Devices; Procedures for Investigational Device Exemptions 16 3732 Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations DEPARTMENT OF HEALTH, registration, premarket notification, 35186) and Obligations of Clinical EDUCATION, AND WELFARE performance standards, premarket Investigators of Regulated Articles (43 Food and Drug Administration 21 CPR Parts 16, 20, 809 and 812 [Docket No. 76N-0324] Medical Devices; Procedures for Investigational Device Exemptions AGENCY: Food and Drug Administration. ACTION: Final rule. SUMMARY: This rule sets forth the procedures and conditions under which investigations of medical devices involving human subjects may be exempt from certain requirements of the Federal Food, Drug, and Cosmetic Act, in accordance with the Medical Device Amendments of 1976. The rule sets out the procedures to obtain an investigational device exemption (IDE); it delineates the responsibilities of sponsors, institutional review boards, and clinical investigators with respect to clinical investigations of medical devices; and the rule also prescribes informed consent requirements and specifies recordkeeping and reporting requirements. EFFECTIVE DATE: The reporting and recordkeeping requirements contained in this rule have been submitted for approval by the Office of Management and Budget (OMB) in accordance with the Federal Reports Act of 1942. This regulation will become effective July 16, 1980, provided that approval of the OMB is received by that date. If OMB does not approve, without change, the reporting and recordkeeping requirements contained in the rule, FDA will revise the rule as necessary to comply with the decision of OMB. FDA will publish a notice in a future issue of the Federal Register concerning OMB's decision on these requirements. FOR FURTHER INFORMATION CONTACT: Joseph L. Hackett, Bureau of Medical Devices (HFK—403), Food and Drug Administration, 8757 Georgia Ave., Silver Spring, MD 20910, 301-427-8162. SUPPLEMENTARY INFORMATION: The Medical Device Amendments of 1976 (Pub. L. 94-295), referred to here as “the amendments,” amended the Federal Food, Drug, and Cosmetic Act (52 Stat. 1040 et seq. (21 U.S.C. 201 et seq.)), referred to here as “the act.” Section 520(g) of the act (21 U.S.C. 360j(g)) sets out requirements that apply to investigational use of medical devices. Section 520(g) authorizes the exemption of devices from provisions of the act that relate to misbranding, approval, banned devices, recordkeeping and reporting requirements, restrictions on distribution of devices, good manufacturing practice requirements, and use of color additives, to permit devices to be shipped for clinical investigations to determine their safety and effectiveness. An investigation is considered approved and may begin 30 days after an application for an IDE is submitted to the Food and Drug Administration (FDA), unless FDA notifies the applicant within 30 days that the application is not approved. An application for an IDE for a banned device must be approved by FDA in writing before the investigation may begin. FDA will enforce this regulation under section 301(q) of the act (21 U.S.C. 331(q)), which prohibits failure or refusal to comply with a requirement prescribed under section 520(g). Section 301(q)(2) also prohibits the submission of reports that are materially false or misleading. In addition, a device is adulterated under section 501(f) and (i) of the act (21 U.S.C. 351(f) and (i)) if the device fails to comply with applicable requirements of the IDE regulation. Adulterated devices may be seized under section 304 (21 U.S.C. 334). Prior Federal Register Documents and ‘Public Hearing In the Federal Register of August 20, 1976 (41 FR 35282), FDA proposed regulations on IDE’s (the original proposal). The proposal was finalized with respect to intraocular lenses (IOL's), but not with respect to other medical devices, by regulations published in the Federal Register of November 11, 1977 (42 FR 58874) and codified in Part 813 (21 CFR Part 813). Paragraph 34 below discusses the regulations that now apply to IOL investigations. Because of the heavy volume of comments and the desire to increase public participation in the development of the IDE regulation, FDA issued a reproposal in the form of a tentative final regulation in the Federal Register of May 12, 1978 (43 FR 20726) (the reproposal). A Federal Register notice of October 6, 1978 (43 FR 46321), extended the deadline for comments from September 11, 1978, to December 5, 1978. This extension was in response to several requests to allow comments on the relation of the reproposal to two related proposed rules published by FDA on August 8, 1978, that is, Standards for Institutional Review Boards for Clinical Investigations (43 FR 17 FR 35210), and to the report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (the Commission) on Institutional Review Boards and Informed Consent. (See the Federal Register of November 30, 1978 (43 FR 56174).) A public hearing on the reproposal was held in Rockville MD, on August 7, 1978. Fourteen persons made presentations at the hearing. A trangcript of the hearing is on file in the office of the Hearing Clerk. FDA, Rockville, MD. Comments offered at the hearing were considered in preparing this final regulation. Decision To Publish Regulation as a Final Rule A comment on the reproposal requested that revisions made in the reproposal be published as another reproposal rather than as a final regulation, to allow more public participation. FDA has elected to publish a final regulation. The changes made in this document are consistent with, and generally are in response to, the written comments received on the original proposal or the reproposal and comments at the public hearing. FDA believes that this final regulation is based on sufficient public participation and that an additional reproposal is neither legally required nor desirable as a policy matter. Relationship to Sponsor/Monitor, Institutional Review Board, Clinical Investigator, and Informed Consent Regulations In the original proposal, Subparts C, D, and E set forth responsibilities of sponsors, institutional review boards (IRB's) and investigators, respectively. The reproposal did not repropose Subparts D and E and portions of Subparts C. FDA did not withdraw thege provisions in the original proposal, but stated its intention that the agency-wide bioresearch monitoring regulations, discussed below, would apply to these aspects of device investigations when those regulations became final. FDA has concluded that the conduct of clinical investigations of drugs, devices, and biologics are sufficiently similar to warrant uniform, agency-wide regulations. For drugs and biologics, these regulations will be revisions of exis*ing requirements in Part 312 (21 CFR Part 312). For devices, the only prese.it requirements for clinical invest;zations are those in § 809.10(c) (21 CFR 809.10(c)) for in vitro diagnostic Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations 3733 products, Part 813 for IOL's, the notice in the Federal Register of March 9, 1973 (38 FR 8419) for acupuncture devices, and Part 312 for devices formerly considered new drugs or antibiotic drugs. The Federal Register of September 27, 1977 (42 FR 49612), contained a proposed regulation on obligations of sponsors and monitors of clinical investigations. In the Federal Register of August 8, 1978, FDA issued proposed regulations on standards for institutional review boards for clinical investigations (43 FR 35186) and obligations of clinical investigators of regulated articles (43 FR 35210). In part because of the report on these matters by the Commisgion (see discussion above) on August 14,1979, FDA reproposed regulations on institutional review boards (44 FR 47699) and a new proposal on informed consent (44 FR 47713). These proposed agency-wide bioresearch monitoring regulations have not yet been published as final rules. FDA has concluded that the time required to prepare agency-wide regulations for final publication would entail unacceptable delays in the application of regulatory safeguards to device development. FDA is concerned about preventing unreasonable risks to subjects of investigations, providing guidance to sponsors who are required to submit premarket approval applications, and avoiding further nonadherence to the statutory timetable for the IDE regulation in section 520(g)(2)(A) of the act. Accordingly, rather than allowing further delay in publication of the final IDE regulation until publication of the final agency- wide regulations, FDA is making final the requirements for sponsors, IRB's, and investigators in Subparts C, D, and E of Part 812 in this document (21 CFR Part 812). Adequate notice and opportunity for comment on these requirements were afforded in the original IDE proposal and, on some matters, in the reproposal as well. To reduce administrative burdens on affected parties, FDA has conformed this final regulation closely to FDA's anticipated final regulations on obligations of sponsors and monitors, and investigators. An exception to this general rule is that this regulation does not contain provisions that were not parts of previous proposals on which public comments have been received. If the final bioresearch monitoring regulations differ from the IDE final regulation, FDA will make conforming changes in the IDE regulation. The IRB and informed consent requirements in this regulation do not reflect many of the provisions present in the August 14, 1879 proposals. The agency stresses that the differences between the final IDE regulation and the August 14, 1979 proposals should not be taken as indications of the agency's decision on the form of final IRB and informed consent regulations. The public comments on the August 14, 1879 proposals are being analyzed, and the final orders will reflect a full consideration of those comments. The IRB and informed consent requirements in this regulation represent relatively basic provisions that are generally consistent with current practice and statutory requirements. - FDA recognizes that there may be some inconvenience if the final IDE regulation is changed to conform to the final bioresearch monitoring regulations. FDA has concluded, however, that any such inconvenience is outweighed by the advantages, discussed above, of having the IDE regulation in effect. Comments on the Reproposal Many comments were received from academic sources, industry, private practitioners, and a public interest group. The comments were constructive and often complex. A surnmary of the comments and FDA's responses to them follow. Effect on Research 1. Several comments stated that few investigators and IRB's will be willing to continue participation in device investigations, in view of the administrative burdens imposed by the IDE regulation. FDA is sensitive to this concern and has changed the final regulation to limit paperwork to essential requirements. Moreover, the final regulation’s applicability to investigations of preamendments devices has been restricted, as discussed below in paragraph 21. Of those investigations now subject to the regulation, only those involving significant risk devices are subject to all requirements of the regulation. A sponsor of an investigation that does not involve a significant risk device (“a nonsignificant risk device investigation") does not need to submit an IDE application to FDA or obtain FDA approval before beginning an investigation, unless FDA notifies the sponsor that approval is required. The sponsor must, however, properly label the device, obtain and maintain IRB approval, ensure that investigators document informed consent, maintain certain basic records, evaluate and submit reports concerning such vital matters as unanticipated adverse device effects, and comply with requirements for monitoring studies, prohibitions 18 against commercialization, and undue prolonging of investigations. A sponsor of a significant risk device investigation must submit an IDE application to FDA. The elements of an application have been simplified. A sponsor need not routinely submit background information on investigators or complete copies of the investigational plan. The general record retention period has been reduced from 5 to 2 years following the later of two dates: The date when the investigation is terminated or completed, or the date when the investigation is no longer needed to support an application for premarket approval or a notice of completion of a product development protocol. FDA believes that the: 2 and other modifications will reduce the cost of investigating a device without weakening the controls required by section 520(g) of the act. The agency has- retained requirements that are critical to protection of subjects in all investigations, e.g., informed consent, institutional review, and reporting of unanticipated adverse device effects. 2. Several comments argued that the reproposal was written in confusing legal jargon. The final regulation is in plain and simple language consistent with legal requirements. 3. A few comments suggested that regulation of clinical investigations should be controlled at the local level and would be better supervised if the control were university based rather than supervised at the Federal level. Section 520(g) of the act requires a sponsor to submit an application to FDA. Therefore, control over significant risk device investigations cannot be, and is not, vested solely in local officials. Local IRB's will, however, play an important role in the control of all device investigations, especially those that do not involve significant risk devices, as discussed further in paragraph 17 of this preamble. Economic Impact 4. Many comments argued that FDA did not properly consider the economic impact of the regulation and that costs to industry will exceed $100 million. FDA does not have definitive data on costs to industry because hard data on costs were not submitted in support of these comments. FDA believes that the final regulation will not have a major economic impact, given the changes in the regulation summarized in paragraph 1. 5. A number of comments stated the reproposal would increase the direct costs of developing a medical device. 3734 Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations One comment estimated the incremental cost to be from $250,000 to $500,000 per device, but did not explain how this estimate was derived. Another comment expressed concern about the unit cost of a product, if the cost of IDE requirements is applied to a device that is produced in limited quantities. Many comments expressed a general concern about the expected cost burdens of the administrative requirements. Other comments observed, however, that the incremental cost is impossible to estimate because it depends on the extent to which current investigational practices satisfy the regulation’s requirements. The changes in the regulation summarized in paragraph 1 will greatly reduce incremental costs of compliance. 6. Several comments addressed the long-range economic impact of the IDE regulation. These comments predicted that the cumulative effect of the regulation would be to discourage medical device research and development in the United States. One comment predicted that the regulation would drive device research and development abroad. It was argued that the regulation would discourage participation of investigators and IRBs, reduce sponsor incentives to develop devices of limited commercial value, discourage noncommercial research (that is, much of the research conducted at universities), and would affect adversely the development of improvements in already marketed medical devices. FDA believes that the implementation of the final IDE regulation will not discourage medical device research and development in the United States. Even the requirements for clinical studies of significant risk devices do not require significant deviation from current research practices in the scientific community. Because of the changes in the regulation summarized in paragraph 1 above, there should be little, if any, change in the willingness of investigators and IRB's to participate in medical device research and little, if any, reduction in sponsors’ incentives to develop devices of limited commercial value or to make improvements in already-marketed devices. 7. A number of comments expressed concern that the reproposal may have a disproportionate impact on small businesses, and these comments imputed a general anticompetitive tendency to the IDE reproposal. To minimize such effects, FDA's Office of Small Manufacturers Assistance is available to guide small firms through the IDE process or-to assist them in preparing the investigational phase of a product development protocol (PDP) under section 515(f) of the act (21 U.S.C. 360e(f)). Moreover, FDA believes that changes made to simplify the IDE regulation will reduce the burden on small business. ‘ 8. Several comments questioned the assumptions in FDA's original inflation impact assessment. The original assessment assumed that the average costs for clinical investigations of significant risk devices would be increased by $125,000 over a 3-year period for each of 150 devices already on thg market, and it projected an increase of $125,000 a year for 3 years for each of the estimated 10 to 20 new devices developed each year. (The estimated number of new devices each year was derived from the number of annual FDA determinations, in response to premarket notifications under section 510(k) of the act (21 U.S.C. 360(k)) and Subpart E of Part 812 (21 CFR Part 812, Subpart E), that devices described in these notifications were not substantially equivalent to devices in commercial distribution before the amendments, and were therefore in class III (premarket approval) under section 513(f) of the act (21 U.S.C. 360c(f)).) Comments suggested that: (a) The cost impact per investigation would or might be higher than the $125,000 to $375,000 range, and (b) in projecting the number of IDE's, FDA overlooked numerous “limited purpose” studies (for example, studies for minor improvements of existing products and studies establishing labeling information) that would also be affected. The comments submitted by the device industry did not contain detailed cost analyses or projections of the number of clinical investigations. FDA has concluded that because the cost of the final regulation will fall primarily on clinical testing of new, significant risk devices, the assumptions in the original assessment are correct. 9. One comment suggested that FDA consider the combined cost impact of related regulations, such as those concerning premarket approval and obligations of sponsors and monitors, clinical investigators, and institutiSnal review boards, rather than the separate cost of each regulation. FDA is sensitive to the issue of cumulative regulatory burden. In developing each of these regulations, FDA has been attentive to the cumulative effects of all of them together. The final IDE regulation reflects an effort to eliminate unnecessary regulatory burdens, and FDA will make similar efforts in 19 preparing the final agency-wide bioresearch monitoring regulations. Detailed evaluation of the cumulative effects of these regulations would not, in any event, affect the general approach of the final IDE regulation because of the need to require compliance with statutory mandates for device investigations. 10. Comments suggested that the inflationary impact assessment should have attempted to estimate benefits as well as cost impacts, and should have included a review of alternative regulatory approaches. FDA rejects these comments. These types of analyses would have been required under Executive Order 11821 (superseded by Executive Order 12044 by notice in the Federal Register of March 24, 1978 (43 FR 12661)) if a major inflationary impact had been identified. However, no such impact was identified. Furthermore, FDA believes that the orginal proposal and the reproposal, coupled with its responses to the comments demonstrate that ample consideration has been given to the benefits of the regulation and to all practical options. 11. One comment asserted that the inflation impact assessment failed to evaluate certain long-range unfavorable effects on the competitive structure of the industry and on the rate of new medical device development. No factual support was submitted to document these concerns. As d~scribed above in paragraph 1, the major requirements of the final IDE regulation apply fully only to investigations of new, significant-risk devices. FDA believes that the IDE regulation will not unduly discourage new product development, reduce competition, or adversely affect small business. Effective Date 12. Several comments suggested extending the effective date of the regulation beyond the 120-day period that was reproposed. FDA agrees that extending the effective date will provide for a more orderly transition period. To provide sponsors with sufficient lead time to comply with the final rule, this regulation will be effective July 16, 1980. Sponsors of new investigations and ongoing long-term investigations may wish to submit applications for FDA review befcre the effective date. FDA will accept and review applications received before the effective date. Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations 3735 General Provisions Scope 13. Numerous comments on the reproposal questioned whether FDA was seeking to achieve the stated objective of “encouraging the discovery and devlopment os useful devices.” FDA is sensitive to concerns that the IDE reproposal might have discouraged innova_ion. Accordingly, FDA has altered the final regulation to minimize interference with device development and costs of preparing an IDE application, while retaining provisions essential to subject protection. See paragraphs 1 and 6 above. 14. One comment argued that the regulation should state that a product for which an IDE has been approved will be exempt from section 501 (21 U.S.C. 351), relating to adulteration, and section 518 (21 U.S.C. 360h), relating to notification of risk and repair, replacement or refund, in addition to those sections enumerated in section 520(g) of the act. FDA disagrees. Section 520(g) of the act does not provide for exemptions from sections 501 and 518, nor is there any reason to grant such exemptions. Applicability 15. Several comments argued that an IDE should not be required for an investigation to expand medical knowledge or conduct fundamental research. FDA agrees with these comments insofar as they concern clinical investigations conducted for purposes other than determination of safety or effectiveness. Accordingly, § 812.2(a) (21 CFR 812.2(a)) has been rewritten to provide that the regulation applies only to clinical investigations of medical devices to determine safety and effectiveness. If the expansion of medical knowledge or the conduct of fundamental research involves an investigation to determine the safety or effectiveness of a device, an IDE will be required. 16. One comment suggested that an IDE should not be required if testing of the device occurs within the boundaries of one State. The comment questioned FDA's authority to act if a sponsor's testing activities are solely intrastate. FDA does not agree with this comment. Neither section 301(q) (21 U.S.C. 331(q)), which prohibits violations of the IDE regulation, nor section 501(i) of the act, which deems a device adulterated if there has been a failure to comply with the IDE regulation, is limited in its applicability to devices that are in interstate commerce. Compare section 301(q) with section 301 (a) through (d), (k), and (0). In addition, section 304(a)(2) of the act (21 U.S.C. 334(a)(2)) authorizes FDA to seize adulterated devices without regard to interstate commerce (United States v. Undetermined Quantities of an Article of Device * * * “Depilatron Epilator,” 473 F. Supp. 913 (S.D. N.Y. 1979)). Also, section 709a of the act (21 U.S.C. 379a) provides that interstate commerce is presumed to exist in any action to enforce the requirements of the act concerning a device. Finally, United States v. Dianovin Pharmaceuticals, 475 F.2d 100 (1st Cir. 1973), and United States v. Pinocchio Brand Oil, 289 F.2d 343 (2d Cir. 1961), hold that the necessary connection with interstate commerce exists if any component of the product was shipped from outside a State. 17. Numerous comments suggested that FDA limit the applicability of the regulation, for example by basing applicability on the degree of risk, or the incremental risk, presented to subjects by use of the device. One comment offered an alternative regulatory scheme under which FDA review would be related to the risk of the clinical investigation and the extent of IRB oversight. FDA agrees with many of the suggestions set forth in these comments and has incorporated them in the final regulation. The final regulation varies the amount of regulatory control, depending on the degree of risk to the subject. Investigations of significant risk devices are subject to detailed regulatory control and require IRB and FDA approval. A sponsor of such an investigation must submit an investigational plan and report of prior investigations to an IRB and an IDE application to FDA. Less regulatory control is exercised over investigations of nonsignificant risk devices. Nonsignificant risk devices include a miscellany of articles such as crutches, elastic knee braces, bedboards, bedpans, medical chairs, and tongue depressors, as ordinarily used. A sponsor of a nonsignificant risk device investigation who meets the conditions set forth in § 812.2(b)(1) is considered to have an approved exemption, without actually having to submit an application, unless notified under § 812.20(a) (21 CFR 812.20(a)) that approval of an application is required. Section 520(g)(2)(A) of the act authorizes FDA to establish conditions for the granting of IDE's. Section 520(g)(2)(B)(i) provides that one of the conditions shall be [a] requirement that an application be submitted to the 20 Secretary before an exemption may be granted and that the application be submitted in such form and manner as the Secretary shall specify.” FDA believes that the provisions in the final IDE regulation concening investigations of devices that do not present a significant risk satisfy this statutory requirement. Under § 812.2(b)(1)(ii), the sponsor must obtain an IRB's approval of an investigation of such a device. Thus, the IRB serves as the surrogate for the Secretary with respect to the receipt and approval of the application. The IRB functions in this capacity under regulations issued by FDA. Moreover, under § 812.2(b)(1)(ii) the sponsor of a nonsignificant risk device investigation is required to explain why the device is not a significant risk device, both in its application to the IRB for approval and in records kept for FDA inspections. In addition, the sponsor of a nonsignificant risk device investigation is required to submit to FDA reports of unanticipated adverse effects, withdrawals of IRB approval, recall requests, failures to obtain informed consent, and, upon request, any additional material that FDA may need to assure the protection of the public health and safety and compliance with the act, applicable regulations, and ethical standards. Thus the sponsor's initial decision about the level of risk is subject to review in all cases by the IRB, and FDA may audit both the sponsor's decision and the IRB's review. In § 812.20(a)(1), FDA has retained the option of requiring submission and FDA approval of an IDE application for a nonsignificant risk device investigation. Furthermore, an IDE for a nonsignificant risk device may be withdrawn under the same procedures that apply to IDE's for significant risk devices. This system of review carries out the purpose of section 520(g)(2)(B) in accordance with the overriding congressional policy set forth in section 520(g)(1) “to encourage, to the extent consistent with the protection of the public health and safety and with ethical standards, the discovery and development of useful devices intended for human use and to that end to maintain optimum freedom for scientific investigators in their pursuit of that purpose.” The regulation’s distinction between significant and nonsignificant risk devices is consistent with this policy and carries out the policy of Executive Order 12044, which provides that regulations shall not impose unnecessary burdens on the economy or private organizations. 3736 Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations Mistakes by sponsors in applying the distinction are likely to be relatively rare. Any mistakes should be detected by the IRB's that are required to review and approve device investigations. IRB's are likely to give investigations of nonsignificant risk devices at least as much attention as could FDA if FDA were to require that applications for IDE's for nonsignificant risk devices be submitted to it. Whereas FDA would be faced with numerous applications, each IRB will review relatively few. To help IRB's carry out their responsibilities for nonsignificant risk device investigations, FDA is requiring investigators to send reviewing IRB's reports of unanticipated adverse device effects, failures to obtain informed consent, and other information about an investigation if requested by an IRB. Sponsors must report to reviewing IRB's concerning evaluation of unanticipated adverse effects, withdrawal of approval by another IRB or FDA, progress of the investigation, recall requests, and other information about an investigation if requested by an IRB, as well as final report. If an IRB determines that an investigation involves a significant risk device, the sponsor must report this determination to FDA, submit an IDE application to FDA, and not begin the investigation except as provided in § 812.30. By dispensing with the sumbission to FDA of applications concerning nonsignificant risk devices, the regulatory system will avoid an unnecessary and costly paperwork burden on sponsors, an excessive processing burden on FDA, and delays in approval, without sacrificing protection of human subjects. FDA has concluded that the protection of human subjects is not fostered by requiring a sponsor to submit an application to FDA for approval before commencing an investigation of a nonsignificant risk device. Protection of the public health and safety and the application of community-based ethical standards are adequately assured by the role of IRB's in reviewing such investigations. Moreover, the statutory language must be interpreted and implemented in light of common sense and available resources. Little or no public benefit would result from the submission to FDA and FDA review of a large volume of applications, the vast majority of which could not possibly present and significant risk to subjects. Moreover, FDA simply does not have, and for the foreseeable future is not likely to have, the resources that would be needed to conduct detailed reviews of all investigations of both significant.and nonsignificant risk devices. An investment of tax dollars and Federal personnel for stringent regulation of nonsignificant risk device investigations is not needed to achieve the objectives of subject protection, and this investment would be wasteful. An attempt by FDA to review all such investigations would dilute the quality of the review of investigations of significant risk devices and would divert resources from more important medical device regulatory activities. The practical result would be both to reduce public protection and to delay unduly the development of useful devices. Exempted Investigations 18. Dev.ces described in § 812.2(c) that are not subject to Part 812 are still subject to other regulatory requirements of the act, for example, those concerning labeling, premarket approval of class III devices, and the good manufacturing practice regulation ir Part 820 (21 CFR Part 820). 19. Several commentseargued that IDE'’s should be requirea only for investigations of class III devices. Under § 812.2 of the final regulation, IDE's will generally not be required for devices other than class III devices. 20. Several comments suggested making the regulation applicable only to studies initiated after the effective date of the regulation. FDA rejects these comments. FDA believes that exempting all ongoing investigations would not provide adequate protection of the public health and safety or assurance of compliance with ethical standards. Section 812.2(b)(2) exempts only those investigations that were begun before the effective date and that are completed on or before 1 year after the date of publication of the regulation. Investigations that will continue for more than 1 year from now will be continuing for a substantial period after the effective date and should be subject to these regulations, just as newly started investigations will be. FDA regards present investigations that will end less than 1 year from now as not continuing for a substantial period. As to these investigations, the burdens of requiring compliance with Part 812 outweigh the benefits. Among the requirements that apply to sponsors of present investigations that are ongoing after 1 year is the requirement that informed consent in accordance with Subpart F be obtained from all subjects still participating in the study, as well as any new subjects. 21. Many comments suggested that preamendments devices, that is, devices in commercial distribution before May 28, 1976, be grandfathered and not 21 subject to the regulation if used or investigated in accordance with labeling in effect at that time. FDA agrees, in part, with these comments. Accordingly, § 812.2(c)(1) (21 CFR 812.2(c)(1)) now provides that the IDE regulation does not apply to a device in commercial distribution before May 28, 1976, if used or investigated in accordance with indications in the labeling in effect at that time, unless the device is a transitional device as defined in § 812.3(r) (21 CFR 812.3(r)). Section 812.2(c)(2) (21 CFR 812.2(c)(2)) contains a similar provision for postamendments devices other than transitional devices that are substantially equivalent to preamendments devices and that are used or investigated in accordance with the indications in the labeling FDA reviewed in determining substantial equivalence. FDA determines substantial equivalence when it reviews premarket notification submissions under section 510(k) of the act and Subpart E of Part 807 of the regulations (21 CFR Part 807, Subpart E). However, § 812.2(d) provides a time limit on the exemptions in § 812.2(c) (1) and (2). A class Ill device exempted under § 812.2(c) (1) or (2) is subject to the IDE regulation after FDA calls for the submission of an application for premarket approval by regulation under section 515(b) of the act, if the sponsor does not submit an application or if FDA disapproves an application that the sponsor submitted. A sponsor of such a device shall obtain an approved IDE for further testing of the device or cease distribution of the device. Similarly, the IDE regulation applies to a class II device that was in commercial distribution with the same labeling immediately before May 28, 1976, or to a substantially equivalent postamendments device, after the date stipulated in an applicable performance standard that the device does not meet. A preamendments device, or a postamendments, substantially equivalent device, that is classitied into class I will never need premarket approval or a standard or, consequently, an IDE. Because of § 812.2(c) (1) and (2), the IDE regulation will apply initially only to investigations of two categories of devices: first, new devices that are not substantially equivalent to preamendments devices and, second, transitional devices, that is, devices that FDA considered new drugs or antibiotic drugs before the amendments. Sections 513(f) and 520(1) of the act classify new devices and transitional devices into class 111, and section 501(f)(1) (B) and (C) Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations 3737 deems these devices adulterated if the sponsor has obtained neither premarket approval under section 515 of the act nor an approved IDE. The IDE regulation thus will not apply to any preamendments device (or postamendments, substantially equivalent device) other than a transitional device until after passage of the temporary grace period from premarket approval that section 501(f)(2)(B) grants such devices. Under this provision, such a device is not required to have premarket approval under section 515 until the later of the following dates: (1) the last day of the 30th calendar month beginning after the month in which the classificationinto class III became effective, or (2) the 90th day after the promulgation of a regulation under section 515(b) of the act calling for submission of premarket approval applications for the device. Section 501(f)(2)(B) enables preamendments devices (or postamendments, substantially equivalent devices) that are not transitional devices to be commercially distributed until expiration of the grace period prescribed therein. FDA has concluded that Congress intended that any preamendments device (and any postamentments, substantially equivalent device) other than a transitional device be exempt from the IDE regulation until expiration of the temporary grace period in section 501(f)(2)(B) for a class II device, or until the effective date of an applicable standard for a class II device. This conclusion is based on several provisions of the act, discussed below. (The discussion in the remainder of this numbered paragraph does not apply to transitional devices.) There is no statutory duty to obtain an IDE unless use of a device for investigational purposes would violate an otherwise applicable section of the act listed in section 520(g)(2)(A), that is, section 502, 510, 514, 515, 516, 519, 520 (e) or (f), or 706 (21 U.S.C. 352, 360, 360d, 360e, 360f, 360i, 360j, or 376). If a sponsor may lawfully distribute a device for commercial purposes without violating one or more of these sections, the sponsor should not have to obtain an IDE to distribute the device lawfully for investigational purposes. FDA interprets the act to mean that the sponsor of a preamendments class UI device (or postamendments, substantially equivalent device) with the labeling then in effect (or the labeling that was reviewed by FDA in determining substantial equivalence) does not need an IDE to continue shipping the device until after expiration of the grace period from premarket approval of 30 months or longer. Similarly, the sponsor of a class II device of a type marketed before the amendments with the same or equivalent labeling does not need an IDE until an applicable performance standard that the device does not meet becomes effective. The original IDE proposal and reproposal would have applied to investigations of preamendments devices and postamendments, substantially equivalent devices, on the theory that a device would not be the subject of an investigation unless it needed an exemption from one of the provisions of the act listed in section 520(g)(2)(A), usually from the misbranding provisions in section 502. FDA has concluded that this theory does not support application of the IDE regulation to a preamendments device during the statutory grace period if that device is being used or investigated under the labeling used immediately before the amendments. Nor does the theory support application of the regulation to a postamendments device that FDA has determined to be substantially equivalent to a device in commercial distribution immediately before the amendments and that is used or investigated in accordance with the indications in the labeling FDA reviewed in determining substantial equivalence. Supporting FDA's conclusion that, during the grace period from the requirement of premarket approval, Congress. did not intend to require investigations of preamendments class III devices (or postamendments, substantially equivalent devices] to be subject to the IDE regulation is the absence of a provision in section 501 of the act, the adulteration provisions, addressing the legality of these" investigations before the effective date of the IDE regulation. As explained above, it is a premise of the IDE provisions in section 520(g) of the act that an IDE is required only if use of a device for investigational purposes would violate an otherwise applicable provision of the act listed in that section. If the investigational use of preamendments class III devices (or postamendments, substantially equivalent devices) were intended to be subject to section 520(g), then any investigational use of these devices before the effective date of the IDE regulation would be illegal, absent a special statutory exemption. Congress knew that sponsors of these devices would need to conduct studies during the time preceding the imposition of premarket approval requirements for 22 their devices: indeed, the very purpose of the statutory grace period was to allow sponsors to develop the data and conduct the studies needed to support approval. See H.R. Rep. No. 95-853, 84th Cong., 2d Sess. 42 (1976). Congress also knew that FDA had begun preliminary device classificalion efforts before enactment of the amendments. /d. at 11, 39; S. Rep. No. 84-33, 94th Cong., 1st Sess. 10-11. These efforts included identification of devices that would likely be classified into class III, the premarket approval category. often because of the lack of adequate testing. It is improbable that Congress meant for sponsors to await the effective date of the IDE regulation before beginning investigations of devices that likely would be classified into class III. In sum, Congress surely would have written the amendments so as to allow investigations of preamendments devices or their postamendments equivalents to continue, or to be initiated, during the period between the enactment date of the amendments and the effective date of the IDE regulation If it was intended that these investigations would eventually be subject to the IDE regulation, there would have been a provision for their temporary dispensation from illegality until the effective date of the regulation. Such a provision was included to permit investigatians of postenactment, not substantially equivalent devices: section 501(f)(2)(A) allows these devices to be distributed solely for investigational use until 90 days after the promulgation of the IDE regulation. Yet Congress did not include a provision for investigations of preamendments devices or postamendments, substantially equivalent devices before the effective date of the IDE regulation. The absence of such a provision, considered in light of the expectation expressed in the House committee report that such investigations would occur, supports FDA's conclusion that Congress did not intend for investigations of preamendments devices or their postamendments equivalents to be subject to the IDE regulation during the statutory grace period from the requirement of premarket approval. The provision for commercial distribution of preamendments class Il devices (and postamendments, substantially equivalent devices) during a 30-month or longer grace period also supports the position that investigations of these devices during this period v.ere not intended to be subject to the IDF regulation. It would be anomalous to interpret one provision of the art 3738 Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations (section 520(g)) as requiring strict safeguards for investigations of these devices when another provision of the same statute (section 501(f)(2)(B)) clearly allows the same device to be distributed commercially during the grace period with preamendments indications in the labeling, subject only to the general controls of the act. Commercial distribution of the device would generally expose many more patients to a device, and to its potential risks, than would its distribution for investigational use. Furthermore, a sponsor of a preamendments device (or a postamendments, substantially equivalent device) that may lawfully be commercially distributed should comply with the general controls provisions of the act, including the provisions from which an IDE would grant an exception, when distributing the device for investigational use. Finally, FDA would encounter enforcement difficulties in applying the usual prohibition against commercialization of an investigational article to a device that is simultaneously being investigated and lawfully marketed. The IDE regulation generally applies, however, if a sponsor of a preamendments device (or a postamendments, substantially equivalent device) seeks to test the safety and effectiveness of the device for a new use, that is, an indication not contained in the labeling immediately before May 28, 1976, or not reviewed by FDA in making its substantial equivalence determination under section 510(k) of the act. In such a case, the sponsor must have an IDE under § 812.2(b)(1), for a nonsignificant risk device, or under § 812.30, for a significant risk device. If the device that the sponsor wants to test for a new use is a diagnostic device, the investigation may be exempt from the IDE regulation under § 812.2(c)(3) and subject only to § 809.10(c). 22. Comments on the reproposal argued that the exemption for diagnostic devices should be extended to devices that do not introduce potentially harmful amounts of energy into the body. FDA rejects these comments because often there is no way to specify an acceptable or safe amount of energy. Investigations of diagnostic devices meeting the conditions set forth in § 812.2(c)(3) of the final regulation are not required to be subject to the IDE regulation. Such investigations either do not truly involve human subjects or present risks so small as to be negligible, or present no risk at all. Consequently, the policy set forth in section 520(g)(1) of the act does not require regulation of investigations of such devices. Even investigational diagnostic products for life-threatening conditions would, if they meet the conditions of § 812.2(c)(3), not present significant risk. Investigations of diagnostic products for life-threatening conditions would, however, present risk and be subject to the regulation if the conditions of § 812.2(c)(3) are not satisfied; for example, if a diagndstic product were used as the basis for diagnosis without confirmation. For example, investigations of the alpha fetoprotein test for prenatal diagnosis of neural tube defects using maternal sera or amniotic fluid will be subject to the IDE regulation and regarded as investigations of a significant risk device. Devices that are designed to emit energy are subject to this regulation because FDA has determined that there is no way to specify an acceptable or safe limit of energy. However, devices such as investigational electrocardiographs and electroencephalographs that are not intended to introduce energy into the body but do so only from leakage are not subject to the final IDE regulation if the sponsor meets the other conditions of § 812.2(c)(3). 23. One comment argued that the reproposal exempted investigational electrocardiographs and electroencephalographs from IDE control. The comment expressed the view that such devices are “life- supporting” or “life-sustaining” and that the testing of such devices should not escape FDA and IRB scrutiny. FDA rejects this comment. For the reasons set forth in the preceding paragraph, FDA believes that investigations of devices that meet the conditions of § 812.2(c)(3) should not be subject to the regulation. These investigations do not present a significant risk to the health, safety, or welfare of a subject when the results are confirmed by another, medically established product or procedure. 24. Comments argued that the exemption for diagnostic devices in the reproposal should be expanded to encompass both use of surplus samples that remain from previously obtained samples and low-risk venipuncture. FDA agrees with the comments. FDA believes that an investigation of an in vitro diagnostic device should not be subject to the IDE regulation if the test uses a previously obtained surplus sample that was taken for noninvestigational purposes and if the results are not used for diagnosis without confirmation. If these conditions are met, it does not matter whether the 23 sample was taken by simple venipuncture or another method, for example, a spinal tap. In either case, no IDE is required. There is no reason to waste surplus samples or to expose subjects to the added risks of obtaining new samples when surplus samples are available. FDA also believes that sampling procedures for experimental tests and procedures employing simple venipuncture should not be subject to IDE control. This procedure is routine in nature, and the risk involved is negligible. FDA has included provisions in the definition of “noninvasive” in § 812.3(k) that implement the policy described in this paragraph. 25. Several comments suggested amending the reproposal to exclude from the IDE regulation's applicability the testing of a combination of more than two lawfully markgted devices, if no safety or effectiveness testing is involved. FDA agrees with these comments. Section 812.2(c)(4) of the final regulation permits testing, without IDE controls, of a combination of two or more lawfully marketed devices, if the testing is not for the purpose of determining safety or effectiveness. 26. Section 812.2(c)(6) provides that a device shipped solely for research on or with laboratory animals is not subject to this regulation if labeled in accordance with § 812.5(c) (21 CFR 812.5(c)). No purpose of section 520(g) of the act would be served by subjecting such a device to other requirements of the regulations. Some nonclinical investigations of devices are, however, subject to the good laboratory practices regulation in Part 58 (21 CFR Part 58). Section 812.5(c) enumerates requirements that previously were proposed under Subpart H—Tests That Do Not Involve Human Subjects, and it condenses these requirements into a single paragraph. 27. Section 812.2(c)(7) provides that a “custom device" as defined in § 812.3(b) is not subject to the IDE regulation unless the device is being used to determine safety and effectiveness for commercial distribution. Section 520(b) of the act exempts custqm devices from the requirements of section 514 (performance standards) and section 515 (premarket approval). An’'FDA regulation (21 CFR 807.56(a)) exempts custom devices from premarket notification under section 510(k) of the act. Because it is not subject to these requirements, a custom device as defined in § 812.3(b) does not need an exemption from these requirements to be shipped or used. If, however, a custom device is used by a practitioner Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations 3739 to conduct what amounts to a clinical investigation to determine safety or effectiveness of a device for commercial distribution, an IDE is required. Furthermore, custom devices are subject to other provisions of the act, except sections 510(k), 514 and 515, and are thus subject to FDA regulatory action in the event of a violation. 28. Numerous comments were received on reproposed § 812.2(d}) concerning custom devices. One comment argued that a provision stating that FDA has discretion to determine whether the specific use of a custom device is subject to the IDE regulation exceeds FDA's statutory authority. FDA rejects the comments. FDA has authority to determine that a custom device is not exempt from the regulation if the device's special regulatory status is being abused, for example, when a device that purportedly is a custom device is in fact being used for investigational purposes. Under § 812.2(c)(7) FDA retains the discretion to determine whether the use of a custom device is an investigation of safety or effectiveness for commercial distribution and is subject to regulation under Part 812. FDA believes that this provision is consistent with the congressional intent expressed in section 520(g)(3) that FDA regulate “testing involving human subjects.” See also H.R. Rep. No. 94-853, 94th Cong., 2d Sess. (1976). The report states at p. 45 that ““[custom] devices are not exempt from otherwise applicable provisions of the proposed legislation, such as provisions with respect to investigational use * * *." 29. Another comment argued that FDA does not have authority to exclude custom devices from the IDE regulation. The comment argued that the omission from section 520(b) of the act of any reference to section 520(g) is a clear sign that FDA has no authority to treat custom devices as it proposed to do under the reproposal. The comment also argued that section 520(g) itself requires that custom devices be subject to the IDE regulation. FDA rejects the comment. The agency interpreted section 520 (b) and (g) of the act and the legislative history quoted in paragraph 27 above. Although it is true that section 520(b) of the act does not include investigational device controls under section 520(g) of the act as one of the enumerated provisions from which custom devices are exempted, it is also true that section 520(g) only applies to a device that needs to have an exemption from one of the enumerated requirements in order to be lawfully shipped or used. Critical among the enumerated requirements from which investigational :levices are exempt are sections 514 and 515 of the act concer: ing performance standards and premarket approval. Because section 520(b) already exempts custom devices from these two sections, there is no need for custom devices to be subject to approved IDE'’s unless their safety or effectiveness is being investigated for commercial distribution. Custom devices are, however, subject to the remaining requirements enumerated in section 520(g) from which investigational devices are exempt, as well asrother device provisions of the act. The sentence in the House Committee Report quoted in paragraph 28 above means that an investigation of a custom device to determine its safety and effectiveness for commercial distribution is subject to the IDE regulation. If a custom device is used for a therapeutic purpose for an individual patient, however, and not for the purpose of determining safety or effectiveness for commercial distribution, the evident congressional purpose reflected in section 520(b) of the act warrants that it not be subject to the IDE regulation. 30. The same comment argued that section 519 of the act with respect to records and reports on devices also requires that custom devices be subject to the regulation. FDA rejects the comment. Nothing in section 519 requires that the IDE regulation apply to use of a custom device that does not involve determination of safety or effectiveness for commercial distribution. Records and reports requirements for investigational devices are imposed under authority of section 520(g)(2)(B) (ii) and (iii), not under authority of section 519 of the act. It is clear both from section 519(b)(2) and from section 520(g)(2)(A) that the two authorities for records and reports requirements are intended to be mutually exclusive. 31. A comment asked who determines that a custom device is exempt from the regulation. This determination is made initially by the physician or dentist, but may be overruled by a manufacturer requested to provide a custom device, an IRB that, under institutional policies, reviews use of custom devices at the institution notwithstanding their exemption from the IDE regulation, or by FDA upon determining whether a custom device is being used to determine safety or effectiveness for commercial distribution. 32. A comment asked whether components of custom devices are subject to the IDE regulation. 24 Components of a custom device are not subject lo Part 812 if they are “integra‘ed” into the custom device, that is, they are being used as parts of the custom device and not as separate and independent devices. If components of a custom device are used as separate and independent devices, the applicability ta them of the IDE regulation is to be determined under other provisions ef § 812.2. 33. A comment argued that FDA's exempting custom devices sanctions engineering judgments by health professionals. FDA acknowledges that in certain instances the customizing of a marketed device or design of a custom device by a health professional does involve engineering judgments. FDA believes that section 520(b) of the act reflects a congressional intent to permit health professionals to make such judgments in the course of their professional practices, so long as they do not cenduct investigations of safety er effectiveness for commercial distributien. Effect on Intraocular Lens (IOL) Investigations 34. The preamble to FDA's regulations on IOL investigational device exemptions, published in the Federal Register of November 11, 1977 (42 FR 58878) and codified in Part 813 of the regulations, stated that Part 813 would be repealed when the IDE regulation is made final. Owing to the delay in development of the final IDE regulation and the advanced state of IOL investigations under Part 813, FDA has concluded that repeal of Part 813 is not warranted. Sponsors, investigators, IRB's, and FDA are thoroughly familiar with Part 813. A change in ground rules at this stage would serve no useful purpose. Moreover, subjecting IOL investigations to new Part 812 rather than to Part 813 would not afford greater subject protection than now exists and could disrupt ongoing investigations. For these reasons, § 812.2(c)(8) provides that Part 812 will not apply to ongoing or newly started IOL investigations. Effect on Investigations Under IND's 35. On its own initiative, FDA has added § 812.2(e), which discusses the effect of the IDE regulation on sponsors having effective IND's under Part 312 for investigations of devices that FDA previously considered drugs on the effective date of the IDE regulation. Section 812.2(e) requires such a sponsor to continue to comply with the requirements of Part 312 until 90 day. after the effective date. To initiate or continue an investigation after this 90- 3740 Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations day period, a sponsor must have an approved IDE. A sponsor who has an effective IND for an investigation of a device and wishes to obtain an IDE to continue that investigation after the 90-day period should inform the Bureau of Medical Devices, FDA, by letter of the IND number and the phases of the investigation that have been completed (Phases I, II, or III). Such letters should be submitted as soon as possible to avoid disruption of ongoing studies. The Bureau will inform the sponsor whether the investigation may continue and what conditions will apply. For example, if FDA determines that the protocol and other procedures being followed under Part 312 satisfy the requirements of Part 812, FDA may consider the investigation to have an approved IDE and may allow it to continue without changes. Sponsors of investigational transitional devices subject to Part 812 that do not have an effective IND before the effective date of this regulation will have to obtain an IDF. (See § 812.3(r) of the regulation for a definition of “transitional device.") Investigations of transitional devices that are significant risk devices are subject to all requirements of Part 812. Investigations of transitional devices that are not significant risk devices must comply only with § 812.2(b)(1) unless FDA informs the sponsor under § 812.20(a) that submission of an application is necessary. 36. Numerous comments were received on the definitions in the reproposal. Many comments stated that certain definitions lacked clarity and were not helpful. Some comments submitted alternative definitions that would have changed the effect of the applicability section. The latter comments have been discussed elsewhere in this preamble. As indicated below, FDA has responded to many of these comments. FDA on its own initiative has deleted the definitions of “investigational plan” and “institutionalized subject" because they are unnecessary. 37. FDA on its own initiative has redefined “custom device" in § 812.3(b). The term “physician or dentist” has been substituted for the term “health professional” to be consistent with section 520(b) of the act. Although section 520(b) authorizes FDA, after opportunity for an oral hearing, to issue regulations allowing specially qualified individuals other than physicians or dentists to obtain and use custom devices, no such regulations have been issued. Thus, at this time, only physicians and dentists qualify for the custom device exemption in the act and the IDE regulation. 38. One comment argued that FDA's definition of “custom device” went beyond the statutory intent, and that the examples given were not well thought out and should be deleted. FDA agrees that the definition of “custom device" should more closely follow the statute. FDA has deleted the requirement that if a custom device is an implant it must be made of “safe and suitable” materials, in response to comment that this provision was vague and unworkable. FDA believes that the examples of custom devices discussed in the reproposal, however, still provide useful guidance on FDA's interpretation of the effect of the act on custom devices. 39. Some comments suggested including psychologists or microbiologists as individuals who couid order custom devices. Other comments sought to retain the term “health professional” but to expand its scope beyond physicians and dentists. FDA rejects these comments because there currently are in effect no regulations under section 520(b) of the act concerning the use of custom devices by individuals other than physicians and dentists. A proceeding for the issuance of such a regulation may be initiated by a citizen petition filed under § 10.30 (21 CFR 10.30) or by FDA on its own initiative. 40. On its own initiative, FDA has added a definition of “implant.” The definition is consistent with the definition in FDA's classification regulation at § 8680.3(d) (21 CFR 860.3(d)). Section 812.3(d) defines “implant” as a device that is placed into a surgically or naturally formed cavity of the human body if it is intended to remain there for a period of 30 days or more. FDA reserves the right to determine that implants placed in patients for shorter periods are also “implants” for purposes of Part 812. 41. One comment suggested that the definition of “institution” in reproposed § 812.3(b) (now § 812.3(e)) be modified to include a clinic or practitioner's office in order to permit clinical investigations to be carried on by sole practitioners. FDA disagrees with the comment. Including a clinic or practitioner's office within the definition does not reflect accurately the common or ordinary meaning of the term. However, excluding clinics and practitioners’ offices from the definition does not, in most cases, preclude sole practitioners from being investigators. If an investigator's work cannot be reviewed by a duly constituted IRB, for example an IRB at an institution in the same 25 locality, the sponsor is required to submit the application, investigational plan, and report of prior investigations directly to FDA in accordance with section 520(g)(3)(A)(ii) of the act. In some cases, however FDA may believe that review by a local IRB is critical to the protection of the rights, safety, and welfare of subjects and will refuse to authorize conduct of an investigation without IRB review. 42. One comment argued that “institution” should not include a manufacturer because a manufacturer should not be required to create an in- house IRB. FDA disagrees. A manufacturer must be subject to the requirements of institutional review if an investigation i: carried out on the manufacturer's premises, for example, using employees as subjects of the investigation. Employees are entitled to the same protections, including IRB review, as other subjects. 43. FDA has shortened and modified the definition of “investigational device’ in § 812.3(g). The term includes transitional devices as defined in ne. § 812.3(r). 44. A comment suggested that FDA permit qualified medical personnel to administer or dispense the device in the absence of, but under the direction of, the primary investigator. FDA does not believe the definition of “investigator” prohibits this practice. No change has been made in the definition. 45. The term “noninvasive” as defined in § 812.3(k) includes devices that penetrate or pierce the nose, ear, or eye. The definition has been clarified to mean intentional penetration or piercing. If misused, virtually any device might penetrate or pierce the body. Only those devices deliberately designed or intentionally used to penetrate or pierce are considered invasive. 46. Comments objected to the reproposed definitions of “substantial risk,” “low risk,” “vital device," and “nonvital device.” Some comments argued that the definitions were too subjective and obscured the issue of risk. FDA agrees with the comments and has replaced the categories used in the reproposal in favor of a simpler distinction between “significant risk devices" and devices that are not significant risk devices (“nonsignificant risk devices”). Under the definition of “significant risk device” in § 812.3(m), most but not all implants would be treated as significant risk devices. However, certain implants, such as many dental amalgams, would not be significant risk devices because they would not present Federal Register / Vol 45, No. 13 / Friday, January 18, 1980: / Rules and Regulations 3741 a serious risk to the health, safety, or welfare of a subject. On the other hand, sponsors of clinical investigations involving investigational contraceptive devices, for example, diaphragms, must submit an IDE application. Although many of these devices are not implants, FDA has determined that investigational: contraceptive devices are: for a use of substantial importance in preventing impairment of human health and present a potential for serious risk to the health, safety, ar welfare of a subject in the event of an unplanned pregnancy. Sponsors are encouraged to contact FDA informally for guidance on whether an IDE application is required for the investigation of a specific device. 47. Several definitions in § 812.3, for example the definition of “subject” in § 812.3(p), differ slightly from the definitions found in proposed FDA bioresearch monitoring regulations. No differences in meaning are intended, and the minor wording differences will be eliminated when the agency publishes the other regulations. 48. FDA, on its own initiative, has added a definition of “termination” in § 812.3(q). The term includes all conditions under which, and reasons for which, a sponsor would stop a clinical investigation before its completion. 49. FDA, on its own initiative, has added a definition of “transitional device” in § 812.3(r). It replaces the term “transitional period,” which appeared in the reproposal at § 812.3(p). 50. FDA has added a definition of “unanticipated adverse device effect,” in § 812.3(8). The term has the same meaning as “serious adverse effect,” which appeared in reproposed § 812.46(c)(1) (21 CFR 812.46(c)(1)). Labeling of Investigational Devices 51. Comments on reproposed § 812.5 argued that the labeling requirements of this section duplicated those in proposed Subpart H. FDA agrees with these comments and has deleted Subpart H from the final regulation. For ease of reference, labeling requirements have been consolidated in § 812.5. 52. Comments questioned whether compliance with § 812.5 would relieve a sponsor from an obligation to comply with § 809.10(c), which requires special labeling for investigational in vitro diagnostic devices, and notifications to FDA of shipment of such devices. FDA has concluded that the sponsor of an investigation of a diagnostic device that meets the conditions of § 812.2(c)(3) for exemption from the IDE regulation should continue to comply with § 809.10(c). The sponsor of an investigation of a diagnostic device that is subject to Part 812 does not have to comply with § 809.10(c). In response ta the comments, FDA is publishing a conforming amendment to § 809.10(c) to clarify the relationship between that provision and Part 812. This amendment. also eliminates the provision in § 809.10(c)(4) requiring compliance with the drug listing regulations in § 207.25 (21 CFR 207.25) when the sponsor of an investigation of an in vitro diagnostic device initiates commercial distribution. Section 809.10(c)(4) is obsolete and is inconsistent with the premarket notification requirements for devices under section 510(k) of the act and Subpart E of Part 807. Promotion of Investigational Devices 53. Section 812.7(a) prohibits sponsors, investigators, and their agents from promoting or test marketing an investigational device until the device has been approved for commercial distribution. This section ensures that investigational devices are not advertised before their claims are established, helps prevent such devices from being distributed too widely, and prevents an IDE from serving as a subterfuge for unapproved marketing. Test marketing of a device, which is prohibited, differs from consumer preference testing of a device, which is authorized. Test marketing involves sale of a device. Consumer preference testing involves tests to determine whether consumers prefer certain packaging or other features of a device unrelated to its safety or effectiveness, but does not involve its sale. Consumer preference testing may involve use of a device so long as the use does not involve testing of safety or effectiveness or put subjects at risk. 54. Comments objected to provisions of the reproposal that prohibited sponsors from charging for the device in certain cases. Comments also objected to provisions that authorized FDA to determine whether a charge for the device is reasonable. Comments argued that FDA has no expertise in determining reasonable costs. FDA recognizes that practical problems may be encountered in administering this provision, but believes that special expertise is not required to determine whether charges are excessive. Many devices, unlike most drugs, are expensive to manufacture, and it is unrealistic to prohibit a sponsor from recovering costs. It is a well-established ethical principle, however, that no profit should be made on experimental drugs or devices. Accordingly, § 812.7(b) prohibits charging for the device a price larger than that needed to recover 26 manufacturing, research, development, and handling costs. FDA has deleted as unnecessary the provision in the guigash propasal fer FDA to determine whether charges are unreasonable. FDA will make: the determinations necessary to enforce § 812.7(b). Waivers 55. Comments on reproposed: § 812.10. objected. to requiring submission of a citizen petition to obtain a waiver. Several comments argued that the procedure was unduly cumbersome and time consuming and required unnecessary paperwork. Other comments stated that, because a citizen's petition is subject to public disclosure, the confidentiality of the original IDE application would be compromised. FDA agrees with these comments. Modified § 812.10 permits sponsors to request waivers by letter. 56. A comment suggested that the regulation specify those requirements of section 520(g) that are not subject to waiver. The comment also suggested that § 812.10 be revised to state that no waiver may be granted that could expose any human subject to undue risk of harm. FDA has revised § 812.10(b) to clarify that FDA may waive only a requirement that FDA finds ie not required by the act. FDA also agrees that no waiver should be granted that could result in harm to subjects, and has further revised the section to clarify that. only requirements that FDA finds are unnecessary to protect the rights, safety, or welfare of human subjects may be waived. 57. Other comments suggested that FDA respond to a waiver request within a specified time, preferably within 30 days. FDA rejects these comments. Waiver requests may range from a simple, one- time variation to very complex matters presenting difficult issues. Due to this variation, FDA concludes that a specified time frame is inappropriate. FDA intends to evaluate quickly all requests for waivers. Import and Export Requirements 58. Section 812.18 (21 CFR 812.18) of the final regulation has been simplified without substantive change. Some comments suggested that § 812.18(b) repeated the statute; others argued that the provisions of § 812.18(b) did not comply with the statute. Some comments suggested the statute itself is unconstitutional with respect to exported devices. FDA has modified § 812.18(b) to require an exporter to “obtain FDA's. 3742 Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations prior approval, as required by section 801(d) of the act.” This modification eliminates any question of deviation from the statutory requirements. The requirements that were described in the original ‘proposal and the reproposal have been deleted because FDA believes that the statute provides sufficient guidance to exporters. The preamble to the reproposal discussed the constitutionality of the export provisions of the statute. 59. A comment objected to the deletion of the requirement in the original proposal that the exporter have, or assure that another person has, complied with the requirements on submittal of an application and on the responsibilities of sponsors. The comment further objected that the reproposal did not require the agency to find that human subjects would not be exposed to undue risks and that the foreign country has adequate mechanisms to control use of the device after export. FDA did not include these requirementsin the reproposal and has not included them in the final regulation because FDA concluded that literal application of these requirements in all cases would be unduly burdensome, would present enforcement difficulties, and was not required by section 801(d) of the act (21 U.S.C. 381(d)). FDA concluded that the statute itself affords adequate protection to subjects of investigations conducted in foreign countries. Under section 801(d), sponsors may obtain FDA's permission to export an investigational device by ‘writing to FDA's Bureau of-Medical Devices a letter enclosing a copy of the foreign government's approval of importation of the device. After verifying the approval, if necessary, and determining that the exportation of the device is not contrary to the public health and safety, the Bureau will approve and export request. When necessary for the protection of the public health and safety, the Bureau may, in selected cases, require the exporter to submit an application and comply with the responsibilities of sponsors or assure that another person complies with these requirements. 60. A comment suggested that FDA respond to export requests within a specified time. FDA rejects the comment. A time limit is not required by the law. Requests may vary from the simple to the complex. Specified time frames for action on export requests are not practical because it sometimes is difficult to verify approvals from foreign countries. All requests will be processed as quickly as circumstances permit. Application and Administrative Action Notification Procedure 61. A number of comments objected to proposed §§ 812.20 and 812.21 because the notification permitted for certain studies required most of the information that is required in a full application for substantial risk, vital device studies. Comments argued that the definition of “vital device” did not provide adequate guidance to determine whether to submit a notification or an application. Some comments suggested inclusion of an abbreviated IDE procedure for low- risk investigations. Comments stated that provisions for submission of summaries of documents, for example a summary of the investigational plan, are more burdensome than requirements to submit the complete document. FDA agrees that the notification procedure in the reproposal largely duplicated the application procedure. Accordingly, FDA has replaced the notification procedure with a set of requirements in § 812.2(b)(1) for investigations of devices that are not “significant risk devices.” These requirements are discussed in paragraphs 1, 17, and 486. Section 812.20(a)(1) requires a sponsor to submit an application to FDA if a significant risk device is to be investigated with human subjects or if FDA notifies a sponsor that an application is required. 62. A comment contended that the notification procedure was inadequate to protect subjects and should be either tightened or abandoned. The comment argued that the procedure placed too much reliance on an IRB's assessment of risk, without providing FDA with enough information to make possible an independent judgment. The comment suggested that a notification be required to include an explanation of the IRB's reasoning, a summary of the evidence on which the IRB relied, a description of the risk involved, copies of any dissents by IRB members, copies of consent forms and informational materials to be given to subjects, a statement as to whether any other IRB has taken adverse action on a similar study, a detailed description of the device, and manufacturing information. FDA disagrees with the comment. IRB's should have a substantial role in all investigations. IRB's can act on FDA's behalf, subject to agency oversight, in reviewing investigations of devices other than significant risk devices. FDA does not accept the comment's assumption that low-risk studies need the same degree of regulation as high-risk studies and that IRB decisions on nonsignificant risk device investigations need close FDA 27 scrutiny. As explained in paragraph 17 above, allowing sponsors to adhere to abbreviated requirements and IRB's to take principal responsibility for review of investigations of nonsignificant risk devices will allow FDA to devote the attention and resources necessary for regulation of significant risk device investigations. A_sponsor is required to submit to the IRB an explanation why the device is not a significant risk device and to provide any other information requested by an IRB, which may include the information listed in the comment. For the reasons stated in paragraph 17 above, FDA does not expect that this approach will expose subjects to risk of harm. Furthermore, FDA retains its ability to oversee such investigations through records inspections and required reports. To help IRB's carry out their responsibility to review nonsignificant risk device investigations, FDA has required that sponsors and investigators submit certain reports to reviewing IRB's. These requirements are discussed in paragraphs 141, 144, 145, and 146. Application Procedure 63. In response to the comments described in paragraph 59 above, FDA has made several changes in the regulation with respect to investigations for which an application must be sumitted to FDA. Once IRB approval has been obtained, a sponsor shall submit to FDA an application that may include either the plan itself or a summary of specified sections of the plan. FDA also has clarified the procedure to be used if an investigation is to be conducted at several institutions. An application may be submitted to FDA as soon as one IRB has approved the investigation after considering the investigational plan and report of prior investigations. FDA approval of the investigation, however, applies only to the institution at which an IRB also has approved it. As each additional IRB approves the investigation, the sponsor shall submit to FDA one or more supplemental applications under § 812.35(b). If an investigation involves testing at several institutions, IRB's should not interpret FDA approval of a part of an investigation at one institution as the basis for approval, without careful review, of a part of the investigation at other institutions. 64. Several comments observed that it might be difficult to obtain local IRB review and requested a clarification of the procedure to follow. FDA recognizes that occasionally a sponsor may encounter difficulty in finding an IRB in a particular location to review a proposed investigation. Section Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations 3743 520(g)(3)(AJ(ii) of the act (21 U.S.C. 360j(g)(3)(A)(ii) authorizes the sponsor to submit the application to FDA if no: IRB exists or if FDA finds IRB review inadequate. FDA believes that a local IRB applying community standards to a proposed investigation generally provides an indispensable form of subject protection. The absence of a local IRB may expose subjects to risk that the local community regards as unreasonably, and FDA may have little capacity to determine what risks are acceptable in that community and to function as an IRB. In accordance with the apparent intent of Congress, however, FDA will attempt to perform the functions of the iocal IRB with respect to an otherwise meritorious investigation if no IRB exists or an IRB's review is inadequate, unless the agency finds that IRB review is critical to subject protection. This policy is described in § 812.20(a)(2). If FDA so finds, a sponsor would have to conduct the investigation at a location where an IRB can review the study, or not conduct it. Contents of an Application 65. In response to comments, FDA has revised § 812.20(b) to simrlify the application requirements. The investigational plan requirements have been integrated with those for the application so that those portions of the investigational plan that may be summarized are distinguished form portions that may not be. 66. Comments argued that FDA should not ask for manufacturing or processing information. FDA disagrees. This information helps FDA to determine the risk presented by the device and whether the device will be manufactured with consistency. Lack of uniformity in making a device could result in investigational devices that vary. Such variation could produce differing results that yield invalid data and require repeated investigations that present further risks. 67. Other comments suggested that the description of facilities required by § 812.20(b)(3) should be omitted if a quality assurance program is in effect FDA disagrees. A quality assurance program consists of procedures necessary to assure and verify confidence in the quality of the process used to manufacture a finished device. For the reasons stated in paragraph 66 above, FDA needs detailed information on manufacturing methods, facilities and controls. A quality assurance program does not provide sufficiently specific information about the manufacturing process to be followed for a particular investigational device. 68. Comments objected to the submission of manufacturing or processing information to an. IRB. This information is now required enly in the application to FDA. An IRB may, however, require submission of manufacturing or processing information if it believes that review of the information is necessary to its decision. Signed Investigator Agreements 69. Section 812.20(b) (4) and (5) differs from the reproposal by requiring that, in: lieu of submitting all signed investigator agreements, sponsors submit an example of the agreements, a list of investigators, and a certification that all investigators listed have signed the agreement. A related provision, § 812.150(b)(4), requires the sponsor to submit to FDA every 6 months a current list of the names and addresses of all investigators participating in the investigation. FDA initiated these changes to avoid unnecessary paperwerk for sponsors and FDA. FDA. can check the current list of those who have signed agreements against its files for adverse information. A sponsor shall submit the actual agreements if FDA so requests under § 812.150(b}(10). In addition, FDA inspectors can verify the list provided by the sponsor against the actual agreements kept in the sponsors’ records to assure that the list is accurate and that investigators are not added until they have signed agreements. These procedures will assure attention to investigator responsibilities and will protect the public without the cumbersome requirement that all individual agreements be sent routinely to FDA. Waste of resources from routine FDA review of signed investigator agreements will be avoided, and FDA will be able to concentrate its limited resources on important scientific aspects of applications. Routine sponsor paperwork submissions are also reduced. In these circumstances, FDA believes that it has regulatory discretion to permit sponsors to maintain the agreements in their files, subject to FDA inspection or submission to FDA on request, and that this approach satisfies the requirement of section 520(g)(3)(C) of the act that the investigators’ agreements be “‘submit[ted} * * * to the Secretary.” Disclosure of IRB Action 70. Section 812.20(b)(8) requires the sponsor te list the mames, locations, and’ chairpersons of all IRB's that have been asked to review the investigation, and ta certify the action concerning the investigation taken by each IRB. Sponsors will thus disclose whether an IRB has approved, disapproved, or 28 terminated am investigation, or found a. device that the sponsor characterized as a nonsignificant risk device to be a significant risk device. Comments argued that prior IRB disapproval or termination of an investigation is irrelevant and that a requirement to disclose such IRB actions in an application might prejudice FDA decisions. FDA disagrees with the comments. Disapproval, suspension, or with of approval suggests the possibility of a flaw in an investigation that should be evaluated before the investigation is approved. If such a previous action were disclosed after an investigation had begun, FDA might have to withdraw approval of the investigation and order it stopped pending further inquiry. In such a case, subjects might be exposed to unnecessary risks, and sponsors and’ investigators might be inconvenienced. 71. Section 812.20(b)(7) requires the sponsor to submit the name and address of any institution at which a past of the investigation may be conducted if that institution is not identified under § 812.20(b)(6). This provision ensures- that FDA has complete information on where an investigation is to be conducted, if an investigator's part of a study is not on the premises of the institution whose IRB has agreed to review the investigator's part of the study. FDA needs this information to review the scope of the investigation and to schedule necessary inspections. 72. A comment suggested that the application disclose any dissent from. IRB approval. FDA rejects the comment. Such disclosure could be implemented only by requiring IRB's to keep records of each dissent. Committee decisions frequently result from divided opinions. If detailed records of dissenting views were required, IRB’s might feel compelled to issue a written opinion approving the investigation despite the lack of an FDA requirement for such an opinion. To require documentation of minority views, therefore, might unnecessarily delay IDE decisions and disrupt IRB operations. Furthermore, such a requirement would commit FDA to review documents that are not likely to yield valuable informatiom Bven if dissents contain useful information, there is too little likelihood that the: same information would not have been discovered by FDA during its review of the application to justify the paperwork burden that would result from a requirenrent that dissents be submitted to FDA. An IRB member may oppose an investigation for reasons relevant to the particular institution but irrelevant to the standards for approval under the act 3744 Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations and these regulations. FDA would therefore find it necessary to distinguish between dissents that have to be submitted to FDA and those that do not, thus burdening IRB's with the requirement that they make this distinction. The collective assessment of the IRB is what matters to FDA in its review of an IRB's judgment. FDA will, in any event, conduct its own independent review of each application. IRB's may choose, however, to maintain records of dissents or summaries of dissents; and IRB's or individual IRB members may notify FDA of dissenting views. Disclosure of Intent To Sell or Charge for the Device 73. Comments argued that FDA has no authority to require disclosure of an intent to sell the device or the amount to be charged and that FDA cannot effectively use the information. FDA rejects the comments. FDA will use the information required by § 812.20(b)(8) in determining whether the device is being commerciaily distributed in violation of the conditions of the IDE. FDA is authorized by sections 301(q). 501(f), 520(g)(2)(B). and 701(a) (21 U.S.C. 371(a)) of the act to impose this requirement. Investigational Plan 74. FDA has made explicit in § 812.25(b) the requirement for a written protocol describing the methodology used in an investigation. This requirement was implied in the original proposal and repropesal. 75. A comment on reproposed § 512.25 suggested that the investigational plan include a description of any characteristics that render the patient population vulnerable. FDA agrees and has included this description as part of a required analysis of risks to subjects, justification for the study, and description of the patient population in terms of the number of subjects and their age, sex, and condition. The term “condition” includes ielevant characteristics that render the patient population vulnerable. This provision focuses on the purpose of investigational controls: Protection of subjects through an analysis of risks, including the manner in which the risks will be minimized. FDA expects the analysis to be brief and to be direc ‘ed to the additional or incremental risks (as distinguished from risks inherent in the subjects’ medical condition) that use of the device presents to the rights, safety, or welfare of subjects. FDA believes that careful analysis of risks by sponsors, IRBs, and FDA will enable regulatory controls to be targeted on those investigations that are most likely to expose subjects to undue risks. 76. Comments suggested that the requirement to submit a description of each important device component was burdensome, and that only those components that increase risk should be described. FDA rejects the comments. Trying to decide which components increase risk and which do not is a difficult and, perhaps, impossible task. IRB's and FDA should be able to review each important component of an investigational device. The requirement is retained in § 812.25(d). 77. Other comments suggested that the investigational plan disclose whether any IRB's had ever suspended, disapproved, or terminated an investigation. FDA agrees, and § 812.25(h) requires sponsors to certify the action by each IRB that has reviewed the investigation. Among the actions required to be reported are findings by another IRB that the investigation involves a significant risk device. 78. Section 812.25(h) duplicates the requirement in the application for a list of the names. Incations, and chairpersons of all IRB's that have been asked to review the investigation. FDA added this provision to enable IRB's to consult with each other concerning an investigation. 79. Section 812.25(j) requires a description in the investigational plan only of any records and reports that are in addition to those required by Subpart G of this regulation. FDA made this chiange to eliminate needless description of records already required by Subpart C. Report of Prior Investigations 80. Comments argued that reproposed § 812.27(d) implied that animal testing must be completed in every case before human testing is initiated. FDA appreciates that some devices cannot be tested in animals before they are tested in humans. FDA has deleted the proposed requirements for prior animal! testing from the final regulation because they did not provide useful guidance as to when and to what extent animal studies would be required. FDA will determine, in its review of IDE applications, whether prior animal testing should have been conducted. IRB's should also look closely at this point. The approach FDA is using here is consistent with its general policy that, where possible, relevant animal testing should be completed before initiating human testing. FDA will not approve an IDE or an application for premarket 29 approval if animal testing should first be completed. 81. Comments suggested that only information relevant to the investigation be submitted, rather than all information relevant to the device. FDA agrees with the comments. Furthermore, § 812.27(b)(1) has been revised to require only a bibliography of relevant publications and copies of all published and unpublished adverse information. To reduce unnecessary paperwork, copies of other significant publications need be submitted only if requested by a reviewing IRB or FDA. Also, § 812.27(b)(2) provides that only a summary of other relevant unpublished information is required. Relevant information includes both information that is adverse and information that supports a proposed investigation. 82. Comments suggested that the IRB, not FDA, should decide on the adequacy of the report of prior investigations. FDA disagrees with the comments. FDA has final responsibility for the proper conduct of device investigations. Therefore, in the case of a significant risk investigation, FDA should review the report of prior investigations and determine its adequacy. Although FDA expects that it will generally concur in IRB assessments, it cannot guarantee tha* it will never overrule an IRB” judgment based on a review of the report of prior investigations. FDA Action on Applications 83. Comments suggested that the criteria for disapproval and withdrawal were similar and should be combined. Other comments noted minor differences between the criteria for disapproval and withdrawal. FDA agrees with the first set of comments. Accordingly, the criteria have been combined in § 812.30. 84. A comment suggested that § 812.30 be revised to prohibit approval of seriously deficient applications. The comment also suggested that safety- related grounds for withdrawal of approval of iDE's should be placed in a separate mandatory withdrawal category, distinct from discretionary grounds for withdrawal. The comment suggested further that the regulation compel FDA to withdraw exemptions in cases of non-safety-related deficiencies that are not corrected within a reasonable time. for example, 60 days after notification. FDA has not adopted the comment. Because FDA will not approve seriously deficient applications, there is no need to include in the regulation a provision prohibiting such approvals. With respect to the suggestion that FDA revise § 812.30(b) to state that FDA “shall” Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations 3745 withdraw approval if certain safety- related grounds exist, the agency would still retain the discretion to determine whether one or more of the specified grounds exist, for example, that it is “unsafe to begin or to continue an investigation,” § 812.30(b)(4). No change in wording can eliminate FDA's discretion to determine whether a ground for action exists. Also, some of the grounds for action in § 812.30 would be characterized as safety-related in some cases but not in others. With respect to the suggested deadline for FDA withdrawals for non-safety-related reasons, FDA believes that such matters are better handled by internal agency procedures than by regulations. Supplemental Applications and Submissions 85. Comments argued that the reproposal’s requirements for supplemental applications were too restrictive and that supplemental applications should be limited to changes affecting the safety of subjects or the validity of the investigation. FDA believes that this was the intent of the reproposal, but has clarified § 812.35, the counterpart provision in the final rule, to reflect clearly this policy. Supplemental applications are required only for the addition of new institutions to an investigation and for changes in the investigational plan that may affect the scientific soundness of the study or the rights, safety, or welfare of subjects. IRB and FDA approvals are required before initiating any such changes, except for deviations from the investigational plan to protect a subject in an emergency. These deviations shall be reported later under §§ 812.150(a)(4) and 812.35(a). 86. Comments suggested that, once an IRB has approved a change in the plan, FDA approval of the change is not needed. - FDA rejects these comments. Sections 812.35(a) and 812.150(a)(4) of the final regulation require that any change in the investigational plan that may affec. its scientific soundness or the rights, safety, or welfare of subjects be approved by both the IRB and FDA. In significant risk device investigations, nonemergency changes that may have such an effect should receive the same prior review as an application. Less important changes in the investigational plan for significant risk device investigations, and any changes in the plan for nonsignificant risk device investigations, need not, however, be reported to FDA. 87. Some comments argued that all deviations from the investigational plan should be approved by the sponsor before FDA or IRB approval is sought. Other comments suggested that such deviations do not require prior FDA or IRB approval. Under §§ 812.110 and 812.150(a)(4), an investigator shall not institute a change in or deviation from the investigational plan without first obtaining the sponsor's approval. If the deviation or change may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, prior IRB and FDA approval also is required. An exception from these requirements is that, in an emergency situation, as described in § 812.35(a), prior approval of a deviation by the sponsor, the IRB, and FDA is unnecessary. Emergency deviations shall be reported later under §§ 812.150(a)(4) and § 812.35(a). These provisions are designed to deter careless deviations from the investigational plan, without unduly restricting an investigator at the scene of the investigation from exercising initiative on behalf of patient rights, safety, or welfare in a medical crisis. Confidentiality of Data and Information 88. Section 812.38(a) of the final regulation states that FDA will not disclose the existence of an IDE unless its existence has been publicly disclosed or acknowledged, until FDA approves an application for premarket approval of the device subject to the IDE, or a notice of completion of a product development protocol for the device becomes effective. This provision, which is based on current FDA policy with respect to notices of investigational exemption for new drugs (IND's), was published in the original IDE proposal. The provision was omitted from the IDE reproposal because FDA had published in the Federal Register of March 28, 1978 (43 FR 12869), correction published in the Federal Register of March 31, 1978 (43 FR 13587), a proposal to change FDA policy regarding disclosure of the existence of applications or notices to conduct research on, or to market, drugs or devices. Under the March 28, 1978 proposal, FDA would disclose the existence of such an applcation or notice whether or not its existence had previously been disclosed or acknowledged. FDA is still reviewing the numerous comments received on the proposal. For now, FDA believes that current policy with respect to disclosure of the existence of IND's should apply to disclosure of the existence of IDE's, and has so provided in § 812.38(a). Section 812.38(b) of the reproposal stated that public disclosure of IDE data and information would be made in accordance with § 314.14 on the confidentiality of data and information 30 in new drug application (NDA) files. In the final regulation, FDA has moved this provision to paragraph (d) of § 812.38 and has revised it to state that NDA confidentiality rules apply only until the effective date of the final regulation concerning the confidentiality of data and information in applications for premarket approval of devices. FDA plans to publish a proposal on procedures for these applications, including confidentiality of the contents of these applications, in the near future. 89. A comment argued that reference in § 812.38 to the drug confidentiality rules in § 314.14 is inappropriate because of the special statutory protections in section 520(c) of the act for device trade secrets and condifential commercial information. FDA rejects the comment. It is true that the act does not contain a provision precisely like section 520(c) that applies to drugs the same protection for trade secrets and confidential commercial information that section 520(c) applies to devices. However, in § 314.14 the agency has construed section 301(j) of the act and 18 U.S.C. 1905 as preventing public disclosure of the same types of information about drugs that section 520(c) treats as confidential. Thus, with respect to public disclosure of trade secrets and confidential commercial information, section 520(c) provides the same degree of protection as section 301(j) and 18 U.S.C. 1905. Accordingly, reference to confidentiality rules applicable to drugs generally is appropriate. As noted above, when final regulations on device premarket appproval applications become effective, these regulations will contain rules for confidentiality of device data and information so that it will no longer be necessary to refer to the drug confidentiality rules in § 314.14. 90. Another comment stated that reference in § 812.38 to the drug confidentiality rules in § 314.14 is inappropriate because of the provisions in section 520(h) of the act for summaries of device safety and effectiveness information. The comment interprets section 520(h) as requiring public disclosure of such information in IDE files, under any circumstances. FDA agrees that it must revise § 812.38 of the reproposal for consistency with section 520(h) of the act and with § 812.30(f) of the reproposal. FDA has therefore revised § 812.38(b) of the final regulation. FDA disagrees with the comment's interpretation of section 520(h) of the act as imposing a requirement for public disclosure of the records contained in IDE files. It is clear from its face that section 520(h) only requires disclosure of 3746 Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations a detailed summary of safety and effectiveness information, not disclosure of the records from which this summary is developed, and does so only when FDA takes one of several specified actions. See also H.R. Rep. No. 94-853, 94th Cong., 2d Sess. 48-51 (1976). Moreover, section 520(h)(3) states that information in a summary “shall be made available subject to” section 520(c) of the act. Section 520(c) specifically describes safeguards for trade secrets and confidential commercial information concerning devices and is discussed in paragraph 89 above. Because of section 520(c), a summary prepared under section 520(h) may not contain trade secret or confidential commercial information, including confidential safety and effectiveness data. 91. One comment argued that safety and effectiveness data should be released only after an applicant has exhausted all administrative and judicial appeals of a denial of an application. FDA agrees but Lciieves no change is required. Under paragraph (f)(2) of § 314.14, referred to in § 812.38(d), FDA will not disclose confidential commercial information not previously disclosed to the public until a final determination is made that an application for premarket approval is unapprovable, and all legal appeals have been exhausted. 92, Other comments objected to the provision for disclosing copies of adverse reaction reports to subjects. FDA rejects these comments and has retained the provision. FDA believes that access by subjects to reports of their adverse reactions is necessary for protection of subjects, an interest that outweighs the concerns of sponsors or investigators that such reports may be used in malpractice or product liability suits. Moreover, disclosure to a subject of such a record about himself or herself is required by the Freedom of Information Act and is consistent with the objectives of the Privacy Act. Sponsor Responsibilities 93. Subpart C prescribes general duties of sponsors. This subpart is a simplified version of provisions in the original proposal and reproposal. Sponsor responsibilities concerning inspection, records, Yeports, and commercialization of the device are set forth in Subpart G. 94. Comments questioned whether independent studies must be conducted concurrently or sequentially. Both concurrent studies and sequential studies can provide . independent proof of device safety and effectiveness. Either approach is satisfactory. The ability to replicate the results of an investigation is the important factor. Because sponsors may terminate investigations for a variety of reasons, for example economic nonfeasibility, Part 812 does not require independent investigations. Independent investigations are, however, required for premarket approval. Investigator Agreements 95. Consistent with the change in § 812.20(b)(5) described in paragraph 69, FDA has initiated a change in the requirement of reproposed § 812.43(b) that a sponsor obtain a signed agreement from an investigator and submit it to FDA with an application. Final § 812.43(c) requires that the sponsor obtain signed agreements, and § 812.145(b) requires the sponsor to maintain them subject to FDA inspection. Sponsors must submit the actual agreements or make them available for inspection if FDA so requests. 96. Section 812.43(c) also simplifies the information required in the investigator's agreement. A curriculum vitae should provide the type of information required by proposed § 812.43(b)(1) (Federal Register of August 20, 1976 (41 FR 35306). 97. Comments on reproposed § 812.43(b)(4) argued that the requirement to disclose to the sponsor whether prior research by an investigator has ever been terminated by a sponsor, an IRB, or FDA is irrelevant and might prejudice approval of the investigation. FDA disagrees with the comments that the information is irrelevant. It may well be relevant to a prediction as to whether the investigator will respect the rights and protect the safety and welfare of subjects and otherwise comply with applicable statutory and regulatory requirements. In addition, a study conducted by an investigator who has been disqualified by FDA may not be accepted in support of a premarket approval application or other application to conduct research on, or market, a product. The investigator's agreement will not be submitted to FDA routinely and will be reviewed only if specifically requested or during an inspection. 98. Comments suggested that an investigator at a teaching hospital in which residents and interns frequently rotate would be required constantly to amend the agreement if, as reproposed § 812.43(b)(5) required, the investigator's agreement must contain the names of subordinate investigators. 31 FDA agrees with the comments. Final § 812.43(c) no longer requires that subordinate investigators be named in a participating supervisory investigator's agreement. The requirement is for sponsors to obtain from each participating investigator a signed agreement to be maintained for FDA inspection or submission to FDA on request. Supervisory investigators’ agreements need not be amended each time a new subordinate investigator is added. Sponsors are, however, required to submit to FDA a current list of names and addresses of clinical investigators (including supervisors and subordinates) at 6-month intervals, in accordance with § 812.150(b)(4). Notice of Approval 99. Comments objected to notifying investigators when premarket approval had been obtained. FDA agrees with the comments and has deleted this requirement. Although it is desirable for investigators to know she regulatory status of products, sponsors generally have an economic incentive to inform investigators that a device has been approved. Accordingly. an FDA requirement for notification of investigators of premarket approval is unnecessary. Securing Investigators’ Compliance 100. A comment suggested that § 812.46 be modified so that the sponsor has a definite time frame, for example 30 days, in which to secure an investigator's compliance, or else discontinue shipments to the investigator or terminate the study. FDA rejects the comment. Although sponsors must terminate the participation of an investigator who fails or refuses to comply with applicable requirements, FDA does not believe it practical to specify a particular time frame in which such termination must occur. The urgency with which a sponsor must act will vary depending on the seriousness of the violations. In some cases, 30 days would be an excessive time frame for securing investigators’ compliance, while in others 30 days would be an inadequate time frame. If experience under the IDE regulation shows that a uniform time frame for investigators’ compliance would be desirable, FDA will add this provision to the regulation. In any event, FDA will consider withdrawing approval of the IDE of a sponsor that fails to secure an investigator's compliance in a timely manner consistent with the seriousness of the violations. Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations 3747 Unanticipated Adverse Device Effects 101. Section 812.46(b)(1) provides for the sponsor to conduct an evaluation of any unanticipated device effect. Section 812.150(b)(1) provides for reporting the results of such evaluations. Comments suggested various time periods for the submission of the reports of special evaluations, for example, 5 days, 2 weeks, and 10 calendar days. FDA believes that 10 working days after the sponsor first receives notice of an effect is sufficient for both completing the evaluation and submitting the results to FDA and all participating investigators and reviewing IRB's. Because IRB's and FDA may not be able to respond on nonworking days, it seems reasonable to base the notification requirement on working days. Termination 102. Section 812.46(b)(2) requires a sponsor who determines that an unanticipated adverse device effect presents an unreasonable risk to subjects to terminate all investigations or parts of investigations presenting that risk as soon as possible, but not later than 5 working days after making this determination and not later than 15 working days after first receiving notice of the effect. If a sponsor obtains sufficient information to warrant termination, the investigation should be terminated immediately. However, administrative difficulties may make immediate termination difficult, particularly if an investigation is conducted at several sites. IRB Responsibilities 103. A simplified version of Subpart D of the original IDE proposal is included in this regulation as Subpart D. IRB responsibilities concerning inspection, records, and reports are set forth in Subpart G. Review of Investigation 104. Section 812.60 has been revised to clarify the purpose of IRB review and the type of inquiry that FDA expects IRB's to conduct. FDA expects an IRB to apply local community attitudes and ethical standards in making a judgment that the benefits to subjects and the knowledge to be gained outweigh the risks. An IRB's judgment involves an evaluation of the ethics of an investigation, including, where relevan, whether children, pregnant women, the elderly, or members of a minority group should participate in an investigation and whether informed consent has been obtained. In determining risks and benefits, the IRB must assess the scientific soundness of the investigation. An investigation that approaches the frontiers of existing knowledge requires a probing and cautious IRB review. IRB Membership 105. Comments on the original proposal objected that IRB's were being required to possess competence that they do not have to review the scientific validity of investigations. In response to these comments, FDA has restated the requirements for membership on an IRB. Section 812.62(d) and (e) requires that IRB members be able to comprehend the nature of the investigation. If additional scientific competence is required, § 812.62(e) permits the use of nonvoting consultants. FDA does not expect an IRB to render judgments as to the adequacy of the statistical and design assumptions on which the investigation is based or other details bearing on the validity of an investigation. An IRB ned not exhaustively examine a well- designed investigation to assure that it yields the maximum scientific results. Nonetheless, an IRB collectively must be able to evaluate the risks and scientific soundness of proposed investigations in order to determine, for example, that an investigation is not disguised quackery or clearly will not yield useful results. In particular, an IRB must be able to review carefully and critically a sponsor's characterization of an investigational device as not presenting a significant risk. If the device does present a significant risk, the investigation may not begin until FDA has approved it. Minority and Sex Representation 106. Comments on the original proposal suggested that an IRB be required to include members of minority racial groups and both male and female members. FDA agrees with the comments, but has not adopted them at this time. An IRB must be broadly representative of the comunity it serves and must not discriminate against any group in its composition, policies, or decisions. FDA encourages IRB's to include in their membership members of minority groups and both women and men. FDA believes, however, that this requirement should be considered in the proceeding initiated by the August 14, 1979 reproposal on Standards for Institutional Review Boards. Conflicts of Interest 107. Section 812.62(f) prohibits investigators and sponsors from participating in the selection of IRB 32 members who will review investigations conducted or sponsored by them. In the case of investigations sponsored by academic institutions, FDA will entertain requests for waivers of this provision. 108. Comments on the original proposal noted that members of an IRB having a conflict of interest seemed to be prohibited from furnishing information requested by the IRB. FDA has revised § 812.65(a)(3) to make it clear that members having a conflict of interest may furnish information to an IRB at its request. Quorum 109. Comments on the original proposal suggested that a quorum include at least one scientist; one licensed physician, and one lay member. FDA agrees with these comments. Section 812.65(a)(2) provides for a quorum to be not less than a majority of the members and to include a licensed physician, a nonphysician scientist, and one member whose primary activities are in a nonscientific field. This requirement ensures a mix of backgrounds and disciplines to enable an IRB to explore all facets of a proposed investigation. 110. Comments objected to the requirement that one lay member, that is, a member whose primary activities are in a nonscientific field, and a licensed physician be present in every quorum because the lay member or physician could exert a veto on IRB deliberations by being absent. FDA disagrees with the comments. Under § 812.65(a)(2), only if the IRB has only one lay member and only one member who is a physician could such a veto occur. FDA believes that protection of the rights, safety, and welfare of subjects is enhanced by a diversity of the members’ backgrounds. FDA believes that the need for diverse points of view requries that all investigations subject to IRB review obtain review by a properly composed IRB. The absence of a lay member might result in a decision that reflects the enthusiasm of the scientific members, but fails to reflect community standards that the lay member helps to represent. FDA has no objection to an institution's disciplining or removing recalcitrant members who fail to attend IRB meetings, or adding sufficient lay members so that absenteeism is not a problem. Such actions are not prohibited by § 812.65(a)(2). 111. Comments suggested that at least one member have a biomedical engineering background to ensure adequate review of those investigations that involve engineering problems. 3748 Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations FDA does not agree that a biomedical engineer member should be required in every case. An IRB may obtain the services of nonvoting consultants when necessary to delve deeply into engineering or scientific matters. FDA expects that members of an IRB will, in any event, render judgments weighing all factors and that they will seek expert assistance if necessary. FDA cautions that a member whose primary activities are in a scientific field, for example, biomedical engineering, will not qualify as a lay member. A biomedical engineer, however, would satisfy the requirement of § 812.62(b) for a scientifically trained member. For purposes of this regulation, a social scientist is considered to be an individual whose primary activities are in a nonscientific field. Thus a social scientist may serve as a lay member on an IRB. IRB Action on an Investigation 112. Several comments asked for clarification of the criteria FDA wants IRB's to use in reviewing investigations. Section 812.65(a)(4) clarifies the criteria for disapproving a clinical investigation. No judgment concerning the statistical validity of the design of an investigation is required. What is required of an IRB that disapproves an investigation is a judgment that the benefits do not outweigh the risks to subjects, that informed consent is inadequate, that the proposed investigation is scientifically unsound, that there is reason to believe that the device is ineffective, or that it is otherwise unreasonable, unsafe, improper, or not in the best interests of the institution to begin or continue the investigation. FDA no longer specifies the factors that an IRB should use in arriving at its decision, but refers to the factors described in § 812.30(b). Subpart F states precisely the factors for evaluating the adequacy of informed consent. 113. Approval with modification under § 812.65(a)(4) is an approval with changes made in the investigational plan. The purpose of such changes usually will be to reduce or eliminate risks to subjects contained in the plan submitted to the IRB. Suspension under § 812.65(a)(4) involves temporary cessation of an investigation, an action short of withdrawal of approval that an IRB may order if it suspects or believes that the rights, safety, or welfare of subjects are in jeopardy, for example due to an adverse device effect. After suspension, an IRB may determine whether approval should be withdrawn. 114. An IRB must disapprove or withdraw approval of an investigation if it finds that any of the conditions set forth in § 812.65(a)(4) is present. In evaluating safety, an IRB should consider only those incremental or increased risks to which the subjects will be exposed by participating in the research, not risks to which subjects are exposed by virtue of their medical conditions. Thus, the risk to be addressed is that presented by the investigational therapy instead of therapy of accepted safety and effectiveness. 115. Comments suggested that the scientific review function be separated from IRB review. Several comments envisioned peer review followed by IRB review. FDA has not adopted these specific comments. Scientific review and subject protection are inseparable. The IRB should assure itself of the scientific soundness of a proposed investigation. The procedures by which the IRB may generate that assurance are not specified. One approach would be for individual members of an IRB with a technical background to comment on the technical aspects of a proposal and its scientific acceptability. If necessary to protect subjects, scientific consultants should be employed. Although this regulation does not mandate peer review, FDA does not object to its use as one mechanism of assuring the scientific soundness of investigations. FDA cautions that because of the many comments received on this aspect of the Aug. 14, 1979 IRB reproposal, further clarification of the role of the IRB in the review of clinical investigations will be found in the IRB final regulation. 116. Comments suggested that [RB approval should be final without further FDA review. FDA rejects these comments. They reflect a view that the IRB has the total responsibility to evaluate an investigation, without further review by FDA. Although FDA expects to concur in most IRB approvals, FDA has a statutory responsibility for final judgments on investigations. Moreover, FDA has a nationwide perspective concerning regulation of medical device research that is not duplicated in local IRB's. Waiver of IRB Review 117. Comments contended that § 812.42(d)(1) of the reproposal would allow waivers of IRB review in situations where this review is required by statute. FDA has deleted the provision for waiver of IRB review in view of strong policy reasons favoring such review, 33 expressed in section 520(g) of the act, the National Commission report mentioned earlier in this preamble, and FDA's August 14, 1979 reproposal on Standards for Institutional Review Boards. Section 520(g)(3)(A) requires submission of an IDE application to FDA where no IRB exists or FDA finds that an IRB's process of review is inadequate. In some such cases, FDA may refuse to approve an application because of the need for IRB review to protect subjects. 118. A comment argued that an IRB should be considered to “exist,” for purposes of section 520(g)(3)(A)(ii), if an IRB exists within a local jurisdiction but not on the premises where the investigation is being conducted. FDA agrees that IRB's can review investigations, or parts of investigations, that are conducted in the same locale but not on the premises of the institution that created the IRB. The regulation allows, but does not require, this review. A requirement in this regulation that an IRB review studies concucted elsewhere than at the institution would cause problems that most IRB's are now unprepared to solve. This issue is better addressed in the proceeding involving the August 14, 1979 IRB reproposal. Independence of IRB Decisions 119. Section 812.85(c) provides that the decision of one IRB on an investigation does not preclude another IRB from reaching a different decision. This provision clarifies the independent nature of IRB decisions. 120. Comments requested clarification of the authority of other institutional officials to review IRB decisions. Some comments suggested that an IRB's decsion should be subject to appeal. FDA disagrees in part with the latter comments. Only an IRB should approve an investigation. FDA believes that only an IRB can bring together the diversity of backgrounds necessary to ensure the protection of human subjects. The value of an IRB's decision to disapprove an investigation would be undermined if it could be overruled. The same considerations do not apply, however, when an IRB approval is overruled by a person or body other than the IRB because human subjects are not thereby exposed to risks that an IRB has determined to be unacceptable. Therefore, under § 812.70, an institution may overrule an IRB decision to approve an investigation. Responsibilities of Investigators 121. A simplified version of Subpart E of the original proposal has been incorporated in this final regulation. Investigator responsibilities concerning Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations 3749 inspections, records, reports, and commercialization of the device are set forth in Subpart G. Informal Requests To Participate in Investigations 122. Comments on the proposal argued that investigators should be permitted to determine whether potential subjects would be interested in participating before obtaining IRB and FDA approval. FDA agrees with these comments. Section 812.110(a) has been rewritten to permit such determinations of interest, short of requests for informed consent. Disqualification 123. Section 812.119 of the original proposal on disqualification of investigators, which received many comments, has been deleted. Disqualification of investigators will be addressed in FDA's final regulation on obligations of clinical investigators of regulated articles. Informed Concent 124. Subpart F, which has not been changed in substance, applies to investigations of significant and nonsignificant risk devices. 125. Several comments suggested that § 812.120 include a procedure for documenting that oral informed consent has been properly obtained. One comment suggested that such a procedure would be appropriate for low- risk studies. . FDA agrees with the latter comment. In the case of a nonsignificant risk device investigation, informed consent need not be evidenced by a written document signed by the subject, if the investigator obtains and documents oral informed consent. Section 812.122 also allows documented oral informed consent in the case of an illiterate subject, or an illiterate representative of an incompetent subject, whether the investigation is of a significant risk or a nonsignificant risk device. The inclusion of a procedure in § 812.122 for documenting oral informed consent from illiterate subjects is not meant to imply that FDA believes that illiterate individuals are, as a general rule, suitable subjects in device investigations. Such a procedure is necessary, however, to cover the situation where a study population includes illiterates, in order to permit those individuals to have the same access to investigational devices that other individuals have 126. Sections 812.122, 812.123, and 812.130 have been shortened and simplified without change in'meaning. For exar ple, the prohibition against obtaining informed consent through coercion, deception, or undue influence also prohibits obtaining informed consent through fraud, deceit, force, or duress. When FDA publishes final agency-wide regulations on informed consent, based on the August 14, 1979 proposal, FDA will publish conforming changes in Subpart F. 127. The requirements of proposed § 812.123(b) that mandate the documentation and reporting of the use of a device without obtaining informed consent are now found in §§ 812.140(a)(3)(i) and 812.150 (a)(5) and (b)(8). 128. A comment on reproposed § 812.123 suggested that the requirement to obtain informed eonsent be waived in those situations where obtaining informed consent would interfere with protection of a subject's bodily function. FDA rejects this comment. Section 520(g)(3)(D) of the act specifies clearly the situations in which the requirement to obtain informed consent may be waived. The only permissible waiver of such consent is if a life-threatening situation exists and it is not feasible to obtain consent from the subject or the subject's legal representative 129. Another comment objected that to comply with Subpart F many hospitals will be required to revise existing informed consent forms. FDA rejects the comment. Revision of forms may, indeed, be necessary, but Congress intended that result when it enacted the amendments and provided specific guidance on the elements of informed consent. 130. A comment suggested that § 812.130 be altered to permit placebo studies. FDA rejects the comment. No change is required because placebo studies are not prohibited. Records and Reports 131. Subpart G, dealing with records, reports, and inspections, consolidates requirements applicable to sponsors, mvestigators, and IRB's. These requirements were previously scattered throughout Subparts C through F of the original proposal and reproposal. Inspections 132. Comments on the original proposal objected that sponsors or investigators should not be held responsible for failure to grant access to facilities for FDA inspection in ceses where the sponsor or investigator lacks proprietary or other authority to grant this access. FDA agrees with the comment. Final § 812.145(a) requires a person who is a sponsor or investigator to permit FDA representatives to inspect those facilities to which the person has authority to grant access. 133. Many comments on the original proposal objected to the provision that required FDA access to patient records and names on the grounds that it violates patient confidentiality and investigator ethics. FDA rejects the comments. FDA believes that the provisions must be retained because inspection is the only feasible way of verifying that actual subjects were used, that their rights were protected, and that reports to sponsors and IRB's were accurate. FDA believes that most subjects would approve of this requirement because it is designed to protect them from unethical practices. FDA advises, however, that this authority will be used carefully Investigators are encouraged to make clear to potential subjects at the time informed consent is obtained that their records may be examined by FDA. Records 134. Section 812.140(a) requires investigators to maintain records of relevant correspondence, device receipt, use, and disposition, subjects’ case history and device exposure, and a current copy of the protocol. FDA may require that other records be kept if FDA determines it is necessary for a category of investigations or a particular investigation. For example, in Part 813 FDA has imposed certan special requirements for investigations of IOL's, to ensure traceability of the devices after implantation. 135. Section 812.140(b) requires sponsors to maintain records of relevant correspondence, device shipment and disposition, signed investigator agreements, and adverse device effects. Relevant correspondence includes copies of materials submitted to FDA in support of an IDE application. Special recordkeeping requirements, discussed in paragraph 138, apply to sponsors of nonsignificant risk device investigations. FDA may require a sponsor to keep other records if FDA determines they are necessary for a category of investigation or a particular investigation. Records of Nonsignificant Risk Device Investigations 136. To implement its decision to reduce regulation of nonsignificant risk device investigations, FDA has added special recordkeeping requirements for sponsors of such investigations. Section 812.140(b)(4) requires these sponsors to maintain records of such investigations in one location and make them available for FDA inspection and copying. 3750 Federal Register / Vol. 45, No. 13 / Friday, January 18, 1980 / Rules and Regulations Required records include: the name and intended use of the device, the objectives of the investigation, a brief explanation of why the device is not a significant risk device, the name and address of each investigator, the name and address of each IRB that reviewed the investigation, a statement of the extent to which the good manufacturing practice regulation in Part 820 will be followed, and a copy of any quality assurance program, and records concerning adverse device effects and complaints. 137. Section 812.140(c) requires that each IRB maintain records of relevant correspondence, membership and its members’ employment relationships, and relevant minutes. Retention Period 138. Comments suggested that the 2- year and 5-year retention requirements for records were confusing and served no useful purpose. In response to the comments, FDA has changed the regulation to require that records be retained for a 2-year period after the later of two dates: The date when the investigation is terminated or completed, or the date when the investigation is no longer required to support approval of an application for premarket approval or a notice of completion of a product development protocol. Transfer of Records Custody 138. Custody of records may be transferred, as reproposed, but the transferee must accept responsibility for such records including the requirement to permit FDA inspection and eopying under § 812.145. FDA must be notifie within 10 working days of such a transfer. The requirement that the transferee accept responsibility and that notice be given to FDA were added to close possible regulatory loopholes. Reporting Requirements 140. Section 812.150(a) requires investigators to submit reports to sponsors, IRB's, and FDA, as specified, on unanticipated adverse device effects, withdrawal of IRB approval, progress of the investigation, deviations from the investigational plan, use of a device without informed consent, termination or completion of an investigation, and other matters upon request by a reviewing IRB or FDA. 141. Comments on the reproposal suggested that IRB's receive reports of unanticipated adverse device effects. FDA agrees with the comments, and § 812.150 (a)(1) and (b)(1) so provide. This change and those described in paragraphs 144, 145, and 146 below will strengthen the ability of IRB's to review investigations. 142. Comments suggested that the time allowed for reporting unanticipated adverse device effects be extended from 5 to 10 days, and that the time period be stated in working days rather than calendar days. FDA agrees with the comments and has amended § 812.150(a)(1) accordingly. 143. Section 812.150(b)(4) requires the sponsor to provide FDA with a current list of investigators at 6-month intervals. This provision applies only to investigations of significant risk devices. The purpose of the list is explained in paragraph 69 above. 144. A comment suggested that sponsors notify all reviewing IRB's when an investigation is terminated or completed. Section 812.150(b)(7) adopts the suggestion with respect to significant risk device investigations. 145.,A comment suggested that progress reports and a final report be submitted to reviewing IRB's. FDA has adopted this comment as well, with respect to both significant risk device investigations and nonsignificant risk device investigations, and § 812.150(b)(5) so provides. 146. A comment suggested that the regulation require sponsors to notify all reviewing IRB's, as well as FDA, of sponsors’ requests to return or dispose of devices. FDA agrees and has amended § 812.150(b){6) accordingly. Therefore, under the Federal Food, Drug, and Cosmetic Act (secs. 301, 501, 502, 520, 701(a), 702, 704, 801, 52 Stat. 1042-1043 as amended, 1049-1051 as’ amended, 1055, 1056-1058 as amended, 87 Stat. 476-477 as amended, 90 Stat. 6565-574 (21 U.S.C. 331, 351, 352, 360j, 371(a), 372, 374, 381)) and under authority delegated to the Commissioner of Food and Drugs (21 CFR 5.1), Chapter I of Title 21 of the Code of Federal Regulations is amended as follows: PART 16—REGULATORY HEARING BEFORE THE FOOD AND DRUG ADMINISTRATION 1. By revising in § 16.1(b)(1) the statutory provision paragraph for section 520(g)(4) and (5) of the act, to read as follows: § 16.1 Scope. * * * * * ) LE BE (1) Statutory provisions: * » * * * Section 520(g)(4) and (5) of the act relating tc disapproval and withdrawal 35 of approval of an application for an investigational device exemption (see §8 812.19(c), 812.30(c), 813.30(d), and 813.35(c)). * « * * * PART 20—PUBLIC INFORMATION 2. By amending § 20.100 by reserving paragraph (c)(32) and adding new paragraph (c)(33), to read as follow: § 20.100 Applicability; cross-referen. 2 to other regulations. * * * * * * * * (c) (32) [Reserved] (33) Investigational device exem, ‘ions in § 812.38 of this chapter. PART 809—IN VITRO DIAGNOSTIC PRODUCTS FOR HUMAN USE 3. By revising § 809.10(c) to read as follows: § 809.10 Labeling for In vitro diagnostic products. - * - " * (c) A shipment or other delivery of an in vitro diagnostic product shall be exempt from the requirements of paragraphs (a) and (b) of this section and from a standard promulgated under Part 861 of this chapter: (1) In the case of a shipment or delivery for an investigation subject to Part 812, if there has been compliance with Part 812; or (2) In the case of a shipment or delivery for an investigation that is not subject to Part 812 (see § 812.2(c)), if the following conditions are met: (i) For a product in the laboratory research phase of development, and not represented as an effective in vitro diagnostic product, all labeling bears the statement, prominently placed: “For Research Use Only. Not for use in diagnostic procedures.” (ii) For a product being shipped or delivered for product testing prior to full commercial marketing (for example, for use on specimens derived from humans to compare the usefulness of the product with other products or procedures which are in current use or recognized as useful), all labeling bears the statement, prominently placed: “For Investigational Use Only. The performance characteristics of this product have not been established.” (iii) The person making a shipment or delivery under paragraph (c)(2)(ii) of this section shall submit to FDA at the address in § 812.19 a notification that such shipments are being made. 4. By adding new Part 812 to read as follows: PART 812—INVESTIGATIONAL DEVICE EXEMPTIONS Subpart A—General Provisions Sec. 812.1 Scope. 812.2 Applicability. 812.3 Definitions. 812.5 Labeling of investigational devices. 812.7 Prohibition of promotion and other practices. 812.10 Waivers. 812.18 Import and export requirements. 812.19 Address for IDE correspondence. Subpart B—Application and Administrative Action 812.20 Application. 812.25 Investigational plan. 812.27 Report of prior investigations. 812.30 FDA action on applications. 812.35 Supplemental applications. 812.38 Confidentiality of data and informa- tion. Subpart C—Responsibilities of Sponsors 812.40 General responsibilities of sponsors. 812.42 FDA and IRB approval. 812.43 Selecting investigators and moni- tors. 812.45 Informing investigators. 812.46 Monitoring investigations. Subpart D—IRB Review and Approval 812.60 IRB composition, duties, and func- tions. 812.62 IRB approval. 812.64 IRB's continuing review. 812.66 Significant risk device determina- tions. Subpart E—Responsibilities of Investigators 812.100 General responsibilities of investi- gators. 812.110 Specific responsibilities of investi- gators. Subpart F—(Removed) Subpart G—Records and Reports Sec. 812.140 Records. 812.145 Inspections. 812.150 Reports. Subpart A—General Provisions § 812.1 Scope. (a) The purpose of this part is to en- courage, to the extent consistent with the protection of public health and safety and with ethical standards, the discovery and development of useful devices intended for human use, and to that end to maintain optimum free- dom for scientific investigators in their pursuit of this purpose. This part provides procedures for the con- duct of clinical investigations of de- vices. An approved investigational device exemption (IDE) permits a device that otherwise would be re- quired to comply with a performance standard or to have premarket approv- al to be shipped lawfully for the pur- pose of conducting investigations of that device.. An IDE approved under § 812.30 or considered approved under § 812.2(b) exempts a device from the requirements of the following sections of the act and regulations issued thereunder: Misbranding under sec- tion 502, registration, listing, and pre- market notification under section 510, performance standards under section 514, premarket approval under section 515, a banned device regulation under section 516, records and reports under section 519, restricted device require- ments under section 520(e), good man- ufacturing practice requirements under section 520(f) (unless the spon- sor states an intention to comply with these requirements under § 812.20(b)(3) or § 812.140(b)(4)(v)) and color additive requirements under sec- tion 706. (b) References in this part to regula- tory sections of the Code of Federal Regulations are to Chapter I of Title 21, unless otherwise noted. § 812.2 Applicability. (a) General. This part applies to all clinical investigations of devices to de- termine safety and effectiveness, except as provided in paragraph (c) of this section. (b) Abbreviated requirements. The following categories of investigations are considered to have approved appli- cations for IDE’s, unless FDA has no- tified a sponsor under § 812.20(a) that approval of an application is required: (1) An investigation of a device other than a significant risk device, if the device is not a banned device and the sponsor: (i) Labels the device in accordance with § 812.5; (ii) Obtains IRB approval of the in- vestigation after presenting the re- viewing IRB with a brief explanation of why the device is not a significant risk device, and maintains such ap- proval; (iii) Ensures that each investigator participating in an investigation of the device obtains from each subject under the investigator's care, informed consent under Part 50 and documents it, unless documentation is waived by an IRB under § 56.109(c). (iv) Complies with the requirements of § 812.46 with respect to monitoring investigations; (v) Maintains the records required under § 812.140(b) (4) and (5) and makes the reports required under § 812.150(b) (1) through (3) and (5) through (10); (vi) Ensures that participating inves- tigators maintain the records required by § 812.140(a)(3)(i) and make the re- ports required under §812.150(a) (1), (2), (5), and (7); and (vii) Complies with the prohibitions in § 812.7 against promotion and other practices. (2) An investigation of a device other than one subject to paragraph (e) of this section, if the investigation was begun on or before July 16, 1980, and to be completed, and is completed, on or before January 19, 1981. (¢) Exempted investigations. This part does not apply to investigations of the following categories of devices: (1) A device, other than a transition- al device, in commercial distribution immediately before May 28, 1976, when used or investigated in accord- ance with the indications in labeling in effect at that time. (2) A device, other than a transition- al device, introduced into commercial distribution on or after May 28, 1976, that FDA has determined to be sub- stantially equivalent to a device in commercial distribution immediately before May 28, 1976, and that is used or investigated in accordance with the indications in the labeling FDA re- viewed under Subpart E of Part 807 in determining substantial equivalence. (3) A diagnostic device, if the spon- sor complies with applicable require- ments in § 809.10(c) and if the testing: (i) Is noninvasive, (ii) does not require an invasive sampling procedure that presents significant risk, (iii) does not by design or intention introduce energy into a subject, and (iv) is not used as a diagnostic procedure without confirmation of the diagnosis by an- other, medically established diagnostic product or procedure. (4) A device undergoing consumer preference testing, testing of a modifi- cation, or testing of a combination of two or more devices in commercial dis- tribution, if the testing is not for the purpose of determining safety or effec- tiveness and does not put subjects at risk. 37 (5) A device intended solely for vet- erinayy use. (6) A device shiped solely for re- search on or with laboratory animals and - labeled in accordance with § 812.5(c). (7) A custom device as defined in §812.3(b), unless the device is being used to determine safety or effective- ness for commercial distribution. (8) An intraocular lens. An intraocu- lar lens shall not be used unless it is subject to an approved IDE under Part 813 or an approved application for premarket approval under section 515 of the act. (d) Limit on certain exemptions. In the case of class II or class III device described in paragraph (c)(1) or (2) of this section, this part applies begin- ning on the date stipulated in an FDA regulation or order that calls for the submission of premarket approval ap- plications for an unapproved class III device, or establishes a performance standard for a class II device. (e) Investigations subject to IND’s. A sponsor that, on July 16, 1980, has an effective investigational new drug ex- emption (IND) for an investigation of a device shall continue to comply with the requirements of Part 312 until 90 days after that date. To continue the investigation after that date, a sponsor shall comply with paragraph (b)(1) of this section, if the device is not a sig- nificant risk device, or shall have ob- tained FDA approval under § 812.30 of an IDE application for the investiga- tion of the device. § 812.3 Definitions. (a) “Act” means the Federal Food, Drug, and Cosmetic Act (sections 201- 901, 52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)). (b) “Custom device” means a device that: (1) Necessarily deviates from devices generally available or from an applica- ble performance standard or premar- ket approval requirement in order to comply with the order of an individual physician or dentist; (2) Is not generally available to, or generally used by, other physicians or dentists; (3) Is not generally available in fin- ished form for purchase or for dis- pensing upon prescription; (4) Is not offered for commercial dis- tribution through labeling or advertis- ing; and (5) Is intended for use by an individ- ual patient named in the order of a physician or dentist, and is to be made in a specific form for that patient, or is intended to meet the special needs of the physician or dentist in the course of professional practice. (¢) “FDA” means the Food and Drug Administration. i (d) “Implant” means a device that is placed into a surgically or naturally formed cavity of the human body if it is intended to remain there for a period of 30 days or more. FDA may, in order to protect public health, de- termine that devices placed in subjects for shorter periods are also “implants” for purposes of this part. (e) “Institution” means a person, other than an individual, who engages in the conduct of research on subjects or in the delivery of medical services to individuals as a primary activity or as an adjunct to providing residential or custodial care to humans. The term includes, for example, a hospital, re- tirement home, confinement facility, academic establishment, and device manufacturer. The terg has the same meaning as ‘‘facility” in section 520(g) of the act. (f) “Institutional review board” (IRB) means any board, committee, or other group formally designated by an institution to review biomedical re- search involving subjects and estab- lished, operated, and functioning in conformance with Part 56. The term has the same meaning as “institution- al review committee” in section 520(g) of the act. (g) “Investigational device’ means a device, including a transitional device, that is the object of an investigation. (h) “Investigation” means a clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device. (i) “Investigator” means an individu- al who actually conducts an investiga- tion, that is, under whose immediate direction the investigational device is administered, dispensed, or used. (J) “Monitor,” when used as a noun, means an individual designated by a sponsor or contract research organiza- tion to oversee the progress of an in- vestigation. The monitor may be an employee of a sponsor or a consultant to the sponsor, or an employee of or consultant to a contract research orga- nization. ‘“Monitor,” when used as a verb, means to oversee an investiga- tion. (k) “Noninvasive,” when applied to a diagnostic device or procedure, means one that does not by design or inten- tion: (1) Penetrate or pierce the skin or mucous membranes of the body, 38 the ocular cavity, or the urethra, or (2) enter the ear beyond the external auditory canal, the nose beyond the nares, the mouth beyond the pharynx, the anal canal beyond the rectum, or the vagina beyond the cervical os. For purposes of this part, blood sampling that involves simple venipuncture is considered noninvasive, and the use of surplus samples of body fluids or tis- sues that are left over from samples taken for noninvestigational purposes is also considered noninvasive. (1) “Person” includes any individual, partnership, corporation, association, scientific or academic establishment, Government agency or organizational unit of a Government agency, and any other legal entity. (m) “Significant risk device” means an investigational device that: (1) Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a sub- ject; (2) Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject; (3) Is for a use of substantial impor- tance in diagnosing, curing, mitigating, or treating disease, or otherwise pre- venting impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or (4) Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. (n) “Sponsor” means a person who initiates, but who does not actually conduct, the investigation, that is, the investigational device is administered, dispensed, or used under the immedi- ate direction of another individual. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-in- vestigator, and the employees are in- vestigators. (0) “Sponsor-investigator’” means an individual who both initiates and actu- ally conducts, alone or with others, an investigation, that is, under whose im- mediate direction the investigational device is administered, dispensed, or used. The term does not include any person other than an individual. The obligations of a sponsor-investigator under this part include those of an in- vestigator and those of a sponsor. (p) “Subject” means a human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or as a control. A subject may be in normal health or may have a medi- cal condition or disease. (q) “Termination” means a discon- tinuance, by sponsor or by withdrawal of IRB or FDA approval, of an investi- gation before completion. (r) “Transitional device” means a device subject to section 520(1) of the act, that is, a device that FDA consid- ered to be a new drug or an antibiotic drug before May 28, 1976. (s) “Unanticipated adverse device effect” means any serious adverse effect on health or safety or any life- threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not pre- viously identified in nature, severity, or degree of incidence in the investiga- tional plan or application (including a supplementary plan or application), or any other unanticipated serious prob- lem associated with a device that re- lates to the rights, safety, or welfare of subjects. § 812.5 Labeling of investigational devices. (a) Contents. An investigational device or its immediate package shall bear a label with the following infor- mation: the name and place of busi- ness of the manufacturer, packer, or distributor (in accordance with § 801.1), the quantity of contents, if appropriate, and the following state- ment: “CAUTION—Investigational device. Limited by Federal (or United States) law to investigational use.” The label or other labeling shall de- scribe all relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings, and precautions. (b) Prohibitions. The labeling of an investigational device shall not bear any statement that is false or mislead- ing in any particular and shall not rep- resent that the device is safe or effec- tive for the purposes for which it is being investigated. (c) Animal research. An investiga- tional device shipped solely for re- search on or with laboratory animals shall bear on its label the following statement: “CAUTION—Device for in- vestigational use in laboratory animals or other tests that do not involve human subjects.” § 812.7 Prohibition of promotion and other practices. A sponsor, investigator, or any person acting for or on behalf of a sponsor or investigator shall not: (a) Promote or test market an inves- tigational device, until after FDA has approved the device for commercial distribution. (b) Commercialize an investigational device by charging the subjects or in- vestigators for a device a price larger than that necessary to recover costs of manufacture, research, development, and handling. (¢) Unduly prolong an investigation. If data developed by the investigation indicate in the case of a class III device that premarket approval cannot be justified or in the case of a class II device that it will not comply with an applicable performance standard or an amendment to that standard, the sponsor shall promptly terminate the investigation. (d) Represent that an investigational device is safe or effective for the pur- poses for which it is being investigat- ed. § 812.10 Waivers. (a) Request. A sponsor may request FDA to waive any requirement of this part. A waiver request, with support- ing documentation, may be submitted separately or as part of an application to the address in § 812.19. (b) FDA action. FDA may by letter grant a waiver of any requirement that FDA finds is not required by the act and is unnecessary to protect the rights, safety, or welfare of human subjects. (c) Effect of request. Any require- ment shall continue to apply unless and until FDA waives it. § 812.18 Import and export requirements. (a) Imports. In addition to comply- ing with other requirements of this part, a person who imports or offers for importation an investigational device subject to this part shall be the agent of the foreign exporter with re- spect to investigations of the device and shall act as the sponsor of the clinical investigation, or ensure that another person acts as the agent of the foreign exporter and the sponsor of the investigation. (b) Exports. A person exporting an investigational device subject to this part shall obtain FDA's prior approv- al, as required by section 801(d) of the act. § 812.19 Address for IDE correspondence. All applications, supplemental appli- cations, reports, requests for waivers, requests for import or export approv- al, and other correspondence relating to matters covered by this part shall be addressed to the Bureau of Medical Devices, Document Control Center (HFK-20), Food and Drug Administra- tion, 8757 Georgia Ave., Silver Spring, MD 20910. The outside wrapper of each submission shall state what the submission is, for example an “IDE ap- plication,” a “supplemental IDE appli- cation,” or ‘‘correspondence concern- ing an IDE (or an IDE application).” Subpart B—Application and Administrative Action § 812.20 Application. (a) Submission. (1) A sponsor shall submit an application to FDA if the sponsor intends to use a significant risk device in an investigation or if FDA notifies the sponsor that an ap- plication is required for an investiga- tion. (2) A sponsor shall not begin an in- vestigation for which FDA's approval of an application is required until FDA has approved the application. (3) A sponsor shall submit three copies of a signed “Application for an Investigational Device Exemption” (IDE application), together with ac- companying materials, by registered mail or by hand to the address in § 812.19. Subsequent correspondence concerning an application or a supple- mental application shall be submitted by registered mail or by hand. (b) Contents. An IDE application shall include, in the following order: (1) The name and address of the sponsor. (2) A complete report of prior inves- tigations of the device and an accurate summary of those sections of the in- vestigational plan described in § 812.25(a) through (e) or, in lieu of the summary, the complete plan. The sponsor shall submit to FDA a com- plete investigational plan and a com- plete report of prior investigations of the device if no IRB has reviewed them, if FDA has found an IRB’s review inadequate, or if FDA requests them. (3) A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and, where appropriate, in- stallation of the device, in sufficient detail so that a person generally famil- iar with good manufacturing practices can make a knowledgeable judgment a0 about the quality control used in the manufacture of the device. (4) An example of the agreements to be entered into by all investigators to comply with investigator obligations under this part, and a list of the names and addresses of all investiga- tors who have signed the agreement. (5) A certification that all investiga- tors who will participate in the investi- gation have signed the agreement, that the list of investigators includes all the investigators participating in the investigation, and that no investi- gators will be added to the investiga- tion until they have signed the agree- ment. (6) A list of the name, address, and chairperson of each IRB that has been or will be asked to review the investi- gation and a certification of the action concerning the investigation taken by each such IRB. (7) The name and address of any in- stitution at which a part of the investi- gation may be conducted that has not been identified in accordance with paragraph (b)(6) of this section. (8) If the device is to be sold, the amount to be charged and an explana- tion of why sale does not constitute commercialization of the device." (9) An environmental analysis report meeting the requirements of Part 25, when requested by FDA. (10) Copies of all labeling for the device. (11) Copies of all forms and informa- tional materials to be provided to sub- jects to obtain informed consent. (12) Any other relevant information FDA requests for review of the appli- cation. (c) Additional information. FDA may request additional information concerning an investigation or revision in the investigational plan. The spon- sor may treat such a request as a dis- approval of the application for pur- poses of requesting a hearing under Part 16. (d) Information previously submit- ted. Information previously submitted to the Bureau of Medical Devices in accordance with this chapter ordinari- ly need not be resubmitted, but may be incorporated by reference. § 812.25 Investigational plan. The investigational plan shall in- clude, in the following order: (a) Purpose. The name and intended use of the device and the objectives and duration of the investigation. (b) Protocol. A written protocol de- scribing the methodology to be used and an analysis of the protocol demon- strating that the investigation is scien- tifically sound. (c) Risk analysis. A description and analysis of all increased risks to which subjects will be exposed by the investi- gation; the manner in which these risks will be minimized; a justification for the investigation; and a description of the patient population, including the number, age, sex, and condition. (d) Description of device. A descrip- tion of each important component, in- gredient, property, and principle of op- eration of the device and of each an- ticipated change in the device during the course of the investigation. (e) Monitoring procedures. The sponsor’s written procedures for moni- toring the investigation and the name and address of any monitor. (f) Labeling. Copies of all labeling for the device. (g) Consent materials. Copies of all forms and informational materials to be provided to subjects to obtain in- formed consent. (h) IRB information. A list of the names, locations, and chairpersons of all IRB’s that have been or will be asked to review the investigation, and a certification of any action taken by any of those IRB’s with respect to the investigation. (i) Other institutions. The name and address of each institution at which a part of the investigation may be con- ducted that has not been identified in paragraph (h) of this section. (j) Additional records and reports. A description of records and reports that will be maintained on the investiga- tion in addition to those prescribed in Subpart G. § 812.27 Report of prior investigations. (a) General. The report of prior in- vestigations shall include reports of all prior clinical, animal, and laboratory testing of the device and shall be com- prehensive and adequate to justify the proposed investigation. (b) Specific contents. The report also shall include: (1) A bibliography of all publica- tions, whether adverse or supportive, that are relevant to an evaluation of the safety or effectiveness of the device, copies of all published and un- published adverse information, and, if requested by an IRB or FDA, copies of other significant publications. 41 (2) A summary of all other unpub- lished information (whether adverse or supportive) in the possession of, or reasonably obtainable by, the sponsor that is relevant to an evaluation of the safety or effectiveness of the device. (3) If information on nonclinical tests'is provided, a statement that all nonclinical tests have been conducted in compliance with applicable require- ments in the good laboratory practice regulations in Part 58, or a detailed de- scription of, and justification for, all differences between the practices used in the tests and those required by Part 58. Failure or inability to comply with this requirement does not justify fail- ure to provide information on a rele- vant nonclinical test. § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date it receives an application. FDA may approve an investigation as proposed, approve it with modifica- tions, or disapprove it. An investiga- tion may not begin until: (1) Thirty days after FDA receives the application at the address in § 812.19 for the investigation of a device other than a banned device, unless FDA notifies the sponsor that the investigation may not begin; or (2) FDA approves, by order, an IDE for the investigation. (b) Grounds for disapproval or with- drawal. FDA may disapprove or with- draw approval of an application if FDA finds that: (1) There has been a failure to comply with any requirement of this part or the act, any other applicable regulation or statute, or any condition of approval imposed by an IRB or FDA. (2) The application or a report con- tains an untrue statement of a materi- al fact, or omits material information required by this part. (3) The sponsor fails to respond to a request for additional information within the time prescribed by FDA. (4) There is reason to believe that the risks to the subjects are not outweighed by the anticipated bene- fits to the subjects and the importance of the knowledge to be gained, or in- formed consent is inadquate, or the in- vestigation is scientifically unsound, or there is reason to believe that the device as used is ineffective. (5) It is otherwise unreasonable to begin or to continue the investigation owing to the way in which the device is used or the inadequacy of: (i) The report of prior investigations or the investigational plan; (ii) The methods, facilities, and con- trols used for the manufacturing, processing, packaging, storage, and, where appropriate, installation of the device; or (iii) Monitoring and review of the in- vestigation. (c) Notice of disapproval or with- drawal. If FDA disapproves an appli- cation or proposes to withdraw ap- proval of an application, FDA will notify the sponsor in writing. (1) A disapproval order will contain a complete statement of the reasons for disapproval and a statement that the sponsor has an oppcrtunity to request a hearing under Part 16. (2) A notice of a proposed withdraw- al of approval will contain a complete statement of the reasons for with- drawal and a statement that the spon- sor has an opportunity to request a hearing under Part 16. FDA will pro- vide the opportunity for hearing before withdrawal of approval, unless FDA determines in the notice that continuation of testing under the ex- emption will result in an unreasonble risk to the public health and orders withdrawal of approval before any hearing. § 812.35 Supplemental applications. (a) Changes in investigational plan. A sponsor shall: (1) Submit to FDA a supplemental application if the spon- sor or an investigator proposes a change in the investigational plan and (2) obtain IRB approval (see § 56.110(b)) and FDA approval of the change before implementation. (b) IRB approvals. A sponsor shall submit to FDA, in a supplemental ap- plication, the certification of any IRB approval of an investigation or a part of an investigation not included in the IDE application. § 812.38 Confidentiality of data and infor- mation. (a) Existence of IDE. FDA will not disclose the existence of an IDE unless its existence has previously been pub- licly disclosed or acknowledged, until FDA approves an application for pre- market approval of the device subject to the IDE; or a notice of completion of a product development protocol for the device has become effective. (b) Availability of summaries or data. (1) FDA will make publicly avail- able, upon request, a detailed sum- mary of information concerning the 42 safety and effectiveness of the device that was the basis for an order approv- ing, disapproving, or withdrawing ap- proval of an application for an IDE for a banned device. The summary shall include information on any adverse effect on health caused by the device. (2) If a device is a banned device or if the existence of an IDE has been publicly disclosed or acknowledged, data or information contained in the file is not available for public disclo- sure before approval of an application for premarket approval or the effec- tive date of a notice of completion of a product development protocol except as provided in this section. FDA may, in its discretion, disclose a summary of selected portions of the safety and ef- fectiveness data, that is, clinical, animal, or laboratory studies and tests of the device, for public consideration of a specific pending issue. (3) If the existence of an IDE file has not been publicly disclosed or ac- knowledged, no data or information in the file are available for public disclo- sure except as provided in paragraphs (b)(1) and (c) of this section. (¢) Reports of adverse effects. Upon request or on its own initiative, FDA shall disclose to an individual on whom an investigational device has been used a copy of a report of adverse device effects relating to that use. (d) Other rules. Except as otherwise provided in this section, the availabil- ity for public disclosure of data and in- formation in an IDE file shall be han- dled in accordance with § 314.14, which concerns the confidentiality of data and information in new drug applica- tions, until the effective date of regu- lations concerning the confidentiality of data and information in applica- tions for premarket approval of de- vices. Subpart C—Responsibilities of Sponsors § 812.40 General responsibilities of spon- sors. Sponsors are responsible for select- ing qualified investigators and provid- ing them with the information they need to conduct the investigation properly, ensuring proper monitoring of the investigation, ensuring that IRB review and approval are obtained, submitting an IDE application to FDA, and ensuring that any reviewing IRB and FDA are promptly informed of significant new information about an investigation. Additional responsi- bilities of sponsors are described in Subparts B and G. § 812.42 FDA and IRB approval. A sponsor shall not begin an investi- gation or part of an investigation until an IRB and FDA have both approved the application or supplemental appli- cation relating to the investigation or part of an investigation. §812.43 Selecting investigators and moni- tors. (a) Selecting investigators. A sponsor shall select investigators qualified by training and experience to investigate the device. (b) Control of device. A sponsor shall ship investigational devices only to qualified investigators participating in the investigation. (¢) Obtaining agreements. A sponsor shall obtain from each participating investigator a signed agreement that includes: (1) The investigator's curriculum vitae. (2) Where applicable, a statement of the investigator’s relevant experience, including the dates, location, extent, and type of experience. (3) If the investigator was involved in an investigation or other research that was terminated, an explanation of the circumstances that led to termi- nation. (4) A statement of the investigator's commitment to: (i) Conduct the inves- tigation in accordance with the agree- ment, the investigational plan, this part and other applicable FDA regula- tions. and conditions of approval im- posed by the reviewing IRB or FDA; (ii) supervise all testing of the device involving human subjects; and (iii) ensure that the requirements for ob- taining informed consent are met. (d) Selecting monitors. A sponsor shall select monitors qualified by training and experience to monitor the investigational study in accord- ance with this part and other applica- ble FDA regulations. § 812.45 Informing investigators. A sponsor shall supply all investiga- tors participating in the investigation with copies of the investigational plan and the report of prior investigations of the device. § 812.46 Monitoring investigations. (a) Securing compliance. A sponsor who discovers that an investigator is 43 not complying with the signed agree- ment, the investigational plan, the re- quirements of this part or other appli- cable FDA regulations, or any condi- tions of approval imposed by the re- viewing IRB or FDA shall promptly either secure compliance, or discontin- ue shipments of the device to the in- vestigator and terminate the investiga- tor’s participation in the investigation. A sponsor shall also require such an investigator to dispose of or return the device, unless this action would jeopardize the rights, safety, or wel- fare of a subject. (b) Unanticipated adverse device ef- fects. (1) A sponsor shall immediately conduct an evaluation of any unantici- pated adverse device effect. (2) A sponsor who determines that an unanticipated adverse device effect presents an unreasonable risk to sub- jects shall terminate all investigations or parts of investigations presenting that risk as soon as possible. Termina- tion shall occur not later than 5 work- ing days after the sponsor makes this determination and not later than 15 working days after the sponsor first received notice of the effect. (¢) Resumption of terminated stud- ies. If the device is a significant risk device, a sponsor may not resume a terminated investigation without IRB and FDA approval. If the device is not a significant risk device, a sponsor may not resume a terminated investigation without IRB approval and, if the in- vestigation was terminated under paragraph (b)(2) of this section, FDA approval. Subpart D—IRB Review and Approval §812.60 IRB composition, duties, and functions. An IRB reviewing and approving in- vestigations under this part shall comply with the requirements of Part 56 in all respects, including its compo- sition, duties, and functions. § 812.62 IRB approval. (a) An IRB shall review and have au- thority to approve, require modifica- tions in (to secure approval), or disap- prove all investigations covered by this part. (b) If no IRB exists or if FDA finds that an IRB’s review is inadequate, a sponsor may submit an application to FDA. §812.64 IRB’s continuing review. The IRB shall conduct its continu- ing review of an investigation in ac- cordance with Part 56. §812.66 Significant risk device determina- tions. If an IRB determines that an inves- tigation, presented for approval under § 812.2(b)(1)(ii), involves a significant risk device, it shall so notify the inves- tigator and, where appropriate, the sponsor. A sponsor may not begin the investigation except as provided in § 812.30(a). Subpart E—Responsibilities of Inves- tigators § 812.100 General responsibilities of inves- tigators. An investigator is responsible for en- suring that an investigation is con- ducted according to the signed agree- ment, the investigational plan and ap- plicable FDA regulations, for protect- ing the rights, safety, and welfare of subjects under the investigator's care, and for the control of devices under investigation. An investigator also is responsible for ensuring that informed consent is obtained in accordance with Part 50 of this chapter. Additional re- sponsibilities of investigators are de- scribed in Subpart G. § 812.110 Specific responsibilities of inves- tigators. (a) Awaiting approval. An investiga- tor may determine whether potential subjects would be interested in partici- pating in an investigation, but shall not request the written informed con- sent of any subject to participate, and shall not allow any subject to patici- pate before obtaining IRB and FDA approval. (b) Compliance. An investigator shall conduct an investigation in ac- cordance with the signed agreement with the sponsor, the investigational plan, this part and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA. (¢) Supervising device use. An inves- tigator shall permit an investigational device to be used only with subjects under the investigator’s supervision. An investigator shall not supply an in- vestigational device to any person not authorized under this part to receive it. (d) Disposing of device. Upon com- pletion or termination of a clinical in- vestigation or the investigator's part 44 of an investigation, or at the sponsor's request, an investigator shall return to the sponsor any remaining supply of the device or otherwise dispose of the device as the sponsor directs. Subpart F—(Removed) Subpart G—Records and Reports § 812.140 Records. (a) Investigator records. A partici- pating investigator shall maintain the following accurate, complete, and cur- rent records relating to the investiga- tor’s participation in an investigation: (1) All correspondence with another investigator, an IRB, the sponsor, a monitor, or FDA, including required reports. (2) Records of receipt, use or disposi- tion of a device that relate to: (i) The type and quantity of the device, the dates of its receipt, and the batch number or code mark. (ii) The names of all persons who re- ceived, used, or disposed of each device. (iii) Why and how many units of the device have been returned to the spon- sor, repaired, or otherwise disposed of. (3) Records of each subject's case history and exposure to the device. Such records shall include: (i) Documents evidencing informed consent and, for any use of a device by the investigator without informed con- sent, any written concurrence of a li- censed physician and a brief descrip- tion of the circumstances justifying the failure to obtain informed consent. (ii) All relevant observations, includ- ing records concerning adverse device effects (whether anticipated or unan- ticipated), information and data on the condition of each subject upon en- tering, and during the course of, the investigation, including information about relevant previous medical histo- ry and the results of all diagnostic tests. (iii) A record of the exposure of each subject to the investigational device, including the date and time of each use, and any other therapy. (4) The protocol, with documents showing the dates of and reasons for each deviation from the protocol. (5) Any other records that FDA re- quires to be maintained by regulation or by specific requirement for a cate- gory of investigations or a particular investigation. (b) Sponsor records. A sponsor shall maintain the following accurate, com- plete, and current records relating to an investigation: (1) All correspondence with another sponsor, a monitor, an investigator, an IRB, or FDA, including required re- ports. (2) Records of shipment and disposi- tion. Records of shipment shall in- clude the name and address of the consignee, type and quantity of device, date of shipment, and batch number or code mark. Records of disposition shall describe the batch number or code marks of any devices returned to the sponsor, repaired, or disposed of in other ways by the investigator or an- other person, and the reasons for and method of disposal. (3) Signed investigator agreements. (4) For each investigation subject to § 812.2(b)(1) of a device other than a significant risk device, the records de- scribed in paragraph (b)(5) of this sec- tion and the following records, consoli- dated in one location and available for FDA inspection and copying: (i) The name and intended use of the device and the objectives of the in- vestigation; (ii) A brief explanation of why the device is not a significant risk device: (iii) The name and address of each investigator: (iv) The name and address of each IRB that has reviewed the investiga- tion: (v) A statement of the extent to which the good manufacturing prac- tice regulation in Part 820 will be fol- lowed in manufacturing the device; and (vi) Any other information required by FDA. (5) Records concerning adverse device effects (whether anticipated or unanticipated) and complaints and (6) Any other records that FDA re- quires to be maintained by regulation or by specific requirement for a cate- gory of investigation or a particular in- vestigation. (¢) IRB records. An IRB shall main- tain records in accordance with Part 56 of this chapter. (d) Retention period. An investigator or sponsor shall maintain the records required by this subpart during the in- vestigation and for a period of 2 years after the latter of the following two dates: The date on which the investi- gation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval application or a notice of completion of a product de- velopment protocol. (e) Records custody. An investigator or sponsor may withdraw from the re- 45 sponsibility to maintain records for the period required in paragraph (d) of this section and transfer custody of the records to any other person who will accept responsibility for them under this part, including the require- ments of § 812.145. Notice of a transfer shall be given to FDA not later than 10 working days after transfer occurs. § 812.145 Inspections. (a) Entry and inspection. A sponsor or an investigator who has authority to grant access shall permit authorized FDA employees, at reasonable times and in a reasonable manner, to enter and inspect any establishment where devices are held (including any estab- lishment where devices are manufac- tured, processed, packed, installed, used, or implanted or where records of results from use of devices are kept). (b) Records inspection. A sponsor, IRB, or investigator, or any other person acting on behalf of such a person with respect to an investiga- tion, shall permit authorized FDA em- ployees, at reasonable times and in a reasonable manner, to inspect and copy all records relating to an investi- gation. (¢) Records identifying subjects. An investigator shall permit authorized FDA employees to inspect and copy re- cords that identify subjects, upon notice that FDA has reason to suspect that adequate informed consent was not obtained, or that reports required to be submitted by the investigator to the sponsor or IRB have not been sub- mitted or are incomplete, inaccurate, false, or misleading. § 812.150 Reports (a) Investigator reports. An investi- gator shall prepare and submit the fol- lowing complete, accurate, and timely reports: (1) Unanticipated adverse device ef- fects. An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an in- vestigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect. (2) Withdrawal of IRB approval. An investigator shall report to the spon- sor, within 5 working days, a with- drawal of approval by the reviewing IRB of the investigator's part of an in- vestigation. (3) Progress. An investigator shall submit progress reports on the investi- gation to the sponsor, the monitor, and the reviewing IRB at regular in- tervals, but in no event less often than yearly. (4) Deviations from the investiga- tional plan. An investigator shall notify the sponsor and the reviewing IRB (see § 56.108(a)(3) and (4) of any deviation from the investigational plan. In the case of an emergency to protect the life or physical well being of a subject, the investigator shall notify the reviewing IRB within 48 hours. Prior approval by the sponsor is required for changes in, or deviations from, a plan. FDA approval under § 812.35(a) is also required. (5) Informed consent. If an investiga- tor uses a device without obtaining in- formed consent, the investigator shall report such use to the sponsor and the reviewing IRB within 5 working days after the use occurs. (6) Final report. An investigator shall, within 3 months after termina- tion or completion of the investigation or the investigator's part of the inves- tigation, submit a final report to the sponsor and the reviewing IRB. (7) Other. An investigator shall, upon request by a reviewing IRB or FDA, provide accurate, complete, and current information about any aspect of the investigation. (b) Sponsor reports. A sponsor shall prepare and submit the following com- plete, accurate, and timely reports: (1) Unanticipated adverse device ef- fects. A sponsor who conducts an eval- uation of an unanticipated adverse device effect under § 812.46(b) shall report the results of such evaluation to FDA and te all reviewing IRB’s and participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereaf- ter the sponsor shall submit such addi- tional reports concerning the effect as FDA requests. (2) Withdrawal of IRB approval. A sponsor shall notify FDA and all re- viewing IRB’s and participating inves- tigators of any withdrawal of approval of an investigation or a part of an in- vestigation by a reviewing IRB within 5 working days after receipt of the withdrawal of approval. (3) Withdrawal of FDA approval. A sponsor shall notify all reviewing IRB’s and participating investigators of any withdrawal of FDA approval of 46 the investigation, and shall do so within 5 working days after receipt of notice of the withdrawal of approval. (4) Current investigator list. A spon- sor shall submit to FDA, at 6-month intervals, a current list of the names and addresses’ of all investigators par- ticipating in the investigation. The sponsor shall submit the first such list 6 months after FDA approval. (5) Progress reports. At regular inter- vals, and at least yearly, a sponsor shall submit progress reports to all re- viewing IRB'’s. In the case of a signifi- cant risk device, the sponsor shall also submit progress reports to FDA. (6) Recall and device disposition. A sponsor shall notify FDA and all re- viewing IRB’s of any request that an investigator return, repair, or other- wise dispose of any units of a device. Such notice shall occur within 30 working days after the request is made and shall state why the request was made. (1) Final report. In the case of a sig- nificant risk device, the sponsor shall notify FDA within 30 working days of the completion or termination of the investigation and shall submit a final report to FDA and all reviewing the IRB’s and participating investigators within 6 months after completion or termination. In the case of a device that is not a significant risk device, the sponsor shall submit a final report to all reviewing IRB’s within 6 months after termination or completion. (8) Informed consent. A sponsor shall submit to FDA a copy of any report by an investigator under para- graph (a)(5) of this section of use of a device without obtaining informed consent, within 5 working days of re- ceipt of notice of such use. (9) Significant risk device determi- nations. If an IRB determines that a device is a significant risk device, and the sponsor had proposed that the IRB consider the device not to be a significant risk device, the sponsor shall submit to FDA a report of the IRB’s determination within 5 working days after the sponsor first learns of the IRB’s determination. (10) Other. A sponsor shall, upon re- quest by a reviewing IRB or FDA, pro- vide accurate, complete, and current information about any aspect of the investigation. Tuesday January 27, 1981 Part IX Health and Human Services Department Food and Drug Administration Protection of Human Subjects; Informed Consent; Standards for Institutional Review Boards for Clinical Investigations; and Clinical Investigations Which May Be Reviewed Through Expedited Review Procedure a7 8942 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 50, 71, 171, 180, 310, 312, 314, 320, 330, 361, 430, 431, 601, 630, 812, 813, 1003, 1010 {Docket No. 78N-0400] Protection of Human Subjects; Infogned Consent AGENCY: Food and Drug Administration. ACTION: Final rule. SumMMARY: The Food and Drug Administration (FDA) is issuing regulations to provide protection for human subjects of clinical investigations conducted pursuant to requirements for prior submission to FDA or conducted in support of applications for permission to conduct further research or to market regulated products. The regulations clarify existing FDA requirements governing informed consent and provide protection of the rights and welfare of human subjects involved in research activities that fall within FDA's jurisdiction. EFFECTIVE DATE: July 27, 1981. FOR FURTHER INFORMATION CONTACT: John C. Petricciani, Office of the Commissioner (HFB—4), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20205, 301-496-9320. SUPPLEMENTARY INFORMATION: In the Federal Register of August 14, 1979 (44 FR 47713), the Commissioner of Food and Drugs proposed regulations concerning standards of informed consent. FDA believed that a complete revision of its requirements relating to informed consent is needed because (1) current regulations had not been comprehensively reviewed in 12 years; (2) actions by the Department of Health and Human Services (HHS) and the Congress suggested the need for, and, desirability of, strengthening and clarifying informed consent requirements as they apply to research that involves human subjects and is intended for submission to FDA; (3) wherever possible, informed consent requirements adopted by FDA should be identical to, or compatible with, HHS regulations; (4) the General Accounting Office (GAO) has recommended changes’in current FDA regulatiops; (5) Congress, in enacting the Medical Device Amendments of 1976 (Pub. L. 94- 295, 90 Stat. 539-583). required that informed consent be obtained before an investigational device is used on a human subject; (8) FDA's Bioresearch Monitoring Program could be conducted more efficiently and effectively with uniform, agency-wide requirements for informed consent; and (7) FDA regulations should take into account the recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission) regarding institutional review boards (IRB's) and informed consent, published in the Federal Register of November 30, 1978 (43 FR 56174). FDA allowed 90 days for comment on the proposal of August 14, 1979 (44 FR 47713). In addition, FDA held three open hearings to give the public an opportunity to comment on both the informed consent proposal and the IRB proposal that was reproposed in the same issue of the Federal Register (44 FR 47699). The hearings were held in Bethesda, MD, on September 18, 1979, San Francisco, CA, on October 2, 1979, and Houston, TX, on October 16, 1979. The comments received at the hearings and the hearing transcripts were made a part of the record of this regulation and are on file in the Dockets Management Branch (formerly the Hearing Clerk's office) along with the written comments received in response to the proposal. Comments were received from clinical investigators, institutional review boards, trade associations, professional societies, drug companies, and private citizens. The substantive comments received and FDA's conclusions about them are discussed below. General Comments . 1. Many comments suggested that FDA's informed consent requirements should be identical to the informed consent requirements adopted by HHS. FDA agrees that uniformity of requirements is desirable and that uniform requirements would be less confusing to investigators who frequently may conduct both research funded by HHS and research involving FDA-regulated products. The substance of the informed consent requirements of the two regulations, with minor differences, therefore, is identical. The minor differences in wording reflect that (1) Part 50 is an interlocking but separate part of FDA's bioresearch monitoring regulations (2) purely behavioral research is not regulated by FDA, and (3) HHS has promulgated its IRB and informed consent requirements together in one subpart which was published in the January 26, 1981 issue of the Federal Register. FDA's bioresearch monitoring regulations when complete will contain separate requirements for and clarify the responsibilities of IRB's, clinical investigators, sponsors and monitors, 48 and nonclinical testing laboratories. FDA does not anticipate that clinical investigators will find the informed consent requirements contained in 21 CFR Part 50 confusing in relationship to the informed consent requirements contained in 45 CFR Part 46. 2. The preamble to the FDA proposal of August 14, 1979 {44 FR 47713) contains an extensive discussion of the history and evolution of the concept of informed consent. FDA pointed out in that discussion that the informed consent provisions for investigational drugs and antibiotics contained in sections 505(i) and 507(d)(3) of the Federal Food, Drug. and Cosmetic Act (21 U.S.C. 355(i) and 357(d)(3)) (the act) differed from the provisions for investigational devices contained in section 520(g)(3)(D) of the act (21 U.S.C. 360j(g)(3)(D)). The majority of comments received in response to FDA's proposal to establish uniform requirements patterned upon section 520(g)(3)(d) of the act were in favor of uniformity. In fact, most comments favored uniform requirements not only for FDA-regulated research but for all research subject to the regulations of either FDA or HHS. One comment, however, questioned FDA's legal authority to conform the statutory requirements of sections 505, 507, and 520 of the act, but commended it, stating that the application of a uniform set of standards for informed consent for all clinical investigations would eliminate some of the confusion which has resulted from the promulgation of varying and sometimes inconsistent policies. Another comment stated that absent a single set of regulations, regulatory chaos would result, unintentional noncompliance would be likely, and the aims of subject protection would be defeated. Two comments argued that because the act established standards for investigations involving drugs that differ from the standards established for investigations involving devices, FDA should perpetuate the different standards in its informed consent regulation. Neither of these comments argued that the concept of informed consent had not changed since the Drug Amendments were enacted in 1962, and neither comment offered any particular investigational situation in which they thought an investigator might reasonably determine, as provided in sections 505(i) and 507(d) of the act, that obtaining informed consent would not be “feasible” or "in an investigator's professional judgment, [would be] contrary to [a subject's] best interests." Only one of the comments objecting to the promulgation of a single standard Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8943 offered any extensive rationale for the objection raised. This comment argued that FDA should perpetuate in its informed consent regulation, the “therapeutic privilege" exemption provided by Congress when it enacted the 1962 Drug Amendments. This comment stated that in choosing to disregard the “therapeutic privilege” exemption, FDA was intruding into both the realm of congressional prerogative and the practice of medicine. According to this comment, the circumstances in which the “therapeutic privilege" ought to apply, were as follows: * * * A departure from the absolute requirement of informed consent is necessitated when “patient psychology” is such that a physician must be free to use a new therapeutic measure, without obtaining the patient's informed consent, if in his judgment it offers help of saving life, re- establishing health, or alleviating suffering. When a drug is being used in a clinical investigation primarily for treatment, the circumstances call forth the standards pertinent to the traditional physician-patient relationship, instead of those applicable to pure research. (Emphasis added.) Basically, this comment assumes that a clinical investigation which involves an investigational article used primarily for treatment is not really an “investigation” at all, but is simply “the practice of medicine,” and the basic objection expressed seems to be that obtaining informed consent could unjustifiably frighten patients away from participation in an investigational study that might provide significant benefits for that individual and/or society as a whole, while presenting little or no risk to the individual participant. FDA has considered the objections raised by these comments, has conducted an extensive review of the current legal requirements for informed consent in the treatment as opposed to the investigational /experimental setting, and finds, for the reasons discussed below, that the uniform approach proposed is justified. ~The “therapeutic privilege” in the context of experimentation has been subject to increased criticism in recent years. In a paper on the Law of Informed Consent prepared for the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (Ref. 1), the authors concluded that nondisclosure based upon a physician's judgment that it is not in the patient's best interest to know, should never be allowed in the experimental setting. The authors of this report, who surveyed international, Federal, and local standards of informed consent, concluded that because the purpose of the “therapeutic privilege" doctrine was to make sure that patients get treatment that physicians believe they need, it could have no application to nontherapeutic experimentation where no treatment is involved. The authors also concluded that, * * * Because of the great potential for abuse, e.g., the withholding of information for convenience or to assure the patient will not reject the treatment, and because the probability of success with an experimental treatment is either not known or very low, this exception should also not be permitted in the case of therapeutic experimentation. Indeed, as has been noted by a number of commentators, in this situation the physician- experimenter may have much more ability to obtain consent for an experiment than he would have from a normal volunteer who neither has an established dependency relation with him nor expects that the proposed experiment might be personally beneficial to him. As Professor Alexander Capron has observed: The “normal volunteer” solicited for an experiment is in a good position to consider the physical, psychological, and monetary risks and benefits to him when he consents to participate. How much harder that is for the patient to whom an experimental technique is offered during a course of treatment! The man proposing the experiment is one to whom the patient may be deeply indebted for past care (emotionally as wel] as financially) and on whom he is probably dependent for his future well-being. The procedure may be offered, despite unknown risks, because more conventional methods have proved ineffective. Even when a successful but slow recovery is being made, patients offered new therapy often have eyes only for its novelty and not for the risks. In order to protect self-determination and promote rational decision-making, more, not less, information should probably be required to be disclosed in the experimental therepy situation than in the purely experimental setting with a normal volunteer (Ref. 1). FDA agrees with the findings contained in the special report on the Law of Informed Consent. The standard of practice regarding informed consent promulgated by Congress in the Drug Amendments of 1962 was the standard that prevailed at that time. It is not the standard of practice today. FDA is concerned that research subjects be adequately protected from abuses of the kind that have taken place in the past (44 FR 47713-17); and is convinced that one way to protect research subjects against abuse is to ensure that they have the opportunity to be adequately informed before they consent to participate. FDA does not believe that promulgating a single standard that reflects both current congressional thinking and current standards 49 regarding the practice of medicine represents an unreasonable encroachment upon the prerogatives of either Congress or the medical community. Congress expressly recognized at the time the Medical Device Amendments of 1976 were passed that, in view of changing social policy and advancing biomedical technology, the informed consent provisions of the Medical Device Amendments should be implemented through regulations based upon the recommendations to be made by the National Commission (Ref. 2). Indeed. the very purpose for which Congress established the National Commission was to assure a thorough review of the basic ethical principles underlying the conduct of biomedical and behavioral research (44 FR 47716). FDA believes that the regulation does not encroach upon the prerogatives of the medical community because a review of court decisions which have involved informed consent casts doubt on whether the so-called “therapeutic privilege” to dispense with informed consent has any continued viability even in the standard practice of medicine. With increasing frequency, courts have held that when a patient is harmed by a treatment to which he or she might not have consented had he or she been adequately informed of the risks involved in that treatment, the doctor's failure to obtain informed consent may result in a finding of liability for negligence. In Cobbs v. Grant, 8 Cal. 3d 229, 502 P.2d 1 (1972). the California Supreme Court discussed at length the thesis that medical doctors are invested with discretion to withhold information from their patients and found that discretion to be extremely limited, stating that, “it is the prerogative of the patient, not the physician, to determine for himself the direction in which he believes his interests lie. To enable the patient to chart his course knowledgeably, reasonable familiarity with the therapeutic alternatives and their hazards becomes essential.” Cobbs, supra, at 242-243. The California Court held that a duty of reasonable disclosure of the available choices with respect to proposed therapy and of the dangers inherently and potentially involved in each choice was an “integral part of the physician's overall obligation to the patient.” Cobbs, supra, at 243. Under the Cobbs rationale, a patient's informed consent is an absolute requirement except in an emergency situation or in a situation in which the patient is a child or incompetent, in which case consent is either implied or sought from a legal 8944 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations guardian. Thus, in Cobbs, the California Court found that consent of the quality required by this regulation should have been obtained from the patient and that it was the patient's prerogative to make the treatment decision based upon adequate information, not the physician's prerogative to limit the patient's choices by limiting the information provided. See generally, Pharmaceutical Manufacturers v. Food Drug Administration, 484 F. Supp. 1179. 1188 (D. Del. 1980). The subject of negligence and informed consent is also discussed at length in Canterbury v. Spence, 464 F.2d 772 (D.C. Cir. 1972), cert. denied, 409 U.S. 1064 (1972), an action involving. among other things, the sufficiency of the information provided to a patient. Beginning with the fundamental premise that, “every human being of adult years and sound mind has a right to determine what shall be done with his own body." the Canterbury court defines “true consent” as the informed exercise of a choice that, in turn, entails an opportunity to evaluate knowledgeably the options available and the risks attendant upon each. Canterbury, supra. at 780. The Canterbury court flatly rejected the suggestion that disclosure of risk be discretionary with the physician, stating that any definition of the scope of disclosure purely in terms of a “professional standard” would be “at odds with the patient's prerogative to decide on projected therapy himself." Canterbury. supra, at 786. The Canterbury court discussed two exceptions to the general rule of disclosure—(1) when the patient is unconscious or otherwise incapable of consenting and (2) when risk-disclosure would be so detrimental as to be unfeasible from a medical point of view. The latter exception, according to the court, must be carefully circumscribed, “for otherwise it might devour the disclosure rule itself. The privilege does not accept the parternalistic notion that the physician may remain silent simply because divulgence might prompt the patient to forego therapy the physician feels the patient really needs.” Canterbury, supra, at 789. The court did not further elucidate the second exception to disclosure other than to limit it to situations in which the patient's reaction to risk information is “menacing.” Id. What, precisely, the court meant by “menacing” is not clear. A Massachusetts Court, however, has found that although disclosure of the potential side-effects of a medication might be “frightening” to a mental patient, that fact alone would not justify a failure to inform. See Rogers v. Okin, 478 F. Supp. 1342, 1387 (D. Mass. 1979). Both Cobbs and Canterbury were decided in 1972. Since 1972 it has become increasingly clear that a lack of informed consent will result in actionable negligence where injury results, and that the physician's duty to inform includes a duty to impart information sufficient to enable a patient to make an informed decision. The courts recognize that standard of informed consent has evolved and that the standard now requires full disclosure in all but the exceptional case. See Dessi v. United States, 489 F. Supp. 722 (E.D.Va. 1980); Rogers v. Okin, 478 F. Supp. 1342 (D. Mass. 1979). It is not for the medical profession to establish a criterion for the dissemination of information to the patient based upon what doctors feel the patient should be told. See Lambert v. Park, 597 F.2d 236, 239 n.7 (10th Cir. 1979). According to Lambert, a standard that requires all material risks to be divulged, * * * Insures the important social policy underlying informed consent, that is, a physician should be required to disclose to his patients all material risks of a proposed procedure even if other doctors in the community or specialty would not have made so full a disclosure. This is simply an application of the well-known tort doctrine that proof of compliance with the applicable “industry” standard will not insulate a defendant from liability when the standard itself is inadequate. /d at 238-239. It seems clear that the current standard of care as defined by case law requires disclosure in the ordinary case of exactly the kind required by this regulation. If such full disclosure is required for nonexperimental treatment, it can hardly be argued that it can be dispensed with when the treatment is experimental. See Ahern v. Veterans Administration, 537 F. 2d 1098 (10th Cir. 1976). The agency, therefore, reaffirms its proposal of a uniform standard governing informed consent. 3. Several comments questioned the applicability of these regulations to studies conducted outside the United States. A few comments stated that standards of protection for human subjects may vary from country to country, and that the United States should not impose its standards on other countries when the human subjects come from those foreign countries in which the studies are being conducted. FDA agrees with the comments, and notes that its policy regarding investigational studies involving drugs and biological products is set out in § 312.20 Clinical data generated outside the United States and not subject to a 50 “Notice of Claimed Investigational Exemption for a New Drug” (21 CFR 312.20). The policy regarding foreign studies and the background to § 312.20 was set out in detail in the preambles to the proposed and final regulation. See 38 FR 24220; September 6, 1973, and 40 FR 16053; April 9, 1975. The agency's policy regarding studies of investigational devices conducted outside the Untied States is similar to that for drugs and biological products and is discussd in the preamble to the recent proposal to establish procedures for the premarket approval of medical devices (PMA), published in the Federal Register of December 12, 1980 (45 FR 81769). oposed § 814.15 of the PMA proposal states the agency policy concerning devices. The Proposed Regulation Part 50 will apply to all clinical investigations regulated by the Food and Drug Administration under sections 505(i), 507(d), and 520(g) of the act, as well as to clinical investigations that support applications for research or marketing permits for products regulated by FDA. These provisions are contained in § 50.1 (21 CFR 50.1) which was promulgated with Subpart C— Protections Pertaining to Clinical Investigations Involving Prisoners as Subjects published in the Federal Register of May 30, 1980 (45 FR 36386). When complete, Part 50 will contain all of FDA's regulations concerning the Protection of Human Subjects. The August 14, 1979 proposal contains all of the definitions applicable to Part 50. The definition of “application for research or marketing permit” (21 CFR 50.3(b)) was made final at the same time as Subpart C—Protections Pertaining to Clinical Investigations Involving Prisoners as Subjects (45 FR 36396), and therefore, is not included here. The definition of that term also may be found as part of Part 56 on Institutional Review Boards (IRB's) which is published elsewhere in this issue of the Federal Register. The definitions made final here are congruent with those made final with Part 56, and many of the comments received in response to the IRB proposals were similar to the comments received in response to the Informed Consent proposal. A discussion of the definitions other than “application for research and marketing permit,” and comments received in response to this and to the prisoner research proposal follow: 4. Several comments suggested that the proposed definition of clinical investigator in § 50.3(c) was too broad and should be limited through the explicit exclusion of particular kinds of Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8945 research such as that involving minimal risk. FDA disagrees. The National Commission stated that even in no-risk or low-risk studies, respect for the rights and dignity of human subjects would require informed consent before participation in any ¢linical investigation. Informed consent is, as stated in § 50.20, required in all research subject to these regulations. 5. Two comments suggested that the proposed wording of § 50.3(d) defining “investigator” should be amended to include the primary investigator who might not be the person who actually conducts the investigation or gives immediate direction to those administering or dispensing the test article. The agency agrees that an investigation may be conducted by several investigators and has modified the language of § 50.3(d) to define the term more broadly. Added to the definition is the language “* * * in the event of an investigation conducted by a team of individuals, is the responsible leader of that team.” 6. On its own initiative, FDA has deleted proposed § 50.3(e) defining “person” because the only time that it is used in these regulations is to refer to a living individual. Although additional definitions for the term are applicable to other FDA regulations, they are not applicable to informed consent. 7. One comment stated that proposed § 50.3(h) defining “subject” could be interpreted to deny the administration of a placebo or other control to an unhealthy human. The agency did not intend the definition of subject to be ambiguous and § 50.3(g) has been slightly modified in this final rule. The definition now clearly states that a subject participates in a clinical investigation either as a recipient of the test article or as a control. 8. Section 50.3(h) defining “institution” replaces § 50.3(i) from the proposed regulations. The revised definition is consistent with the HHS definition and includes any entity including manufacturers, hospitals, and nursing homes. 9. The proposed definition of “institutionalized subject” has been deleted from the final regulations. Because the scope of coverage extends to human subjects, whether or not institutionalized, there is no need for a separate definition for institutionalized subjects at this time. 10. One comment questioned inclusion of cosmetics in proposed § 50.3(k) because cosmetics are not subject to premarket approval and therefore should not be included in the definition of “test article.” The agency agrees and has deleted the term from § 50.3(k) of the final rule, defining “test article.” Because cosmetic studies are not submitted to FDA in support of an application for research or marketing permit, they are not subject to Part 50. 11. One comment suggested that FDA adopt the HHS definition of “minimal risk.” FDA agrees with the comment, and has revised the definition in § 50.3(1) accordingly. This definition takes into account the fact that the risks in the daily life of a patient are not the same as those of a healthy individual, and uses the risks in daily life as the standards for minimal risk. 12. Section 50.3(m) defining “legally authorized representative’ has been revised slightly from the definition proposed by FDA so that it is identical to the HHS definition. 13. One comment on proposed § 50.20 suggested that incomprehensible consent forms would be useless to human subjects and that FDA should require that information be communicated to subjects in language they can understand. FDA agrees that information given to human subjects should be in language they can understand, and notes that the National Commission also made this recommendation. Section 50.20 has been reworded to require that information given to the subject or the subject's legally authorized representative be in language that is understandable to the subject or the representative. 14. One comment suggested that all minimal risk studies be exempted from the requirements for informed consent. The agency does not agree. Both the HHS regulations and the FDA regulations reflect the belief that even minimal risk studies require the informed consent of human subjects before they may participate in a research study. Informed consent is, therefore, a uniform requirement for all investigational studies, no matter how low risk an investigator may believe them to be. 15. One comment suggested that the IRB should determine when informed consent would be necessary. Another comment suggested that low-risk and no-risk studies be exempted from the requirement of informed consent. FDA disagrees and rejects the comments. Sections 505(i), 507(d) and 520(g) of the act (21 U.S.C. 355(i), 357(d) and 360j(g)) require that FDA promulgate regulations for the exemption of drugs and devices for investigational use. These sections of 51 the act direct FDA to promulgate regulations that will ensure that informed consent will be obtained from each subject or each subject's legally authorized representative as a condition to the issuance of the exemption. The National Commission stated that even in no-risk or low-risk studies, respect for the rights and dignity of human subjects would require informed consent before participation in any clinical investigation. FDA agrees with this position and requires that informed consent be obtained from each subject or representative before a subject may participate in a clinical investigation. The only exception from the requirement which applies to individual situations and not to categories of studies as a whole, is the provision in § 50.23 for emergency use of a test article. 16. One comment stated that FDA lacked the authority to reject a study if the requirement for informed consent were not followed. The comment further stated that in order for FDA to reject a study, the noncompliance with the regulatory requirements must affect the scientific validity of the data generated. FDA disagrees with the comment. The Federal Food, Drug, and Cosmetic Act also requires that these regulations have due regard for the interests of patients (21 U.S.C. 355(j)(1) and 21 U.S.C. 357(g)(1)) or be consistent with ethical standards (21 U.S.C. 360j(g)(1)). Therefore, FDA believes it possesses the necessary statutory authority to reject studies where informed consent has not been obtained even though the scientific validity of the data generated may not have been affected, and it reserves the right to do so where circumstances so warrant. 17. Several comments argued that the proposed requirements of § 50.21 concerning the effective date of the regulations were too complicated, too burdensome, and not really necessary for the great number of studies. These comments suggested that the revised informed consent requirements apply only to individuals entering a clinical investigation after the effective date of the regulation. The agency has considered these comments and agrees that only prospective application of the new uniform informed consent provisions will be required. The requirements of both Part 50 and Part 56 will become effective at the same time, that is, July 27,1981, and will be applicable only to clinical investigations that begin on or after this date. In determining that the requirements need apply only prospectively, the agency has taken a number of factors 8946 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations into account. It has balanced the cost of compliance against the possible added protections to be gained by research subjects, and has determined that the potential cost of imposing the requirements retroactively outweighs the potential gain. The informed consent regulations that will continue to be in effect until the effective date of Part 50 have assured that at least minimum standards of informed consent have been met in studies initiated before the effective date of this regulation. In addition, the agency believes that where an inspection reveals deficiencies in the informed consent obtained in a particular ongoing study, correction can be obtained administratively. Further, at the time an IRB performs its continuing review, the IRB may require correction of deficiencies if, in its judgment, such correction is required. The agency believes, therefore, that prospective application will be sufficient. 18. One comment on proposed § 50.23(a)(2), the exception provided for situations in which communication with the subject is not possible, stated that, as written, the section could apply when a subject spoke only a foreign language. The agency does not agree. For the exception to apply, all four requirements of the subsection must be met. Inability to communicate in the context of § 50.23(a) clearly means that the subject is in a coma or unconscious. The exception is to be invoked only in emergency situations. 19. One comment stated that the exception requirements of proposed § 50.23 were too restrictive ‘and should be modified to allow an investigator to proceed without consent in a nonlife- threatening but “serious” emergency. The agency does not agree. The requirements of § 50.23 are based on section 520(g)(3)(D) of the act. Those requirements are quite explicit and allow that consent be dispensed with only if the emergency situation is “life threatening.” The comment is rejected. Elements of Informed Consent Many comments were received on the eleven basic and five additional items proposed in § 50.25 as the elements of informed consent. Many of these comments suggested that there were too many elements proposed, that they were duplicative, and that they would simply confuse research subjects. Other comments suggested that the elements proposed were too few and suggested the addition of other items of information to the list of elements proposed. The individual comments are discussed below. 20. Several comments said that the statement that an IRB had approved the solicitation of subjects to participate in the research, required by proposed § 50.25(a){1), could mislead human subjects into thinking that because the study had been approved by an IRB there was no need for them to evaluate for themselves whether or not they should participate in the study. FDA agrees with these comments and has deleted this requirement from the final regulations. Proposed § 50.25(a)(1) and (2) have been combined. 21. Several comments stated that the proposed requirements contained in § 50.25(a)(2), regarding the scope and aims of the research would require explanations that were both too complex and too lengthy to be meaningful to subjects. Another comment asserted that the word “scope’ was so vague as to be meaningless while “aims” was synonymous with “purposes.” All of these comments suggested that § 50.25(a)(2) should be simplified so that subjects receive only meaningful information. The agency agrees with the comments and has rewritten the section for clarity. The requirement now reads: “an explanation of the purpose of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of those procedures which are experimental.” 22. Several comments on proposed § 50.25(a)(3) (renumbered as § 50.25(a)(2) in the final rule) objected to including a statement of the likely results if an experimental treatment should prove ineffective. A few comments pointed out that in some studies involving cancer chemotherapies, it would be unkind to include such a statement in the informed consent document because the likely result of ineffective treatment would be death. Other comments pointed out that an explanation of the likely results of an ineffective treatment would not be applicable in a study of normal, healthy volunteers because there would be no difference to them if the treatment failed. FDA agees with the comments and has deleted the specific language regarding ineffective treatment from the regulation. The agency points out, however, that if an ineffective treatment would result in either a foreseeable risk or discomfort it would have to be described in any case under § 50.25(a)(2). 23. One comment on proposed § 50.25(a)(3), (4), and (5) suggested that investigators should be required, where possible, to give test subjects quantified comparative estimates of risks and 52 benefits of experimental and alternative treatments. FDA agees that, were it always possible to quantify the risks, benefits, and comparative treatments for purposes of estimation, such quantification would be required. The basis elements represented by § 50.25(a)(2), (3), and (4), do require that human subjects be given a description of any reasonably foreseeable risks or discomforts, benefits, and a disclosure of appropriate alternative procedures or courses of treatment. FDA believes that where such descriptions or disclosures can contain quantified comparative estimates of risks and benefits, they should do so. Where such well-defined estimates are not possible, however, the agency believes that the information required to be disclosed will be sufficient. The agency does not believe that imposing such a strict requirement for every case would be realistic or appropriate. 24. One comment stated that FDA's preliminary assessments of an experimental drug's therapeutic significance should routinely be made available to subjects of drug testing and that this should be included as a basic element of informed consent. FDA does not agree. FDA's preliminary assessment of the therapeutic significance of an experimental drug or device is based on the same data that are available to an IRB at the time of its initial or continuing review. To the extent that an IRB believes that preliminary data assessment is appropriate to include in a consent form, it may so require. 25. One comment on proposed § 50.25(a)(4) (§ 50.25(a)(3) in the final rule) urged the agency to add a specific requirement that a subject be told if it is reasonably anticipated that the study will neither improve nor relieve his or her condition. The agency does not agree that such specific language need be added. Adequate disclosure of risks (8 50.25(a)(2)), benefits (§ 50.25(a)(3)). and appropriate alternative treatments (§ 50.25(a)(4)) will provide sufficient information to a subject to enable the subject to decide whether or not to participate. When use of a test article clearly will not benefit a particular condition, that fact should be made known as a reasonably foreseeable risk. 26. One comment stated that the requirement that benefits be described would be meaningless to normal, healthy volunteers because they would receive no benefit, and therefore, suggested that this requirement be deleted from § 50.25(a) and included in Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8917 § 50.25(b). Additional elements of informed consent. FDA rejects the comment. The agency believes that even if subjects receive no personal benefit from the study, others may receive some benefit, and, where it may reasonably be expected that others may benefit, that information should be disclosed. 27. One comment on proposed § 50.25(a)(5) (§ 50.25(a)(4) in the final rule) stated that a mere disclosure of appropriate alternative treatments would not be sufficient, and suggested that an investigator should have to describe the risks and benefits of such alternatives. The agency believes that the requirement, as worded, is sufficient. Any explanation of “appropriate alternative treatments” that did not contain some explanation of the risks and benefits of the alternatives would not be a true “disclosure.” The agency believes that the full description sought by the comment is required by the element as written. 28. Another comment on proposed § 50.25(a)(5) suggested that the consent form should merely state that alternative treatments are available. FDA disagrees and rejects the comment because it is important for a human subject to have specific information about alternative treatments in order to evaluate the risks and benefits of experimental treatment. Therefore, except for being renumbered, § 50.25(a)(4) remains unchanged in the final regulation. 29. Several comments on proposed § 50.25(a)(6) suggested that a statement that “new information" developed during the course of the research be provided to the subject, would not be appropriate in every study. In particular, these comments stated that such a statement would be irrelevant to either a single-dose clinical study or a study of extremely short duration. FDA agrees that the statement should not be required in every case and has, therefore, made this provision an “additional” element to be required when appropriate and is issuing it as § 50.25(b)(5) in the final rule. When appropriate, in this case, will mean in every study of sufficient duration, which the agency believes can be decided by the IRB. 30. Several comments on proposed § 50.25(a)(6) stated that the term “new information" is too all-encompassing and would be extremely difficult to interpret. A few comments suggested that “significant new findings" would be an appropriate substitute for “new information.” FDA agrees with the comments and has substituted “significant new findings" for “new information.” Thus, only relevant substantive information that might affect a subject's willingness to continue participation in the study need be communicated. 31. One comment stated that proposed § 50.25(a)(6) was unnecessary because it is implicit in every clinical investigation that an ethical and conscientious researcher would inform subjects if new risks or side effects were noted. One comment suggested that the requirement was unnecessary because other regulations require prompt notification and withdrawal of treatment following the occurrence of serious adverse reactions. FDA disagrees with these comments. FDA believes that an investigator should be required to advise subjects of new risks or adverse .eactions that may affect the subjeci's willing and continued participation in the study. Therefore, even though an ethical investigator would notify subjects of newly determined risks or adverse reactions, and other regulations require prompt reporting to the IRB and FDA of these findings, FDA believes that the investigator should be explicitly required to tell subjects of significant new findings, when necessary and appropriate. The comments are rejected. 32. A number of comments objected to the requirement, contained in proposed § 50.25(a)(7) (§ 50.25(a)(5) in the final rule), that research subjects be informed in advance of their participation in an investigation that FDA may inspect the subject's records. Several of these comments asserted that if subjects were so informed they would refuse to participate in FDA-related investigations. The agency does not believe that telling subjects that their records might be inspected by FDA will be a serious deterrent to subject participation. Medical records are frequently subject to third party review (e.g., insurance companies) and, although it may be true that informing potential subjects that study records may be inspected by FDA may deter some subjects from participation, that fact can scarcely be cited as a reason not to inform. Indeed, it is particularly important that any subject who feels strongly that his or her study records ought not be seen by anyone other than the clinical investigator be told ahead of time that an expectation of total privacy is not realistic in the context of clinical research being conducted for submission to FDA. As discussed in the preamble to the proposal, FDA believes in the protection 53 of subject privacy, and FDA does not routinely inspect subject records. However, the agency must inspect such records when it has reason to believe that the consent of the subjects was not obtained or when there is reason to believe that the study records do not represent actual studies or do not represent actual results obtained. Where an individually identifiable medical record is copied and reviewed by the agency, the record is properly safeguarded within FDA and is used or disseminated under conditions that protect the privacy of the individual to the fullest possible extent consistent with laws relating to public disclosure of information (e.g., Freedom of Information Act and Privacy Act) and the law enforcement responsibilities of the agency. Clinical studies are submitted to FDA to obtain an approval to market a regulated product, and the agency must be able to verify the basis for an approval whenever either a question of validity of results or subject rights arises. Moreover, not all raw data produced in the course of a clinical investigation involves “patient records” of the kind envisioned by many of the comments. Many clinical investigations are short-term and involve subjects who may or may not be patients. There may or may not be a doctor-patient relationship between the clinical investigator and the subject and there may or may not be an expectation on the part of the subject that the records of his or her participation in the investigation will be treated as confidential. Subjects who participate in clinical investigations are frequently paid to participate, and, in such cases, the relationship between the investigator and the subject will be a contractual one. For example, in those cases in which a sponsor or monitor will review the subjects’ records, the subjects should be so informed. It is particularly important that any subject who has an expectation of privacy regarding the subject's records of participation in FDA-regulated research be informed about the extent to which these records will be kept confidential so that any subject who feels strongly about the records may refuse to participate. The agency believes that providing this information to a subject is both fair and necessary. The motivation of subjects who participate in clinical research varies widely, and the agency does not believe that providing this information will prevent vast numbers of subjects from agreeing to participate. The comments do not require any change in § 50.25(a)(5). 8948 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 33. Several of the comments on proposed § 50.25(a)(7) objected that the requirement of a notice in the consent document that FDA might inspect subject records constituted a request that subjects waive their legal rights to privacy as a condition to giving their informed consent. One comment stated that proposed § 50.20 prohibits inclusion in informed consent documents of exculpatory language that waives or appears to waive a subject's legal rights. As an alternative to proposed § 50.25(a)(7), several comments suggested that the regulation be revised to provide that FDA would seek permission from individual patients to inspect or copy their records if the need arose. The agency rejects all of these comments. The basis of FDA's right to inspect subject records was discussed both in the preamble to the proposal (44 FR 47721) and in the response to comment 32 in this preamble. The agency is not requiring any subject to “waive” a legal right. Rather, the agency is requiring that subjects be informed that the “legal right” to privacy that they might expect in other contexts does not apply in the context of regulated research. FDA need not “seek permission” when the need to inspect such records arises because to do so would, in essence, delegate improperly an authority vested in the agency by Congress. 34. Two comments noted that because FDA states in the preamble to the proposal that it has the right to copy medical records containing the names of research subjects when there is reason to believe that consent was not obtained, or there is doubt that the records represent actual studies or actual results obtained, proposed § 50.25(a)(7) should provide that the consent form also inform the research subject that identifying information may be inspected and copicd by FDA. FDA believes that the required statement, as phrased, is sufficient. The language, therefore, as issued in § 50.25(a)(5) of this final rule is unchanged. 35. One comment stated that many institutions would not wish to include the notice required by § 50.25(a)(5) on all their consent forms. Therefore, there would have to be a separate consent form for FDA-regulated research. This comment suggested that this requirement be deleted. FDA rejects the suggestion. While it may be true that some institutions do not wish to have the notice of possible FDA inspection of subject records on all of their consent forms, the agency believes it is important that human subjects included in FDA-regulated research be aware that FDA might need to see their records. FDA believes that consent forms should be individualized for each study in any case, because standardized consent forms could not possibly take into account all the elements necessary to obtain adequate informed consent for every clinical investigation. 36. Several comments on proposed § 50.25(a)(9) (§ 50.25(a)(6) in the final rule) stated that because of the possibility of unanticipated injuries, it would be impossible to describe in advance the nature of any compensation and medical treatment for injury that might occur as a result of the study. Several comments stated that it would be difficult, if not impossible, to distinguish between those injuries that are compensable and those that are not. These comments misunderstand the requirement. All that is required is a statement that compensation or medical treatment are or are not available if unanticipated injuries occur and of what they consist. Such a statement will be adequate if it merely states that medical care will or will not be provided in the event of injury and describes the extent of available compensation. if any. Compensation for injury may vary with the extent of the injury or may be limited. A description so stating will be adequate. 37. One comment suggested that because proposed § 50.25(a)(10) was merely an extension of § 50.25(a)(8), they should be combined. The agency agrees. Proposed § 50.25(a)(8) required an offer to answer any questions the subject or the subject's representative might have about the research, the subject's rights, or related matters. Proposed § 50.25(a)(10) required that the subject be told whom he or she should contact if harm occurred or if there were questions. These two requirements have been combined and published in this final rule as § 50.25(a)(7). This provision requires that subjects be given an explanation of whom to contact for answers to pertinent questions about the research and research subject's rights, and whom to contact in the event of a research-related injury to the subject. 38. One comment on proposed § 50.25(a)(8) stated that although the clinical investigator could respond to questions concerning the research, the clinical investigator was not necessarily the appropriate person to answer questions about the subject's rights. While the comment may be true, the final regulation issued as § 50.25(a)(7) does not require that one particular person answer all questions raised by 54 the subject. Rather, the regulation requires that a subject be told whom to contact regarding particular problems. Where one person cannot respond to all the questions, more may and should be designated. The agency believes that the final regulation clarifies this provision. 39. One comment suggested that the information regarding whom to contact was merely a procedural item and that it should, therefore, not be a “basic” element of § 50.25(a) but should be made an “additional” element of proposed § 50.25(b). FDA disagrees. The items of information required to be disclosed under “additional elements,” § 50.25(b)(1) through (6), are those items that are either irrelevant to some categories of research (i.e., single-dose studies) or items that are discretionary and that may be required by the IRB. The information regarding whom to contact is equally important in all studies, should be required to be provided in every case, and therefore is retained in § 50.25(a)(7) of this final rule. 40. Two comments suggested that proposed § 50.25(a)(11) (§ 50.25(a)(8) in the final rule), as worded, might be interpreted to mean that a subject who was being paid to participate in a clinical investigation could receive full payment even if he or she dropped out. These comments suggested that the provision be revised to state that a subject could discontinue participation. “without loss of already earned benefit.” The agency does not agree that the provision should be revised. In any study in which a subject is paid, the contractual agreement may specify the basis of compensation and, therefore, the degree of “entitlement.” If, in such a case, full payment requires completion of the study, and a subject fails to complete the study, he or she will not be “entitled” to full compensation. All that is required is that a full'-explanation be provided. The agency does not find that the wording of § 50.25(a)(8) is ambiguous on this point and the comments are rejected. 41. One comment on proposed § 50.25(b) stated that the regulations could allow IRB's and investigators to deny human subjects information necessary for informed consent because that information was listed under “Additional elements." FDA disagrees with this interpretation. The elements of informed consent listed as “additional” are not needed in every clinical investigation. However, when any of those additional elements would be appropriate, § 50.25(b) requires that the additional information be provided to the subject. Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8949 42. Several comments suggested that the “Additional elements" of proposed § 50.25(b) be required as basic because they are all material to informed consent. FDA disagrees with the suggestion. The elements listed as “additional” are not material to every clinical investigation. For example, the requirement of § 50.25(b)(5) in the final rule that significant new findings be communicated to the subject if those findings might affect the patient's willingness to continue participation in the study, is not relevant to single-dose studies. 43. One comment on proposed § 50.25(b)(1) suggested that this “additional” element as written was overbroad. The agency does not agree that the element is overbroad. However, for clarity, § 50.25(b)(1) has been revised and has been shortened by deleting the second sentence. 44, Two comments suggested that proposed § 50.25(b)(2) be deleted. The comments argued that the required information was inherent in the required disclosure of foreseeable risks or discomforts and that providing information about foreseeable circumstances under which a subject's participation may be terminated would be impractical because such possible circumstances were “infinite.” The agency disagrees. Not every hypothetical circumstance in which a subject's participation might be terminated need be disclosed. The regulation requires only a discussion of anticipated circumstances. It might well be sufficient to state that a subject's participation might be terminated when, in the judgment of the clinical investigator, it is in the subject's best interests although in such a case some illustrative situations should be provided. For clarity, the word “anticipated” has been substituted for the word “forseeable"” as used in the proposed regulation to describe circumstances. 45. One comment on proposed § 50.25(L}(3) suggested that the requirement that information on possible additional costs “to others” besides the subject be provided was unclear, would have infrequent application, and could be misleading because it might refer to additional costs to the investigator or the sponsor. The agency agrees and has deleted the words “to others.” Section 50.25(b)(3) now requires that information be provided only on possible resulting additional costs to the subject. 46. One comment on proposed § 50.25(b)(5) (§ 50.25(b)(4) in the final rule) stated that providing information on the consequences of a decision to withdraw from a study was unnecessary because the information would duplicate the requirements of other sections of the informed consent regulations. The agency does not agree. There may be studies in which specific information on the consequences of a decision to withdraw will be of particular importance. The information need only be provided in those cases. IRB review should help identify those studies in which the information would be appropriate. 47. As discussed in responses to comments 29 through 31, the proposed requirement of § 50.25(a)(6) to provide to all subjects in any investigation, a statement regarding new * information” has been determined to be more appropriately an additional element of consent and included in the final rule as § 50.25(b)(5). 48. A number of comments on proposed § 50.25(b)(4) (§ 50.25(b)(6) in the final rule) stated that disclosing the name of the sponsor, the responsible institution, and who was funding the study would add nothing to the quality of a subject's consent because none of the items of information were likely to be important to a subject's decision to participate in research. The agency agrees that, for the most part, the items of information proposed need not be specifically provided and has, therefore, deleted the language regarding funding, responsible institution, and sponsor. Because the approximate number of subjects participating may have a bearing on a subject's decision to participate, however, that requirement is retained in § 50.25(b)(6). Where multi-institutional studies are involved, an indication of the number of institutions and the approximate number of subjects will be sufficient. 49. On the agency's own initiative, two new paragraphs have been added to § 50.25. Section 50.25(c), which states that the requirements of these regulations are not intended to preempt any applicable Federal, state, or local laws which require additional information to be disclosed, is added to make the pdticy clear and to conform to the HHS language. Section 50.25(d), which states that these regulations are not intended to limit the authority of a physician to provide emergency medical care to the extent permitted under other applicable statutes, was initially proposed as § 50.23(d). It has been finalized without change and moved to conform to the HHS placement. 55 50. Section 50.27 requiring an investigator to document informed consent has been revised and shortened. The language of the section conforms to the language of the HHS regulation. 51. Several comments stated that to require a long, detailed consent form would be confusing and would detract from the intended purpose of the regulation that relevant information about a study be conveyed to the human subject. The agency, as noted in responses to comments on proposed § 50.25, has simplified the informational requirements of the regulation and has required that the information given to a subject be in understandable language. FDA recognizes that the documentation of informed consent represents only one part of the entire consent process. The consent form itself is merely an aid to assure that a required minimum of information is provided to the subject and that the subject consents. The entire informed consent process involves giving the subject all the information concerning the study that the subject would reasonably want to know; assuring that the subject has comprehended this information; and finally, obtaining the subject's consent 0 participate. The process, to be meaningful, should involve an opportunity for both parties, the investigator and the subject, to exchange information and ask questions. The consent form, thus, should not be viewed as an end point. Rather, it is the beginning. The agency concludes that the comments do not justify any specific changes to § 50.27, although, as stated in comment 50, the regulation has for other reasons been revised and shortened. 52. One comment stated that the documentation of informed consent by a short form will not ensure that subjects understand the oral explanations. The comment further stated that subjects would have to rely solely on the interpretation given to them by the investigator. FDA disagrees with the comment. The same quantum and quality of information, i.e., that information required by § 50.25, must be provided to a subject whether a long form, a short form, or no form is used (see also § 56.109(c)). The fact that a short form is used to document informed consent does not mean that the subject will get less information than if handed a long, detailed written document. When a “short form" is used, the IRB must first approve a written summary of what is tg be said, and a witness must be present to attest to the adequacy of the consent process and to the voluntariness of the 8950 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations subject's consent. Section 50.27(b)(2) also requires that a copy of that summary be given to the subject. FDA believes that in many cases an oral presentation and written summary will be an effective method of disclosing necessary information. All the “form” provides, in either case, is evidence that the information required by § 50.25 has been provided to a prospective subject. The “form” itself cannot subsitute for the communicative process that it represents and, as noted in response to comment 51, it is not intended to. 53. The agency received no comments on the proposed conforming amendments and except for combining the proposed amendments relating to Parts 50 and 56, they are issued as proposed. 54. On its own initiative, the agency is revising 21 CFR 312.20(b)(1)(iv) by replacing the 1964 Declaration of Helsinki with the revised version adopted by the World Medical Assembly in 1975. The Declaration, first adopted by the World Medical Assembly in 1964 (see 44 FR 47715), was revised by that group, and the revision adopted at the 29th World Medical Assembly held in Tokyo, in October 1975. The revision includes a number of new requirements, among them the requirement that a research protocol be reviewed by a specially appointed independent committee. 55. On its own initiative, the agency is also adopting amendments to the Investigational Device Exemptions (IDE) regulations (21 CFR Part 812) to conform them to Part 50. The IDE regulations were promulgated by FDA on January 18, 1980 (45 FR 3732) after the August 14, 1979 proposal of these regulations. References The following material has been placed on file in the Dockets Management Branch, Food and Drug Administration, Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857, and may be seen by interested persons from 9 a.m. to 4 p.m., Monday through Friday. 1. Annas, G. J., “The Law of Informed Consent to Human Experimentation: An Introduction with Specific Reference to the Hospital Patient and the Normal Volunteer,” prepared for the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, NIH Contract No. NO1-HU-8-2120, June 1976. 2. HR. Rept. No. 94-1090, 84th Cong., 2d Sess. (1976). Therefore, under the Federal Food, Drug, and Cosmetic Act (secs. 408, 408, 409, 502, 503, 505, 506, 507, 510, 513-518, 518-520, 701(a), 706, and 8901, 52 Stat. 1049-1053 as amended, 1055, 1058 as amended, 55 Stat. 851 as amended, 52 Stat. 463 as amended, 68 Stat. 511-517 as amended, 72 Stat. 1785-1788 as amended, 74 Stat. 399-407 as amended, 76 Stat. 794-795 as amended, 90 Stat. 540-560, 562-574 (21 U.S.C. 346, 346a, 348, 352, 353, 355, 356, 357, 360, 360c— 360f, 360h-360j, 371(a), 376, and 381)) and the Public Health Service Act (secs. 215, 301, 351, 354-360F, 58 Stat. 690, 702 as &mended, 82 Stat. 1173-1188 as amended (42 U.S.C. 216, 241, 262, 263b- 263n)) and under authority delegated to the Commissioner of Food and Drugs (21 CFR 5.1), Chapter I of Title 21 of the Code of Federal Regulations is amended as follows: SUBCHAPTER A—GENERAL PART 50—PROTECTION OF HUMAN SUBJECTS 1. In Part 50: a. In § 50.3 by adding paragraphs (a) and (c) through (m), to read as follows: § 50.3 Definitions. * * * * * (a) “Act” means the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201-902, 52 Stat. 1040 et seq. as amended (21 U.S.C. 321-392)). (c) “Clinical investigation” means any experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the Food and Drug Administration under section 505(i), 507(d), or 520(g) of the act, or is not subject to requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit. The term does not include experiments that are subject to the provisions of Part 58 of this chapter, regarding nonclinical laboratory studies. (d) “Investigator” means an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject, or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team. (e) ‘Sponsor’ means a person who initiates a clinical investigation, but who does not actually conduct the investigation, i.e., the test article is administered or dispensed to or used involving, a subject under the immediate direction of another individual. A person other than an individual (e.g., corporation or agency) that uses one or 56 more of its own employees to conduct a clinical investigation it has initiated is considered to be a sponsor (not a sponsor-investigator), and the employees are considered to be investigators. (f) “Sponsor-investigator’” means an individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject. The term does not include any person other than an individual, e.g., corporation or agency. (g) “Human subject” means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient. (h) “Institution” means any public or private entity or agency (including Federal, State, and other agencies). The word “facility” as used in section 520(g) of the act is deemed to be synonymous with the term “institution” for purposes of this part. (i) “Institutional review board” (IRB) means any board, committee, or other group formally designated by an institution to review biomedical research involving humans as subjects, to approve the initiation of and conduct periodic review of such research. The term has the same meaning as the phrase “institutional review committee” as used in section 520(g) of the act. (j) “Prisoner” means any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures that provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing. (k) “Test article” means any drug (including a biological product for human use), medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the act or under sections 351 and 354-360F of the Public Health Service Act (42 U.S.C. 262 and 263b-263n). (1) “Minimal risk" means that the risks of harm anticipated in the proposed research are not greater, considering probability and magnitude, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. (m) “Legally authorized representative’ means an individual or Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8951 judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's particpation in the procedure(s) involved in the research. b. By adding new Subpart B to read as follows: Subpart B—Informed Consent of Human Subjects Sec. 50.20 General requirements for informed consent. 50.21 Effective date. 50.23 Exception from general requirements. 50.25 Elements of informed consent. 50.27 Documention of informed consent. Subpart B—Informed Consent of Human Subjects § 50.20 General requirements for informed consent. Except as provided in § 50.23, no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence. § 50.21 Effective date. The requirements for informed consent set out in this part apply to all human subjects entering a clinical investigation that commences on or after July 27, 1981. § 50.23 Exception from general requirements. (a) The obtaining of informed consent shall be deemed feasible unless, before use of the test article (except as provided in paragraph (b) of this section), both the investigator and a physician who is not otherwise participating in the clinical investigation certify in writing all of the following: (1) The human subject is confronted by a life-threatening situation necessitating the use of the test article. (2) Informed consent cannot be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from, the subject. (3) Time is not sufficient to obtain consent from the subject's legal representative. (4) There is available no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject. (b) If immediate use of the test article is, in the investigator's opinion, required to preserve the life of the subject, and time is not sufficient to obtain the independent determination required in paragraph (a) of this section in advance of using the test article, the determinations of the clinical investigator shall be made and, within 5 working days after the use of the article, be reviewed and evaluated in writing by a physician who is not participating in the clinical investigation. (c) The documentation required in paragraph (a) or (b) of this section shall be submitted to the IRB within 5 working days after the use of the test article. § 50.25 Elements of informed consent. (a) Basic elements of informed consent. In seeking informed consent, the following information shall be provided to each subject: (1) A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental. (2) A description of any reasonably foreseeable risks or discomforts to the subject. (3) A description of any benefits to the subject or to others which may reasonably be expected from the research. (4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject. (5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records. (6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained. 57 (7) An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject. (8) A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. (b) Additional elements of informed consent. When appropriate, one or more of the following elements of information shall also be provided to each subject: (1) A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable. (2) Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent. (3) Any additional costs to the subject that may result from participation in the research. (4) The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject. (5) A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject. (6) The approximate number of subjects involved in the study. (c) The informed consent requirements in these regulations are not intended to preempt any applicable Federal, State, or local laws which require additional information to be disclosed for informed consent to be legally effective. (d) Nothing in these regulations is intended to limit the authority of a physician to provide emergency medical care to the extent the physician is permitted to do so under applicable Federal, State, or local law. § 50.27 Documentation of informed consent. (a) Except as provided in § 56.109(c), informed consent shall be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject's legally authorized representative. A copy shall be given to the person signing the form. (b) Except as provided in § 56.109(c), the consent form may be either of the following: 8952 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations (1) A written consent document that embodies the elements of informed consent required by § 50.25. This form may be read to the subject or the subject's legally authorized representative, but, in any event, the investigator shall give either the subject or the representative adequate opportunity to read it before it is signed. (2) A “short form" written consent document stating that the elements of informed consent required by § 50.25 have been presented orally to the subject or the subject's legally authorized representative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subject or the representative. Only the short form itself is to be signed by the subject or the representative. However, the witness shali sign both the short form and a copy of the summary, and the person actually obtaining the consent shall sign a copy of the summary. A copy of the summary shall be given to the subject or the representative in addition to a copy of the short form. 8956 PART 812—INVESTIGATIONAL DEVICE EXEMPTIONS 16. Part 812 is amended: a. In § 812.2 by revising paragraph (b)(1)(iii) to read as follows: §812.21 Applicability. (b) * ow (ay «++ (iii) Ensures that each investigator participating in an investigation of the device obtains from each subject under the investigator's care, informed consent under Part 50 and documents it, unless documentation is waived by an IRB under § 56.109(c). b. In § 812.3 by revising paragraph (f) to read as follows: § 812.3 Definitions. * « - * - (f) “Institutional review board" (IRB) means any board, committee, or other group formally designated by an institution to review biomedical research involving subjects and established, operated, and functioning in conformance with Part 56. The term has the same meaning as “institutional review committee” in section 520(g) of the act. c. In § 812.20 by removing paragraph (a)(2), and by redesignating (a)(3) as (a)(2) and revising it, and by redesignating (a)(4) as (a)(3) as follows: §812.20 Application. (a) . ho. (2) A sponsor shall not begin an investigation for which FDA's approval of an application is required until FDA has approved the application. »- * - » * d. In § 812.35 by revising paragraphs (a) and (b) to read as follows: 8957 §812.35 Supplemental applications. (a) Changes in investigational plan. A sponsor shall: (1) Submit to FDA a supplemental application if the sponsor or an investigator proposes a change in the investigational plan and (2) obtain IRB approval (see § 56.110(b)) and FDA approval of the change before implementation. (b) IRB approval. A sponsor shall submit to FDA, in a supplemental application, the certification of any IRB approval of an investigation or a part of an investigation not included in the IDE application, e. By adding new § 812.42 to read as follows: 58 §812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both approved the application or supplemental application relating to the investigation or part of an investigation. f. By revising the heading of Subpart D to read as follows: Subpart D—IRB Review and Approval g. By revising § 812.60 to read as follows: § 812.60 functions. An IRB reviewing and approving investigations under this part shall comply with the requirements of Part 56 in all respects, including its composition, duties, and functions. h. In § 812.62 by revising the section beading and the section to read as follows: IRB composition, duties, and § 812.62 IRB approval. (a) An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all investigations covered by this part. (b) If no IRB exists or if FDA finds that an IRB's review is inadequate, a sponsor may submit an application to FDA. i. By adding new § 812.64 to read as follows: § 812.64 IRB's continuing review. The IRB shall conduct its continuing review of an investigation in accordance with Part 56. j. By adding new § 812.66 to read as follows: § 812.66 Significant risk device determinations. If an IRB determines that an investigation, presented for approval under § 812.2(b)(1)(ii), involves a significant risk device, it shall so notify the investigator and, where appropriate, the sponsor. A sponsor may not begin the investigation except as provided in § 812.30(a). k. In § 812.100 by revising the second sentence to read as follows: § 812.100 General responsibilities of investigators. * * * An investigator also is responsible for ensuring that informed consent is obtained in accordance with Part 50 of this chapter.* * * - * * * * 8957 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations Subpart F [Removed] 1. Part 812 is amended by removing Subpart F—Informed Consent and marking it “Reserved.” m. In § 812.140 by revising paragraphs (c), (d), and (e) to read as follows: §812.140 Records * * * * * (c) IRB records. An IRB shall maintain records in accordance with Part 56 of this chapter. (d) Retention period. An investigator or sponsor shall maintain the records required by this subpart during the investigation and for a period of 2 years after the latter of the following two dates: The date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval application or a notice of completion of a product development protocol. (e) Records custody. An investigator or sponsor may withdraw from the responsibility to maintain records for the period required in paragraph (d) of this section and transfer custody of the records to any other person who will accept responsibility for them under this part, including the requirements of § 812.145. Notice of a transfer shall be given to FDA not later than 10 working days after transfer occurs. n. In § 812.150 by revising paragraph (a)(4) to read as follows: §812.150 Reports. (a) LE I (4) Deviations from the investigational plan. An investigator shall notify the sponsor and the reviewing IRB (see § 56.108(a)(3) and (4) of any deviation from the investigational plan. In the case of an emergency to protect the life or physical well being of a subject, the investigator shall notify the reviewing IRB withing 48 hours. Prior approval by the sponsor is required for changes in, or deviations from, a plan. FDA approval under § 812.35(a) is also required. * * * * 8958 21 CFR Parts 16 and 56 [Docket No. 77N-0350] Protection of Human Subjects; Standards for Institutional Review Boards for Clinical Investigations AGENCY: Food and Drug Administration. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA or agency) is establishing standards governing the composition, operation, and responsibility of institutional review boards (IRBs) that review clinical investigations, involving human subjects, conducted pursuant to requirements for prior submission to FDA or conducted in support of applications for permission to conduct further research or to market regulated products. These regulations and the protection of human research subjects regulations adopted by the Department of Health and Human Services (HHS or Department) published in the January 26, 1981 issue of the Federal Register, establish a common framework for the operation of IRBs that review research funded by HHS and research conducted under FDA regulatory requirements. Compliance with these regulations is intended to provide protection of the rights and welfare of human subjects involved in clinical investigations. EFFECTIVE DATE: July 27, 1981. FOR FURTHER INFORMATION CONTACT: John C. Petricciani, Office of the Commissioner (HFB—4), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20205, 301-496-9320. SUPPLEMENTARY INFORMATION: In the Federal Register of August 8, 1978 (43 FR 35186), FDA published proposed standards for IRBs for clinical investigations. Interested persons were given until December 6, 1978 to submit written comments on the proposal. By notice in the Federal Register of December 15, 1978 (43 FR 58574), FDA extended the comment period to June 6. 1979. During the comment period, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission) submitted its report and recommendations on [RBs and informed consent, and that document was published in the Federal Register of November 30, 1978 (43 FR 56174). In its report, the National Commission recommended revision of the current HHS IRB regulations (45 CFR Part 46). On August 14, 1979 (44 FR 46799), FDA withdrew the August 8, 1978 proposal and published a revised proposal that it had developed in conjunction with HHS in response to the recommendations made by the National Commission. In addition, the agency held three hearings under § 15.1(a) (21 CFR 15.1(a)) of the administrative practices and procedures regulations in: (1) Bethesda, Maryland, on September 18, 1979; (2) San Francisco, California, on October 2, 1979; and (3) Houston, Texas, on October 16, 1979. These hearings were 59 intended to provide an open forum to present views on the regulations and to foster greater consideration of the proposal among the scientific community, regulated industry, and the public. (Transcripts of these hearings are on file with the Dockets Management Branch (formerly the Hearing Clerk's office) (HFA-305), FDA.) For the reasons set forth in paragraph 1, the sections of the regulation have been reorganized and renumbered to be parallel with the Department's regulations. The following table correlates the new sections with those proposed. Old section New section No corresponding section 56.6. 56.21, 56.25 56.26, and 56.34. 56.80, 56.81, and 56.87. 56.82 and 56.87. 56.83. 56.86. 56 8, 56.9, 56.87, and 56.90 we 56.9. .. 56.15, 56.21, 56.25 56.185, and 56.195. .... No corresponding section. .... 56.202, 56.206, and 56.210. .. 56.213. .. 56.219. .. 56.215. FDA will seek Office of Management and Budget (OMB) clearance of the reporting and recordkeeping requirements contained in these regulations prior to the effective date. If OMB does not approve the reporting and recordkeeping requirements without change, the agency will revise the regulations to comply with OMB's recommendations. The agency received 145 comments on the original proposal and 179 comments on the reproposal. In addition, approximately 100 people appeared at the three public hearings. Following is 4 summary of the significant comments received and FDA's response to them: General Comments 1. One of the overriding themes in the comments was that the agency should adopt the same final regulations as the Department. FDA agrees that the Department's and the agency's regulations should be as consistent as possible, and it recognizes that if such consistency is achieved, IRBs that deal with both FDA and other HHS components will be able to follow a uniform standard. Therefore, FDA participated with other components of the Public Health Service in an intra- departmental task force whose goal wag to achieve the maximum degree of Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations consistency possible in the Department's and the agency's IRB and informed consent regulations. Drawing heavily on the comments received by both HHS and FDA, the task force made substantial progress toward achieving its goal. As a result, the structrual and functional requirements for IRBs in FDA's regulations are identical to those in the Department's regulation. FDA and HHS have adopted the same definitions for “institution” (§ 56.102(d)) and “minimal risk" (§ 56.102(h)), and identical provisions relating to IRB membership (§ 56.107), IRB functions and operations (§ 56.108), IRB review of research (§ 56.109), expedited review (§ 56.110), criteria for IRB approval of research (§ 56.111), review by an institution (§ 56.112), suspension or termination of IRB approval of research (§ 56.113), cooperative research (§ 56.114), and records (§ 56.115). In addition, the organization of the two sets of IRB regulations is now consistent. While exact congruity between the Department's and the agency's regulations is not possible because of differences in statutory authority and scope of activity, FDA believes that these regulations are as identical as possible with the regulations that are being adopted by HHS for the protection of human subjects who participate in research funded by the Department. 2. Several comments suggested that FDA adopt the assurance mechanism that is contained in the Department's regulations. FDA has decided not to adopt this mechanism. Although consistency with the Department's regulations is important, the agency finds that other factors make adoption of the assurance mechanism inappropriate. FDA has determined that the benefits of the entrance into the assurance process of the IRBs that are subject to FDA jurisdiction, but not otherwise to HHS jurisdiction, do not justify the increased administrative burdens that would be placed on institution by requiring them to submit assurance materials to the Department's Office of Protection from Research Risks (OPRR), or the increased burden on the Government of processing those assurance submissions. FDA will rely instead on the dissemination of these regulations and on appropriate educational efforts, together with inspections of IRBs, to assure compliance by IRBs with these regulations. 3. One comment stated that while there should be an organized group to establish guidelines, standards, procedures, and educational activities that assure the high quality and performance of IRBs, that group should not come from within the Government. The comment stated that institutions themselves, or other interested parties independent of the Federal Government, would organize for these purposes. While FDA would welcome such an organization, the agency points out that none presently exists. As discussed in paragraph 8 of this preamble, FDA has been charged by Congress with the responsibility of protecting the rights and welfare of human subjects who participate in research that comes within the agency's jurisdiction. Therefore, it is necessary for the agency to publish these regulations to fulfill that responsibility. 4. Three comments stated that FDA does not have legal authority to adopt these regulations. Two comments stated that section 701(a) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 371(a)) cannot be used as a grant of authority to regulate any subject the agency selects. The comments argued that the subject matter of regulatioris must be within the substantive authority of the agency, and that there is no mention anywhere in the act that the agency can require that clinical investigations be reviewed by an IRB. Two comments suggested that the proposed regulations should therefore be republished as guidelines. FDA rejects these comments. The agency presented a thorough discussion of its authority to require IRB review in the preamble to the August 8, 1978 proposal at 43 FR 35197. As the agency pointed out in that preamble, its authority to adopt these regulations is derived from several sections of the act. In section 520(g)(3)(A)(i) of the act (21 U.S.C. 360j(g)(3)(A)(i)). congress directed the agency to include in its investigational device exemption (IDE) regulations (21 CFR Part 812) a requirement that an applicant for an IDE submit the plan for research to the local “institutional review committee” that “* * * has been established in accordance with regulations of the [Commissioner] * * *." Under § 56.102(e) of these regulations, “institutional review committee" is synonomous with “institutional review board.” Although there are no corresponding explicit provisions with regard to the other clinical investigations covered by these regulations, the Supreme Court has recognized in Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 653 (1973), that FDA has authority that “is implicit in the regulatory scheme, not spelled out in haec verba” in the statute. 60 As stated in Morrow v. Clayton, 326 F.2d 36, 44 (10th Cir. 1963): However, it is a fundamental principle of administrative law that the powers of an administrative agency are not limited to those expressly granted by the statutes, but include, also, all of the powers that may be fairly implied therefrom. See Mourning v. Family Publications Service, Inc., 411 U.S. 356 (1973); see also National Petroleum Refiners Association v. FTC, 482 F.2d 672 (D.C. Cir. 1973). Sections 505(i), 507(d), and 520(g) of the act (21 U.S.C. 355(i), 357(d). and 360j(g)) require that the agency issue regulations that establish the conditions under which drugs and devices will be available for investigational use. Those sections of the act direct the agency to issue regulations to protect the public health in those investigations. FDA has determined (43 FR 35197) that a requirement of IRB review of an investigation is essential to safeguard the rights and welfare, and consequently, the health, of the human subjects involved in the study. In addition, sections 505(j)(1) and 507(e) of the act require that the regulations adopted under sections 505(i) and 507(d) reflect due regard for the ethics of the medical profession and the interests of patients. There is a similar requirement in section 520(g)(1) of the act that the investigations conducted under that section be consistent with ethical standards. Because IRB review is intended to focus on the ethical acceptability of studies and on the protection of human subjects, FDA believes that the requirement of IRB review will ensure that there is due regard for the ethics of the medical profession and for the interests of patients in the investigations covered by these regulations. Finally, under section 701(a) of the act, the agency is empowered to issue regulations for the efficient enforcement of the act. In assessing the validity of regulations issued under section 701(a), the basic question is whether the statutory scheme as a whole justifies promulation of the regulation. National Confectioners Association v. Califano, 569 F.2d 690, 693 (D.C. Cir. 1978). As explained in the preamble to the August 8, 1978 proposal, IRB review is very important in helping FDA to assure that the rights and welfare of human subjects are protected in clinical investigations regulated by the agency because IRBs require modifications in or disapproval of those clinical investigations that present unreasonable risk in relation to the benefits and knowledge to be gained. See also 43 FR 35197. Therefore, 8960 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations the agency has determined that these regulations are essential to enforcement of the agency's responsibilities under sections 406, 409, 501, 502, 505, 506, 507, 510, 513, 514, 515, 516, 518, 519, 520, 706, and 801 of the act, as well as the responsibilities of FDA under sections 301, 351 and 354-360F of the Public Health Service Act. 5. Several comments questioned how the regulations would affect the interaction in clinical investigations of IRBs, sponsors, monitors, and ivestigators. One comment stated that these regulations may make an IRB feel liable for tasks that are the responsibility of a sponsor. The IRB regulation is one of five regulatory elements in FDA's bioresearch Monitoring Program. That program is designed to assure the quality and integrity of the research that is subject to the agency's jurisdiction. In addition to the two FDA regulations published in this issue, the Bioresearch Monitoring Program includes proposed regulations to establish obligations of clinical investigators (proposed August 8, 1978 (43 FR 35210)), obligations of sponsors and monitors of clinical investigations (proposed September 27, 1977 (42 FR 49612)), and good laboratory practice regulations (21 CFR Part 58). The agency has attempted to include in each bioresearch monitoring regulation only the specific obligations of the entity that the regulation covers. Although the IRB regulations obviously include matters of interest to both sponsors and clinical investigators, an IRB should have no problem determining the boundaries of its obligations. The agency recognizes, however, that the bioresearch monitoring entities are intimately related and interdependent, and that there are certain well- established relationships among IRBs, clinical investigators, and sponsors of clinical investigations. Consequently, the agency believes that it should not impose any unnecessary requirements that would disrupt those relationships. For example, because IRBs usually do not have any direct contact with sponsors, FDA has eliminated from these regulations any requirement that an IRB contact a sponsor. The clinical investigator has the responsibility of keeping the sponsor informed of IRB actions. 6. Several comments claimed that the proposed regulations contained unnecessary, irrelevant, and repetitive rules which would serve as a deterrent to research. These regulations are intended to establish the basic framework for IRBs and their parent institutions. They differ from those proposed in 1978 and 1979 in that FDA has included in the final regulations only the essential organizational and procedural requirements for IRBs and has not specified in detail how those . requirements are to be met. Because of the great diversity in institutions, research activities, and organizational structures covered by these regulations, FDA has decided that there must be sufficient flexibility in the regulations to allow IRBs and their parent instituitions to meet these requirements in a manner that best suits their organizational needs. As a result of this approach, FDA has accepted the thrust of the comments and, as detailed in responses to comments regarding specific sections of the proposal, has deleted a number of the proposed provisions from these final regulations. 7. Several comments suggested that the proposed regulations be withdrawn because they offer no real protection to anyone. FDA rejects this suggestion. These rules provide minimum standards for review of clinical investigations by IRBs to ensure that the rights and welfare of human subjects will be protected in the investigation. Once these regulations are adopted, if institutions select reasonable and appropriate individuals for the IRBs, the IRB review process will provide a significant safeguard for human subjects in research. 8. Other comments suggested that the objectives of these regulations could be achieved through existing common law and State regulations. FDA disagrees with these comments. Congress has charged the agency with the responsibility of protecting the rights and welfare of human subjects who participate in research that comes within FDA's jurisdiction. Consequently, the agency cannot rely on existing common law or State regulations. The only way the agency can assure that adequate protections exist nationally is by adopting regulations that define what protections are necessary and that require that those protections be extended to all human subjects in research within the agency's jurisdiction. FDA is adopting these regulations because only through properly constituted and well- functioning IRBs can the agency be assured that the rights and welfare of human subjects are being protected before a study starts, and that the study is ethically acceptable. 9. One comment stated that Congressional and FDA investigations have amply demonstrated that some IRBs, if left free from systematic oversight, will not adequately carry out their obligations. Several other 61 comments stated that what is needed is an open and trusting relationship between FDA and IRBs. FDA believes that these regulations, when coupled with FDA's inspection program, strike the appropriate balance between the conflicting approaches to the regulation of IRBs presented by these contrasting comments. The Federal Government cannot bear alone the burden of protecting the rights and welfare of human subjects. Investigators, institutions, and sponsors must share in this responsibility. If IRBs follow these regulations, they will protect human subjects. However, if the agency finds serious deficiencies in the IRB review process at a particular institution, the agency will take appropriate action, as provided for in these regulations. 10. A few comments raised questions about the costs of IRB review. The comments pointed out that there are administrative costs associated with an IRB, and they raised questions about who would pay those costs. One comment stated that a sponsor should be able to provide compensation to IRBs, provided that it does not participate in the selection of IRB members. FDA recognizes that there are administrative costs associated with IRB review. Because, under these regulations, there is no single administrative model, for example, a single institution may have multiple IRBs, or a single IRB may review studies for several institutions, FDA believes that it is inappropriate for it to prescribe a method for reimbursement for administrative costs, and that the parties themselves should resolve this matter. FDA's statement in the preamble to the August 8, 1978 proposal regarding proposed § 56.26(a) that IRB members should not be compensated for services did not mean that administrative costs such as consultation fees, travel } expenses, typing services, paper and supplies, meeting rooms, etc., could not be paid by the sponsor or institution. 11. One comment suggested that institutional review would significantly increase the costs of clinical investigations. The agency rejects this comment. FDA estimates the cost of IRB review of a clinical investigation to be approximately $100. Consequently, compared to the total costs of a clinical investigation, the costs of IRB review are insignificant. 12. One comment criticized the absence of data in the Economic Impact Assessment (EIA) of the proposed regulation, but did not dispute the Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8961 . agency's conclusion that the regulation would not cause a major impact. The EIA stated that the IRB regulation would “provide for extension of an IRB concept to areas where it has not previously been used" (i.e., to studies involving noninstitutionalized subjects) and increase some of the review group's administrative activities, but that these additional costs would not approach the $100 million cost threshold for a major impact. The data underlying that conclusion follow. The agency estimates that 2,000 IRBs are reviewing or have reviewed studies submitted for FDA approval. Approximately 500 of these IRBs have submitted a General Assurance to HHS that they are in compliance with departmental regulations. An agency study (Office of Planning and Evaluation Study 47, “Results of the Institutional Review Board's Pilot Compliance Program,” April 1978) found that these IRBs review an average of 11 studies per month, amounting to a total of 66,000 reviews annually. The study also found that IRBs that had not submitted a General Assurance to HHS review an average of five studies per month, amounting to a total of 90,000 reviews annually, and that more than 50 percent of these IRBs were already in compliance with the administrative and procedural requirements. Institutional Review boards will incur some additional costs, in part for more thorough review and followup of investigations and in part because there will be additional studies subject to IRB review. FDA estimates that the incremental costs will be $7.5 million. This estimate was derived by assuming that the expansion of IRB review to studies using noninstitutionalized subjects will add one-third, or $52,000, more reviews. According to one estimate, a review by an IRB with a General Assurance now costs about $100 (William A. Check, “Protecting and Informing Human Research Subjects,” JAMA, 243 (1980), 1985-1993.) Thus, the costs of the added reviews are $5.2 million. If we further assume that the average IRB without a General Assurance now spends $75 per review, the added cost to bring their reviews into compliance with agency regulations is $2.3 million. This $75 average cost derives from the assumption that the IRBs already in compliance (50%) spend $100 per review and the generous assumption that the remaining IRBs (50%) will double their present review costs to come into compliance. The EIA also attributed potential agency compliance costs to the regulation. However, there will be little, if any, incremental costs to the agency, given present budgetary constraints. 13. One comment requested that these regulations grant IRB members limited liability in the case of malpractice suits. FDA lacks the authority to grant limited liability to IRB's or their members. That authority resides in Congress and in the State legislatures. Although it is impossible to limit liability or to ensure against law suits, the agency believes that the chances for a successful suit against an IRB or its members are greatly diminished if the IRB has complied with these regulations and any applicable State law in reviewing the proposed research. See, e.g., Davis v. Marathon Oil Co., 64 111. 2d 380, 356 W.E. 2d 93 (1976). 14. Several comments questioned the applicability of these regulations to studies conducted outside the United States. A few comments stated that standards of protection for human subjects may and do vary from country to country, and that the United States should not impose its standards on other countries when the human subjects come from those foreign countries in which the studies are being conducted. FDA agrees with the comments and notes that its policy regarding investigational studies involving drugs and biological products is set forth in § 312.20 Clinical data generated outside the United States and not subject to a “Notice of Claimed Investigational exemption for a New Drug” (21 CFR 312.20). The policy regarding foreign studies and the background to § 312.20 was set forth in detail in the preambles to the proposed and final regulations. See 38 FR 24220 (September 6, 1973) and -40 FR 16053 (April 9, 1975). The agency's policy regarding studies of investigational devices conducted outside the United States is similar to that for drugs and biological products and is discussed in the preamble to the recent proposal entitled “Proposed Procedures for the Premarket Approval of Medical Devices,” published in the Federal Register of December 12, 1980 (45 FR 81769). Section 814.15 of that proposal states the agency's policy concerning devices. The Proposed Regulation 15. Numerous comments objected to the statement in proposed § 56.1 Scope (§ 56.101 in the final regulations) that compliance with these regulations would help to assure the quality and integrity of data submitted to FDA. These comments argued that it is neither the responsibility nor within the competence of an IRB to assure the quality and integrity of data. The comments stated that the primary 62 functions of an IRB are to assure the ethical acceptability of a particular study and to assure that human subjects are adequately protected. One comment argued that IRBs would be converted into consultants for sponsors if they were required to review the quality and integrity of data. A number of comments asserted that review of the validity and integrity of data on an ongoing basis would be an undue burden on IRBs. A number of comments objected on similar grounds to including review of research methods among the criteria for approval of a clinical investigation. The comments argued that the IRB should focus on its primary task of risk assessment, and that the scientific evaluation, validation, and justification necessary for a study should be the obligation of the clinical investigator responsible for the study and of the sponsor. During the process of reviewing the comments and developing IRB regulations with other components of the Department, FDA became convinced that a number of IRB obligations included in the 1978 and 1979 proposals were inconsistent with the generally accepted view of the scope of IRB review. Consequently, the agency decided to reconsider whether to impose those obligations. One of the obligations most difficult to delineate was the extent to which an IRB must consider the scientific aspects of a research proposal. FDA acknowledges that the primary responsibilities of an IRB are to assure that human subjects are adequately protected, are not exposed to unnecessary risks, and are provided with enough information about a study so that they can give effective informed consent. However, the agency believes that is is impossible to divorce completely considerations of science from those of ethical acceptability and of protection of human subjects. Some type of scientific review is necessary to determine whether the risk to which subjects are exposed is reasonable. Thus, FDA has decided to delete from § 56.101 all references to any responsibility on the part of IRBs to assure the validity and reliability of data, because the agency is concerned that reference to such an obligation could be interpreted as imposing on IRBs the obligation to exercise primary scientific review responsibilities for clinical studies. IRBs have no such obligation. However, FDA believes that the IRB, the institution, and the clinical investigator share an obligation to assure that a review of the scientific merits of a proposal is conducted. FDA believes that an IRB cannot reasonably 8962 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations review a study or make a valid risk assessment, unless there has been a positive assessment of the scientific merits of the research. 16. Numerous comments objected that proposed § 56.1 did not limit the scope of IRB review of clinical investigations to exclude those that are conducted outside of an institution. These comments suggested that the other elements of FDA's Bioresearch Monitoring Program provide sufficient protection for human subjects who are not institutionalized. FDA rejects these comments and declines to change § 56.101 in response to them. Human subjects, whether institutionalized or not, are entitled to the protections that these regulations offer. The agency agrees that the other elements of the Bioresearch Monitoring Program provide important protections to human subjects. However, as the agency pointed out in paragraph 5, the elements of that program are closely related and interdependent. IRB review is necessary to ensure that the rights and welfare of human subjects are protected, and that the subjects are adequately informed prior to the start of a study. 17. One comment questioned whether these regulations would require physicians practicing in their offices to obtain IRB review of their proposed clinical investigations. Another comment suggested that physicians practicing in their offices should have a centrally located IRB available for their use. Physicians who practice in their offices and who wish to conduct clinical investigations for a sponsor or as sponsor-investigators are required to comply with these regulations to obtain a research permit. The agency recognizes, however, that in some instances such physicians (and other health professionals who would otherwise qualify for a research permit) may not be affiliated with an institution or have direct access to an IRB. In those instances, FDA advises that several options are available to the physician. A sponsor-investigator who is unaffiliated with an institution with an IRB can comply with this requirement by obtaining review at an institution whose IRB conforms with these regulations or by submitting the research proposal to an IRB created under the auspices of a local or State government health agency, a community hospital, a private or public medica] school, a county or State medical society, the State medical licensing board, an independent nonprofit group such as a foundation or society interested in a particular health concern, e.g., kidney disease or family planning, or an organization involved in intergroup communications, e.g., the American Arbitration Association. A private physician who wants to conduct clinical research for a sponsor, in addition to these options, may use an IRB created by the sponsor. 18. One comment suggested that optometrists in private practice be exempted from the requirements of these regulations. FDA rejects this suggestion. The agency believes that human subjects involved in any clinical investigation subject to FDA jurisdiction (except for those specifically exempted) need the protections that these regulations afford, regardless of whether the study is being conducted by optometrists, medical doctors, dentists, or other health professionals. 19. Several comments objected to the inclusion of cosmetic studies within the scope of these regulations. These comments pointed out that cosmetic studies are not subject to submission to the agency for premarket approval and therefore should not be subject to a requirement of IRB review. FDA agrees with the comments and has modified § 56.101 to exclude cosmetic studies from the scope of the IRB regulations. 20. Several comments urged that FDA not include over-the-counter (OTC) drugs in the scope of Part 56. In the preamble to the 1978 proposal at 43 FR 35189, FDA announced: ‘The Commissioner believes the purposes and processes of IRB review are now so widely accepted, and its value so generally recognized, that all clinical investigations should undergo such review unless circumstances clearly make it unnecessary, or infeasible, or contrary to the patient's interest. Consistent with that determination, FDA has decided to require IRB review of all clinical investigations (except those exempted under § 56.104 or for which a waiver has been obtained under § 56.105) of test articles that are intended to be submitted to the agency in support of an initial or supplemental research or marketing permit. However, because the agency recognizes the lower risk associated with studies of marketed OTC drugs, and because the agency wishes to minimize the administrative burden created by these regulations, FDA has decided to include studies with marketed OTC drugs, and other drug or biologic studies for which an IND is not required (e.g., bioavailability studies with a marketed drug), on the list of procedures that can receive expedited review. 21. One comment argued that FDA has no authority to require IRB review of 63 OTC drugs because OTC drugs are not unapproved new drugs within the meaning ol section 505(i) of the act. That an OTC drug is being reviewed under the procedures established in 21 CFR Part 330 does not mean that the drug is not an unapproved new drug under section 505 of the act. One of the purposes of establishing the OTC review was to make certain scientific and legal determinations with regard to a drug's status under section 505 of the act. In making those determinations, under OTC review procedures, the agency will consider data on a drug ingredient that interested persons may submit. To develop these data, investigators may conduct tests for submission to the agency that may present risks to human subjects. These tests should therefore be subject to review by IRB's. As discussed in paragraph 4 of this preamble, the agency has authority under section 701(a) of the act to promulgate regulations to implement section 505 (as well as other sections of the act) that requires such review of these studies. Therefore, it is within the legal authority of the agency to include investigations of drugs under consideration in the OTC review within these regulations. 22. A few comments objected to the inclusion of low risk or no risk studies within the scope of these regulations. The comments suggested that because risk is so low in these studies, and because FDA has rules governing informed consent, no IRB review is needed. A few comments argued that IRB review would not add any protections for human subjects in low risk studies. FDA believes IRBs should review studies even when there is minimal risk, to assure that (1) there is, in fact, only minimal risk; (2) adequate information is given to the subject or a legally authorized representative, so that effective informed consent can be given; (3) the study is ethically acceptable; and (4) the study complies with the requirements in these regulations. FDA also points out that it has modified these regulations to provide for expedited review of certain studies involving minimal risk (§ 56.109). A notice listing the eligible categories of studies is published elsewhere in this issue of the Federal Register. 23. One comment suggested that use of an investigational drug in an emergency situation should be exempted from IRB review. The agency recognizes that there is a practical need to provide a mechanism for the emergency use of a test article in a single patient. After examining various options, FDA has elected to exempt the emergency use of test articles from the Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8963 IRB review requirement and so provides in new § 56.104(c). The agency advises, however, that it views emergency use of a test article as being an uncommon occurrence, and that it will examine the circumstances of emergency use on a case-by-case basis to assure that emergency procedures are not being used to circumvent IRB review. FDA also points out that it has conditioned this exemption on a report of the emergency use to the IRB within 5 working days of its occurrence. FDA would expect that the IRB that receives the report by a clinical investigator on an emergency use, as required by § 56.104(c) and § 50.23(c), will examine each case to assure itself and the institution that the emergency use of the test article was justified. FDA also advises that while it has exempted emergency use of test articles from the requirement of prospective IRB review, this exemption does not release the clinical investigator from any other obligation imposed by other regulations or by the institution in which the emergency use is undertaken. Finally, the agency advises that a “subsequent use,” as referred to in the regulation, would be any use of the test article that occurs more than 5 days after its initial emergency use. 24. On its own initiative, FDA has eliminated proposed § 56.3(f) defining “institutionalized subject” because that term does not appear anywhere in Part 56. FDA has eliminated the definition of “person” in proposed § 56.3(i) because that term is used in these regulations only to denote an individual. 25. Several comments stated that the proposed definition of “clinical investigation" in proposed § 56.3(c) (now § 56.102(c)) is too broad and confusing. FDA disagrees. The definition was drafted to include all studies within FDA's jurisdiction that are subject to the requirements of prior submission to the agency or that may be submitted to the agency in support of a research or marketing permit. The comments are rejected. 26. One comment stated that proposed § 56.3(c) should clearly state that a clinical investigation is always medical in nature and always involves human subjects. FDA has attempted, whenever possible, to make the IRB regulations identical with those of the Department. To facilitate this goal, FDA has not defined “clinical investigation” to include only those studies that are medical in nature. As a result, this term is interchangeable with the term “research” as that term is defined by HHS. Because these terms are interchangeable, the same wording can be used in provisions in both FDA's and the Department's regulations. Section 56.102(c) in the final regulations is revised to clarify this fact and to conform with the HHS regulations. FDA points out that § 56.102(c) already states that human subjects must be involved in a “clinical investigation.” 27. Two comments stated that proposed § 56.3(d) defining “institution” was too broad. As stated in paragraph 1 of this preamble, FDA has revised § 56.102(d) to conform its definition of “institution” with that of the Department. “Institution” is now defined as any public or private entity. Although this definition is perhaps even broader than the proposed definition, the definition itself does not define the scope of those regulations. That scope is clearly set out in § 56.101. IRB review will now be required for all clinical investigations that support applications for research or marketing permits for products regulated by FDA. As noted in the 1978 proposal, it may no longer be strictly appropriate to call the process “institutional review" because the process is no longer tied to “institutions” as they were previously defined (43 FR 35188). Because the concept of institutional review is well understood by the research community, and because no better terminology has been suggested, the terminology has been retained. 28. One comment suggested that contract laboratories should be added to the proposed definition of “institution.” The revised definition of “institution™ in § 56.102(d) includes any entity. A contract laboratory clearly would come within the purview of the regulations. 29. Two comments expressed concern about including manufacturers in the definition of “institution.” One comment stated that the definition would include manufacturers who use their employees as subjects in the course of routine product testing, even though the manufacturers did not intend to use the data from that testing in support of a research or marketing permit. The intent of these regulations is to protect human subjects in clinical investigations that are subject to FDA jurisdiction. Therefore, the definition of “institution” must be broad enough to include manufacturers who use employees as test subjects in such research. However, only clinical investigations that are regulated by FDA under sections 505(i), 507(d), and 520(g) of the act or that are intended to support applications for research or marketing permits for products regulated by FDA are within FDA jurisdiction. Therefore, routine product testing, in which the 64 data are not intended to be used in support of a research or marketing permit or to support the safety and effectiveness of a regulated article, would not be subject to these regulations. 30. On its own initiative, FDA has modified the definition of “institutional review board" in proposed § 56.3(e) (now § 56.102(g)) to clarify that the primary purpose of an IRB is to assure the protection of the rights and welfare of human subjects. 31. One comment stated that HHS and FDA should have a common suitable definition of “institutional review board.” FDA points out that HHS has chosen not to include a definition of “institutional review board” in its regulations. FDA believes, however, that the agency's definition is compatible with the traditional use of the term by HHS and the biomedical community. FDA concludes that its definition of “institutional review board" in § 56.102(g) is suitable. 32. One comment suggested that FDA and HHS should collaborate on common terminology and definitions for the terms “subject” and “human subject.” The scope of research supported by the Department includes behavioral research that FDA does not regulate. At the same time, the scope of research regulated by FDA includes veterinary research that HHS, other than FDA, does not regulate and that, for obvious reasons, are not subject to these regulations. Therefore, it is appropriate for FDA to use the term “human subject” to clarify the scope of the regulation, and to define the scope of the term “human subject” as in § 56.102(e) more narrowly than has HHS. Section 56.102(e) has been revised to relate specifically to the types of research that are subject to FDA jurisdiction. 33. One comment stated that proposed § 56.3(1) could be read to require that there must be a therapeutic benefit for all subjects who participate in an investigation and thus to eliminate all Phase I studies. The comment asked that this confusion be clarified. The revised definition of “human subject” § 56.102(e) establishes that no therapeutic benefit for the participant from the research is required. The revision clarifies that these regulations do not eliminate Phase I studies. 34. One comment suggested that the proposed definition of “subject” be used in all regulations and guidelines dealing with clinical investigations. Whenever possible, FDA has tried to use consistent definitions in each of its bioresearch monitoring regulations. 8964 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 35. One comment stated that a definition of “informed consent” is needed in Part 56. FDA does not believe that the concept of informed consent can be adequately defined in a single “definition.” Because the concept of informed consent is complex and should apply to any clinical investigation, FDA is publishing its provisions concerning informed consent separately in Part 50 to apply to all aspects of biomedical research in human subjects. 36. Several comments pointed out that an investigator may not always conduct an investigation or provide immediate direction under which a test article is administered, even though the investigator does exercise a supervisory role. These comments suggested a number of modifications in the proposed definition of “investigator” in § 56.3(g) (now § 56.102(h)). . FDA recognizes that a single investigator does not always immediately direct the administration of the test article. Therefore, FDA has revised § 56.102(h) to reflect more accurately the functions of investigators. 37. Several comments stated that the proposed definition of “minimal risk” in § 56.3(h) (now § 56.102(i)) should be the same as the HHS definition. One comment stated that the proposed FDA definition was too narrow. FDA agrees with the comments and has rewritten § 56.102(i) to match the revised HHS definition. The definition in these final regulations takes into account the fact that risks encountered in the daily lives of healthy individuals may not be the same as risks encountered in the daily lives of others, and that “minimal” risk should mean that no risk in addition to that already encountered in the daily life of the individual will arise from the study. FDA points out to those IRB's and investigators involved with medical devices that the term “minimal risk" used in Part 56 is different from the term “non significant risk” that is used in the IDE regulations. “Non significant risk” is used to describe a medical device. “Minimal risk” is used to describe an investigation and involves different criteria from the ones used to determine that a device poses a “non significant risk.” Thus, IRB's and investigators cannot assume that an investigation with a “non significant risk" device poses only a “minimal risk” for the purpose of Part 56. 38. One comment stated that cosmetics should not be included in proposed § 56.3(n), which defined “test article.” As stated in paragraph 19 of this preamble, cosmetics are excluded from the scope of the IRB regulations. The word “cosmetic” is deleted from § 56.102(1). 39. One comment stated that a definition of “substantial risk" is needed in the IRB regulations. FDA disagrees with this comment. Having defined “minimal risk,” there is no need to demarcate the levels of risk any further. All studies with greater than minimal risk are treated the same under these regulations. 40. Many comments on proposed § 56.5 (now § 56.103) objected to the requirement of IRB review of clinical investigations that are conducted outside of an institution. Most of these comments overlap with or are identical to comments on § 56.101 Scope. The agency responded to these comments in paragraphs 15 through 18 of this preamble. The general objections will not be discussed further here. 41. Several comments on proposed § 56.5 stated that to require IRB review of studies involving non- institutionalized subjects will result in a tremendous additional burden on IRBs. One comment argued that, as a result of the regulations, it might become necessary for institutions to employ full- time reviewers, which would decrease the quality of persons serving on IRBs. FDA disagrees with these comments. The agency does not expect that any existing IRBs will be overwhelmed with new studies. FDA has exempted all studies that begin before the effective date of these regulations from the requirement of IRB review (see § 56.104). Also, as discussed in paragraph 17 of this preamble, the agency anticipates that where the need arises to accommodate studies with non- institutionalized subjects, new IRBs will be formed by professional societies, local medical societies, etc. 42. One comment on proposed § 56.5 stated that IRBs formed to review research conducted by physicians in their private practices will pose a large problem because sponsors will be reluctant to deal with them out of fear that the IRBs will not properly review studies under these regulations, and, as a result, FDA will refuse to accept studies that the IRBs review. FDA rejects this comment. The agency has made every effort to make these regulations as clear and precise as possible. The agency stands ready to answer any question an IRB may have abour these regulations. Consequently, there should be no reason for an IRB to be seriously out of compliance with Part 56. FDA emphasizes that the agency expects it to be a rare occurrence for studies reviewed by an IRB to be rejected because of the IRB's noncompliance with these regulations. 65 This expectation is discussed further in paragraph 46 of this preamble. 43. Another comment on proposed § 56.5 suggested that device manufacturers should be allowed to set up IRBs to review protocols and patient consent forms for use by individual clinical investigators. FDA agrees and points out that these regulations allow any manufacturer to set up an IRB. The agency advises, however, that one of the primary responsibilities of an IRB is to be sensitive to the concerns of the community in which the study will be conducted. Therefore, an IRB formed by a manufacturer or a sponsor must be aware of, and give full consideration to, those concerns. 44, Two comments stated that provision should be made in the final regulations for FDA to accept studies without IRB review where no IRB exists. FDA rejects these comments. All human subjects of FDA regulated research (except for human subjects of the research specifically exempted by § 56.104 or for which a waiver has been granted under § 56.105 of these regulations) are entitled to the protection of IRB review. FDA is not willing to permit human subjects to be deprived of this protection simply because an IRB is not available locally. Although local review is preferable, FDA has never established local review as a rigid requirement. If an IRB is not available locally, review can be sought at an IRB established in any of the ways discussed in paragraphs 17 and 41 of this preamble. 45. A number of comments objected to proposed § 56.5(a) (now § 56.103(a)) because of the requirement that an application for a research permit must be reviewed and approved by an IRB before it could be accepted by FDA. One comment stated that it was wasteful to require IRB review of a study when FDA may later reject the application. Several comments stated that IRB review should take place after FDA has given its approval or, at a minimum, be concurrent with FDA review. The agency has considered these comments and has modified § 56.103(a) to respond to the concerns. IRB review and approval will be required before any human subjects may enter into a clinical investigation. However, the IRB may review the study before, during, or after FDA conducts its review. 46. Two comments on proposed § 56.5(b) (now § 56.103(b)) suggested that data from a clinical investigation that were not subject to initial review by an IRB might be acceptable despite the absence of a review. One comment argued that if the agency does not Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8965 consider the data, it might deprive members of the public of the opportunity to use a test device that will benefit them. This comment suggested that the problem could be dealt with by permitting an investigation to be approved by an IRB after the fact. FDA rejects these comments. Post hoc review by an [RB is contrary to the purposes of [RB review. FDA believes it possesses the statutory authority to reject the data from a study. even though the scientific validity of the data generated may not have been affected. when the clinical investigation did not receive IRB review, or when the clinical investigation was under the review of a disqualified [RB or was conducted at a disqualified institution. Although the agency may not reject the data in every case, it reserves the right to do so when circumstances so warrant, and § 56.103(b) has been modified accordingly. The agency will consider, among other factors, the risks to human subjects that would be created if it rejected the data and required that the study be redone. 47. One comment stated that FDA should not require IRB approval for studies being conducted after premarket approval of a regulated article has been granted by the agency. The comment misunderstands the scope of these regulations, as stated in § 56.101. These regulations govern studies of regulated articles that are conducted for submission to FDA. Studies that are not intended to be submitted in support of an initial or supplemental research or marketing permit do not fall within the purview of these regulations. The agency believes, however, that the best protection for human subjects would be for all clinical studies to be reviewed by an IRB. 48. Many comments objected to the provision in proposed § 56.6 that would have waived the requirement for IRB review of clinical investigations begun prior to the effective date of these regulations only if those studies were completed within 1 year of the effective date. Some comments suggested that studies should be exempted if they were completed within 2 years. Others suggested that studies be exempted if completed within 3 years. Ten comments urged that the regulations should apply only to studies begun after the effective date. FDA has decided to exempt all studies that were begun before the effective date of these regulations and that were not otherwise subject to a requirement of IRB review under FDA regulations before that date, and § 56.104(b) so provides. The agency believes that the administrative burden that would be created by requiring IRB review of studies that were begun before the effective date of Part 56 far outweighs any benefits to human subjects that might be created. If the requirement was extended, the large number of studies that IRBs would suddenly have to review would prevent them from reviewing new proposals and from undertaking their continuing review of previously approved research. FDA believes that [RBs should be free to concentrate on the latter two types of research. However, FDA advises that any expansion of a study that would otherwise be exempt under § 56.104 (a) or (b) to include a new institution will be subject to IRB review. Thus, if a new institution is added to a multicentered study of an investigational drug or device after the effective date of these regulations, IRB review must be conducted at the new institution. 49. FDA received numerous comments about proposed § 56.6(b), which would have established the circumstances in which the requirement of IRB review could be waived. Several comments objected to this provision on the ground that human subjects would not be adequately protected if a waiver were granted. FDA is in substantial agreement with the latter comments. However, the agency recognizes that there may be circumstances in which a waiver would be appropriate. Therefore, FDA has revised the waiver provision (§ 56.105) to provide a sponsor or a sponsor- investigator with an opportunity to request that the agency waive some or all of the IRB requirements. A waiver may be granted by the responsible Bureau. The agency cautions, however, that it anticipates using the waiver provision only in special circumstances, upon a showing that a waiver is in the interest of patients who are subjects, and that an alternate mechanism for assuring the protection of human subjects is available. FDA also advises that, at the present time, it will consider applications for a waiver for those investigational new drug applications that have been commonly termed “compassionate INDs" or “treatment INDs" or for the distribution of investigational drugs under an investigational new drug exemption for the treatment of patients when alternate therapy is not available or is less effective. FDA also points out that because the statute requires IRB review of device studies, the agency will not waive the requirement of IRB review in those cases. 50. One comment suggested that the FDA regulations concerning membership 66 of an IRB should be identical to the HHS regulations. FDA agrees, and the agency has rewritten proposed §§ 56.21, 56.25, 56.26. and 56.34 (now § 56.107) to conform to the revised HHS requirements. 51. Several comments stated that FDA should not require racial and cultural diversity of IRB members because this requirement may be inappropriate to the community that the IRB serves, and because this requirement has no relevance to the competence of persons who serve on an IRB. One comment stated that the IRB regulations are an inappropriate place to implement affirmative action plans. These comments misinterpret § 56.107(a). The regulation does not require racial and cultural diversity in all cases. It requires that the racial and cultural backgrounds of the members be sufficiently diverse to assure that the IRB will be sensitive to the attitudes and concerns of the community and to the human subject population. 52. One comment suggested that it would be helpful if the term “cultural background” was defined. FDA has used the term “cultural background” in § 56.107(a) to encompass such socio-economic characteristics as age, economic status. and ethnic origin. 53. One comment suggested that provision be made in the regulations for an [RB to include alternate members. Although § 56.107(a) does not explicitly provide for alternate members, it would allow an IRB to adopt written procedures (see § 56.108) for using alternate members in the IRB's deliberations in case one of the regular members is absent or is disqualified from considering a proposal because of a conflict of interest. FDA points out, however, that the names of any alternate members must be included on the list of IRB members required by § 56.115(a)(5). 54. Several comments stated that there was no basis for requiring an IRB to have members of both sexes. Two comments suggested that a balance of men and women might not always be possible, and therefore, the requirement should be amended to read, “if possible.” FDA rejects these comments. The agency believes that to achieve a reasonable ethical perspective, IRB membership should be comprised of both men and women. Section 56.107(b) does not require that the number of men and women be equal. Rather, it requires that the IRB not be made up only of men or only of women. FDA points out that this requirement does not mean that members of both sexes are required to Federal Register / Vol. 48, No. 17 / Tuesday, January 27,1981 / Rules and Regulations be present for a quorum. No comments pointed to any specific situations in which it would not be possible to find competent men and competent women to serve on an IRB. 55. Several comments stated that the standards for IRB membership in the proposed regulations were too restrictive. The comments urged that FDA adopt more flexibile requirements on the make-up of an IRB. Three comments pointed out that it would not always be appropriate to have a physician or to have a scientist on a five-member board. In contrast, one comment stated that the proposed requirements for IRB composition were too vague. FDA recognizes that it cannot specify in detail the composition of an IRB that would be appropriated to review each of the diverse types of studies that are included within FDA jurisdiction. Therefore, FDA has rewritten § 56.107 to allow an institution great flexibility in the make-up of its IRB. The regulation sets forth the minimum requirements that FDA believes must be met if an IRB's advice and counsel are to receive respect. In addition to the racial and cultural diversity discussed in paragraph 51 of this preamble, an IRB must possess the professional competence to review the research activities it considers (§ 56.107(a)). It may not be made up of members of one profession (§ 56.107(b)). An IRB must include at least one member whose primary concerns are in nonscientific areas (§ 56.107(c)), and at least one member must have no connection to the institution except for his or her membership on the IRB (§ 56.107(d)). FDA has eliminated the requirement that an IRB must include at least one physician and one scientist in all cases. This change was made in consultation with HHS to achieve identifical requirements and takes into consideration the need for some flexibility in the make-up of IRBs that review FDA-regulated research. However, FDA emphasizes that § 56.107 (a) requires that IRBs have as members persons with the professional competence necessary to review the proposed research. For example, FDA would expect that an IRB that reviews investigational new drug studies will include at least one physician. 56. One comment suggested that it would be helpful if the term “nonscientist’” was defined. FDA believes that the examples given in § 56.107(c).of the types of individuals “whose primary concerns are in nonscientific areas” adequately explain this term. 57. One comment stated that in spite of the recommendation of the National Commission that an IRB that regularly reviews research that has an impact on vulnerable subjects should include persons who are primarily concerned with the welfare of those subjects, no provision for special representation of vulnerable subjects was contained in the proposed regulations. FDA disagrees with this comment. Such a requirement is contained in § 56.107(a). 58. One comment recommended that rather than setting out a specific number of lay persons to serve on an IRB, the regulation should establish a minimum proportion of the membership that is to be nonscientists. FDA disagrees with the comment. The standards set forth in these regulations are minimum standards that must be met by an IRB. If an institution or IRB wishes to exceed these standards and have a certain proportion of the IRB members be nonscientists, it is free to do so. However, an IRB must retain the necessary expertise to effectively review any protocol submitted to it, and therefore, it may need a number of scientists (whether medical doctors, dentists, technical staff, or others) on the IRB. FDA believes that, except for minimum standards, it should not dictate how many people should be from a specific profession. 59. One comment objected to the exclusion from membership on an IRB of immediate family members of a person affiliated with the institution. This comment stated this requirement would put severe restraints on recruiting IRB members in academic communities. FDA points out that § 56.107(d) does not exclude members of the immediate family of a person affiliated with an institution from being members of an IRB. However, none of those family members may serve as the nonaffiliated member of the IRB. This rule is consistent with the National Commission's recommendation. FDA believes that even in small academic communities in IRB can find at least one person willing lo serve on the IRB who is not affiliated with the institution and who is not the immediate family member of a person affiliated with the institution. 60. Many comments stated that under proposed § 56.26 (now § 56.107(e)), members of an IRB who selected other members would be precluded from conducting research. Several comments stated that the requirement should only be that an IRB member may not participate in the IRB's initial or continuing review of a clinical investigation in which the member has a conflicting interest. One comment suggested that the section should be 67 modified so that no investigator would select IRB members solely to review his or her own investigation. One comment stated that IRBs at larger institutions had sufficient numbers of members to permit members to disqualify themselves if they felt there was a conflict of interest. FDA agrees that revision is needed and has rewritten § 56.107(e) to coincide with the corresponding section in the Department's regulations. This requirement now provides that no member of an IRB may participate in the IRB's initial or continuing review of any clinical investigation in which the member has a conflicting interest. FDA believes that the IRB or the institution should determine what constitutes a conflicting interest. 61. One comment suggested that for each local IRB to seek consultative opinions on studies proposed for many research centers is redundant and would hinder the timely initiation of important research. FDA agrees with this comment. Cooperative review of multi-institutional studies is expressly authorized by § 56.114. Expert technical opinion can be provided by a central source, so that each IRB can use that opinion to evaluate the study in light of the ethical standards of the local community. 62. One comment on proposed § 56.34 (now § 56.107(f)) suggested that consultants be allowed to vote with an IRB. FDA. rejects this comment. The decision of an IRB must represent the judgment of the members of the IRB. Although consultants should provide information about the ethical acceptability of a study, FDA believes it would be a distortion of their function to permit them to vote. Therefore, § 56.107(f) prohibits consultants from voting. 63. One comment on proposed § 56.80 Now § 56.108(a)) suggested that the requirement in the 1978 proposal that an IRB adopt written procedures for the initial and continuing review and monitoring of clinical investigations be modified to delete the requirement of “Monitoring.” The comment argued that the sponsor was primarily responsible for monitoring. FDA deleted the term “monitoring” from reproposed § 56.80 in the August 14, 1979 document. FDA has further rewritten § 56.108(a) in these final regulations to match the HHS section. However, FDA points out that IRBs are responsible for the continuing review of a study to ensure that the rights and welfare of human subjects are protected. Therefore, FDA would expect IRBs to review studies at a frequency consistent Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8967 with the risks and to consider those data that bear on the rights and welfare of the human subjects. (See paragraph 89 below.) 64. One comment stated that instead of uniformity among IRBs. there will probably be diversity because each IRB will be able to establish its own regulations within the loose Federal framework. FDA agrees that each IRB will be able to establish its own procedures within the Federal framework, which represents minimum standards. An institution or IRB is free to impose greater standards of protection for human subjects than those required by these regulations. As stated previously. FDA does not believe that it should provide detailed directions to IRBs on how they are to comply with these regulations. How the IRBs meet the general standards should be left to each individual IRB and institution. 65. A few comments stated that IRBs are being forced into a "police role” as opposed to an ethical review in an atmosphere of trust and cooperation. FDA disagrees with the comments. There is no requirement that IRBs treat investigators with less cooperation than in the past. However, it is up to the IRB to assure itself, by whatever method it deems appropriate, and to assure FDA that the rights and welfare of human subjects are being protected. FDA encourages IRBs and clinical investigators io cooperate and interact with each other in a nonadversarial manner. Nevertheless, FDA considers it an appropriate requirement that IRBs develop procedures to determine whether there is a need for verification. from sources other than the investigators, that there has been no material change in certain protocols since their previous review. Verification is not required by FDA but should be an available avenue when, in the opinion of the IRB, verification will provide necessary protections for subjects involved in greater than minimal risk research. 66. Several comments on proposed § 56.81 objected to defining a quorum in terms of specific professional groups that must be represented. These comments asserted that such a requirement could have the effect of giving one member of the IRB the power to prevent the IRB from meeting by refusing to appear. A few comments suggested possible remedies to this situation, including adopting a rule that any member who missed two consecutive meetings of an IRB without good cause would automatically be dismissed. As stated previously, FDA believes that, within the framework of these regulations, each institution or IRB should set up its own rules and procedures governing IRB membership and attendance. However, FDA believes that it is important that a person whose primary concerns are in nonscientific areas be present when the IRB conducts its business because that member represents an important element of diversity. Therefore, FDA has retained in § 56.108(b) the requirement that the nonscientific member must be present for there to be a quorum. To ensure that a nonscientific member will be present, an IRB may wish to have more than one member whose primary concerns are in nonscientific areas. 67. Several comments stated that FDA should allow meetings to take place by conference calls. These comments argued that effective dialogue can occur between IRB members on conference calls without forcing the members to be physically present in one room. Although FDA, like HHS, encourages meetings to take place with members physically present in the room, FDA also recognizes that in some cases time and commuting expense would favor conference calls. As long as each IRB member can actively participate in any discussion of a protocol and has all pertinent material before the call, FDA has no objection to allowing meetings to occur in such a fashion and will consider meetings that take place by conference call to be “convened” meetings. These meetings must follow the same requirements (minutes, etc.) as meetings with members physically present. 68. One comment stated that the proposed requirement in § 56.87(b) (now § 56.108(c)) that an IRB report any serious or continuing noncompliance by investigators with the IRB's determinations to the institution and to FDA extends beyond the intended role of an IRB. FDA rejects this comment. During the course of its continuing review of a study, an IRB may become aware that a clinical investigator has not complied with its requirements or determinations. If the noncompliance is serious enough. an IRB may withdraw its approval of the investigation. Disciplinary action against the investigator may also be in order. Consequently, FDA has required in § 56.108(c) that the IRB report an investigator's serious noncompliance to the bodies that have authority to take action against the investigator—the institution and FDA. 69. One comment on proposed § 56.87(b) agreed that it was appropriate for IRBs to report any noncompliance 68 with the requirements of the IRB to FDA. but the comment stated that IRBs should also have authority to suspend the investigator until the situation is reviewed by FDA. Under § 56.113, the IRB is authorized to suspend or terminate its approval of any research that is not being conducted in accordance with the IRB's requirements or that has resulted in unexpected serious harm to human subjects. Where appropriate, action against a clinical investigator may be taken by FDA, or by the institution either directly or through the IRB if that authority is delegated to the IRB by the institution. 70. One comment stated that it was unclear in proposed § 56.82 whether a complete review of a proposed investigation is necessary if minor changes in the protocol, requested by the IRB, are agreed to by the investigator and the sponsor. FDA believes that it is up to each individual IRB to decide whether it wants to review the study completely or merely to note that the requested changes have been made. However, the [RB must maintain documentation of ~ changes made (§ 56.115(a)(2)). FDA has rewritten § 56.109(a) to match the corresponding section in the Department's regulations. This section provides that the IRB shall review and shall have authority to approve, to require modifications in, or to disapprove all research within FDA's jurisdiction. 71. Many comments objected to proposed § 56.82(a) because they interpreted the proposed regulations to require IRBs to conduct a scientific review of pertinent prior animal and human studies with the test article, as well as ethical review. A few comments stated that IRBs may not wish to see the complete animal studies but may wish to see only the conclusions from those studies. . FDA has deleted the requirement of review of prior studies from § 56.109(a). FDA emphasizes that it would not expect an IRB to’ conduct a scientific review of a study except to the extent necessary for the IRB to assure itself that the human subjects will not be needlessly placed at risk. However, an IRB is free to review prior studies, in whole or through summaries. 72. On its own initiative, FDA has added § 56.109 (b) and (c) to these regulations to make explicit an IRB's obligations with regard to the informed consent materials that are to be given to human subjects by the investigator (see Part 50 published elsewhere in this issue of the Federal Register). Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 73. One comment suggested that FDA explicitly authorize IRBs to require that human subjects in studies involving greater than minimal risk be given a cooling off period in which to consider the information that they have been given as part of the informed consent process. FDA does not agree that there is a need to make such an explicit authorizatien. Implicit in the IRB's authority to review the information given to human subjects as part of informed consent is the authority to require that a specific period of time must lapse between when the information is presented to a potential subject, and when the subject must decide whether to participate in the investigation. 74. One comment suggested that informed consent materials be sent to FDA for approval before the start of a study. FDA disagrees with this suggestion. Because IRB review includes an assessment of the adequacy of informed consent, FDA does not believe that prior approval of informed consent materials by FDA is necessary for all of the clinical investigations submitted to the agency. However, FDA points out that it may review consent materials if they are submitted as part of an application for a research permit or during the course of an inspection of an IRB or clinical investigator. 75. Many comments objected to the requirement in the proposed regulations that the IRB notify the investigator or sponsor in writing that it has received the proposed investigation. A few comments stated that the actual paperwork used by an IRB to conduct its business is its own responsibility. Another comment, however, stated that both the investigator and the sponsor need to be informed of IRB activities, so both should be notified when the study is received for review. FDA agrees that this requirement should be deleted from the final regulation. The decision of the IRB to approve or not to approve the study, rather than the date of receipt of the study for review, is the information that must be communicated to the investigator (see § 56.109(d)). 76. Several comments suggested that an IRB has no relationship to the sponsor but only to the investigator and the institution. These comments suggested that, consequently, an IRB should not have to communicate at all with the sponsor. As explained in paragraph 5 of this preamble, FDA agrees with these comments and has deleted from § 56.109(d) the requirement that the IRB notify the sponsor. 77. Several comments objected to the requirement contained in the proposed regulations that an IRB must approve or disapprove an investigation as soon as possible after receipt of the proposal. These comments suggested that this requirement could be interpreted to mandate that special meetings be convened merely because a study was submitted or could lead to confusion about what “as soon as possible” meant. FDA agrees with these comments and has deleted this requirement from the final regulations. 78. One comment on proposed § 56.87 (now § 56.109(c)) stated that it was unclear how often an IRB should review research covered by these regulations. Section 56.109(c) explicitly states that review shall occur at intervals appropriate to the degree of risk but not less than once per year. 79. Several comments stated that in the provisions for continuing review of research by an IRB, FDA is attempting to delegate its authority to enforce the act to a group of private citizens. One comment stated that this provision would make the IRB into an investigator for FDA. These comments stated that the act does not grant FDA authority to make such a delegation. FDA rejects these comments. FDA is not delegating its authority to enforce the act. However, unanticipated risks are sometimes discovered during the course of an investigation, and new information sometimes comes to light showing that the risks in a study are not justified. Periodic review will assure that these risks are promptly brought to the IRB's attention and will provide extra protection to subjects. Consequently, FDA believes periodic review by an IRB is essential if an IRB is to adequately protect the rights and welfare of the human subjects involved in a clinical investigation. In paragraph 4 of this preamble, FDA already discussed its authority to adopt requirements that protect human subjects and there is no need to repeat that discussion here. 80. One comment suggested that these regulations should authorize IRBs to require investigators to provide human subjects with any new knowledge about a test article that is developed during the course of a study. FDA and HHS have both provided as an additional element of informed consent that significant new findings developed during the course of the research that may affect the human subject's willingness to continue to participate must be provided to the subjects. Section 50.25(b)(5) of FDA's 69 informed consent regulations published elsewhere in this issue of the Federal Register so provides for investigations that fall within the jurisdiction of FDA. The comment does not require any change in Part 56. 81. Several comments on proposed § 56.83 (now § 56.110) offered suggestions of different types of studies that should receive expedited review. FDA has carefully reviewed these comments, along with the comments on expedited review received by HHS, and has developed a list of procedures that, if they involve no more than minimal risk, can receive expedited review. Publication of the list is provided for in new § 56.110. FDA had decided that expedited review should play a much more important role under the final regulations then the agency originally proposed. After reviewing the comments, FDA believes that it is unnecessary to require that a full IRB meet to consider every study. For studies that present minimal risk, expedited review strikes the appropriate balance between protection of patient and minimizing the burdens imposed by these regulations. The expedited review list has been separated from the text of these regulations and is published as a notice elsewhere in this issue of the Federal Register. FDA views this list as being subject to change and encourages public comment on what additional classes of research should be included in this list. The agency will publish appropriate revisions of the list in the Federal Register as the need arises. FDA also points out that the Department is publishing a slightly different list, but the differences are caused by the fact that HHS funds many types of studies that do not fall within FDA jurisdiction. 82. One comment on proposed § 56.83 suggested that because some changes in protocol are universally accepted as minor, they should be listed in the regulations. Another comment suggested that “minor change” should be specified to avoid confusion. FDA disagrees with these suggestions. The scope of investigations regulated by FDA is so broad that FDA does not believe that it is feasible for the agency to list all of the different changes that might be considered to be minor. The agency advises that it considers that changes that result in increased risk to human subjects are not minor. However, FDA is unable to generalize about whether changes that apparently do not entail increased risk are minor. For example, the agency recognizes that a substantial increase in the number of human subjects above that originally approved by the IRB might be Federal Register / Vol. 46, No. 17 / Tuesday. January 27, 1981 / Rules and Regulations 8969 considered to be a minor change in some clinical studies but a major change in others. Therefore, FDA believes that itis up to the IRB to determine on a case-by-case basis whether a proposed change in a protocol is minor. The agency intends to provide additional guidance on this issue in the educational program that it will conduct with the Department. The comments are rejected. 83. On its own initiative, FDA has added new § 56.110(c), which matches the HHS requirement, so that all members of an IRB will be kept informed of the studies approved under the expedited review procedure. FDA believes that it is important that all IRB members know what studies are being approved at that institution. An IRB is free to adopt specific procedures for keeping individual members informed. New § 56.110(d), which is also identical to the HHS provision, permits FDA to suspend an IRB's use of expedited review when it becomes necessary to protect the rights or welfare of the human subjects involved in a study. Although it is unlikely that this provision will be used by the agency except in the most unusual circumstances, FDA believes that it is important, to protect human subjects, to retain this flexibility in the regulation. 84. Several comments on proposed § 56.86(a) (now § 56.111(a)(1)) objected to IRB review of research methods, stating that IRBs are not qualified to conduct such review, and that IRB's primary responsibility is not to determine the scientific merit of the study. FDA agrees with these comments. It has drafted § 56.111(a)(1) to focus on the risks to subjects. FDA reemphasizes that IRBs need not conduct scientific reviews of clinical investigations except to the extent necessary to determine that human subjects will not be exposed unnecessarily to risk. 85. One comment on proposed § 56.86(c) asserted that the meaning of the phrase “safest procedures” is unclear. FDA agrees and has revised § 56.111(a)(1)(i) to clarify the intent of the regulations with respect to risk. 86. One comment suggested that FDA adopt the HHS language on use of procedures being performed for diagnostic or treatment purposes, when these gpocedures are appropriate. FDA agrees with the comment and has adopted language in § 56.111(a)(1)(ii) to match the HHS requirement. The IRB should ensure that if procedures that are to be used in a study are already being used on a human subject for diagnostic or treatment purposes, the research procedures will be coordinated with the diagnostic or treatment procedures to avoid unnecessary repetition of the procedures. 87. Two comments suggested that proposed § 56.86(d) requiring that “risks to subjects be reasonable” and that “the importance of the knowledge to be gained should be considered” needed clarification. FDA has rewritten § 56.111(a)(2) to match the HHS requirement. FDA advises that in a placebo-controlled trial, for example, no immediate benefit to the placebo group would be anticipated, so that the risks to that group must be reasonable in relation to the importance of the knowledge to be gained in the research. The regulations now state that the IRB shall not consider possible long-range effects of the knowledge gained in the research as a - risk of conducting the research. Only those risks that relate to the particular human subjects involved in the investigation must be considered by the IRB. 88. Two comments on proposed § 56.86(b) (now § 56.111(a)(3)) stated that the term “equitable” was ambiguous and needed further explanation. FDA disagrees with the comments. Special subgroups of the population should not have to bear a disproportionate amount of the risks of research that benefits others. The subjects of an investigation should not come from any particular group simply because it is convenient for the investigator to draw from that group. Scientific design and alternate human subject populations should be considered in assessing whether the selection of subjects is “equitable.” For example, the IRB should require that the investigator justify the proposed involvement in the study of hospitalized patients, of other institutionalized persons, or of disproportionate numbers of racial or ethnic minorities or persons of low socioeconomic status. The comments are rejected, and § 56.111(a)(3) is published as proposed. 89. One comment questioned the meaning of the requirement in proposed § 56.86(g) (now § 56.111(a)(6)) that, where appropriate, data be monitored. Where appropriate, IRB's should require that the research plan make adequate provision for monitoring the data collected to ensure the safety of human subjects. This procedure might be an appropriate requirement in large scale clinical trials or in studies with a high degree of risk. The IRB may require the use of data safety monitoring boards in order to meet the ~»quirements of this provision. Thus, if it uecomes clear that 70 risks are greater than anticipated, or that the benefits do not justify the risks of the research, the IRB is informed and can act on the information. This provision matches the HHS requirement. 90. One comment suggested that each IRB should set out guidelines for determining at what point in each experiment one treatment is shown to be safer and more effective than alternate treatments or no treatment. FDA disagrees with this suggestion. IRBs generally will not have the scientific consistence to make such a judgment. The determination whether and at what point in an investigation a test article has been shown to be safe and effective in accordance with th. requirements of the act is a determination that must be made by the investigator, the sponsor, and, ultimately, FDA. The comment does not require any change in the regulations. 91. One comment stated that the regulations should protect vulnerable groups, such as minorities. The comment stated that neither the HHS nor the FDA proposed requirement was sufficient in this regard. FDA has rewritten § 56.111(b) (and HHS has rewritten the corresponding provision in its regulations) to require that the IRB assure that appropriate additional protections are provided if the human subjects are from a vulnerable group. 92. One comment stated that before exposing human subjects to risk, an IRB should be required to make a determination that treatment is available for injuries that may arise from the research. FDA disagrees in part with this comment. Section 50.25(a)(6) of the informed consent regulations requires that the subject be told if treatment for injuries is available. It should then be up to the subject to decide if he or she wishes to participate in the study. However, FDA agrees that the IRB should determine whether the investigator has made adequate provision for emergency medical care, if it appears that such emergency care may become necessary during the course of the investigation. 93. One comment suggested that IRB's should follow human subjects after completion of the study, unless the investigator can show that it is not necessary to do so. FDA disagrees and rejects the suggestion. If anyone should follow subjects after completion of the study, it is the investigator or the sponsor. IRBs are generally not in a position to follow human subjects. If an IRB believes that it is necessary to do so to protect the subjects, it can require as part of the 8970 Federal Register / Vol. 46, No. 17 | Tuesday, January 27, 1981 / Rules and Regulations protocol that the investigator follow subjects after the completion of the study. 94. Several comments on proposed § 56.8 stated that a means is needed for an investigator, a sponsor, or an institution to appeal an IRB ruling. FDA has renumbered § 56.8 as § 56.112 in the final regulations to conform with those issued by HHS. The National Commission did not recommend that there be a mechanism for appeal from IRB determinations. However, there is nothing in § 56.112 that would prevent an institution from formulating an appeals mechanism, so long as the final ruling body is an IRB that satisfies the requirements of Part 56. Appeal of an adverse IRB determination to other institutional bodies that do not meet the requirements of Part 56 is not allowed under the regulation. 95. One comment questioned why officials at an institution could overrule IRB approval but not IRB disapproval of a study. Another comment stated that § 56.8 might abrogate the authority of the head of and institution. Review and approval of a proposed clinical investigation by an IRB should not preclude a subsequent decision by the institution itself to reject the investigation. Officials of the institution take into account factors other than ethical acceptability and patient protection in deciding whether to authorize a particular investigation. For example, IRBs do not make decisions regarding the priority of funding studies or policy on whether to conduct a certain type of study at the institution. Therefore, FDA believes that institutional officials should have the authority to overrule an IRB's decision to approve a study. At the same time, FDA has decided not to authorize an institution to overrule and IRB'’s rejection of a study. If an institution had that authority, and IRB would become merely advisory, and its responsibilities would be eliminated. The comments do not warrant any change in the regulations. 96. Several comments on proposed § 56.92 stated that the sponsor should be given notice of a decision by an IRB either to suspend or to terminate approval of a clinical investigation. FDA rejects these comments for the reasons explained in paragraphs 5 and 76 of this preamble. 97. One comment on proposed § 56.92 (now § 56.113) stated that once FDA has acted on an application for a research permit, it would be unfair to allow an IRB to suspend its approval of a particular clinical investigation. FDA disagrees with the comment. An IRB focuses on different factors in its review of a proposed investigation than the agency considers in deciding whether to grant a research permit. Consequently, approval of a proposed investigation by either an IRB or FDA does not preclude the other entity from suspending or terminating the approval of the investigation at a later date. 98. FDA has deleted from the final regulations the criteria for disapproval and suspension or termination of approval of a clinical investigation that were proposed in § 56.90. Section 56.113 now states that an IRB may suspend or terminate its approval of research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected serious harm to subjects. This section now conforms to the HHS provision. The agency believes that the section, as revised, adequately specifies general criteria for the suspension or termination of the IRB's approval of an ongoing study. The section also requires that the IRB promptly notify FDA of its actions. Where necessary, FDA can, in turn, take any steps necessary to assure that the subjects are protected. 99. Several comments objected to the requirement in proposed § 56.90 that, after suspending or terminating approval of an investigation, the IRB make recommendations to FDA about the care of the human subjects of that investigation. The comments argued that it was the responsibility of a physician, and not an IRB, to make such recommendations. FDA agrees with the comments and has deleted this requirement from the final regulations. The agency believes that this requirement inappropriately imposed medical responsibilities on an IRB. The responsibility for human subjects in a study for which IRB approval has been suspended or terminated is more properly shared by the clinical investigator, the institution, and the sponsor. 100. Section 56.114 in the final regulations was proposed as § 56.9. That section has been rewritten for clarity but there is no change in its intent. It is now consistent with the corresponding provision in the HHS regulations. The purpose of this section is to assure IRBs that FDA will accept reasonable methods of joint review. Thus, an IRB need not re-review a study that has already received approval from another IRB, unless it chooses to do so. However, FDA advises that the requirement for the IRB to be sensitive to such factors as community attitudes (§ 56.107(a)) is applicable to § 56.114. The IRB's records must include, either in 71 the minutes or elsewhere, documentation of agreement that a specific study will be reviewed cooperatively. 101. Two comments on proposed § 56.185 (now § 56.115) suggested that the records of an IRB should be maintained by the institution rather than by the IRB. FDA agrees that, in some cases, it may be more feasible for an institution to maintain the records of an IRB. Consequently, FDA has rewritten § 56.115(a) to provide that either the institution or the IRB may be responsible for preparing and maintaining adequate records of IRB activities. 102. One comment stated that it is unreasonable to require IRBs to keep records because they lack adequate. storage facilities. FDA advises that if an institution delegates the responsibility to maintain records to an IRB, it must also provide the IRB with adequate facilities to do so. The comment does not justify any change in § 56.115. 103. One comment suggested that proposed § 56.185 should spell out every record that the agency wants an IRB to ‘keep. The comment stated that the proposed requirements were not sufficiently detailed. FDA disagrees with this comment. Section 56.115(a) in the final regulations sets forth the minimum records that an institution or an IRB must keep to document the activities of the IRB. The IRB or the institution is free to maintain additional records if it chooses. However, FDA does not believe that any more extensive recordkeeping by the IRB or the institution is necessary. 104. Five comments objected that the documentation FDA proposed to require was an unnecessary burden on IRBs. These comments argued that the proposed documentation is not necessary to protect the rights and welfare of human subjects. FDA rejects these comments. The agency believes that the records that an IRB or an institution must maintain under § 56.115(a) provide significant evidence of whether the procedures utilized by the IRB are adequately protecting the human subjects of the investigations that the IRB is reviewing. For example, when an IRB approves the use of a "short form,” for informed consent as provided in § 50.27(b)(2), FDA would expect the IRB to retain in its files a copy of the written summary of the oral presentation of informed consent information that is given to human subjects in the clinical investigation. Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8971 105. Several comments stated that proposed § 56.185(d) (now § 56.115(a)(2)), which requires that the minutes of an IRB meeting include a summary of the discussion of substantive issues, is not reasonable. FDA agrees.in part with the comments. The National Commission recommended, and FDA agrees, that it is important to maintain detailed minutes of IRB meetings. However, FDA decided to reduce the burden on IRBs by requiring that the minutes contain: (1) A basis for IRB action only when the research is disapproved or requires modification; and (2) A written summary of the IRB discussion and resolution only when it involves controversial issues. FDA does not believe that summarizing the discussions of controverted issues in the minutes will have a chilling effect on those discussions because FDA does not require the identification of specific individuals with specific comments in the summaries. 106. One comment suggested that minutes could be kept by an audio tape recording, which would be complete and more accurate than any summary. FDA agrees that a tape recording is a more complete record of the meeting. However, FDA advises that retention of complete recordings of meetings does not relieve an IRB of its obligation under § 56.115(a)(2) to keep at least brief written summaries of its meetings that must be available for inspection. 107. A few comments stated that the voting records of individual members should not be kept. The comments stated that this requirement would have a chilling effect on IRB members. FDA believes the requirement has been misunderstood. Proposed § 56.185 did not include such a requirement nor does § 56.115 of the final regulations. Section 56.115(a)(2) requires only that the number of members voting for and against a study be kept. While the members attending the meeting would also be recorded in the minutes, individual voting records are not required. 108. Three comments objected to any requirement that voting records be kept. FDA disagrees with these comments. The voting records must be included in the IRB records for FDA to document that a majority of those members present voted in favor of conducting a particular study at that institution. 109. One comment suggested that individual voting records of IRB members should be submitted to FDA, so that even if a member objected to a study but was overruled by the other members, the objection would come to the attention of FDA. The agency could then take appropriate action. FDA disagrees with this suggestion. Section 56.115(a)(2) already requires that votes of an IRB be recorded, and that any controverted items discussed be summarized in the minutes of IRB meetings. Consequently, there is no need to record individual members’ voting records. In addition, except in the most extreme circumstances, FDA does not believe that it should second guess a properly constituted and well- functioning IRB on the ethical acceptability of a study. 110. Several comments objected that the records about the members of an IRB that were required in the proposed regulations were overly burdensome. The recordkeeping requirements in § 56.115(a)(5) have been limited to provide that only information that necessarily bears on the IRB's impartiality and expertise must be maintained. 111. One comment stated that the record retention time required by proposed § 56.195 (now § 56.115(b)) disregarded the possibility that problems might not appear for 20 to 30 years. This comment suggested that the regulations should be changed to require that records be kept 7 years for adults and 25 years for minors and pregnant women. Although an institution is free to adopt a longer requirement, FDA has decided to match the HHS provision that records must be kept a minimum of 3 years. The agency believes that the 3- year requirement strikes an appropriate balance between the need to retain records and the administrative burdens involved. Although some problems may not become apparent for 20 years or more, those instances are so rare that the agency concludes that they do not justify an absolute requirement that all IRB records be retained for such an extended period of time. In addition, FDA reviews IRBs on a 2-year cycle. Thus, the 3-year requirement will ensure that all of the important records of the IRB will be available for FDA review. If, however, an institution or an IRB believes that in a particular study it would be appropriate to retain the IRB records longer to protect the human subjects involved, the institution or the IRB is of course free to do so. 112. One comment stated that the period that IRBs or institutions are required to retain records should be consistent with the record retention requirements in the proposed regulations regarding obligations of sponsors and monitors of clinical investigations and the proposed 72 regulations regarding obligations of clinical investigators. FDA rejects this comment. The records covered by these regulations are quite different than those that are proposed to be required under the sponsor-monitor and clinical investigator regulations. Therefore, the agency believes that the three sets of regulations need not be consistent on this point. Fhe agency believes it is more appropriate to keep § 56.115(b) consistent with the corresponding provision in the HHS regulations. FDA believes that the 3-year period satisfies the needs of the agency while not imposing an unreasonable administrative burden on IRBs or their parent institutions. 113. A few comments suggested that records could be maintained by microfiche, microfilm, or other similar photographic method, if the records are properly verified as being accurate reproductions of the original records. FDA agrees with these comments. There is nothing in these regulations that would prevent records from being reproduced and retained in this manner. 114. Many comments objected to the requirement in proposed § 56.15(a) that FDA be allowed to copy patient medical records during an IRB inspection. Most comments stated that IRBs do not have individual patient records. Other comments questioned whether FDA was requiring IRBs to obtain those records. Many comments stated that there were problems with confidentiality if IRBs were to obtain individual patient medical records and maintain them in the files for 5 years after completion of a clinical investigation to which the IRB records relate. Many comments stated that if this information is needed by the agency, it is available from either the sponsor or clinical investigator and should be obtained through proper legal channels from those persons. In response to the comments, FDA has deleted from the final regulations any requirement that patient records be maintained by an IRB or that patient records be made available to FDA during an inspection of an IRB. If it becomes necessary for FDA to see the medical records of individual patients, adequate authority exists under the act for FDA to obtain those records from the clinical investigator or sponsor. Also, because IRBs would rarely have individual medical records, FDA wants to assure IRBs that there is no need to obtain individual patient records to comply with the requirements of § 56.115. 115. One comment suggested that IRBs do not have to submit to inspection by 8972 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations FDA because inspections require warrants. FDA rejects this comment and declines to change § 56.115(b) to respond to the comment. As discussed in the preamble to the 1978 proposal, FDA has authority to inspect an IRB, in many cases, without the IRB's permission. Under section 704(a) of the act (21 U.S.C. 374(a)), FDA may inspect establishments in which certain drugs or devices are processed or held and may examine research data that would be subject to reporting and inspection under sections 505(i) or (j), 507(d) or (g). 519, or 520(g) of the act. Under section 704(e) (21 U.S.C. 374(e)), FDA may inspect certain required records concerning devices. Thus, most sponsors and many investigators of investigational new drugs and investigational devices, and the institutions at which such studies are conducted, are subject to FDA inspection whether they consent or not. FDA advises that if an IRB refuses to permit inspection, FDA may, under § 56.115(c), reject the studies conducted under review of that IRB from supporting an application for a research of marketing permit, or the agency may seek a warrant to inspect. However, there is no requirement that FDA obtain a warrant before inspection. 116. Two comments stated that inspections were too long, and that FDA should provide more detail about how inspections are to be conducted. FDA has recently mailed an information sheet on the inspection process to the approximately 1,500 individuals, institutions, and organizations that have communicated with the agency previously about IRB's. FDA also sponsored a workshop on IRB compliance activities on November 7, 1980 (announced in the Federal Register of September 26, 1980; 45 FR 63929). The agency will distribute the transcript of the workshop to interested parties; will evaluate the workshop as well as written comments on it; and will then decide whether to make modifications in the current inspection program. The transcript and the information sheet are on file under Docket No. 80N-0399 in FDA's Dockets Management Branch (HFA-305), Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857. The transcript and any comments on it may be seen in that office between 9 a.m. and 4 p.m., Monday through Friday. The comments do not require any change in the regulation. 117. A few comments on proposed § 56.15(b) (now § 56.115(c)) stated that FDA has no authority to refuse to consider a clinical investigation in support of an application for a research or marketing permit if the IRB refuses to allow inspection by FDA officials. Some of the comments stated that FDA should have the burden of showing that the validity of the study is adversely affected by the IRB's refusal to allow inspection. As stated in the preamble to the 1978 proposal, if follows from the authority to issue regulations establishing standards for IRBs that FDA also has the authority to prescribe the terms on which it will accept data generated in a clinical investigation reviewed by an IRB. Therefore, the agency may refuse to consider data from a clinical investigation in support of an application for a research or marketing permit, unless the IRB that reviewed the investigation consents to an inspection by FDA. The connection between an IRB's refusal to permit an inspection and the agency's refusal to consider data is clear. FDA is charged by statute with the obligation of ensuring the protection of the rights and welfare of the human subjects who participate in clincial investigations involving articles subject to sections 505(i), 507(d), and 520(g) of the act. In performance of that obligation, the agency has adopted these regulations requiring IRB review. However, FDA has a concomitant obligation to ensure that these regulations are observed. FDA must verify that IRBs are operating in accordance with these regulations, and it must have access to the IRBs and their records to do so. When an IRB refuses to permit FDA to inspect its records, FDA cannot verify that the IRB is properly constituted and operating correctly. Consequently, the agency cannot be assured that human subjects have been given the protection that the IRB mechanism is intended to afford, and it may be appropriate for the agency to refuse to accept the data from the studies that the IRB has reviewed. However, FDA points out two additional facts: First, before rejecting the data from a clinical investigation, the agency will review each study to determine whether the risks created by requiring the study to be re-done outweigh the benefits of rejecting the data. Second, FDA expects that it will be a very rare occurrence for an IRB to refuse to allow an inspection by FDA personnel. FDA has found that the vast majority of IRBs are cooperative at the time of inspection. The comments do not justify any change in § 56.115(c) from the regulation as proposed. 118. A few comments stated that it is unfair for the agency to “punish” the 73 sponsor of a study by refusing to accept the data from a study that was reviewed by an IRB that refused to allow FDA inspection. FDA has already explained in paragraphs 46 and 117 above that it will not automatically reject data. FDA also points out that, with these regulations (see § 56.120 et seq.), the agency has available more direct administrative actions against institutions and IRBs for noncompliance. Thus, the agency may apply sanctions directly against the entity that refused inspection. However, there may be occasions when it would be appropriate for the agency to also refuse to accept data, and FDA has reserved that option. 119. FDA received numerous comments criticizing the provisions of Subpart K of the proposed regulations (now Subpart E) relating to the disqualification of IRB's. In response, FDA has simplified and streamlined Subpart E of the final regulations. FDA has also shifted the focus of the administrative sanctions for noncompliance from the IRB to the institution. The agency recognizes that an IRB is created by and is responsible to the institution. Consequently, it is the duty of the institution to assure that its IRB meets the obligations imposed by Federal statute and regulations. FDA believes that when an IRB is found not to be in compliance with the regulations, and the institution to which the IRB is responsible does not take positive steps to correct the deficiencies, the appropriate response is to take action against the institution. However, there are exceptions to this rule. If an IRB is not directly responsible to a single institution, e.g., where an IRB reviews clinical investigations for more than one institution, and the IRB is found not to be in compliance with these regulations, FDA believes it would be appropriate to take action directly against the IRB. A second exception is the situation in which an IRB is one of several directly responsible to a single institution, e.g., where an IRB reviews certain kinds of clinical investigations at the institution, and where an IRB is found not to be in compliance with these regulations. FDA believes that it may not be appropriate to disqualify all the IRBs at the institution because one is out of compliance. Therefore, FDA will take action against the individual IRB, and not against the institution, when the institution has taken all appropriate steps within its power to correct the IRB's deficiencies, but the IRB remains out of compliance. Section 56.120(c) reflects the agency's shift in focus to the institution. However, the regulation also provides that FDA Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8973 may take action against an IRB or a component of the parent institution if the agency determines that it is appropriate to do so under the facts of the particular case. 120. Several comments on proposed § 56.202(c) suggested that the lesser regulatory actions that were referred to in the proposed regulations should be listed. FDA accepts these comments. Section 56.120(b) has been added to the final rule to set forth the lesser administrative actions that the agency may take if FDA finds deficiencies in the operation of an IRB and to describe the circumstances in which these lesser administrative actions may be used by the agency. 121. Two comments stated that notification of other Federal agencies of a possible IRB disqualification, as provided in the proposed regulations, would presume that IRB is guilty before it had an opportunity for a hearing and would make it difficult to recruit members. FDA rejects these comments. In most instances, FDA will not advise other Federal or State agencies of deficiencies in the operation of an IRB, unless the agency decides to disqualify the IRB or its parent institution. However, in § 56.120(b)(4), the agency has reserved the right to do so if it finds serious deficiencies in the operation of an IRB during an inspection. In addition, FDA, as an agency of HHS, will share knowledge gained from inspections with other agencies within the Department, including the National Institutes of Health. 122. A few comments stated that FDA should exhaust all other remedies before disqualification. Other comments suggested that the IRB should have an opportunity to correct or refute the deficiencies found by FDA. Section 56.121(a) of the final regulations provides that disqualification proceedings will not be instituted by the agency, unless the agency determines that grounds for holding a hearing exist, and the institution or the IRB has failed to take adequate steps to correct the deficiencies listed in the letter sent by the agency under § 56.120(a). 123. One comment stated that if FDA decided to retain the disqualification mechanism, the regulations should clearly state that disqualification will be used only in the most extreme cases and not on a routine basis. FDA agrees with this comment. Disqualification will be used by the agency only when it is necessary to protect the rights and welfare of human subjects, and after the institution or IRB has refused or has continuously failed to comply with these regulations. FDA hopes never to use this sanction, and, based on the demonstrated willingness of institutions to correct deficiencies in their IRBs, the agency does not expect to use this sanction except in the most extraordinary circumstances. However, the agency believes that it is important to retain the option to disqualify an institution or an IRB if it becomes necessary to do so to protect human subjects. 124. Several comments pointed out that nowhere in the act is disqualification mentioned. These comments consequently concluded that FDA lacks the authority to disqualify IRBs. FDA disagrees and rejects these comments. FDA has previously discussed its authority to promulgate these regulations (see paragraphs 4 and 117 of this preamble). Inherent in that authority is the authority to enforce these regulations. Disqualification is an essential element of the enforcement mechanism adopted by the agency. Without such an enforcement mechanism, compliance with these regulations would be voluntary, and these regulations would be nothing more than guidelines that would not adequately protect human subjects. 125. A few comments suggested that disqualification of an IRB or an institution would only hurt the sponsor, because studies reviewed by the IRB would not be accepted by FDA. The comments stated that sponsors exert little control over IRBs and have little opportunity to ensure that IRBs comply with these regulations. FDA believes that it has responded to these concerns in paragraph 118 of this preamble. FDA would suggest that a sponsor assure itself, through the clinical investigator, that the IRB that reviews the clinical investigation protocol meets FDA requirements. 126. Several comments suggested that FDA should send notice of the initiation of proceedings to disqualify an IRB or its parent institution to all investigators and sponsors whose studies are under the review of the IRB. FDA rejects this suggestion. FDA believes it would be an unreasonable expenditure of agency resources for it to send out such notices prior to a hearing. While a great deal of effort would have to be expended in putting together a list of sponsors and investigators involved with the institution and in sending them notices, the reason for the notice could be easily mooted if the IRB comes into compliance, or if FDA decides against disqualification. The agency believes that its resources are better spent after the hearing, notifying all interested 74 parties it can identify that the agency has decided to disqualify the institution or the IRB. FDA advises that this notification may require publication of the disqualification decision in the Federal Register. 127. One comment suggested that an additional provision should be inserted into the final regulations to allow the IRB 30 to 60 days to prepare for the hearing, except where the safety of the human subjects requires immediate action. FDA rejects this suggestion. Hearings under these regulations will be conducted in accordance with the requirements for a regulatory hearing before the FDA set forth in 21 CFR Part 16. Adequate time to prepare for a regulatory hearing is afforded under those regulations. 128. Several comments objected to the grounds for disqualification set forth in proposed § 56.202 (now § 56.121(b)). One comment argued that a blanket statement that disqualification could be based on a failure to comply with any regulations regarding IRBs would open the door to harassment and abuse of this system. Two comments stated that although it would be appropriate to disqualify an IRB if its noncompliance adversely affected the rights and safety of human subjects, it made no sense to disqualify an IRB because its noncompliance affected the validity of a study. FDA has revised the grounds in § 56.121(b) for disqualification. To assure that the remedy is invoked only when appropriate, § 56.121(b)(1) provides that an IRB's failure to comply must be repeated to be grounds for disqualification (see paragraph 129). Noncompliance that adversely affects the validity of an investigation is no longer a basis for disqualification (§ 56.121(b)(2)). 129. Two comments stated that failure to comply with these regulations should not trigger disqualification. One of these comments stated that FDA should have to show a willful intent not to comply. FDA disagrees with these comments. Although disqualification will not be used lightly, the agency should not have to show that the IRB or the institution did nof intend to comply with the regulations. Repeated failure to comply may or may not indicate a willful intent, but it is sufficient to trigger disqualification. Section 56.121(b)(1) of the final regulations so provides. The important point is that the failure to comply is repeated and not an isolated event, Of course, a flat refusal to comply with these regulations could also trigger disqualification. 8974 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 130. Three comments stated that the regulations should provide that the agency will advise a sponsor of the disqualification of an IRB that is reviewing studies of that sponsor. FDA accepts this comment and has revised § 56.121(c) to so provide. The agency will notify any sponsor of which it is aware that has had studies reviewed by the disqualified IRB. This notification may require publication of the disqualification decision in the Federal Register. 131. Several comments questioned whether an institution has to replace its IRB after the IRB is disqualified. Because FDA has shifted the focus of these regulations from the IRB to the institution, disqualification will usually be directed at the institution itself. In order for the IRB of a disqualified institution to be in compliance with these regulations, the institution would have to be reinstated. The situation is somewhat different for institutions with more than one IRB or for institutions whose studies are reviewed by an IRB that serves several institutions. As discussed in paragraph 119 above, FDA may disqualify the IRB rather than the institution in such situations. Those institutions are then free to establish a new IRB, to replace the disqualified IRB, but FDA would not require them to do 80. An institution with several IRBs may choose to have another IRB that is competent to assume the responsibilities of the disqualified IRB. For example, the institution would assign an IRB that normally reviews drug studies the responsibility to assume the review of drug studies that were previously under the review of a disqualified IRB. However, FDA would find unacceptable the assignment of those duties to an IRB that normally reviews behavioral research, whose members lack the professional competence necessary to review drug studies. 132. Several comments stated that investigations reviewed by an IRB before.disqualification should not automatically be presumed to be unacceptable. A few stated that only the particular studies where deficiencies were found should be unacceptable to FDA. FDA disagrees in part with the comments. FDA believes that if it is necessary to disqualify an institution or an IRB, the agency cannot be assured that any study conducted at that institution or reviewed by that IRB provided for the rights and welfare of the human subjects. Because disqualification will not be undertaken lightly, the deficiencies that required disqualification are likely to be so pervasive that they had an effect on mere than one study. Therefore, FDA believes that any study reviewed by a disqualified IRB or conducted at a disqualified institution is suspect. However, as stated previously in paragraph 46 of this preamble, the agency will review the studies conducted as a disqualified institution or reviewed by a disqualified IRB to decide on a case-by-case basis whether to reject the data. 133. One comment expressed concern that confidential information would be disclosed to the public during the disqualification process. A few comments stated that no data, clinical reports, or records regarding particular studies ought to be disclosed. Section 56.122 provides that the determination of the agency to disqualify an institution and the administrative record regarding that determination are disclosable to the public under the agency's public information regulations. Under § 20.61 (21 CFR 20.61), any trade secret or confidential commercial information in the administrative record is exempt from disclosure. Under § 20.63, medical and similar files, the disclosure of which would constitute a clearly unwarranted invasion of personal privacy, are also exempt. Therefore, there is no basis for concern that confidential information will be disclosed, and the comments are rejected. 134. One comment stated that adverse publicity caused by disqualification would make recruitment for IRBs very difficult. FDA recognizes that some adverse publicity may arise from a disqualification of an IRB or an institution. However, because IRBs play such an important role in the protection of human subjects, and because disqualification will be undertaken only when there has been a serious disregard by an IRB or an institution of its responsibilities, FDA believes it is appropriate to retain the disqualification mechanism and the provisions allowing the agency to publicly disclose the fact of the disqualification at the discretion of the agency. 135. One comment stated that because an IRB is created to serve an institution, any disqualification should be of the institution, and the burden of reinstatement should be placed upon that institution. FDA generally agrees with these comments and, except for the situations discussed in paragraph 119 of this preamble, has changed the focus of disqualification and reinstatement to the institution. To be reinstated pursuant to § 56.123, an institution must adequately demonstrate to FDA how the concerned IRB will comply with these regulations. FDA does not believe that it should spell out exactly how the institution should demonstrate how compliance with these regulations will be assured, because institutions may choose different methods of assuring such compliance. 136. Three comments stated that additional sanctions against individual members of an IRB would make it difficult to recruit members to serve on any IRB. FDA disagrees with these comments. Other sanctions will be used in cases where disqualification of the institution or the IRB might not be the appropriate action, e.g., where individual.nembers of an IRB submit false information to the Federal Government, which is a criminal offense. The agency does not believe that qualified people will be deterred from serving on an IRB by the fact that they will be held accountable if they break the law. 137. One comment stated that in light of the other sanctions referred to in proposed § 56.215 (now § 56.124) disqualifications would be superfluous. FDA disagrees with this comment. As stated in paragraph 123 of this preamble, while FDA expects to use disqualification only rarely, it is important that the agency retain the option to use it if the need arises. In some situations, disqualification may be a more appropriate remedy than criminal sanctions. In other situations, it may be necessary to institute disqualification proceedings in conjunction with criminal proceedings to assure that human subjects will be adequately protected. 138. FDA is adopting the conforming amendments as proposed. However, in accordance with the principles of common sense, the amendments proposed separately but applicable both to Part 50 and Part 56 have been combined and are included with FDA's informed consent final rule published elsewhere in this issue of the Federal Register. 139. On its own initiative, the agency is also adopting amendments to the IDE regulations (21 CFR Part 812) to conform them to Part 56. The IDE regulations were promulgated by FDA after the August 14, 1979 reproposal of these regulations. However, the agency has decided not to amend the IDE regulations for intraocular lenses (21 CFR Part 813). The ongoing intraocular lens investigations are exempt from the requirements established by these regulations under § 56.104(a). Therefore, it would not be appropriate to modify Part 813 at this time. In addition, the agency is revising Forms FD-1571, 1572, and 1573 in 21 CFR Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8975 312.1(a) to conform them to these regulations. FDA stated in the 1978 proposal (43 FR 35198) that it would revise these forms at the time the final IRB regulations were adopted. Therefore, under the Federal Food, Drug, and Cosmetic Act (secs. 406, 408. 409, 501, 502, 503, 505, 506, 507, 510, 513- 516, 518-520, 701(a), 706, and 801, 52 Stat. 1049-1054 as amended, 1055, 1058 as amended, 55 Stat. 851 as amended, 59 Stat. 463 as amended, 68 Stat. 511-518 as amended, 72 Stat. 1785-1788 as amended, 74 Stat. 399-407 as amended. 76 Stat. 794-795 as amended, 90 Stat. 540-546, 560, 562-574 (21 U.S.C. 346, 346a, 348, 351, 352, 353, 355, 356, 357, 360, 360c-360f, 360h-360j, 371(a), 376, and 381)) and the Public Health Service Act (secs. 215, 351, 354-360F, 58 Stat. 690, 702 as amended, 82 Stat. 1173-1186 as amended (42 U.S.C. 216, 241, 262, 263b- 263n)) and under authority delegated to the Commissioner of Food and Drugs (21 CFR 5.1), Chapter I of Title 21 of the Code of Federal Regulations is amended as follows: 2. By adding new Part 56, to read as follows: PART 56—INSTITUTIONAL REVIEW BOARDS Subpart A—General Sec. 56.101 Scope. 56.102 Definitions. 56.103 Circumstances in which IRB review is required. 56.104 Exemptions from IRB requirement. 56.105 Waiver of IRB requirement. Subpart B—Organization and Personnel 56.107 IRB membership. Subpart C—IRB Functions and Operations 56.108 IRB functions and operations. 56.109 IRB review of research. 56.110 Expedited review procedures for certain kinds bf research involving no more than minimal risk, and for minor changes in approved research. 56.111 Criteria for IRB approval of research. 56.112 Review by institution. 56.113 Suspension or termination of IRB approval of research. Sec. 56.114 Cooperative research. Subpart D—Records and Reports 56.115 IRB records. Subpart E—Administrative Action for Noncompliance 56.120 Lesser administrative actions. 56.121 Disqualification of an IRB or an institution. 56.122 Public disclosure of information regarding revocation. 56.123 Reinstatement of an IRB or an institution. 56.124 Actions alternative or additional to disqualification. Authority: Secs. 406, 408, 409, 501, 502, 503. 505, 506, 507, 510, 513-516, 518-520, 701(a). 706, and 801, Pub. L. 717, 52 Stat. 1049-1054 as amended, 1055, 1058 as amended, 55 Stat. 851 as amended, 59 Stat. 463 as amended, 68 Stat. 511-518 as amended, 72 Stat. 1785-1788 as amended. 74 Stat. 399-407 as amended, 76 Stat. 794-795 as amended, 90 Stat. 540-546, 560, 562-574 (21 U.S.C. 346, 346a, 348, 351, 352, 353, 355, 356, 357, 360, 360c-360f, 360h-360j, 371(a), 376, and 381), secs. 215, 301, 351, 354 360f, Pub. L. 410, 58 Stat. 690, 702 as amended, 82 Stat. 1173-1186 as amended (42 U.S.C. 216, 241, 262, 263b-263n). Subpart A—General Provisions § 56.101 Scope. (a) This part contains the general standards for the composition, operation, and responsibility of an Institutional Review Board (IRB) that reviews clinical investigations regulated by the Food and Drug Administration under sections 505(i), 507(d), and 520(g) of the act, as well as clinical investigations that support applications for research or marketing permits for products regulated by the Food and Drug Administration, including food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products. Compliance with this part is intended to protect the rights and welfare of human subjects involved in such investigations. (b) References in this.part to regulatory sections of the Code of Federal Regulations are to Chapter I of Title 21, unless otherwise noted. § 56.102 Definitions. As used in this part: (a) “Act” means the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201-902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 321-392)). (b) “Application for research or marketing permit” includes: (1) A color additive petition, described in Part 71. (2) Data and information regarding a substance submitted as part of the procedures for establishing that a substance is generally recognized as 76 safe for a use which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food, described in § 170.35. (3) A food additive petition, described in Part 171. (4) Data and information regarding a food additive submitted as part of the procedures regarding food additives permitted to be used on an interim basis pending additional study, described in § 180.1. (5) Data and information regarding a substance submitted as part of the procedures for establishing a tolerance for unavoidable contaminants in food and food-packaging materials, described in section 406 of the act. (8) A “Notice of Claimed Investigational Exemption for a New Drug” described in Part 312. (7) A new drug application, described in Part 314. (8) Data and information regarding the bioavailability or bioequivalence of drugs for human use submitted as part of the procedures for issuing, amending, or repealing a bioequivalence requirement, described in Part 320. (9) Data and information regarding an over-the-counter drug for human use submitted as part of the procedures for classifying such drugs as generally recognized as safe and effective and not misbranded, described in Part 330. (10) Data and information regarding an antibiotic drug submitted as part of the procedures for issuing, amending, or repealing regulations for such drugs, described in Part 430. (11) An application for a biological product license, described in Part 601. (12) Data and information regarding a biological product submitted as part of the procedures for determining that licensed biological products are safe and effective and not misbranded, as described in Part 601. (13) An “Application for an Investigational Device Exemption,” described in Parts 812 and 813. (14) Data and information regarding a medical device for human use submitted as part of the procedures for classifying such devices, described in Part 860. (15) Data and information regarding a medical device for human use submitted as part of the procedures for establishing, amending, or repealing a standard for such device, described in Part 861. (16) An application for premarket approval of a medical device for human use, described in section 515 of the act. (17) A product development protocol for a medical device for human use, described in section 515 of the act. 8976 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations (18) Data and information regarding an electronic product submitted as part of the procedures for establishing, amending, or repealing a standard for such products, described in section 358 of the Public Health Service Act. (19) Data and information regarding an electronic product submitted as part of the procedures for obtaining a variance from any electronic product performance standard. as described in § 1010.4. (20) Data and information regarding an electronic product submitted as part of the procedures for granting, amending, or extending an exemption from a radiation safety performance standard, as described in § 1010.5. (21) Data and information regarding an electronic product submitted as part of the procedures for obtaining an exemption from notification of a radiation safety defect or failure of compliance with a radiation safety performance standard, described in Subpart D of Part 1003. (c) “Clinical investigation" means any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the Food and Drug Administration under section 505(i), 507(d), or 520(g) of the act, or need not meet the requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be later submitted to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit. The term does not include experiments that must meet the provisions of Part 58, regarding nonclinical laboratory studies. The terms “research,” “clinical research,” “clinical study,” “study,” and “clinical investigation” are deemed to be synonymous for purposes of this part. (d) “Emergency use” means the use of a test article on a human subject in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval. (e) “Human subject” means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient. (f) “Institution” means any public or private entity or agency (including Federal, State, and other agencies). The term “facility” as used in section 520(g) of the act is deemed to be synonymous with the term “institution” for purposes of this part. (g) “Institutional Review Board (IRB)" means any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects. The primary purpose of such review is to assure the protection of the rights and welfare of the human subjects. The term has the same meaning as the phrase “institutional review committee” as used in section 520(g) of the act. (h) “Investigator” means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject) or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team. (i) “Minimal risk" means that the risks of harm anticipated in the proposed research are not greater, considering probability and magnitude, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. (j) “Sponsor means a person or other entity that initiates a clinical investigation, but that does not actually conduct the investigation, i.e., the test article is administered or dispensed to, or used involving, a subject under the immediate direction of another individual. A person other than an individual (e.g., a corporation or agency) that uses one or more of its own employees to conduct an investigation that it has initiated is considered to be a sponsor (not a sponsor-investigator), and the employees are considered to be investigators. (k) “Sponsor-investigator” means an individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject. The term does not include any person other than an individual, e.g., it does not include a corporation or agency. The obligations of a sponsor-investigator under this part include both those of a sponsor and those of an investigator. (1) “Test article’ means any drug for human use, biological product for human use, medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the act or under sections 351 or 354-360F of the Public Health Service Act. 77 § 56.103 Circumstances in which IRB review is required. (a) Except as provided in §§ 56.104 and 56.105, any clinical investigation which must meet the requirements for prior submission (as required in Parts 312, 812, and 813) to the Food and Drug Administration shall not be initiated unless that investigation has been reviewed and approved by, and remains subject to continuing review by, an IRB meeting the requirements of this part. The determination that a clinical investigation of this part. (b) Except as provided in §§ 56.104 and 56.105, the Food and Drug Administration may decide not to consider in support of an application for a research or marketing permit any data or information that has been derived from a clinical investigation that has not been approved by, and that was not subject to initial and continuing review by, an IRB meeting the requirements may not be considered in support of an application for a research or marketing permit does not, however, relieve the applicant for such a permit of any obligation under any other applicable regulations to submit the results of the investigation to the Food and Drug Administration. (c) Compliance with these regulations will in no way render inapplicable pertinent Federal, State, or local laws or regulations. § 56.104 Exemptions from IRB requirement. The following categories of clinical investigations are exempt from the requirements of this part for IRB review: (a) Any investigation which commenced before July 27, 1981, and was subject to requirements for IRB review under FDA regulations before that date, provided that the investigation remains subject to review of an IRB which meets the FDA requirements in effect before July 27, 1981. (b) Any investigation commenced before July 27, 1981, and was not otherwise subject to requirements for IRB review under Food and Drug Administration regulations before that date. (c) Emergency use of a test article. provided that such emergency use is reported to the IRB within 5 working days. Any subsequent use of the test article at the institution is subject to IRB review. § 56.105 Waiver of IRB requirement. On the application of a sponsor or sponsor-investigator, the Food and Drug Administration may ‘waive any of the requirements contained in these Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8977 regulations, including the requirements for IRB review, for specific research activities or for classes of research activities, otherwise covered by these regulations. Subpart B—Organization and Personne! § 56.107 IRB membership. (a) Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution. The IRB shall b€ sufficiently qualified through the experience and expertise of its members, and the diversity of the members’ backgrounds including consideration of the racial and cultural backgrounds of members and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects. In addition to possessing the professional competence necessary to review specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. The IRB shall therefore include persons knowledgeable in these areas. If an IRB regularly reviews research that involves a vulnerable category of subjects, including but not limited to subjects covered by other parts of this chapter, the IRB should include one or more individuals who are primarily concerned with the welfare of these subjects. (b) No IRB may consist entirely of men, or entirely of women, or entirely of members of one profession. (c) Each IRB shall include at least one member whose primary concerns are in nonscientific areas; for example: lawyers, ethicists, members of the clergy. (d) Each IRB shall include at least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution. (e) No IRB may have a member participate in the IRB's initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB. (f) An IRB may, in its discretion, invite individuals with competence in special areas to assist in the review of complex issues which require expertise beyond or in addition to that available on the IRB. These individuals may not vote with the IRB. Subpart C—IRB Functions and Operations § 56.108 IRB functions and operations. In order to fulfill the requirements of these regulations, each IRB shall: (a) Follow written procedures (1) for conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution, (2) for determining which projects require review more often than annually and which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review, (3) for insuring prompt reporting to the IRB of changes in a research activity, (4) for insuring that changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to the human subjects; and (5) for insuring prompt reporting to the IRB of unanticipated problems involving risks to subjects or others. (b) Except when an expedited review procedure is used (see § 56.110), review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are in nonscientific areas. In order for the research to be approved, it shall receive the approval of a majority of those members present at the meeting. (c) Be responsible for reporting to the appropriate institutional officials and the Food and Drug Administration any serious or continuing noncompliance by investigators with the requirements and determinations of the IRB. § 56.109 IRB review of research. (a) An IRB shall review and have authority to approve, require modifications in (to secure approvalj, or disapprove all research activities covered by these regulations. (b) An IRB shall require that information given to subjects as part of informed consent is in accordance with § 50.25. The IRB may require that information, in addition to that specifically mentioned in § 50.25, be given to the subjects when in the IRB's judgment the information would meaningfully add to the protection of the rights and welfare of subjects. (c) An IRB shall require documentation of informed consent in accordance with § 50.27, except that the IRB may, for some or all subjects, waive the requirement that the subject or the subject's legally authorized representative sign a written consent 78 form if it finds that the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context. In cases where the documentation requirement is waived, the IRB may require the investigator to provide subjects with a written statement regarding the research. (d) An IRB shall notify investigators and the institution in writing of its decision to approve or disapprove the proposed research activity, or of modifications required to secure IRB approval of the research activity. If the IRB decides to disapprove a research activity, it shall include in its written notification a statement of the reasons for its decision and give the investigator an opportunity to respond in person or in writing. (e) An IRB shall conduct continuing review of research covered by these regulations at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research. § 56.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. (a) The Food and Drug Administration has established, and published in the Federal Register, a list of categories of research that may be reviewed by the IRB through an expedited review procedure. The list will be amended, as appropriate, through periodic republication in the Federal Register. (b) An IRB may review some or all of the research appearing on the list through an expedited review procedure, if the research involves no more than minimal risk. The IRB may also use the expedited review procedure to review minor changes in previously approved research during the period for which approval is authorized. Under an expedited review procedure, the review may be carried out by the IRB chairperson or by one or more experienced reviewers designated by the chairperson from among members of the IRB. In reviewing the research, the reviewers may exercise all of the authorities of the IRB except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the non-expedited procedure set forth in § 56.108(b). (c) Each IRB which uses an expedited review procedure shall adopt a method for keeping all members advised of research proposals which have been approved under the procedure. 8978 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1881 / Rules and Regulations (d) The Food and Drug Administration may restrict, suspend, or terminate an institution's or IRB's use of the expedited review procedure when necessary to protect the rights or welfare of subjects. § 56.111 Criteria for IRB approval of research, (a) In order to approve research covered by these regulations the IRB shall determine that all of the following requirements are satisfied: (1) Risks to subjects are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. (2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies that subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility. (3) Selection of subjects is equitable. In making this assessment, the IRB should take into account the purposes of the research and the setting in which the research will be conducted. (4) Informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accordance with and to the extent required by Part 50. (5) Informed consent will be appropriately documented, in accordance with and to the extent required by § 50.27. (6) Where appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. (7) Where appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. (b) Where some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as persons with acute or severe physical or mental illness, or persons who are economically or educationally disadvantaged, appropriate additional safeguards have been included in the study to protect the rights and welfare of these subjects. § 56.112 Review by institution. Research covered by these regulations that has been approved by an IRB may be subject to further appropriate review and approval or disapproval by officials of the institution. However, those officials may not approve the research if it has not been approved by an IRB. § 56.113 Suspension or termination of IRB approval of research. An IRB shall have authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected serious harm to subjects. Any suspension or termination of approval shall include a statement of the reasons for the IRB's action and shall be reported promptly to the investigator, appropriate institutional officials, and the Food and Drug Administration. § 56.114 Cooperative research. In complying with these regulations, institutions involved in multi- institutional studies may use joint review, reliance upon the review of another qualified IRB, or similar arrangements aimed at avoidance of duplication of effort. Subpart D—Records and Reports §56.115 IRB records. (a) An institution, or where appropriate an IRB, shall prepare and maintain adequate documentation of IRB activities, including the following: (1) Copies of all research proposals reviewed, scientific evaluations, if any, that accompany the proposals, approved sample consent documents, progress reports submitted by investigators, and reports of injuries to subjects. (2) Minutes of IRB meetings which shall be in sufficient detail to show attendance at the meetings; actions taken by the IRB; the vote on these actions including the number of members voting for, against, and abstaining; the basis for requiring changes in or disapproving research; and a written summary of the discussion of controverted issues and their resolution. (3) Records of continuing review activities. (4) Copies of all correspondence between the IRB and the investigators. (5) A list of IRB members identified by name; earned degrees; represéntative capacity; indications of experience such as board certifications, licenses, etc., sufficient to describe each member's chief anticipated contributions to IRB deliberations; and any employment or other relationship between each 79 member and the institution; for example: full-time employee, part-time employee, a member of governing panel or board, stockholder, paid or unpaid consultant. (8) Written procedures for the IRB as required by § 56.108(a). (7) Statements of significant new findings provided to subjects, as required by § 50.25. (b) The records required by this regulation shall be retained for at least 3 years after completion of the research, and the records shall be accessible for inspection and copying by authorized representatives of the Food and Drug Administration at reasonable times and in a reasonable manner. (c) The Food and Drug Administration may refuse to consider a clinical investigation in support of an application for a research or marketing permit if the institution or the IRB that reviewed the investigation refuses to allow an inspection under this section. Subpart E—Administrative Actions for Noncompliance § 56.120 Lesser administrative actions. (a) If apparent noncompliance with these regulations in the operation of an IRB is observed by an FDA investigator during an inspection, the inspector will present an oral or written summary of observations to an appropriate representative of the IRB. The Food and Drug Administration may subsequently send a letter describing the noncompliance to the IRB and to the parent institution. The agency will require that the IRB or the parent institution respond to this letter within a time period specified by FDA and describe the corrective actions that will be taken by the IRB, the institution, or both to achieve compliance with these regulations. (b) On the basis of the IRB's or the institution's response, FDA may schedule a reinspection to confirm the adequacy of corrective actions. In addition, until the IRB or the parent institution takes appropriate corrective action, the agency may: (1) Withhold approval of new studies subject to the requirements of this part that are conducted at the institution or reviewed by the IRB; (2) Direct that no new subjects be added to ongoing studies subject to this part; (3) Terminate ongoing studies subject to this part when doing so would not endanger the subjects; or (4) When the apparent noncompliance creates a significant threat to the rights and welfare of human subjects, notify relevant State and Federal regulatory agencies and other parties with a direct Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Rules and Regulations 8979 interest in the agency's action of the deficiencies in the operation of the IRB. (c) The parent institution is presumed to be responsible for the operation of an IRB, and the Food and Drug Administration will ordinarily direct any administrative action under this subpart against the institution. However, depending on the evidence of responsibility for deficiencies, determined during the investigation, the Food and Drug Administration may restrict its administrative actions to the IRB or to a component of the parent institution determined to be responsible for formal designation of the IRB. § 56.121 Disqualification of an IRB or an institution. (a) Whenever the IRB or the institution has failed to take adequate steps to correct the noncompliance stated in the letter sent by the agency under § 56.120(a), and the Commissioner of Food and Drugs determines that this noncompliance may justify the disqualification of the IRB or of the parent institution, the Commissioner will institute proceedings in accordance with the requirements for a regulatory hearing set forth in Part 16. (b) The Commissioner may disqualify an IRB or the parent institution if the Commissioner determines that: (1) The IRB has refused or repeatedly failed to comply with any of the regulations set forth in this part, and (2) The noncompliance adversely affects the rights or welfare of the human subjects in a clinical investigation. (c) If the Commissioner determines that disqualification is appropriate, the Commissioner will issue an order that explains the basis for the determination and that prescribes any actions to be taken with regard to ongoing clinical research conducted under the review of the IRB. The Food and Drug Administration will send notice of the disqualification to the IRB and the parent institution. Other parties with a direct interest, such as sponsors and clinical investigators, may also be sent a notice of the disqualification. In addition, the agency may elect to publish a notice of its action in the Federal Register. (d) The Food and Drug Administration will not approve an application for a research permit for a clinical investigation that is to be under the review of a disqualified IRB or that is to be conducted at a disqualified institution, and it may refuse to consider in support of a marketing permit the data from a clinical investigation that was reviewed by a disqualified IRB as conducted at a disqualified institution, unless the IRB or the parent institution is reinstated as provided in § 56.123. § 56.122 Public disclosure of information regarding revocation. A determination that the Food and Drug Administration has disqualified an institution and the administrative record regarding that determination are disclosable to the public under Part 20. § 56.123 Reinstatement of an IRB or an institution. An IRB or an institution may be reinstated if the Commissioner determines, upon an evaluation of a written submission from the IRB or institution that explains the corrective action that the institution or IRB plans to take, that the IRB or institution has provided adequate assurance that it will operate in compliance with the standards set forth in this part. Notification of reinstatement shall be provided to all persons notified under § 56.121(c). § 56.124 Actions alternative or additional to disqualification. Disqualification of an IRB or of an institution is independent of, and neither in lieu of nor a precondition to, other proceedings or actions authorized by the act. The Food and Drug Administration may, at any time, through the Department of Justice institute any appropriate judicial proceedings (civil or criminal) and any other appropriate regulatory action, in addition to or in lieu of, and before, at the time of, or after, disqualification. The agency may also refer pertinent matters to another Federal, State, or local government agency for any action that that agency determines to be appropriate. Effective date. This regulation shall become effective July 27, 1981. (Secs. 406, 408, 409, 501, 502, 503, 505, 506, 507, 510, 513-516, 518-520, 701(a), 706, and 801, 52 Stat. 1049-1054 as amended, 1055, 1058 ds amended, 55 Stat. 851 as amended, 59 Stat. 463 as amended, 68 Stat. 511-517 as amended, 72 Stat. 1785-1788 as amended, 74 Stat. 399- 407 as amended, 76 Stat. 794-795 as amended, 90 Stat. 540-560, 562-574 (21 U.S.C. 346, 346a, 348, 351, 352, 353, 355, 356, 357, 360, 360c~360f, 360h-360j, 371(a) 376, and 381); secs. 215, 301, 351, as amended (42 U.S.C. 216, 241, 262, 263b-263n)) Dated: January 19, 1981. Jere E. Goyan, Commissioner of Food and Drugs. [FR Doc. 81-2688 Filed 1-26-81; 8:45 am] BILLING CODE 4110-03-M 80 21 CFR Part 50 [Docket No. 78N-0049] Protection of Human Subjects; Prisoners Used as Subjects in Research; Correction AGENCY: Food and Drug Administration. ACTION: Correction. SUMMARY: In FR Doc. 80-16578 appearing at page 36386 in the Federal Register of Friday, May 30, 1980, the following correction is made in the first column of page 36391: In § 50.1 Scope, in paragraph (a) the word “prisoner” is removed. FOR FURTHER INFORMATION CONTACT: Agnes Black, Federal Register Writer (HFC-11), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443-2994 Dated: January 19, 1981. Jere E. Goyan, Commissioner of Food and Drugs. [FR Doc. 81-2689 Filed 1-21-81; 8:45 am] BILLING CODE 4110-03-M 8980 Federal Register / Vol. 46, No. 17 / Tuesday, January 27, 1981 / Notices DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. 77N-0350] Protection of Human Research Subjects; Clinical Investigations Which May Be Reviewed Through Expedited Review Procedure Set forth in FDA Regulations AGENCY: Food and Frug Administration. ACTION: Notice. SUMMARY: This notice contains a list of research activities which institutional review boards may review through the expedited review procedures set forth in FDA regulations for the protection of human research subjects. FOR FURTHER INFORMATION CONTACT: John C. Petricciani, Office of the Commissioner (HFB—4), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20205, 301-496-9320. SUPPLEMENTARY INFORMATION: Elsewhere in this issue of the Federal Register, the Food and Drug Administration (FDA) is publishing final regulations establishing standards for institutional review boards (IRBs) for clinical investigations relating to the protection of human subjects in research. Section 56.110 (21 CFR 56.110) of the final IRB regulations provides that the agency will publish in the Federal Register a list of categories of research activities, involving no more than minimal risk, that may be reviewed by an IRB through expedited review procedures. This notice is published in accordance with § 56.110. The agency concludes that research activities with human subjects involving no more than minimal risk and involving one or more of the following categories (carried out through standard methods), may be reviewed by an IRB through the expedited review procedure authorized in § 56.110. (1) Collection of hair and nail clippings in a non-disfiguring manner; of deciduous teeth; and of permanent teeth if patient care indicates a need for extraction. (2) Collection of excreta and external secretions including sweat and uncannulated saliva; of placenta at delivery; and of amniotic fluid at the time of rupture of the membrane before or during labor. (3) Recording of data from subjects who are 18 years of age of older using noninvasive procedures routinely employed in clinical practice. This category includes the use of physical sensors that are applied either to the surface of the body or at a distance and do not involve input of matter or significant amounts of energy into the subject or an invasion of the subject's privacy. It also includes such procedures as weighting, electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, diagnostic echography, and electroretinography. This category does not include exposure to electromagnetic radiation outside the visible range (for example, x-rays or microwaves). (4) Collection of blood samples by venipuncture, in amounts not exceeding 450 milliliters in an eight-week period and no more often than two times per week, from subjects who are 18 years of age or older and who are in good health and not pregnant. (5) Collection of both supra- and subgingival dental plaque and calculus, provided the procedure is not more invasive than routine prophylactic scaling of the teeth, and the process is accomplished in accordance with accepted prophylactic techniques. (8) Voice recordings made for research purposes such as investigations of speech defects. (7) Moderate exercise by healthy volunteers. (8) The study of existing data, documents, records, pathological specimens, or diagnostic specimens. (9) Research on drugs or devices for which an investigational new drug exemption or an investigational device exemption is not required. This list will be amended as appropriate and a current list will be published periodically to the Federal Register. Dated: January 19, 1981. Jere E. Goyan, Commissioner of Food and Drugs. [FR Doc. 81-2690 Filed 1-21-81; 3:59 pm] BILLING CODE 4110-03-M 81 Investigational Device Exemption Regulation QUESTIONS AND ANSWERS The following questions on the investigational device exemption (IDE) regulation and on Parts 50 and 56 have been frequently asked during conferences and in letters and telephone calls to the Bureau of Medical Devices. Future policy decisions may change some of the answers given here. They are, therefore, offered as interim guidance. The IDE regulation (21 CFR 812) was published January 18, 1980, and became effective July 16, 1980. Since that time, FDA published changes in the IDE regulation on September 5, 1980, and April 10, 1981 as well as additional regulations clarifying the requirements that govern informed consent (Part 50) and the composition, operation, and responsibilities of institutional review boards (IRBs), (Part 56). Parts 50 and 56 became effective July 27, 1981. Questions on this document and on Parts 812, 50, and 56 may be addressed to: Program Management Staff Bureau of Medical Devices (HFK-403) Food and Drug Administration 8757 Georgia Avenue Silver Spring, MD 20910 (301)427-8162 TABLE OF CONTENTS Part 812: Investigational Device Exemption Regulation SUBPART A: General Provisions BROPE (8810.1)... ....cvnirermnmcmnmmer tr rrnnr nm aas sis hana (3) Applicability (8812.2)... ott ee 3) Investigations Subject to INDs (§812.2[e]) .......................... (9) Definitions (8812.3). .. iii eee (10) Labeling of Investigational Devices (§812.5)....................... (11) Prohibition of Promotion and Other Practices (8812.7)............. (12) Import and Export Requirements (§812.18)......................... (13) 83 SUBPART B: Application and Administrative Actions Application (§812.20). ... count ie (13) Investigational Plan ($812.25). «cvovvvuunssnnnnrsrnunsnnrnsnsnmnss (14) Report of Prior Investigations (§812.27)......................... (14) Supplemental Applications (§812.35).............iiniiiiiii.... (14) Confidentiality of Data and Information (§812.38) ............... (15) SUBPART C: Responsibilities of Sponsors General Responsibilities of Sponsors ($812.40) ................... (16) Selecting Investigators and Monitors (8812.43) ................... (16) Monitoring Investigations (§812.46).................ciuinienn.. (17) SUBPART D: IRB Review and Approval.................cccvinunn... (18) SUBPART E: Responsibilities of Investigators Specific Responsibilities of Investigators (§812.110) .............. (18) SUBPART F: Reserved. ......... cuttin (18) SUBPART G: Records and Reports Records (§812.140). .. oot ie te ete teeta (18) Inspections (§812.145). ..... courtier. (18) RePOTtS (§812.150). . ouverte ete eee e eee eee eee (19) Part 50: Informed Consent of Human Subjects Regulation............... (21) Part 56: Institutional Review Boards Regulation ........................ (22) Other QUESTIONS . ...... iii tt eee eee eee (26) 84 (3) PART 812: INVESTIGATIONAL DEVICE EXEMPTION REGULATION SUBPART A: General Provisions Scope (§812.1) Q If the sponsor of a device investigation has an approved IDE, is the manufacturer of the device subject to the device GMP regulation? A No. A sponsor of a significant risk device investigation is required, however, to describe the methods, facilities, and controls used for the manufacture, processing, packing, storage, and, if appropriate, installation of the device. If the sponsor intends to comziy with the GMP regulation, the IDE application should state so. The sponsor of a nonsignificant risk device investigation who intends to comply with the GMP regulation should keep on file a statement of the extent to which this regulation will be followed. Q Are devices with an approved IDE exempt from section 501 on adulteration or section 518 on notification and other remedies? A No. An investigational device i:ay be considered adulterated under section 501(i) if the sponsor or investigator fails to comply with a requirement of the IDE regulation (21 CFR Part 812). Section 518 is applicable, however, only to devices in commercial distribution, and since investigational devices are not to be commercialized, section 518 is not relevant to devices with an approved IDE. Applicability (§812.2) Q when is an IDE application required for a nonsignificant risk device? A Following the IRB approval of a nonsignificant risk investigation, the investigation is deemed to have an approved IDE, and an application to FDA is not necessary. 85 (4) The IDE regulation allows FDA to require that an application be submitted for a nonsignificant risk device; nevertheless, FDA anticipates that such a requirement will be rare. This may occur (1) if reports of unanticipated adverse reactions suggest that the device presents a significant risk; (2) if FDA inspections indicate that a sponsor's risk assessment is in error; or (3) if an IRB determines that a device is a significant risk device. If a device has several uses, one of which involves significant risk, are investigations of the nonsignificant risk uses subject to the significant risk requirements of the IDE regulation? No. If a device is being tested for a use that does not present significant risk, it is subject only to those sections of the IDE regulation applicable to nonsignificant risk devices, If that same device is used in an investigation that presents significant risk, it is subject to the full IDE requirements for that use. The IDE regulation states that sponsors are required to maintain IRB approval. What does this mean? This means the sponsor must ensure that the investigation meets IRB requirements. An IRB must review clinical investigations at least once a year. Must sponsors of nonsignificant risk device investigations submit investigational plans and reports of previous investigations to IRBs to obtain their approval? The IDE regulation does mot state which materials must go to IRBs. The IRB regulation (21 CFR Part 56), however, specifies the criteria and procedures by which an IRB may approve FDA-regulated research. In particular, 21 CFR 56.111(a) requires an IRB, before approving research, to determine that the following requirements are satisfied: 0 Risks to subjects are minimized. 0 Risks to subjects are reasonable in relation to the anticipated benefits and the knowledge to be gained. 86 (5) o Selection of subjects is equitable. o Informed consent is obtained.and documented in accordance with 21 CFR Part 50. o Where appropriate, the research plan makes adequate provision for monitoring the data collected to ensure subject safety, to protect subject privacy, and to maintain data confidentiality. The IRB regulation allows IRBs to determine what information is needed to satisfy these requirements, and FDA encourages reasonable, independent decision-making among IRBs. For certain investigations, an IRB may desire minimal information upon which to base a decision. For other investigations, an IRB may need as much information as normally appears in an IDE application to FDA, even though the IRB may subsequently determine, in light of this information, that the investigational device does mot present a significant risk. Are devices in commercial distribution before May 28, 1976, enactment date of the Amendments, exempt from IDE requirements? In general, yes. The IDE regulation exempts pre-Amendments devices, other then "transitional" devices, if they are used or investigated in accordance with labeling in effect before May 28, 1976. For class II devices, this exemption expires on’ the effective date of a regulatory performance standard. If the devices do not meet the performance standard, they may be distributed only under an approved IDE. For class III pre-Amendments devices, this exemption expires 90 days after the effective date of the FDA regulation or order calling for a PMA submission, or on a later date specified by FDA. Are all devices marketed after May 28, 1976, subject to the IDE regulation? Except for "transitional" devices, the IDE regulation exempts post-Amendments devices that FDA has determined to be substantially equivalent to pre-Amendments devices if they are used according to the labeling that FDA reviewed when determining substantial equivalence. This exemption does not apply to a class II device after a performance standard is established for the device under section 514 of the FD&C Act or to a class III device after an order calling for the submission of a PMA is issued under section 515(b). 87 (6) Must a sponsor ask FDA whether a device is substantially equivalent to a pre-Amendments device before initiating a clinical investigation? No, but FDA encourages this practice. A determination from FDA may prevent a sponsor's spending money and effort for substantially equivalent devices. Certain device features that FDA considers in determining substantial equivalence are listed in 21 CFR 807.87. What kind of testing is exempt from the IDE regulation? The following testing is exempt: 0 Consumer preference testing of devices, testing of a modification, or testing of a combination of two or more devices in commercial distribution if the testing is not to determine safety and effectiveness and does not put subjects at risk. 0 Fundamental research testing for purposes other than determining the safety and effectiveness of a device for human use. o Testing of devices (1) that are legally in commercial distribution if the testing accords with the device's labeling; (2) that are intended solely for veterinary use; or (3) that are shipped solely for research on or with laboratory animals and are labeled appropriately. o Testing of diagnostic devices that comply with diagnostic device labeling requirements under 21 CFR 809.10 and that meet exemption criteria. In addition, the IDE regulation does not apply to fabrication of a custom device if the device is not being tested to determine safety and effectiveness for purposes of commercial distribution or to an intraocular lens subject to an approved IDE under 21 CFR Part 813. What is the difference between "testing which is noninvasive" and "testing which does not require an invasive sampling procedure that presents significant risk?" "Testing which is noninvasive" focuses on the device and means that the device is "noninvasive" as defined in the IDE 88 (7) regulation. For example, a stethoscope would be a device for which testing is noninvasive. A laparoscope involves invasive testing. The phrase "testing which does not require an invasive sampling procedure that presents significant risk" focuses not on the device, but rather on how the sample to be analyzed with an in vitro diagnostic device is obtained. For example, obtaining a throat culture for microbiological testing would be an invasive sampling procedure that does not present significant risk. A spinal tap would, on the other hand, present significant risk. If a diagnostic device investigation is exempt from the IDE regulation, must the sponsor comply with any other requirements? If the device is in commercial distribution, the sponsor must meet all applicable requirements of the FD&C Act. If the device is not in commercial distribution, the sponsor must comply with the in vitro diagnostic product labeling requirements and any applicable BRH requirements. The device investigation will remain exempt, however, only if the sponsor ensures that the device results are confirmed with an established diagnostic device or procedure. A sponsor who wishes to export an investigational device must meet the export requirements for investigational devices. Is a device that introduces energy into a subject's body a significant risk device? Such a device would usually be a significant risk device. If a radiation-emitting investigational device is subject to the IDE regulation, is it also subject to the BRH regulations? An IDE grants exemption from certain provisions of the FD&C Act; it does not grant exemption from other Federal, State, or local regulations. Certain radiation-emitting electronic products may also be investigational medical devices; these are subject to regulations enforced by BRH, e.g., product performance standards for products such as lasers and diagnostic X-rays. Under these regulations, however, some 89 > > (8) variances may be granted. Such variances must be applied for separately under BRH procedures. FDA will make every effort to coordinate the process to avoid duplicative paperwork, e.dg., one submission may reference another. What is meant by the phrase "testing of a modification"? This refers to testing a change in a commercially available device. For example, anesthesiologists may alter commercially available anesthesiology devices to suit particular hospital or patient conditions. A smaller breathing circuit may be substituted for pediatric use or the tubing lengthened or shortened, depending on the configuration of the operating room. To be exempted from the IDE regulation, however, this testing must not be for the purpose of determining safety and effectiveness and must not put subjects at risk. Are custom devices exempt from the IDE regulation? Yes, if the devices are not being tested to determine safety or effectiveness for purposes of commercial distribution. Custom devices are still subject to all provisions of the FD&C Act except sections 510(k), premarket notification; 514, performance standards; and 515, premarket approval. Does the IDE regulation apply to the components of significant and nonsignificant risk devices? Yes. The regulation applies to a "device" as defined in the FD&C Act. Any components, accessories, and parts used with the device and not used as separate and independent devices are subject to the regulation. The investigational plan must include a description of important device components. Are acupuncture devices investigational devices? Yes. This was announced in the FEDERAL REGISTER notices of March 9, 1973, and November 2, 1979. 90 (9) Investigations Subject to Notices of Claimed Investigational Exemption for a New Drug (INDs) (§812.2(e)) Q A Are transitional devices exempt from the IDE regulation? No device is exempt because it is transitional. (For a definition of "transitional device," see the last question and answer under the next section, Definition § 812.3.) Can a transitional device be either a significant risk device or a nonsignificant risk device? Yes. How are the transitional devices affected by the IDE regulation? New investigations of transitional devices are subject to the IDE regulation. Transitional device investigations begun prior to July 16, 1980, however, are required to have approved IND applications. These investigations will be subject to INDs until 90 days after the effective date of the IDE regulation. To continue an investigation after October 14, 1980, there must be an approved IDE. If an IND clinical investigation was campleted before October 14, 1980, however, an IDE is not necessary. If a clinical investigation involves a significant risk device, the sponsor, unless directed otherwise by FDA, must notify the FDA of the IND number and describe the status of the investigation. After reviewing this information, FDA will inform the sponsor of any additional requirements. In order that the study not be disrupted, this information should be submitted as soon as possible. If an IND clinical investigation does not involve a significant risk device, the limited records and reports requirements for clinical investigations of nonsignificant risk devices must be followed. 91 (10) Definitions (§812.3) Q A > Is it possible for a device implanted for less than 30 days to be a significant risk device? Yes. FDA may declare such a device to be a significant risk device, but the determination would be made on a case-by-case basis. For example, the determination that a diaphragm is a significant risk device is based on the intended use of the device rather than on its nature as an implant. What is meant by the term "investigational testing"? This is testing to determine the safety or efficacy of a device and may involve either preclinical or clinical investigations. The IDE regulation applies only to clinical investigations of devices. Nevertheless, the regulation does contain labeling requirements for investigational devices shipped for animal research. May a consumer preference test involve human subjects? No. This testing involves humans, but not as subjects. The regulation defines a subject as a participant in the testing of an investigational device to determine if it is safe and effective, What are transitional devices? Transitional devices are those devices that were, or would have been, regulated as new drugs for which INDs or new drug applications (NDAs) were required before the approval of the Medical Device Amendments. Soft contact lenses and surgical sutures are examples of transitional devices. The official notice on transitional devices appeared in the FEDERAL REGISTER of December 16, 1977. That notice discusses transitional devices in greater detail. 92 (11) Labeling of Investigational Devices (§812.5) Q A How should investigational devices covered by an approved IDE be labeled? The labeling must contain the name and place of business of the manufacturer, packer, or distributor; the quantity of contents; all relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings, and precautions; and the statement: "Caution - Investigational Device. Limited by Federal (or United States) law to investigational use." How should an investigational device be labeled when it is shipped from a sponsor's plant to another sponsor facility for repacking? In this instance the investigational device should be labeled: "Caution: For manufacturing, processing, or repacking." When the device leaves the repacker, it should carry the information specified in the previous answer. How should devices undergoing consumer preference testing be labeled? There is no labeling prescribed for a device undergoing consumer preference testing. The device should be labeled according to the labeling requirements for a marketed product. What are the labeling requirements for investigational in vitro diagnostic devices? The labeling of an investigational in vitro diagnostic device that is exempt from the requirements of the IDE regulation must comply with 21 CFR 809.10(c). This investigation must also meet the exemption criteria listed in 21 CFR 812.2(c)(3). All other investigational in vitro diagnostic devices, significant or nonsignificant risk, must comply with the applicable requirements of the IDE regulation and must be labeled in accordance with 21 CFR 812.5. 93 (12) May investigational device labeling contain safety or effectiveness claims? No. The labeling may not represent the device to be safe or effective for the purpose for which it is being investigated. Prohibition of Promotion and Other Practices (§812.7) Q A Does the prohibition on commercialization authorize FDA to audit a sponsor's financial records? Yes. If an audit is necessary for FDA to determine whether a sponsor's charge for a device exceeds the costs of manufacturing, research, development, and handling, FDA may demand proof that no profit has been earned. A sponsor may have to submit certain financial records to demonstrate that the prohibition against commercialization has not been violated. Does the prohibition against promotion of an investigational device apply to investigators as well? Yes. Investigators must not represent to potential subjects that investigational devices are safe and effective for the purposes for which they are being investigated. Investigators may publish the results of investigations in scientific journals and may express their veiws based upon their experience with devices. Reprints of such articles, however, cannot be used to promote investigational devices. May a device investigation conducted under an approved IDE application be continued after a PMA has been submitted? Yes, if the investigation remains within the framework of the approved IDE. If the PMA is not approved because the data presented is not sufficient to establish safety and efficacy, the investigation may be continued provided the testing is still within the framework of the IDE protocol. If FDA determines that premarket approval cannot be justified, the investigation must be promptly terminated. If a PMA is approved, there is no need for an IDE. FDA may occasionally require postapproval studies, e.g., long-term toxicity studies, which may be conducted without an IDE. 94 (13) Import and Export Requirements (§812.18) Q Are all investigational devices subject to FDA export approval? A Yes, Q How does a sponsor obtain FDA export approval? A The sponsor must write FDA requesting permission and stating that the device (1) meets the foreign purchaser's specifications; (2) is not in conflict with the laws of the country to which it is intended for export; (3) is shipped with labeling on the outside of the package that states the device is intended for export; and (4) is not sold or offered for sale in domestic commerce unless FDA authorizes sale of the device. The sponsor must provide documentation, in English, from the appropriate agency or individual in the foreign country that the oountry approves the device for import. FDA reviews these requests and responds to the sponsor in writing. SUBPART B: Application and Administrative Actions Application (§812.20) Q If FDA requests additional information concerning an investigation, what options does the sponsor have in responding? A The sponsor may decide whether to give the information to FDA. If the choice is made not to give FDA this information, the sponsor may treat the request as FDA disapproval of an IDE application and may ask for a hearing under 21 CFR Part 16. The sponsor may also decide not to initiate the investigation. 95 (14) Investigational Plan(§812.25) Q Must a sponsor supply FDA with each of the various types of A Q A informed consent forms to be used in a significant risk device investigation? Yes. A copy of each type of form must be submitted to FDA as part of the IDE application. What is meant by the phrase "sponsor certification of IRB action"? This means a sponsor's statement of an IRB's action on an investigation, e.g., disagreement with the sponsor's risk assessment, approval, denial, or approval with conditions. Report of Prior Investigations (§812.27) Q Is previous animal testing required in all instances? A No, mot for all devices. If animal testing is relevant, it should all be completed before an IDE application is submitted. FDA will mot approve the application until such testing is completed. Generally, animal testing must be conducted in compliance with the good laboratory practice regulation. Supplemental Applications (§812.35) Q Must a sponsor notify FDA of all changes made in the manufacturing process during a significant risk device investigation or only of significant changes? Sponsors must submit a supplemental application only for significant changes. A significant change is one that might affect the scientific soundness of the investigation or the rights, safety, or welfare of subjects, e.g., substitution of a different sterilization method. 96 (15) Is IRB approval required before a nonemergency change in the investigational plan? If the investigator or sponsor proposes a change that might affect the scientific soundness of the investigation or the rights, safety, or welfare of the subjects, IRB and FDA approval must be obtained. Otherwise, only sponsor approval is required. what is the time limit for FDA review of supplemental applications? Within 30 days after receiving the application, FDA notifies the sponsor of its decision, i.e., approval, disapproval, approval with modifications, or request for additional information. Confidentiality of Data and Information (§812.38) Q A Will FDA release information in a pending or approved IDE under the FOI Act or under section 520(h) of the FD&C Act? No IDE data is released until (1) FDA determines that the information had been previously disclosed to the public; (2) FDA approves a PMA for a device subject to an IDE; or (3) the device has in effect a PDP notice of completion. Once an IDE application is approved, the existence of an application or data or information in the file is not disclosed unless FDA determines that it is in the public interest to release a summary of selected portions of the safety and effectiveness data, a subject in the investigation requests information on adverse effects, or FDA on its own initiative discloses this information to a subject. FDA discloses data and information in an IDE file in accordance with FDA regulations governing the confidentiality of data and information in NDAs and INDs. Upon request, FDA will release a summary of safety and effectiverness information on a banned device IDE application that FDA has approved or disapproved or for which FDA has withdrawn approval. 97 (16) SUBPART C: Responsibilities of Sponsors General Responsibilities of Sponsors (§812.40) Q A Must all investigations have sponsors? Who can serve as the sponsor of an investigation? All investigations must have sponsors. A sponsor may be any person or group (e.g., manufacturer, educational institution, hospital, or Government agency) who initiates a clinical investigation and is willing to accept a sponsor's responsibilities. An investigator may also be a sponsor- investigator. Selecting Investigators and Monitors (§812.43) Q A Who is responsible for the selection of investigators? What criteria should be used in the selection process? Sponsors are responsible for selecting investigators and should establish selection criteria based on the training and experience required to investigate the safety and effectiveness of devices. May a health professional, such as a nurse or therapist, be qualified as an investigator? May a nurse or other health professional use the device under supervision of an investigator? Yes. A nurse, therapist, etc., may be an investigator if the individual's training and experience satisfy the requirements the sponsor has established. A health professional who is not an investigator may in some instances use a device under the supervision of an investigator. 98 a7) Monitoring Investigations (§812.46) Q Must IDE investigations be monitored? Who has this A responsibility? Yes, and sponsors are responsible for ensuring proper monitoring of investigations. This generally includes: o Ensuring that investigators follow signed investigator agreements. 0 Evaluating immediately unanticipated adverse effects, and reporting the results to FDA. o Securing compliance of devices or, if necessary, discontinuing their shipment to investigators. o Ensuring that unused devices are disposed of properly. What are the responsibilities of a manufacturer who discovers a physician conducting a clinical investigation of a significant risk device for a use other than the use for which the device may legally be cammercially distributed? In this instance, the physician would be considered a sponsor-investigator and would be responsible for obtaining an approved IDE. The manufacturer should stop shipping the device unless the manufacturer or the physician is willing to serve as a sponsor and to submit an IDE application. If an investigator continues to use a significant risk device after a sponsor has terminated an investigation and has requested that all devices be returned, what steps should the sponsor take? The sponsor should notify FDA and the IRB. How may a significant risk device investigation that has been terminated be resumed? It may be resumed through the same steps necessary to allow an investigation to begin, e.g., IRB review and approval and a submission to FDA. (18) SUBPART D: IRB Review and Approval SUBPART E: Responsibilities of Investigators Specific Responsibilities of Investigators (§812.110) Q A What must be done with unused devices at the end of a significant risk device investigation? They must be returned to the sponsor or otherwise disposed of as the sponsor directs. SUBPART F: Reserved SUBPART G: Records and Reports Records (§812.140) Q If a device investigation is exempt from the IDE regulation, are there other recordkeeping requirements that the sponsor or device manufacturer must meet? If the device is not in commercial distribution, there are no recordkeeping requirements. If it is in commercial distribution, the manufacturer must comply with the recordkeeping requirements of the FD&C Act, e.g., GMP recordkeeping requirements. Inspections (§812.145) Q A Are there IDE compliance programs established to inspect records of an investigation? Yes. Under the Bio-Research Monitoring Program, FDA inspects sponsors, monitors, IRBs, and investigators. The specific compliance programs are: 7378.808 - Good Laboratory Practice Program, Non-Clinical Laboratories; 7378.809 - 100 (19) Institutional Review Board Program; 7378.810 - Sponsor/Monitor Program; and 7378.811A ~~ Clinical Investigators Follow-up. They are currently available fram FDA upon request through FOI. Q when FDA inspects an investigator at an institution, is the institution's approval required? A No. It is not necessary for the clinical investigator to obtain approval fram the institution before permitting an FDA inspection. The institution, however, will be notified by FDA that an inspection is pending. Inspections will be conducted during normal business hours and. the FDA investigators will identify themselves and present their credentials. It may be necessary for the clinical investigator to obtain permission fram the institution to take the FDA investigator to a portion of the institution where the clinical investigator may not have access. Reports (§812.150) Q Must an IRB be notified if an emergency change is made in the investigational plan to protect the life or physical well-being of a subject? A Yes. The sponsor and the reviewing IRB must be notified no later than five working days after the emergency occurred. Q Will a sponsor be subject to administrative sanctions for failing to make the proper notifications to FDA, IRBs, and others? If so, what penalties may be involved? A Yes. The penalties would vary depending on the nature of the violation, e.g., failure to make a notification, falsification of a report, an incamplete report, the reason for the violation, and the importance of the item addressed in the notification. Penalties could vary widely from termination or suspension of investigations to criminal prosecution. 101 (20) If an investigation is being reviewed by several IRBs, must the sponsor send progress reports of the investigation to all reviewing IRBs? Yes. What kind of information is required in progress reports and in final reports? The IDE regulation does not specify the kind of information required in progress reports, but they generally should contain information specified by IRBs to enable them to review progress. They could include summary information, such as the number of patients, investigators, and IRBs; adverse reactions or complications; results or conclusions reached to date; laboratory data; estimation of the progress of the investigation toward its conclusion; results of monitoring; and discontinuance of patients and the reasons for the discontinuance. A final report should contain the information included in the progress report, identification as a final report, and the reasons for completion or termination of the study. A sponsor presents an investigation to several IRBs and explains that the device is a nonsignificant risk device. Some of the IRBs agree, but other IRBs believe it is a significant risk device. May the sponsor begin the investigation at those institutions at which IRBs agreed with the nonsignificant risk determination? Technically, yes. The IDE regulation requires, however, that the sponsor report to FDA those instances in which IRBs determined the device to be a significant risk device. FDA recommends the sponsor request FDA's guidance before initiating the investigation in the situation described. FDA makes its determination on a case-by-case basis. 102 (21) PART 50: INFORMED CONSENT OF HUMAN SUBJECTS REGULATION Must clinical investigators revise informed consent forms to conform to the requirement of the informed consent of human subjects regulation (21 CFR Part 50) for subjects entering the study after July 27, 198172 If the study cammenced after July 27, 1981, consent must be obtained in accord with 21 CFR Part 50. (For clarification of "cammenced," see the last question and answer under the next section, Part 56: Institutional Review Boards Regulation. ) What are the responsibilities of the investigator, sponsor, and IRB for ensuring adequate informed consent? For either significant or nonsignificant risk device investigations, the investigator must obtain and document informed consent in accordance with section 50.27 of FDA's informed consent regulation (21 CFR Part 50). The investigator must document use of a device without informed consent and must report such use to the sponsor and the reviewing IRB within five working days after the occurrence. The sponsor must ensure that adequate informed consent is obtained and must provide FDA with a copy of any report of device use without informed consent within five working days of receiving such a report. The sponsor of a significant risk device investigation must submit, as part of the IDE application, copies of all forms and informational materials to be provided to subjects in obtaining informed consent. The IRB must judge the adequacy of informed consent and must disapprove an investigation or withdraw approval if informed consent is inadequate. what are the differences in the required elements of informed consent of 21 CFR Part 50 and Part 812? The following items previously required by the IDE regulation are not required by 21 CFR Part 50: o an explanation of the nature of the investigational device; 103 (22) ©O an explanation of likely results should the procedures fail; and © a description of the scope of the investigation, including the number of subjects involved. The following additional elements are now required by 21 CFR Part 50: O0 a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and noting the possibility that FDA may inspect the records; o for research involving more than a minimal risk, an explanation as to whether any compensation and/or medical treatments are available in the event of injury and, if so, what they consist of, or where further information may be obtained; and O an explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights or in the event of research-related injury to a subject. The additional items listed in section 50.25(b) are to be provided when appropriate. PART 56: INSTITUTIONAL REVIEW BOARDS REGULATION If no IRB exists or a sponsor cannot find an IRB willing to review the sponsor's investigation, may an independent IRB or group be established outside an academic or health care institution? Yes. Some situations might require establishing an independent IRB. For example, a sponsor might use investigators not affiliated with an institution; an investigation might be conducted in physicians' offices; or manufacturers might conduct investigations using their own facilities with their employees as subjects. FDA recommends that the sponsor first attempt to contract with a commercial testing laboratory or a contract research organization to establish an IRB. If unable to contract for 104 > (23) IRB review, the sponsor may establish an IRB. If unable to establish an independent IRB by either of these methods, the sponsor may submit documentation of these efforts to obtain IRB review and may request FDA to review the application without previous IRB review. In lieu of an IRB, will FDA review investigations? Under only the most unusual circumstances does FDA intend to perform patient risk reviews. It is difficult for FDA to perform these reviews because of the need to apply local community standards in reviewing the acceptability of risks associated with clinical investigations. May a sponsor financially assist an IRB? Yes. A sponsor may provide financial support for reasonable administrative assistance, such as clerical assistance. Must an IRB have a general assurance number? No, mot for an IRB to review a clinical investigation of a medical device. It is required, however, if an institution seeks DHHS funding. May an institution have more than one IRB? Yes. How does the sponsor protect confidential information submitted to an IRB? The sponsor should designate in the IDE application any information the sponsor believes to be proprietary. A sponsor may wish to negotiate with the institution an agreement in which the institution assures that the IRB members have been advised .of the data's proprietary nature and that the IRB members will not disclose any such information. 105 (24) Who is responsible for the selection of IRB members? The regulation does not specifically address this responsibility. The administration of the institution at which the IRB functions is responsible for the selection process. If an institution has requirements that conflict with FDA's IDE requirements, which requirements prevail? FDA's IDE requirements will prevail, unless FDA grants a waiver. An institution may impose conditions for conducting a study that are additional to FDA requirements, but an institution may not alter, delete, or lessen FDA requirements. Who is responsible for monitoring the composition and continuing performance of IRBs? Institutions have the primary responsibility for this, but FDA must ensure that IRBs operate in accordance with 21 CFR Part 56, the IRB regulation, which became effective July 27, 1981. IRBs are inspected as part of the FDA bioresearch monitoring program. Through training, FDA investigators became familiar with the IRB responsibilities. FDA inspects IRBs that are reviewing significant risk device investigations. Many of these IRBs review nonsignificant risk device investigations, and FDA examines these reviews. What does the term "scientific soundness" mean? This refers to an assessment by an IRB or by FDA about the design of a clinical investigation, A judgment that an investigation is scientifically sound reflects, among other things, that the investigation has specific and well-defined objectives and that it has the potential to yield useful knowledge that warrants exposing patients to the specific risks involved. 106 (25) Q May an institution subject an investigation to several types of review in addition to IRB review, e.g., peer or departmental review? A Yes. An institution may properly withhold approval of an investigation until the protocol has undergone a multifaceted review. FDA requires only IRB approval. An institution may require more extensive review if it decides this is required for patient protection or for any other reason. The IRB serves, however, as the spokesperson for the institution on patient protection. Under the IRB regulation, an institution may not overrule an IRB disapproval. Q How will the IRB regulation (21 CFR Part 56) affect IRBs that were in compliance with the requirements of the IDE regulation? A The IRB regulation exempts any investigation that commenced before July 27, 1981, and that was subject to the requirements for IRB review under FDA regulations before that date, provided the investigation remains subject to review of an IRB that meets the FDA requirements in effect before July 27, 1981. Q How does FDA interpret the term "commence" for purposes of applicability of the IRB regulations? A A clinical investigation "commences" on the date an application for an IDE or IDE supplement is received by FDA or by an IRB, as required. Thus, an IRB reviewing an IDE or IDE supplement received on or after July 27, 1981, must be in compliance with the new IRB regulations. 107 (26) OTHER QUESTIONS Can a sponsor campensate an investigator without creating a conflict of interest? Yes. The campensation of an investigator by a sponsor is not considered conflict of interest. Who decides if a device is ineffective? FDA makes the determination if a device should be approved for marketing as part of its review of safety and effectiveness data. An IRB, a sponsor, or FDA may decide to terminate an investigation prior to its scheduled completion if there is reason to believe that the device is ineffective or unsafe. In an emergency, is FDA approval required before shipping an investigational device to an investigator if that investigator is not part of the investigation or if there is no approved IDE for the investigation? No. FDA allows an investigational device to be used in a true emergency or in a humanitarian situation if the institution or its IRB approves such use in the particular situation. FDA requests notification from the sponsor when an investigational device has been used this way. After completing a clinical investigation in accordance with the IDE regulation, what must be done to obtain FDA approval to market the device? If a device manufacturer believes, according to data obtained from the investigation, that the device is substantially equivalent, the manufacturer should submit a premarket notification known as a 510(k) to FDA. If FDA determines the device to be substantially equivalent, it may be marketed. Devices determined not to be substantially equivalent are automatically placed in class III and must undergo premarket approval or be reclassified into class I or class II before they may be marketed. 108 Extract from an Unofficial Sample Format: Application for an Investigational Device Exemption for a Significant Risk Device mply wit C istry atio m . ns airmen, Morton: Cl ged APPLICATION FOR AN INVESTIGATIONAL Page 1 of DEVICE EXEMPTION TO THE FOCC AND DRUG Copy of ADMINISTRATION FOR A SIGNIFICANT RISK DEVICE (Regulation published in the Federal Register Vol. 45, January 18, 1980, p.p. 3732-3759) Envelope must be labeled “APPLICATION FOR INVESTIGATIONAL DEVICE EXEMPTION." Send three (3) copies of this form and all appendices by registered mail, or hand-deliver, to: Bureau of Medical Devices Document Control Center (HFK-20) Food and Drug Administration 8757 Georgia Ave., Silver Spring, MD 20910 TITLE OF PROJECT: — ss v 5 NAME OF DEVICE: _ — - This project is to be conducted by a separate sponsor and investigator. This project is to be conducted by a sponsor-investigator SPONSORING ORGANIZATION OR INDIVIDUAL MONITOR OF INVESTIGATION (check one) Name: Sponsor Address SE Investigator —___Sponsor-Investigator City: Sr QP ccmmmm—— —OR— Authorized Signature: & Name (print): ER EE Name: Title: To Title: Telephone: ( ) ————— Organization (if any): ___ — PERSON TO CONTACT WITH ADMINISTRATIVE Address: __ _ _ QUESTIONS City: _ — State: at INBIND:. oii imi ————— ira rr Zip: Country Title: co Telephone: ( } Ere ———— Address: —_— i City: State: NATURE OF STUDY Zip: ___ Country: __ EE I Telephone: ( Yc ————————————————— 1. Type of application (check one) PERSON TO CONTACT WITH TECHNICAL QUESTIONS rrr NEW BPRHIEBIOR Name: ah a ee — Aadition to pending application # Title: __ ——— Addition to approved application # Address: 2. Type of research (check one) Feasibility study (new device) . — Modification of an approved device City: Zip: New use for an approved device Telophone: ( C0) Banned device - TT —____ Other (specity): _ MANUFACTURER OF DEVICE (check one) 3. Is the device life supporting? (check one) Sponsor - Yes No Investigator 4. Location of device (check one) Sponsor-Investigator — Implanted External —_OR— 5. Test duration in each subject (check one) — Two weeks or less Name: - — Up toone year Address: Longer than one year City: State: 6. Total number of subjects to be studied under this p41. ES | | |. A application (see Section 2.2A) _ 109 APPLICAT aor ION FOR AN i INV ADMINISTRATION ". THE Foo ava: FOR A SIGNIFICANT RISK K DEVICE Page 2 of Copy sins Of CONTENTS 1.0 REP ORT OF P| RIOR INV ESTIGAT IONS PAGE 11 Bi iblio 2 Rosary. of Published Int 20 13 Cartiicaion ne Nanci Information... IGATION : Nonclini TON} sn sm we A YIRIGIABON +e v1 st reve 21 Purpose L PLAN Laboratory Studies Bisa 22 Protocol 23 Ri www ~ Risk/Benefit Analysis 24 Descri nefit Analysis | mamm— page 3 of ——— “ Copy ——— of —— APPLICATION FOR AN INVESTIGATIONAL DEVICE EXEMPTION T0 THE FOOD AND DRUG ADMINISTRATION FOR A SIGNIFICANT RISK DEVICE NVESTIGATIONS 812.2702) tion (812.27 bd) f published \nforma REPORT OF PRIOR | 14 Bibliography o ublications. whether adverse Of supportive that are relevant to an evalua A en to twe el publications will num! t Provide a bibliography of p tion of the safety and ettectiveness of the device. fice. Review an sur articles are especi \y de able. Assign @ reference citation. (Note that copies of all published al information must be included 8S Appendix G.) 1.0 citation For infor . mation and Mr. Willi /or copies ASAIO om Fl og egulatory Tra man ee c/o Medical . Devi 44 Pierce ice Consultants, Inc Watert ; own, . Massachusetts 02172 (617) 924-8444 fidential. 0 Check this box if and only if material on this page is considered con 110 VIC, wasn, yy DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service a WEALTH © . s %,, nnd Food and Drug Administration 8757 Georgia Avenue Silver Spring MD 20910 JAN 27 1982 Mr. William A. Morton Chairman, ASAIO Standards Committee 44 Pierce Road Watertown, Massachusetts 02172 Dear Mr. Morton: The Bureau of Medical Devices (BMD) has reviewed the draft of the ASAIO Standards Committee's document, How to Comply with the Food and Drug Administration's "Investigational Device Exemption (IDE)" Regulations, Including an Application Form (Revised), that you sent to us for comment. As you know, the Investigational Device Exemption (IDE) regulation does not specify a form on which IDE applications should be submitted. The form prepared by your committee appears to cover the requirements of the IDE regulation published in the FEDERAL REGISTER of January 18, 1980, and amended September 5, 1980; January 27, 1981; and April 10, 1981. We cannot endorse the use of this form. Nevertheless, FDA will accept IDE applications submitted on this form as well as on any other form that provides the information required by the IDE regulation. Your efforts to help clinical investigation sponsors through the development of a common format for IDE applications are commendable. If we can be of further assistance, please let me know. Sincerely, Victor Zafra Acting Director Bureau of Medical Devices 1m A Brief Summary of the GOOD LABORATORY PRACTICE REGULATIONS FOR NONCLINICAL LABORATORY STUDIES FRIDAY, DECEMBER 22, 1978 PART ll DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Food and Drug Administration NONCLINICAL LABORATORY STUDIES Good Laboratory Practice Regulations federal register The Good Laboratory Practice Regulations prescribe good laboratory practices for conducting nonclinical laboratory studies designed to support applications for research or market permits for a number of FDA-regulated products, including medical devices for human use. 113 Nonclinical laboratory studies include any in vivo or in vitro experiments in which a test article is studied in a test system under laboratory conditions to determine its safety. The term "nonclinical laboratory studies does not include: « clinical studies, or studies involving human subjects, or « basic exploratory studies conducted to determine the chemical or physical charateristics of a test article, or whether it has any potential utility. In the case of medical devices, applications for research or marketing permits involving safety data may include: o an application for an investigational device exemption (CFR 812) « an application for premarket approval of a medical device (Section 515, FD and C Act) « a product development protocol for a medical device (Section 515), and « data and information on a medical device submitted as part of required procedures for classifying it (Section 513), or for establishing a performance standard or requesting a variance or exemption from a performance standard (Section 514). For copies of this regulation, contact: Office of Small Manufacturers Assistance (HFK-60) (301) 427-7184 at 8757 Georgia Avenue, Silver Spring, Maryland 20910 <34q 114 # U. S. GOVERNMENT PRINTING OFFICE : 1983 381-177/311 Wiki (028LAB0OSKLS