Investigator’s
Handbook

A Manual for Participants

in Clinical Trials of

Investigational Agents Sponsored by the
Division of Cancer Treatment

National Cancer Institute

Cancer Therapy Evaluation Program
Division of Cancer Treatment |

| National Cancer Institute (v ©)
Bethesda, Maryland 20892
“235283085
Pu
 

Table of Contents

 

 

 

 

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Part A Sponsors, Research Bases, and the Investigator ................... . . . . . | 9
2. The SPONSOT . . oo... 10
2.1 How NCI Funds Research .................... 00 0. 11
2.2 Preclinical Drug Development ...................................... 12
2.3 Collaboration Between Sponsors:
NCI and the Pharmaceutical Industry ..................... .......... 12
2.4 Private Support of Trials Sponsored and Funded by NCI ............... 13
2.5 Private Support of Trials Sponsored but Not Funded by NCI ........... 13
2.6 The Investigational New Drug Application ......................... .. 14
2.7 The New Drug Application ...................cou uuu... 15
3. The Research Base and the Investigator ............................ .. 16
3.1 Definition and Purpose of a Research Base for Clinical Trials. .......... 16
3.2 Activities of the Research Base ..................................... 17
Part B The Development of a Clinical Trial .................. ...... .... .. .. .. ... 21
4. Phase I Trials of Cytotoxic Drugs ........................... IEEE Fhe 22
4.1 Scientific Policies of CTEP ................ 0. i. 2
4.2 Who is Eligible to Study Phase I Drugs ............................. 24
4.3 Which Organizations Can Conduct Phase I Studies. ................... 25
4.4 Who is Eligible to Administer Phase I Drugs ...................... ... 25
4.5 How to Obtain Information About Phase I Drugs. .................... 25
5. Phase II Trials ............. 26
5.1 Scientific Policies of CTEP ................ i. 26
5.2 Who is Eligible to Study Phase II Drugs. ............................ 30
5.3 Who is Eligible to Administer Phase II Drugs ........................ 31
5.4 Restriction on Participation in Phase II Studies ................... .... 31
5.5 How to Obtain Information About Phase II Drugs .................... 31
5.6 The Letter of Intent. .......... 32
6. Phase III Trials. ............ 34
6.1 Scientific Policies of CTEP ................. iii. 34
6.2 Who is Eligible to Conduct Phase III Trials ....................... ... 35
6.3 Coordination of Planning with CTEP Staff ..................... ..... 35
Part C The Planning and Execution of a Clinical Trial ....................... . . .. 37
7. The Drafting of a Protocol ....................................... . 38
7.0 Title Page o.oo 38
7.2 The Essential Elements of a Protocol ................................ 39
7.3 Informed Consent ............ 42
7.4 Model Protocols . ......... 42
8. Protocol Review and Approval at NCI. .............................. 43
8.1 The Protocol and Information Office. ............................... 43
8.2 How to Submit a Protocol .............. 43
83 IRB Approval ...... 44
8.4 Protocol Review ........... 44
8.5 Protocol Approval .......... 46
 

Table of Contents (continued)

 

Part D

 

8.6 AMENAMENLS . «© ott ttt tee ee 46
8.7 Reactivation of Studies ..........iut iii 47
B.8 Study SAMS «vvvvnrivs smsms sims AIBA IRIE ERI BITS Hom an ww ww nn 47
9. Ordering Investigational Drugs from NCI ............................ 48
9.1 How to Place Drug Orders... 48
9.2 Particular Points tO NOE .. o.oo ee 49
9.3 Routing of Drug Requests ...: sins nsurrmsnssmimammrnommrmen san snes 49
0.4 Affiliates and Drug Orders... :csivissistnvsmspsmarminme manne nom es 50
9.5 Requests for the Non-Protocol Use of Investigational Drugs ............ 5
0.0 THC OFURIS. ov vr cnvcrmumn vmsmesmoin sasma sme Ridhimamash gos ems es 51
9.7 Requests for Non-Clinical Use of Investigational Drugs ................ 51
10. Responsibility for Reporting of Results to CTEP ...................... 52
10.1 IOEOAUCHION. © «cvvvvmvcmr mama vm rmr emis bs BREE EHEB ES BREESE men 52
10.2 Reporting Requirements of Phase I Trials ............................ 53
10.3 Reporting Requirements of Phase II and III Studies ................... 54
10.4 Retention of Records ....... coun 55
10.3 Reporting T0 IRDBS w.oviviusnmrmimnimsmmemaamomeas enews oman ss sms bu 55
11. Adverse Drug Reactions ...................c..oiiirriiinunnnnnnnnn. 56
11.] Phase 1 Studies. cv mvcm sms nme sos is imi a cREMEE $Rsms s MID sw simn vn 57
11.2 Phase land 111 Studies ..........ci vi iviririvnsesrvrnnrvnmnsnsnnss 57
11.3 Where tO RePOIt. . oot e tte eee 58
11.4 Adverse Drug Reactions with Non-Investigational Drugs. ............... 58
11.5 Adverse Drug Reactions and Routine Reporting of Toxic Events ......... 58
11.6 Actions Taken by CTEP on Reports of Adverse Drug Reactions ......... 58
The Organization of a Clinical Trial ..................................... 61
12. The Investigator and Protocol Chairman:
Roles and Responsibility .............. 62
12.1 The INVESHIZAtOT . . oot i tee e ee ee eee eee 62
12:2 The Protocol. CRAITNAN: oss ss mem ms ms amass sess sm meme mem sins nn oom 64
13. Affiliate Investigators. . ............ 65
13.0 Definition ....oviiiiiii iinet tern rinresasarunananaannsens 65
13.2 Requirements of an Affiliate Investigator. ............................ 66
13.3 Responsibilities of Affiliate Investigators .................. nt. 66
13.4 Responsibilities of Research Bases for Affiliates ....................... 67
14. Who May Administer Investigational Drugs .......................... 68
14.1 Restrictions to Physicians Registered as Investigators with CTEP ........ 68
14.2 Administration of Investigatioal Drugs by Non-Registered Physicians... .. 69
15. Accountability and Storage of Investigational Drugs ................... 70
15.1 Procedures for Drug Accountability and Storage ...................... 70
152 Drug RetUINS .....oivvi iii iiiiir inna sansasnneaanasssannnans 71
15.3 Verification of Compliance ...........coviiiiiviniuraenrrerreesenns 71
15.4 Handling of Antineoplastic Agents ...............oooiiiii een. 71
16. Monitoring and Quality Assurance ................... 72
101 INLTONUCHION «sn anno as Bon 53 TEBE HED ANE LES Ewa wa swan #0 da 72
16.2 Protocol Compliance ........ cuir iineearnririarasenanas 22
16.3 DAA ACCUTACY + «vv vr vn sms nn sme sme sens isinensonivonnessnss vanes 73
16.4 Procedural RequUIr€mMents . . .......ouuiuit teas 73
16.5 Components of the Quality Assurance Program
Implemented by CTEP ........oivtivnimivrsnivmmnrninccnianimsni ns 74
16.6 Informed Consent and the Monitoring Program. ...................... 76
16.7 Dealing with Problems Identified at Site Visits ........................ 77
 

 

Part E

 

Non-Research Use of Investigational Drugs ............................... 79
17: OUOUP TC i ininvini nth imi ime is i oimaibt me rms mr dmn mins ohn nn me has 80
17.1 Definition ...... oi 80
17.2 Placement of a Drug into Group C ................ iii... 80
17.3 Current Group C Drugs ..........couiiii 80
17.4 Use of a Group C Drug .........oo iii 80
17.5 Requesting a Group /C DIU. oc cuv vis iotmsimims sme ns is eosmbanans ne 81
17.6 Responsibilities When Using Group C Drugs ......................... 81
18. Special Exceptions .............. 82
18.1 Definition .... o.oo. 82
18.2 Criteria for Approval of a Special Exception Request .................. 82
18.3 Requesting a Special Exception Drug ...................... 0.0... 83
18.4 Responsibilties of Physicians Administering

Special Exception Drugs ............o i 83
APPENdices. . . ..... 85

I. Policy Statement - Relationships Between the Pharamaceutical Industry

and Therapeutic Trials in the Clinical Cooperative Groups Supported

by the National Cancer Institute. ....................c.vuuurnon... 89
II. Policy Statement on the Conduct of Phase I Trials in Children. ....... 95
I. ‘CTEP Organizational CHAIL. ; cs wuivsnsins stint anim ins ins@edni®s 101
—List of Key Addresses and Telephone Numbers. .................. 102
IV. FDA Statement of Investigator (FDA-1573)........................ 105
V. New Drug Studies Group Application Guidelines. .................. 109
VI. Letter of Intent Submission Form................................ 113
VII. Informed Consent Checklists. .................................... 117
Vill. Protocol Submission CHecKiSIS. ..ocusniamsmiis mr sninsatnsmnsnsm 121
LX: CTD ClOSSATY csv 25 sma 05.05.4655 5 8mm bw em are wesw wns wm wos v tom 0 9 04 000 125
X. Clinical Drug Request (NIH-986)................................. 131
XI. Revised Guidelines for Reporting Adverse Drug Reactions. ........... 135
—Drug Experience Report (FDA-1639). ............................ 141
XII. NCI Investigational Drug Accountability Record Form. ............. 145
XIII. Recommendations for Handling Cytotoxic Agents, National Study
Commission on Cytotoxic Exposure. ............................. 149

XIV. NCI Procedure for Management of Investigational Drugs Acquired

for Compassionate Treatment of Individual Patients................ 157
 

1. Introduction

 

Over the past few years the Division
of Cancer Treatment (DCT), National
Cancer Institute (NCI), has developed
policies concerning various aspects of
clinical drug development. They are
intended to ensure patient safety and
to provide the National Cancer
Program with the most effective drug
development program possible. In this
handbook, we explain the policies and
procedures of the DCT with respect to
the clinical use of its investigational
drugs. Some DCT policies are a direct
result of the regulatory requirements
of the Food and Drug Administration
(FDA) and the Department of Health
and Human Services (DHHS). Others
are not directly mandated by law or
regulation but are the result of a
consensus among DCT staff, the DCT
Board of Scientific Counselors and
leaders in the community of clinical
investigators.

We have also described in this volume
the specific procedures that the NCI
has in place to implement its policies.
Oncologists, nurses, pharmacists,
research administrators, and data
managers should find the information
presented here of assistance in
practical matters connected with
protocol writing and submissions,
reporting requirements, drug account-
ability, and a host of other subjects.
Specific policies and procedures are
constantly in evolution; through them
NCI aims to provide a flexible and
responsive system within the con-
straints imposed by regulation and the
size and scope of the program.

With respect to drug development, the
NCI acts both as a funding agency
and as a sponsor (in the sense used
by FDA) of clinical research. The
DCT has broad responsibility for this
effort. Within the DCT the Cancer
Therapy Evaluation Program (CTEP)
designs and implements the develop-
ment plans for new agents. Aside
from the purely scientific and medical
issues involved in such planning,
CTEP utilizes two particular adminis-
trative tools: (a) it files Investigational
New Drug Applications (INDs) with
the FDA permitting DCT to act as a
drug sponsor; (b) it is responsible for
the contracts and cooperative agree-
ments under which most clinical
testing takes place. In this handbook
we shall refer to DCT as the drug
sponsor and the ‘‘proprietor’” of the
drug development program. We shall
refer to CTEP wherever the efforts of
CTEP staff specifically come into
play. We shall reserve the use of NCI
for more general contexts including
overall support of clinical trials.

We welcome the reader’s comments
on the content of this volume and
how future editions may be made
more useful.

Daniel F. Hoth
Robert E. Wittes
 

 

 

Part A

 

Sponsors, Research When investigators perform DCT in the conduct of
Bases, and clinical trials two Orgsnize: Sinica! Iria ve A ci
: tions are crucial—the spon- iscuss the vital role of the

the Investigator sor of the trial and the research base in support of
research base. The next two the investigator. As is the
sections discuss the pur- case with all types of
poses and features of each. research, clinical trials
In particular we describe cannot take place without
the role of the DCT as a a substantial institutional
sponsor of investigational commitment.

drug trials; as a sponsor
DCT is responsible for the
overall direction of the
process of drug develop-
ment, as well as its prac-
tical implementation. Of
course, DCT is not the
only sponsor of trials
involving new anticancer
agents; the activity of
private pharmaceutical
firms has increased drama-
tically in recent years. We
outline here the basis of
the relationship among
DCT, private firms, and
investigators supported by

 

 
 

2. The Sponsor

 

10

The development of new anticancer
agents is a long and complex process.
Successes have been significant. The
fact that many aggressive neoplasms
are now curable with chemotherapy is
the best possible evidence that agents
with selectivity against cancer can be
identified and used effectively. On the
other hand, oncologists are well aware
that for many common tumors sys-
temic treatment is unsatisfactory. The
motivation to develop better therapy is
therefore as powerful as ever. With the
increased understanding of the malig-
nant process, due to recent and future
advances in molecular biology and
biochemical pharmacology, there is
every reason to expect that drug
development will proceed along
increasingly rational lines in the
future.

The process of drug development is
often divided into preclinical and
clinical components. Although this
division is operationally useful, it
should be recognized that a continual
interplay and crossfeeding exists
between the preclinical and clinial
arenas. Evidence of synergy or of the
effectiveness of combined modality
approaches in experimental models,
for example, has provided the major
motivation for a very large number of
clinical trials. The converse is also
true; clinical observations have from
time to time given rise to new lines of
basic investigation.

Historically, the most important effec-
tor in the discovery and development
of new anticancer agents has been the
NCI. The prominence of NCI’s role
in cancer drug development has no
parallel elsewhere in developmental
pharmacology. The justification for
such intensive involvement of a
government agency in research and
development is clear: significant
improvement of cancer treatment is in
the public interest and in the past

there has been insufficient involvement
on the part of the pharmaceutical
industry. This is in contrast to the
impressive role of the private section
in the development of many other
classes of drugs, such as antibiotics,
anti-inflammatory agents, and endo-
crine agents. Current trends suggest
an increasing interest by industry in
anticancer drugs. Even so, NCI re-
mains the largest sponsor of research
with antineoplastic agents; currently
well over 100 compounds are in
various stages of clinical testing, and
a far greater number are in preclinical
development.

As part of this massive effort the NCI
funds a clinical trials network which
includes cooperative groups, new drug
development contractors, and other
investigators at cancer centers and uni-
versity hospitals. More than 5000
investigators from about 500 insti-
tutions participate in this effort.

In the United States, clinical research
with experimental drugs is closely
regulated. The ultimate authority for
assuring the safety of the public in
matters relating to drugs and medical
devices rests with the Food and Drug
Administration. FDA regulations,
which are specific implementations of
the Food, Drug and Cosmetic Act,
define the terms under which clinical
work with experimental agents may
proceed. Since these regulations have
the force of law, they must be heeded
by all those involved in clinical trials
with investigational agents, including
NCI, pharmaceutical firms, and inves-
tigators. An organization or individual
who assumes legal responsibilities for
 

 

= 2.1 How NCI Funds
Research

supervising or overseeing clinical trials
with investigational agents is termed a
sponsor. In the United States the DCT
and private pharmaceutical firms
sponsor such research in cancer. The
designation obviously implies a sub-
stantial commitment of resources.

In addition, the Public Health Service
Act mandates a number of safeguards
for the rights and welfare of individ-
uals who are involved as subjects of
the research. Regulations of HHS,
administered by the Office for Pro-
tection from Research Risks (OPRR)
at the National Institutes of Health
(NIH), specify the requirements to
ensure adequate protections for
human subjects. Clinical investigators
and institutions taking part in the
clinical trials network are responsible
for meeting the requirements of the
HHS regulations.

As sponsor of an investigational drug,
DCT, and specifically CTEP, is re-
sponsible for seeing that clinical trials
proceed safely and rationally from the
initial dose-finding studies through to
a definitive evaluation of the role of
the new drug in the treatment of one
or more specific cancer(s). Fulfillment
of this goal obviously requires the
active participation of CTEP staff
throughout the entire process.

A full discussion of the means by
which the NCI funds research is
beyond the scope of this handbook.
Whether support by grant, contract,
or cooperative agreement, however, the
process of peer review is central.
Government officials can only provide
monies to investigators in the context
of mechanisms involving peer review;
this process requires formal applica-
tion by the investigator and (usually)
multiple levels of evaluation. Once an
application is approved the NCI
cannot provide more funding than is

stipulated by the judgment of peer
review and the National Cancer
Advisory Board. Additional awards
can, of course, be made after review
and formal approval of a supplemen-
tal application. The provision of drugs
for clinical studies is a separate issue
and does not imply that NCI will
provide funding for these same
studies.
 

 

= 2.2 Preclinical Drug
Development

= 2.3 Collaboration
Between Sponsors:
DCT and the
Pharmaceutical
Industry

12

The DCT could not effectively
accomplish its overall aims in drug
development without a very extensive
preclinical effort. The Developmental
Therapeutics Program (DTP), and the
Biological Response Modifiers
Program (BRMP), within the DCT
are both heavily committed to the
discovery and development of new
antineoplastic agents. Readers are
referred to a summary of the objec-
tives, methods, and status of DCT’s
preclinical drug development program
in Driscoll, JS: The Preclinical New
Drug Research Program of the
National Cancer Institute, Cancer
Treatment Reports, 68: 63-76, 1984.

At present many anticancer drugs in
clinical development by CTEP are
also being developed by a pharma-
ceutical firm. Although the involve-
ment of the pharmaceutical industry
in research on antineoplastics is not
new, the maturing of medical
oncology as a specialty and the
advent of successful drug treatment of
many cancers has stimulated
industry’s interest in cancer treatment
to an unprecedented degree.

Collaboration between DCT and the
pharmaceutical industry may occur at
any step along the drug development
process. Private firms often submit
compounds to DCT for testing and
joint development. Compounds may
be submitted for antitumor screening,
for preclinical toxicology, or for
clinical testing. Conversely, if a
compound is discovered by DCT, the
involvement of a private firm is
sought as early in development as
possible, since DCT does not take
drugs to market. The early involve-
ment of a pharmaceutical firm
permits substantial cost sharing
between public and private sectors,
and can hasten by several years the
availability of effective drugs for all
cancer patients.

Development plans for a new agent,
therefore, are often a collaborative
effort between DCT and a private
firm. These plans are heavily influ-
enced by the findings and opinions of
the clinical investigators working with
the agent. In this joint effort, DCT
and the private sector share the com-
mon goal of defining the contribution
of a new agent to cancer treatment as
expeditiously as possible. However,
since the “‘bottom lines’ of DCT and
a pharmaceutical firm are clearly
different, the DCT may be more will-
ing than a private firm to sponsor
certain kinds of exploratory trials that
will not lead directly to FDA approval
of new or extended indications.

The three-way relationship among
clinical investigators, the DCT, and
private industry involves complex
problems in coordination, in estab-
lishing priorities, and in the allocation
of limited resources. To facilitate the
necessary interactions, CTEP has
developed a policy on the nature of
the relationship between the partici-
pants. The policy, which formally
recognizes the involvement of the
private sector in the support of
clinical trials, is articulated in a
document entitled ‘Policy Statement-
Relationships between Pharmaceutical
Industry and Therapeutic Trials in the
Clinical Cooperative Groups
Supported by the National Cancer
Institute’ (see Appendix I).
 

 

= 2.4 Private Support of
Trials Sponsored and
Funded by NCI

= 2.5 Private Support of
Trials Sponsored but
not Funded by NCI

As private support for clinical trials in
cancer becomes more widespread,
investigators holding grants, contracts,
or cooperative agreements from the
NCI should carefully consider what
are the allowable allocation of re-
sources provided by a private sponsor
for a trial already having NCI sup-
port. Investigators must make certain
that Federal funds are not used to
cover those costs of research that are
also supported by private resources.
Grants management personnel at the
NIH and auditors from the DHHS
are required to scrutinize such
arrangements closely and may take
steps to recover Federal funds that
have been used inappropriately.

In the specific case of the clinical
cooperative groups the Terms of
Award of NCI’s agreements with the
groups have been modified to permit
them to accept industrial support,
provided that industry funds are used
for the support of additional costs
generated as a direct result of the
interest of a pharmaceutical firm in a
particular clinical trial. Such costs
might include additional laboratory
tests or special requiremeats for data
collection.

In the case of trials funded under
Phase I and Phase II/III contracts,
the provision of resources for tasks
not supported by Federal funds may
or may not be appropriate; all such
agreements should be submitted to the
contracting officer for prior approval.

Private support of an unfunded trial
sponsored under an IND held by
DCT may be appropriate under cer-
tain circumstances. However, there
should be a written agreement be-
tween the protocol chairman and the
private firm; this agreement should
also be sent to the Chief, Investiga-

tional Drug Branch (IDB), CTEP. In
general, CTEP will favor the provision
of data from trials of this kind to a
private firm. These arrangements may
not be exclusive, (i.e. may not serve to
prohibit the supply of data to another
party) however, unless CTEP has pre-
viously agreed with the firm that
exclusivity is appropriate. In any case
the obligations of the investigator to
DCT as the sponsor, as detailed
throughout this handbook, remain
unchanged.

13
 

 

= 2.6 The Investigational
New Drug Application

14

Any organization seeking to sponsor
clinical trials with experimental drugs
must first submit an IND to the
FDA#* The IND is the legal
mechanism under which experimental
drug research is performed in the
United States.

No experimental drugs may be
administered to patients for research
in the U.S. without an IND. *

All sponsors have obligations specified
in regulations of the FDA. The DCT,
as a component of an agency in the
DHHS, is just as accountable as a
pharmaceutical firm for meeting
FDA’s IND regulations.

*The use of the term sponsor is generally
reserved for organizations assuming broad
responsibilities for the development of a drug. It
is also possible, but unusual, for an individual
investigator to hold an IND.

+ An IND must be filed to perform clinical
studies under the following conditions:

1. When an investigational agent is manu-
factured in one state or country and trans-
ported to another state or country for
clinical use.

2. When the bulk material (or components of
the agent) is manufactured in one state or
country and transported to another state or
country for further processing, formulation,
or for final fill.

Although situations arise in which an agent is
manufactured and tested within a state, tech-
nically, if any component of that clinical
product (from the diluent to the vials and
labels) is obtained from another state or
country, the FDA could require an IND to be
filed and all the requirements to be adhered to.

The initial IND submission by the
sponsor to FDA is a lengthy docu-
ment that sets forth the experimental
rationale for human testing, including
results of animal toxicology studies,
manufacturing data, purity and
stability information, and an initial
plan of clinical investigation.

After a sponsor has submitted an
IND, the FDA has 30 days to com-
plete its review. If FDA has any
objections, it may place a hold on the
initiation of any or all clinical trials
with the agent. In highly unusual
circumstances, the sponsor may
request a waiver of the 30-day waiting
period. Please note that these are
matters between the sponsor and the
FDA. No investigator may initiate
patient treatment on a protocol using
DCT drugs until receiving written
notice of approval from CTEP.

The IND is the official record at the
FDA of the sponsor’s clinical research
with the drug. Under FDA regulation,
CTEP must maintain the IND as an
accurate, timely repository of all infor-
mation concerning clinical use of the
drug, including all protocols, adverse
reactions, and an annual report of the
results of all clinical trials, plus any
new relevant preclinical (particularly
toxicologic) data. Obviously this
means that there can be no use of the
experimental drug without the knowl-
edge and prior approval of the
SpONSOT.
 

 

» 2.7 The New Drug
Application

After clinical trials have shown that
the new drug is safe and effective,
there is reason to make the drug
generally available to patients and
physicians. The formal process in the
U.S. by which this occurs is the
approval by FDA of a New Drug
Application (NDA) submitted by a
private sponsor; as noted previously
the NCI does not submit NDAs since
it does not market products. The
applicant seeks FDA's approval for
one or more specific indication(s).
Review and approval of an NDA is
based on the demonstration of safety
and efficacy assessed from detailed
reports of the clinical trials, parti-
cularly randomized controlled studies.
The contribution of a new drug in the
treatment of a disease is demonstrated
unambiguously if the drug is the only
variable between the treatments.

The specific endpoints which consti-
tute satisfactory evidence of efficacy
(e.g., response rate, quality of life,
survival) are a matter of continuing
discussion. On the advice of its
Oncologic Drugs Advisory Committee
(a panel of outside experts in clinical
oncology), the FDA has tended in re-
cent years not to regard tumor shrink-
age per se as important evidence for
efficacy in the absence of a positive
measurable effect upon survival or
quality of life. The subjective nature
of many assessments of quality of life
has made it an infrequently used basis
for an NDA. Clearly the least
controversial and most stringent
measure of efficacy is a survival bene-
fit for the population treated with the
new agent. Although FDA regulations
do not strictly require that a demon-
stration of increased survival be by
randomized controlled trials, the
FDA's guidelines make clear that this
study design is certainly the preferred
one whenever feasible.

The approval of the NDA is a critical
milestone not only for the pharma-

ceutical firm but also for the clinical
investigator, the practicing oncologist,

the NCI, and the general public. An
affirmative decision by the FDA
permits the pharmaceutical firm to
market and promote the drug for the
approved indication(s). Once a drug is
marketed, no Federal regulation pre-
vents any licensed physician from
prescribing it for any indication
he/she deems appropriate.

For the practicing oncologist, NDA
approval means that the drug is
readily available for routine treatment
of patients. The practitioner no longer
has to devise protocols without re-
search intent, simply for the purpose
of obtaining the drug for patient care.
No longer must he/she use the cum-
bersome procedures for obtaining
compassionate INDs from the FDA to
treat individual patients.

For the clinical investigator, NDA
approval means that it may be more
difficult to recruit patients for further
clinical trials with the drug, since use
of the drug is no longer restricted to
patients on research protocols.

For the NCI, NDA approval marks a
step forward in the development of
effective cancer therapies. Although
DCT’s role as a sponsor of clinical
trials focusing on the approved agent
usually decreases dramatically at that
point, the NCI continues to sponsor
further research with commercially
available drugs through its general
support of clinical trials.

For the general public NDA approval
means that a new effective agent is
now available on the widest possible
basis. It is admittedly also true that a
drug that was formerly available
without cost for research purposes is
no longer free to the patient after
NDA approval. For financial reasons
the DCT has found it necessary to
discontinue the distribution of vir-
tually all marketed drugs, except for
certain clinical trials of particularly
high priority.

15
 

3. The Research
Base and
the Investigator

 

= 3.1 Definition and
Purpose of a Research
Base for Clinical Trials

A research base is an entity which
assumes a broad range of responsi-
bilities and functions for the support
of clinical trials conducted under its
name. Examples of research bases in-
clude cancer centers and cooperative
groups. The research base supports
the investigator in developing,
organizing, implementing, and
analyzing clinical trials. It assumes
responsibility for the quality of the
research, both in concept and
execution, and has an important role
in assuring patient safety.

An effective research base enhances
the investigator’s research in several
specific ways. It provides assistance in
developing protocols and obtaining
approval by sponsoring agencies. It
often offers centralized data manage-
ment and statistical consultation. An
effective research base should also
provide the opportunity for internal
peer review and quality assurance.

Obviously the research base enhances
its own scientific credibility by assum-
ing responsibility for the quality of
the scientific ideas and the care with
which they are tested. These activities
may also be an economical way of
supporting multiple clinical inves-
tigations simultaneously.

In short, a research base provides an
institutional source of support and
assistance for the activities of protocol
chairmen and investigators. Clinical
cooperative groups are examples of
research bases whose functions are
described in this section. Many of the
same considerations about organiza-
tion for support of clinical research
apply to any cancer center or single
institution.
 

 

a 3.2 Activities of the
Research Base

The research base may assist the
clinical investigator in many activities
and may assume primary responsi-
bility in several.

3.2.1 Protocol Development

3.2.1.1 Scientific Review - Many
research bases have procedures for
review of the science of a clinical
trial, either at the concept stage or at
the time a protocol is written. This
review is distinct from the task of the
Institutional Review Board (IRB),
which may or may not view as part

of its charge a critical scientific review.

Ideally, a scientific review assists the
investigator in focusing his/her ideas
and perhaps in identifying other
useful scientific resources within the
research base. This process should
facilitate research and assist in the
testing of new ideas. Careful review
may be particularly important for
Phase III trials, because of the very
substantial commitment of time,
patients, and resources involved.

3.2.1.2 Biostatistical Consultation -
The design of a Phase II or III trial
should be based on sound statistical
principles. Issues such as sample size,
stopping rules, endpoints, and the
feasibility of relating endpoints to
objectives are pivotal to a successful
trial. Statistical expertise should be
provided by a research base.

3.2.2 Protocol Administration - Since
most protocols require multiple levels
of approval, and since policies of the
various sponsoring agencies may differ
and change with time, a research base
can provide valuable assistance to the
investigator in obtaining these ap-
provals. Establishment of a centralized
mechanism for submitting and track-
ing a protocol through the necessary
approvals, including the IRB, saves
individual investigators a very large
expenditure of time and effort that is
much better directed elsewhere. A
research base with multiple CTEP-
sponsored protocols could efficiently
assume the responsibility for com-
municating status changes, amend-
ments, results reports, publications
and other pertinent protocol
administration information to the
CTEP.

17
 

 

18

3.2.3 Establishment of an Affiliate
Program - The participation of
affiliate investigators often contributes
to the success of cancer clinical trials.
The research base must be as con-
cerned about the quality of research
performed by its affiliate investigators
as that of its own staff.

CTEP has established a set of guide-
lines to assist research bases in devel-
oping a policy toward affiliate investi-
gators (see Section 13). Each research
base participating in investigational
drug trials sponsored by DCT should
develop its own affiliate policy in
accord with these guidelines. This
policy should be submitted to the
Head, Quality Assurance and Compli-
ance Section (QACS), RAB, CTEP.

The most important components of
these guidelines are that the research
base should, (a) define qualifications
necessary for affiliate investigators and
(b) periodically review their perfor-
mance. Such reviews of performance
should include site visits by investi-
gators from the research base.

3.2.4 Drug Accountability and
Storage - Although FDA regulation
places the responsibility for maintain-
ing accountability for the use of
investigational drugs with the inves-
tigator, an institution may assume
these responsibilities for the inves-
tigators on its staff and assure itself
of compliance with Federal require-
ments (see Section 15).

3.2.5 Reporting of Results to CTEP -
The results of trials involving IND
drugs must be reported to the spon-

sor. The cooperative groups, as
research bases, inform CTEP directly
of their results. In all other cases,
such reporting is the responsibility of
the protocol chairman (see Section
10).

3.2.6 Data Management and

Statistics - Since most cancer clinical
trials involve professional staff other
than the protocol chairman, adequate
collection of clinical data is a complex
task which must be integrated into the
medical practices of the institution.
Furthermore, data collection is best
done as data are generated; this
practice promotes protocol compliance
and permits the protocol chairman to
monitor the study’s progress. For
these reasons, data management
organized and supported at the
department or institution level is
usually more efficient and reliable
than that which is left to the
individual investigator. Centralized
data management is obviously not
required of institutions performing
NClI-supported trials but its
advantages seem clear. In the
experience of CTEP’s site visit
monitoring program (see Section 16)
the quality of execution of clinical
trials is better in institutions that
provide central support for data
management.
 

 

3.2.7 Quality Assurance - This term,
as discussed in detail in Section 16,
applies to three features of the
conduct of clinical trials.

a Data Accuracy - Is the data in the
research record an accurate reflection
of the primary medical record?

» Protocol Compliance - To what
extent was the protocol followed?
Are the reported results based on
the treatment set forth in the
protocol? If not, was there good
reason for departing from the
protocol and are these reasons fully
documented in the research records
and any resultant publications?

= Procedural Requirements - Were all
necessary approvals obtained? Was
the informed consent process
adequate?

A quality assurance program permits
the research base to satisfy itself that
each participating investigator is
fulfilling his responsibilities. It also
provides the research base with data
about the quality of execution of its
clinical research, and it provides the
investigator an opportunity to learn
from an external evaluation of his
performance. In its most constructive
form, this process constitutes a peer
review of performance and improves
the quality of clinical research.

The implementation of these activities
takes many forms. Section 16
describes the existing procedures of
the cooperative groups and CTEP for
quality assurance. Although CTEP
does not require single institutions to
establish internal quality assurance
programs, the inclusion of this subject
in this section is intended to draw
attention to the potential value of this
activity for any research base. CTEP
staff will assist any research base
which desires assistance and advice in
developing these programs.

19
 

Part B

The Development
of a
Clinical Trial

The following three
sections explain CTEP
policies for each phase of
clinical investigation with
experimental drugs. For
each phase we outline our
scientific objectives as a
drug sponsor. We also
describe which physicians
are eligible to study and
administer investigational
drugs. These two aspects
of drug use—study and
administration—are for-

mally quite separate issues.

In general, eligibility to
study NCI investigational
agents is restricted to
institutions and physicians
approved by peer review;
these individuals may in-
clude new drug develop-
ment contractors, coopera-
tive group members, phy-
sicians affiliated with
approved cancer centers,
and recipients of investi-
gator—initiated clinical
research project grants
(ROI, POI). The applica-

 

tion of this general rule to
each phase of drug devel-
opment is explained in
detail. Except in certain
explicitly defined circum-
stances outlined in the
following sections, the
administration of experi-
mental agents is restricted
to these investigators.

We also describe how
investigators may obtain
information about
individual experimental
drugs and CTEP plans for
their development.
 

4. Phase 1
Trials of
Cytotoxic Drugs

 

= 4.1 Scientific Policies
of CTEP

22

4.1.1 Planning of Phase I Trials -
CTEP prospectively plans the Phase 1
development of each drug. Selection
of schedules for clinical trial is based
on experimental data (see 4.1.4 for
details). Usually each schedule is
examined in not more than two
studies. From the results of the Phase
I and clinical pharmacology studies,
CTEP and its collaborating investi-
gators decide which schedules are to
be taken into Phase II. If the need
exists, a second schedule may later be
examined comparatively in selected
tumors to better define the therapeutic
index.

4.1.2 Objectives - Phase I trials
determine a safe dose for Phase II
trials and define acute effects on
normal tissues. In addition, these
trials examine the drug’s pharma-
cology and may reveal evidence of
antitumor activity. Therapeutic intent
is always present in Phase I trials;
indeed, anticancer drugs are not tested
in patients unless preclinical activity
studies have already demonstrated
evidence of significant activity in
laboratory models.

Animal toxicology studies carried out
prior to Phase I trials provide the
investigator with (a) estimates of a
starting dose for clinical trials and (b)
prediction of the likely effects of the
drug on normal tissues. These data
provide the investigator with clues
which help focus clinical observation
of the patient. The dose is increased
gradually by some defined procedure
until a level is found which produces
limiting but tolerable toxicity and/or
clear signs of therapeutic activity.
Phase I trials define acute effects that
occur with a relatively high frequency
on normal tissues.

Continued careful observation during
Phase II and III trials is essential to
identify less frequent acute toxic
effects, as well as cumulative and
chronic toxicities.

4.1.3 Patient Selection - Patients
eligible for Phase I must have con-
firmed malignant disease which is not
amenable to conventional forms of
therapy or for which there is no
standard treatment. Patients should
have normal organ function, in order
that the investigator may reliably
distinguish drug effects from disease
effects. When there is impairment of
a major organ, drug treatment may
produce increased toxicity because of
decreased clearance or additive injury
to the organ. Since most cancer drugs
will ultimately be used in some
patients having impairment of major
organ function (particularly cardiac,
hepatic, and renal) it is reasonable to
explore their use in such patients
through Phase I trials explicitly
designed to determine safe doses and
pharmacology in these settings. CTEP
will consider sponsoring such trials
selectively after the initial trials in
patients with normal organ function.

4.1.4 Schedule Selection - The number
of separate schedules studied in Phase
I is determined by several factors,
including evidence of schedule
dependency in experimental in vivo
systems, pharmacokinetics, mechanism
of action if known, and existing
clinical data with similar compounds
suggesting superiority of a particular
schedule.

Drugs which are highly schedule-
dependent in preclinical models are
usually brought into Phase I on the
putatively optimal schedule.

Since the correlation between schedule
dependency in preclinical models and
in the clinic is not firmly established,
however, some drugs may be candi-
dates for a broader array of schedules.
DCT is prospectively evaluating the
ability of experimental models to
predict the schedule dependency of
efficacy, toxicity, and pharmaco-
kinetics. For drugs showing no
 

 

particular schedule dependency in
models, two extremes of schedules
(e.g., single bolus dose per course and
5-day continuous infusion) are
generally examined.

4.1.5 Starting Dose - The starting dose
of a Phase I trial, as derived from
preclinical toxicology, is 1/10th of the
MELDj( (mouse equivalent of the
LDjo) in mg/m 2, unless that dose is
toxic in any species tested; in the
latter case the trial begins at a lower
dose that has been shown to produce
no more than minimal and reversible
effects in the most sensitive species
tested.

4.1.6 Dose Escalation - Doses are
escalated according to a scheme in
which the initial increments are large
and decrease rapidly as biologic
effects become evident. Most com-
monly a modified Fibonacci plan is
employed. The exact schema may be
affected by the steepness of the dose-
toxicity curve in animal models. In all
cases the goal is to arrive at the
recommended Phase II dose with the
fewest number of escalations consis-
tent with patient safety; this procedure
minimizes the number of patients
receiving biologically inactive doses.
The DCT is actively evaluating alter-
nate methods of dose escalation,
based on the use of blood level data
(see below).

At each dose level a minimum of
three patients not previously treated
with the new drug should be entered.
Escalation to the next level should not
occur until the safety of the current
level has been established. Usually this
means that at least three patients each
will have been observed for the entire
course interval (e.g., 3-5 wks).

4.1.7 Pharmacokinetics - The role of
pharmacokinetics in Phase I is now
receiving increasing emphasis, with
specific focus on the possible use of
such data to guide dose escalation.
Human data on the pharmaco-
kinetics of a parent compound and
active metabolites, taken together with
similar preclinical data in vivo, will be
extensively analyzed over the next
several years of Phase I trials to
identify new approaches to dose
escalations. This work is being
coordinated by the Blood Level
Working Group, composed of
investigators in several programs of
the DCT. Investigators developing
Phase I trials should consider
pharmacokinetic determinations an
integral part of a Phase I study. Since
this may be limited by the availability
of suitable methodologies, investi-
gators should check with the IDB
drug monitor before writing a
protocol.

23
 

 

= 4.2 Who is Eligible to
Study Phase I Drugs

24

4.2.1 Contractors - CTEP’s primary
resources for Phase I trials are institu-
tions awarded contracts for these
studies. Principal investigators are
selected through competitive peer
review in response to periodic solici-
tations from DCT* These contracts
are usually awarded for 3 to 5 years.
DCT has two distinct contract
programs for Phase I trials:

= Phase I/pharmacokinetics of
cytotoxic agents in adults.

= Phase I trials of biologic response
modifiers in adults.

4.2.2 Ad Hoc Phase I Investigators -
Under unusual circumstances, other
qualified investigators may be selected
by CTEP to perform a Phase I study
of a particular drug. Such studies are
unfunded (see Section 2.1). Investiga-
tors may be selected because of
unique expertise or research experience
relevant to the drug, the availability of
certain patient populations, or labora-
tory facilities to perform special
studies. In all cases such investigators
must have demonstrated competence
to conduct a Phase I study with
anticancer drugs.

Ad hoc Phase | investigators must
fulfill all CTEP requirements for trials
conduct, as defined in this section,
and for reporting of data as described
in Section 10.

*When NCI seeks offerors for a contract, it
issues a Request for Proposal (RFP). Notices of
the availability of RFP are published in the
“NIH Guide to Grants and Contracts)” which is
widely distributed to universities in the U.S.
They are also announced in the ‘Commerce
Business Daily,” which announces all U.S.
Government contract solicitations.

An investigator wishing to perform an
ad hoc Phase I trial should send a
letter to the Chief, IDB, CTEP,
outlining the proposed study in
concept and identifying the specific
capabilities unique to the proposal.
Please note that CTEP is not solicit-
ing proposals under this heading and
will be extremely sparing in approving
such applications. Approval is made
on a study-by-study basis and does
not qualify an investigator for general
eligibility to test DCT drugs in Phase
I as is the case with the Phase I
contractors.
 

 

= 4.3 Which Organizations
Can Conduct Phase I
Studies

= 4.4 Who is Eligible to
Administer Phase I
Drugs

= 4.5 How to Obtain
Information About
Phase 1 Drugs

Phase 1 trials will be conducted by
single institutions. Multicenter trials
will not be approved, with the excep-
ion of pediatric Phase I studies (see
Appendix II, Policy Statement on the
Conduct of Phase I Trials in
Children).

All Phase I drugs will be administered
only at the institutions listed on the
approved protocol under the super-
vision of the protocol chairman.
These drugs should not be sent to
referring physicians, except with
written permission of the CTEP.

4.5.1 Clinical Brochure - This docu-
ment contains all relevant information
about the drug, including animal
screening, preclinical toxicology, and
detailed pharmaceutical data. Also
included, if available, is a summary of
current knowledge about pharma-
cology and mechanism of action.
CTEP maintains a clinical brochure
for each investigational drug. Bro-
chures may be obtained from the
Head, Drug Regulatory Affairs
Section (DRAS), Regulatory Affairs
Branch (RAB), CTEP.

4.5.2 CTEP Letter - This newsletter
contains announcements of the
approval of new drugs for clinical
trials by the Decision Network
CommitteeX Circulated every 2-3
months, the “CTEP Letter’ is an
important means of communication
between CTEP and the community of
Phase I investigators. It is distributed
to a restricted mailing list, including

*The Decision Network Committee advises the
Director, DCT regarding which drugs will be
developed and in what priority order. It is
composed of staff members of the DCT.

principal investigators of the new drug
development contracts, chairpersons of
cooperative group and the new agents
committees, and selected others.

4.5.3 IDB Physicians - Each DCT
investigational drug is assigned to a
IDB staff physician, who coordinates
its clinical development. Phase I
investigators are advised to discuss a
proposal with this physician before
writing a formal protocol. IDB
strongly encourages investigators to
submit a Letter of Intent for Phase I
trials (see Section 5.6). Relevant
telephone numbers and addresses can
be found in Appendix III.

4.5.4 Other Information - Phase |
investigators should carefully read
Sections 7, 8, 10, 11, 12, 15 and 16,
much of which is relevant to issues
arising with Phase I drugs.

25
 

5. Phase II Trials

 

= 5.1 Scientific Policies
of CTEP

26

5.1.1 Drug Development
Considerations

5.1.1.1 Planning and Coordination of
Phase II Trials by CTEP - As a spon-
sor DCT must devise and implement
a plan for Phase II trials of new
drugs. An adequate Phase II plan,
while conceptually straightforward, is
often difficult to execute. A reasonable
plan presupposes answers to the
following questions:

= What doses and schedules that have
emerged from Phase I ought to be
carried forward into Phase 11?

= What diseases should be targeted
for testing?

= How does the new drug fit into
CTEP’s priority list for various
targeted disease studies? (For
example, do we regard an analog
of cisplatin as constituting a higher
priority than a novel structure for
testing in ovarian or head and neck
cancer?)

= How does the new drug fit into the
priorities of the clinical investigators
that form the core of the NCI-sup-
ported clinical trials network?

=» How can the CTEP assure that
each agent receives an adequate test
in each disease that is studied?
How many studies should be
mounted in each disease category?
What kinds of patients are suitable
for study entry? What are suitable
stopping rules for Phase II trials?

The plan of Phase II development is
prepared by CTEP staff during late
Phase I and is announced in the
“CTEP Letter’

5.1.1.2 Single Agent Phase II Studies -
A Phase II study determines (a)
whether a drug has antitumor activity
and (b) estimates the response rate in
a defined patient population.

In addition, well designed Phase II
trials do not permit the entry of more
patients than necessary to ensure
detection of a medically significant
level of activity.

Phase II studies are disease-oriented.
The various tumor types are tested in
Phase II as distinct clinical entities,
since each has differing prognostic
factors, eligibility requirements, and
patterns of responsiveness to a
particular drug. As there may be
many unknown or uncontrollable
factors contributing to variability in
outcome, CTEP attempts to sponsor
two Phase II trials in each of the
tumor types.

The goal of these initial Phase II
trials is to determine whether the new
drug has activity against particular
cancers. These trials, therefore, serve
as a screen for further study. For this
reason, every effort should be made to
avoid false results. Although false
positive results are certainly undesir-
able, false negative Phase II results are
especially misleading, since the
discovery of a potentially useful
antitumor agent may be significantly
delayed or overlooked altogether.

CTEP has adopted guidelines con-
cerning eligibility requirements based
on patient characteristics that appear
to have a particular impact on likeli-
hood of response. Specifically, for
initial Phase II studies we currently
seek trials which restrict patient
eligibility to the minimum extent of
prior therapy consistent with ethical
medical practice. Protocols for the
 

 

initial Phase II trials of a drug whose
MTD has been well characterized
should restrict patient entry in the
following ways:

» For diseases which currently lack
effective systemic therapy (e.g.,
carcinomas of the large bowel,
kidney, liver, and pancreas, as well
as malignant melanoma), trials
should be limited to patients with
no prior chemotherapy.

» For diseases in which chemotherapy
may cause objective regression of
tumors but with little or no impact
on survival, entry of patients with
no prior therapy will also be
sought, whenever possible (e.g.,
carcinomas of the head and neck,
cervix, esophagus, prostate, bladder,
stomach, and non-small cell lung).

In certain situations which present
legitimate clinical dilemmas (e.g.,
extensive small cell lung cancer,
disseminated indolent lymphomas,
and breast cancer), patients who
have received prior treatment with
no more than one regimen may be
entered on study, provided that
performance status is excellent.

= For diseases which are potentially
curable with systemic treatment
(e.g., acute leukemias, diffuse non-
Hodgkin’s lymphomas, Hodgkin’s
disease, testicular cancer, limited
small cell lung cancer, and ovarian
cancer), patients having the mini-
mum extent of prior treatment
compatible with current ethical
standards of care are required.

This policy will have the following
desirable consequences:

s Patients initially entered into phase
II trials will have the best chance of
benefit from treatment and should
be able to tolerate any toxicities of
therapy better than patients with
poorer performance status, drug-
resistant disease, and possible com-
promised major organ function
from prior chemotherapy.

» Fewer patients are exposed to
inactive drugs.

s The chance of missing potentially
active agents will be minimized.

Clearly the population of patients
defined in this way is highly selected
and the results of these initial trials
will not necessarily be representative
of the drug’s activity in the general
population of patients with the
disease in question. Once a new agent
shows significant activity in this
initial, relatively favorable subset of
patients, eligibility criteria in sub-
sequent studies will permit entry of
patients with less favorable prognostic
characteristics, so that such patients
may have an opportunity to benefit
from an active agent. In this second
stage of the new agent’s Phase II
evaluation, a more accurate assessment
of its activity in the general popula-
tion of patients with cancer may be
obtained. CTEP anticipates sponsor-
ing no more than two such studies for
each disease in which the drug shows
significant activity.

5.1.1.3 Combining Drugs - As a
general rule, two or more drugs
should be combined when there is
definite evidence of the activity of
each alone against a particular cancer.
We believe that the most rational
approach to the development of a new
cancer drug dictates that it should not
be combined with another drug(s)

27
 

 

28

until it has shown reproducible evi-
dence of activity in at least two
single-agent trials in a disease. Alter-
natively, or in addition, combinations
may be proposed when there is a
rationale firmly grounded on labora-
tory evidence that is relevant to the
clinical circumstance.

In the past much development of drug
combinations occurred intuitively;
oncologists combined two, three, or
more putatively active agents in
uncontrolled studies of antitumor
effect and toxicity. To be sure some
very real therapeutic advances were
achieved by this process, but the lack
of a systematic and stepwise approach
and the frequent absence of proper
control groups has often left the
oncology community in the uncertain
position of not knowing whether
results with a particular regimen
represented progress or not. More
particularly, the overall impact of a
new agent on both efficacy and
toxicity may remain unclear without a
systematic approach. Finally, the
process of NDA approval is impeded
when available data do not elucidate
the specific contribution of the new
agent.

Clearly any intelligently designed and
flexible drug development program
must provide room for both
approaches. Well conceived small pilot
trials testing new hypotheses will
always have an important place in the
developmental therapy of cancer. We
shall, however, continue to pay close
attention to the rationale behind all
proposed combinations and shall
continue to ask whether certain
proposals for therapeutic research
might not be better approached by a
Phase III design rather than Phase II.

Although the activity of a single agent
is the most common basis for its
inclusion in a combination, CTEP will

certainly consider other rationales.
There may be substantial laboratory
evidence of synergy between two
cancer drugs. Such evidence is parti-
cularly compelling if it is also based
on a knowledge of mechanism of
action. Alternatively, a drug inert
against cancer might be added
because of evidence that it alters the
pharmacodynamics or pharmacokine-
tics of the cancer drug. For example,
the nitroimidazoles are being tested as
both radio- and chemosensitzers, even
though they themselves have no anti-
tumor activity. In such cases, CTEP
will carefully scrutinize the rationale
and evidence offered in support of a
proposal based on these kinds of
considerations.

When combination studies are sub-
mitted to CTEP for review, therefore,
it is particularly important to make
clear the goals, background, and
rationale of the proposal. If experi-
mental results in the laboratory are
the basis for the study, they should be
relevant to the clinical circumstance
and cited in adequate detail. If pre-
liminary clinical results are the moti-
vation, they should be similarly cited;
unpublished results should be pro-
vided as part of the background or in
an attachment to the protocol docu-
ment. If the trial proposes a feasibility
pilot, the protocol should state clearly
what kinds of results the investigators
would regard as medically significant
and where they would propose to go
next if a significant result is obtained.
We are not requesting a detailed plan
of a follow-up study or detailed
speculations about likely outcomes.
Rather, we are seeking an understand-
ing of how the pilot proposal will fit
into a strategy of development of the
new therapeutic idea.
 

 

5.1.2 Individual Protocol
Considerations

5.1.2.1 Single Disease Studies - Each
tumor type should be considered for
Phase II study separately. With few
exceptions, this means that there
should be separate protocols for each
tumor type. If there is a compelling
reason for including several under one
protocol, such as uncommon tumors,
then there should be separate state-
ments for each tumor type regarding
(a) eligibility requirements, including
extent of prior treatment (b) accept-
able sites for measurable disease (c)
response criteria, and (d) accrual
objectives.

5.1.2.2 Eligibility Requirements

a Tumor types - For each proposed
tumor type there should be separate
statements on eligibility.

a Prior therapy - Because it is clear
that the extent of prior cytotoxic
chemotherapy is an important
determinant of probability of
response, CTEP is seeking trials
which restrict patient eligibility to
the minimum extent of prior
therapy consistent with ethical
medical practice (see Section
5.1.1.2).

= Measurability of Disease - To define
quantitatively the antitumor activity
of a drug, patients in Phase II trial
must have measurable disease
parameters.

In certain diseases common sites of
involvement are either not bidimen-
sionally measurable or the tech-
niques for assessment do not permit
quantifiable measurement. Under
these circumstances tumor response
may be evaluated without quantifi-
cation by an investigator; in such
cases it is particularly desirable that

responses be assessed by more than
one observer. Examples include
bone metastases, lymphangitic
pulmonary disease, and many
parenchymal brain lesions.

a Performance Status - Under most
circumstances entry to initial Phase
II studies should be confined to
patients who are largely ambulatory
(ECOG = 2). Patients should be
expected to survive a sufficient
period of time so that adequate
observations can be made.

« Organ Function - Evidence that the
function of major organs is normal
is required. This includes creatinine
< 1.5; cardiac function at least
Grade 2, pulmonary function
moderately compensated, and no
neurologic, gastrointestinal or
endocrine impairment that would
compromise the safe use of the
investigational agent.

5.1.2.3 Accrual and Statistical Con-
siderations - The accrual goals of a
study should be specified in advance
with a maximum number of patients
stated explicitly. Justification for the
target sample size, in terms of preci-
sion of estimation or levels of type I
and type II error, should be provided.
The accrual rate of eligible patients
which can be realistically anticipated
should be given.

Mechanisms should be in place for
early stopping of negative trials.

29
 

 

 

= 5.2 Who is Eligible to
Study Phase II Drugs

30

The following categories of physicians
are eligible to serve as investigators in
Phase II trials.

5.2.1 Cooperative Groups - All regis-
tered physicians of the cooperative
group including those at full member
institutions, in Community Clinical
Oncology Programs (CCOP), at
cancer control, or at affiliate
institutions.

N.B. A cooperative group may have
policies which place further restric-
tions on investigator eligibility.

5.2.2 Cancer Centers - Staff physicians
at institutions designated as
comprehensive or clinical cancer cen-

ters by the NCI. Such physicians may be:

» Staff physicians within the Center.

= Physician members of CCOPs for
which that center is the research
base.

= Physicians affiliated with cancer
centers (see Section 13 for further
details on the affiliate policies of
CTEP).

5.2.3 Affiliates -Physicians affiliated
with a research base may participate
as investigators on CTEP’s Phase II
and III drug trials provided that:

ms The affiliation is formalized. Its
terms should be in writing and
based on the CTEP policies on
affiliates. (see Section 13).

= Each investigator is registered with
CTEP by having submitted a signed
FDA-1573 (see Section 12 and
Appendix IV).

5.2.4 New Drug Development
Contractors - This category includes
those with Phase I or Phase 11/111
contracts.

5.2.5 New Drug Studies Group - As
stated previously, eligibility to test
DCT drugs is generally restricted to
institutions and individuals approved
by peer review. We recognize however
that there may be other clinical
researchers highly qualified to conduct
these trials, and whose participation
might benefit the NCI drug develop-
ment program. CTEP has therefore
established the ‘‘New Drug Study
Group’ as a separate category of
eligibility to conduct Phase II trials.

CTEP intends that applications for
this category will only be approved
sparingly and in circumstances in
which there is a direct scientific
benefit to the DCT drug development
program, usually because the appli-
cant has a unique resource of some
type. To apply for this designation, an
investigator should submit a document
which sets forth the information
specified in Appendix V, New Drug
Studies Group Application Guidelines.
Approval of this application by CTEP
will qualify a New Drug Studies
Group to submit protocols for Phase
II and Phase III trials.

The obligations of investigators
approved under this category are
precisely the same as for those at
cancer centers.

5.2.6 Multicenter Phase II Trials -
CTEP expects that Phase II trials will
be performed only at the proposing
research base. If a protocol chairman
wishes to collaborate with other
institutions not formally affiliated
with his research base, the protocol
should include a description of the
procedures by which the collaborating
institutions will manage the conduct
of the protocol and should list on the
protocol face sheet each institution
and the name of responsible
investigator at each. The protocol
should specifically address the issues
described in Section 7.2.14
 

 

= 5.3 Who is Eligible to
Administer Phase 11
Drugs

= 5.4 Restriction on
Participation in Phase
II Studies

« 5.5 How to Obtain
Information About
Phase II Drugs

For a particular clinical protocol,
physicians who may administer DCT
investigational drugs are those
registered (see Section 14) with CTEP
and:

= who are members of any research
base or formally designated affiliate
which is listed on the face sheet
of the protocol; and

= any others who are individually
named on the face sheet of the
protocol.

Administration of drugs by any other
physicians is explained in Section 14.

Please note that CTEP may restrict
the testing of any investigational drug
to a very limited number of locations.
Although most drugs proceed to a
Phase II program open to all eligible
investigators, some are restricted to
single centers or to specific centers
until a safe, reliable Phase II dose has
been defined and CTEP and the
investigator community are confident
that the drug is ready for general
testing among all investigators. These
decisions are announced in the
“CTEP Letter?’

5.5.1 Clinical Brochure - This docu-
ment contains all relevant information
about the drug, including animal
screening, preclinical toxicology, and
detailed pharmaceutical data. Also
included, if available, is a summary of
current knowledge about
pharmacology and mechanism of
action. The brochure contains a full
description of the clinical toxicities
that have been seen in clinical trials.
CTEP maintains a clinical brochure
for each investigational drug it
sponsors; they may be obtained from
the address listed in Appendix III.

5.5.2 “CTEP Letter’’ - This news-
letter, published every 1-3 months,
contains announcements of prelimin-
ary findings of interest. Each issue
features several drugs and outlines the
interest of CTEP in seeking further
trials. The ““CTEP Letter’ is an
important source of information for
principal investigators of contracts at
cancer centers, chairmen of coopera-
tive groups and of the groups’ new
agents committees, and selected
others.

5.5.3 IDB Physician - Each DCT
investigational drug is assigned to an
IDB staff physician who is responsible
for coordinating its clinical
development. When an investigator
has important concerns about the
design of a contemplated trial, he/she
should contact that physician.

31
 

 

= 5.6 The Letter of
Intent

32

5.6.1 Definition - The Letter of Intent
(LOI) is an investigator’s declaration
of interest in conducting a Phase II
trial with a specific investigational
drug in a particular disease. Approval
of the LOI by CTEP reserves that
“slot” for the investigator’s protocol
if it is submitted within a defined
timeframe (see Section 5.6.7) and
signifies agreement that the
investigator shall submit a protocol
based on the terms stated in the LOI.

5.6.2 Purpose - CTEP has devised the
LOI system to maximize the efficiency
and fairness by which experimental
drugs are allocated to investigators for
study. Proper use of the system
ensures both CTEP and investigators
of a steady flow of new agents into
the clinical trials system. It enables
CTEP to plan the development of
several agents simultaneously. For the
investigator, the LOI system also
promotes much saving of time and
effort, since its use should spare
him/her the writing of a protocol that
might not be approved. Protocols
submitted subsequent to favorable
review of an LOI are much more
likely to be approved without request
for major modification, since many of
the crucial features of a Phase 11
proposal must be specified in the LOI
itself. The system also provides the
investigator with an opportunity to
explore the proposal with CTEP staff
at the concept stage.

5.6.3 Ground Rules for the LOI
System - LOIs should be submitted
for all Phase II trials that include a
DCT investigational drug. They
should be submitted according to the
following schedule:

= Drugs Beginning Phase II - In late
Phase I, the ““CTEP Letter” will
carry an announcement of a dead-
line for submission of LOIs for the
initial round of Phase II trials.

us All Other Phase II Trials - After
this deadline has passed, investiga-
tors may submit LOIs at any time.

Each Phase II protocol should be
preceded by an approved LOI. How-
ever, CTEP will consider any phase II
proposal from an investigator eligible
to use investigational drugs. Our
experience demonstrates that protocols
submitted without a previously
approved LOI are more likely to be
rejected as unnecessarily duplicative or
needing major modification.

5.6.4 Submission of LOIs - In order
to adequately review the LOI, CTEP
must have the following information:

ms Drug(s), doses and schedule of
administration

= Tumor type

= Patient characteristics, including
extent of prior therapy and
performance status

= Projected accrual rate and target
sample size. Citing recent perfor-
mance in studies on the same
patient population will be helpful.

=» Approximate date of study
initiation.

s Other studies in the same patient
population which will be open
simultaneously with the proposed
study. If there are such studies, a
priority list or flow diagram will
speed CTEP review.

All of this information should be
provided on the LOI Submission Form
(Appendix VI) and submitted to the
Protocol and Information Office
(P10), CTEP.
 

 

Cooperative group LOIs must be
cosigned by the protocol chairman
and either the group chairman or the
group’s executive officer.

Drug Development Contractor LOIs
must be cosigned by the contract
principal investigator.

We encourage protocol chairmen to
submit, where appropriate, a letter
accompanying the LOI which explains
in greater depth the rationale, where
not obvious, or any unique features of
the study. Such additional explanation
is not usually necessary for single-
agent Phase II trials but may assist in
the review of more complex proposals
involving experimental drugs.

5.6.5 Review of LOI’s - On receipt of
an LOI, CTEP sends an acknowledge-
ment to the investigator. Letters of
Intent are reviewed by the CTEP
Protocol Review Committee (PRC)
within 30 days of submission.

5.6.6 Criteria for Review of an LOI -
At the time of LOI review the PRC
has available information on other
studies in that drug/disease combina-
tion by other investigators, and other
studies in the proposed disease by the
investigator submitting the LOI. The
committee considers the following in
its deliberations:

» Study design, including dose,
schedule, and comparison groups, if
relevant.

a The characteristics of the patient
population to be studied, parti-
cularly the extent of prior chemo-
therapy and performance status.

= The feasibility of the projected
accrual, including an assessment of
the past performance of the
investigator in that tumor type.

» Competing studies of the
investigator in that disease.

a All other protocols and LOIs for
that drug/disease combination from
other sources.

= Any unique features to the
proposal.

A letter of approval or disapproval
together with any comments is sent to
the proposer.

5.6.7 After LOI Approval - Following
approval of a LOI, the LOI source
has 60 days in which to submit a
protocol. At 45 days a reminder letter
is sent notifying him/her that the LOI
will shortly expire. After the 60 day
period has expired, CTEP will not be
bound by previous approval of an
LOL.

5.6.8 Information About the Status of
an LOI - Further information about
the status of a particular LOI may be
obtained by calling the LOI Coordina-
tor in the IDB (see Appendix III).

33
 

6. Phase III Trials

 

= 6.1 Scientific Policies
of CTEP

34

If significant activity is observed in
any disease during Phase II, further
clinical trials usually study a com-
parison of the new drug with standard
(or other experimental) agent(s). If
reasonable standard treatment can be
defined for the disease in question, we
generally wish to know whether the
new agent constitutes a significant
contribution to the therapeutic arma-
mentarium. A variety of trial designs
may be suitable, according to the state
of the art of treatment in the particu-
lar disease. Probably the most satis-
factory one is the controlled trial
which compares the new drug to a
standard single agent or a standard
regimen plus the experimental agent to
the standard regimen alone. Whatever
design is selected, however, an
appropriate control group must exist
and relevant endpoints must be used
to measure relative effects. Of greatest
medical importance, of course, are
relative survival and quality of life.
Other measures, such as complete
remission rate or disease-free survival,
may also be of interest.

These studies, which attempt to isolate
the role of a new agent in the treat-
ment of a specific cancer, are of
obvious importance to industrial
sponsors, since the results are pivotal
in applications to register the drug for
commercial distribution. They are of
no less importance to the oncology
community, since such approval makes
the drug generally available for patient
care. The results of such trials may be
of great medical importance as well.
If the control group is properly
selected and the experimental treat-
ment is constructed as imaginatively
as possible, such trials may yield
valuable information for the care of
cancer patients.

Every protocol must contain a section
that discusses the study design and
the plan for evaluation of the data.
The major objectives of the study
should be stated as hypotheses to be
tested and a target sample size should
be clearly specified. Justification for
the sample size goal, in terms of
precision of estimation or levels of
type I and type II error, should be
provided. In a Phase III study, it is
insufficient simply to give the number
of patients to be accrued on each
arm. The protocol should specify the
test to be used to compare the treat-
ment groups, and the probabilities of
drawing incorrect conclusions when
performing this test with the proposed
sample size should be given. The
magnitude of improvement in out-
come which can be reliably detected
using the planned sample size should
also be specified. The accrual rate of
eligible patients per year which can be
realistically anticipated should be
stated and documented.

If evaluation of treatment effect will
require use of nonrandomized con-
trols, a thorough description of the
control group to be employed should
be part of the protocol. This descrip-
tion should include a detailed discus-
sion of comparability issues and
analytic techniques.
 

 

= 6.2 Who is Eligible to
Conduct Phase III
Trials

= 6.3 Coordination of
Planning with CTEP
Staff

Phase III trials may be submitted
from any source eligible to submit a
Phase II trial (see Section 5.2).

Since the sample sizes required for
such studies are quite large, however, a
multicenter approach is frequently the
only feasible one. It is expected, there-
fore, that the clinical cooperative
groups will be the major research
bases for such trials. Proposals for
Phase III studies from single institu-
tions should be very specific in docu-
menting adequate accrual potential.

Furthermore, if the proposal includes
collaboration with institutions not
formally affiliated with the research
base, the protocol should include a
description of the procedures by
which the collaborating institutions
will manage the conduct of the
protocol (see Section 7.2.14).

Large clinical trials involve years of
effort and a substantial expenditure of
resources. Accordingly, a certain
amount of coordination is necessary
for the optimal planning of specific
studies of this type. Staff members of
CTEP are in an excellent position to
advise investigators on the existence of
other proposed or ongoing studies
which are closely related or even
identical to ones being planned. In
addition CTEP staff can advise inves-
tigators contemplating large-scale trials
concerning the concordance of the
proposed trial with CTEP program
goals. The intent here is not to
control or direct but rather to offer
helpful advice.

We therefore invite investigators to
discuss ideas for large-scale clinical
trials with CTEP staff while these
ideas are still in the concept stage.
The appropriate contact is either the
IDB physician responsible for the
drug or the CIB physician responsible
for coordinating trials in the specific
disease (Appendix III).

Optimally, investigators should submit
a letter describing the hypothesis to be
investigated, the general design of the
contemplated trial, plus relevant
information on accrual capabilities,
etc., to document feasibility. CTEP
can then formally review and provide
a Program response to these concepts,
commenting on study originality and
programmatic interest.

35
= = a —
 

Part C

The Planning and
Execution

of a

Clinical Trial

 

 

The following five sections
provide a detailed descrip-
tion of the responsibilities
of the investigator for the
implementation of a clini-
cal trial, from the drafting
of the protocol to comple-
tion of the study. They are
intended to guide both the
protocol chairman and the
participating investigator
and outline NCI policies
on the responsibilities of
each in the execution of a
clinical trial.
 

 

7. The Drafting
of a
Protocol

 

= 7.1 Title Page

38

A protocol is the detailed written plan
of a clinical experiment. This section
details the essential features of a
protocol. Careful attention to the
following material will expedite the
review of your protocol by CTEP.

The protocol’s face sheet is the
primary source of identifying
information for the Protocol and
Information Office (PIO) of CTEP,
for the drug distribution system, for
the IND file at FDA, and for the
listing of the protocol in Physician
Data Query (PDQ) System. Each
protocol submitted to CTEP, there-
fore, must have a title page or face
sheet which contains the following
items:

= Date of document.

= Local protocol number (i.e.,
institution or group number).

= Title of study.

= Protocol chairman, including his/
her name, institution/cooperative
group, address, and phone number.
A trainee may not be protocol
chairman (see Section 12.2.2).

= Full name of institution/group
submitting the study.

ms List of each participating
institution/group.

as For DCT-supplied IND drugs, a
listing of each drug by name and
NSC number.

Cooperative groups may summarize by
specifying ‘‘all group members’’ or
“restricted to ...”” and list
institutions.

Protocols from sources other than the
cooperative groups should specify
each institution or site participating in
the study, together with a responsible
physician and telephone number at
each.
 

 

= 7.2 The Essential
Elements of a Protocol

Every protocol must include the
following elements:

7.2.1 Objective(s) - The objectives
should be stated clearly. They
generally should be stated as
hypotheses to be tested. The study
design should be capable of answering
the questions posed by the objectives.
The statistical section should clearly
state how the data will be analyzed in
relation to each of the objectives.

7.2.2 Background and Rationale -
Sufficient background information
should be included so that the
rationale for the study is clear. Any
unpublished data relevant to the
rationale should be included either in
this section or, if extensive, as an
appendix to the protocol submission.

7.2.3 Patient Eligibility Criteria - The
issues here have been discussed previ-
ously (see Sections 4.1.3 and 5.1.2.2).
Studies with objective response as an
endpoint should include clear state-
ments specifying whether tumor sites
to be followed for response must be
measurable, what criteria must be
fulfilled to consider disease measur-
able, whether evaluable disease is
permitted, and if so, at what sites.

7.2.4 Treatment Plan - Specify proto-
col treatment clearly so that it can be
followed by all medical personnel.

7.2.5 Pharmaceutical Information -
For each drug and dose form, include
a pargraph(s) on its preparation, dilu-
tion, stability, method of administra-
tion, and known clinical toxicities.
The supplier of each drug should also
be specified. (e.g., NCI, pharmaceuti-
cal company, commercially available)

7.2.6 Procedures for Patient Entry on
Study - Procedures for patient entry,
whether randomized or non-random-
ized, should be specified. Required
information includes the telephone
number of the randomization desk or
protocol registration, office, and the
patient characteristics and stratifica-
tion factors (if any) to be provided at
the time of entry. Telephone randomi-
zation is preferred; however, if another
method is to be used, it should be
described. Patients should generally be
registered on study prior to beginning
treatment.

7.2.7 Criteria for Response

Assessment - The criteria for scoring
responses should be included. These
should be specific for both measurable
and evaluable disease. Disease-specific
criteria are often required and should
clearly indicate acceptable means of
measurement, i.e. CAT scans, radionu-
clide scans, ultrasound, etc.

7.2.8 Monitoring of Patients - Specify
how patients will be followed for
assessment of treatment toxicity and
therapeutic effect. A table of follow-
up parameters which incorporates the
schedule as described is particularly
useful.

Protocol authors should carefully
review the clinical brochure for all
IND drugs to be sure that they have
included all reasonable measures to
monitor known toxicities.

7.2.9 Dose Modification for Toxicity -

The plan of dose change for toxicity
should be stated for each study drug.

39
 

 

40

7.2.10 “Off Study’ Criteria - Criteria
for terminating protocol treatment
and/or removing a patient from treat-
ment or from study should be
specified.

7.2.11 Statistical Considerations - An
adequate statistical section discusses
the study design in relation to the
objectives of the study and the plan
for the evaluation of the data.
Specifically:

a Total sample size (Phase II studies
should specify a maximum number
of patients).

= Error levels (alpha and beta) in
Phase III studies.

a Differences to be detected for
comparative studies.

= Size of the confidence interval to be
constructed around the estimated
outcome.

= Estimated accrual rate and/or study
duration, with supporting
documentation.

= Stopping rules, including procedures
for monitoring the progress of the
trial to implement early
termination.

= Expected outcome parameters as
appropriate (response rate, time to
progression, surival times, etc.).

a All studies should specify a
maximum number of patients.

7.2.12 Records to be Kept - Specify
the document on which each of the
following is to be recorded, where it is
to be sent, and on what schedule.

s On study information, including
patient eligibility data and patient
history.

= Flow sheets, or other forms for
interim monitoring.

» Specialty forms for pathology,
radiation, or surgery when required.

a Off-study summary sheet, including
a final assessment by the treating
physician.

7.2.13 Participation - All protocol
treatments and observations will be
made by investigator-physicians
affiliated with a research base (see
Section 3) and registered with CTEP.
Under certain defined circumstances,
it may be appropriate for interim
treatments to be administered by
certain physicians not registered with
CTEP (other than trainees, who are
assumed to be under the supervision
of a registered investigator). In such
cases, the protocol should state:

m Precisely what responsibilities these
physicians will assume, including
response assessment, and toxicity
reporting.

wu The intervals at which a patient
should be evaluated by a physician-
investigator at the research base.

See Section 14 for further details con-
cerning which physicians may actively
participate in a clinical trial involving
DCT investigational drugs.
 

 

7.2.14 Multicenter Trials - If a
research base other than a cooperative
group wishes to collaborate with other
institutions or investigators not affili-
ated with its research base, CTEP
expects that:

s The protocol will be conducted as a
single research effort and data from
each participating investigator will
be included in the analysis of
results.

s The protocol chairman will be the
single liaison with the CTEP
Protocol and Information Office.
The protocol chairman, or designee
will coordinate the development,
submission, and approval of the
protocol as well as its subsequent
amendments, and all other report-
ing requirements as described in
Sections 8.8 and 10.

a The protocol chairman will be
responsible for the conduct of the
study and the monitoring of its
progress; he/she will (a) review all
case report forms from each parti-
cipating investigator; uncritical
acceptance of summary data alone
from other institutions is not
sufficient, and (b) have ultimate
responsibility for all reporting to
CTEP.

s The protocol will include the fol-
lowing information in addition to
that specified in Section 7.2:

— Title Page: This should include
the name of each participating
institution and the name of the
responsible investigator at each.

— Procedures for patient entry:
Usually there should be one lo-
cation at the institution of the
protocol chairman authorized to
register patients. If not, then
alternative arrangements should
be stated, together with an
indication of how stopping rules
will be implemented.

— Records to be kept: The case
report forms should be of a
common format and in accord
with Section 10.

— Monitoring: Particular attention
should be paid to describing the
procedures for monitoring the
progress of a multicenter trial
including, (1) how adverse drug
reactions will be reported, and
(2) the frequency by which the
required records will be sent to
the protocol chairman.

— Quality Assurance: State the
methods by which the accuracy
of the data submitted from the
collaborating institutions will be
verified.

— Drug Ordering: In most cases
each participating institution will
order DCT supplied investiga-
tional drugs directly from CTEP
according to the procedures in
Section 9.

w There will be only one version of
the protocol and each participating
institution will use that document.
It should not be rewritten or modi-
fied by any other than the protocol
chairman who is solely responsible
for formulating protocol amend-
ments after CTEP approval.

41
 

 

= 7.3 Informed Consent

= 7.4 Model Protocols

42

Each informed consent document must
be protocol-specific and contain the
elements required by Federal regula-
tion. These regulations do not specify
the language of the document but
provide a list of elements which must
be addressed in the text of the consent
form. A checklist has been included
in Appendix VII to assist you.

The use of a model informed consent
outline by a research base can assure
inclusion of the essential elements and
permits tailoring of the protocol-
specific elements to the needs of
individual studies.

CTEP will not approve a protocol if
its consent form fails to address each
of these elements adequately.

Protocol authors should be certain
that the description of toxicities of
each investigational agent is complete
and balanced. You should consult the
clinical brochure for information
about known toxicities.

The proliferation of word processors
has greatly eased the life of the
protocol writer. Since the essential
elements of a protocol are standard
for a given class of studies, many
clinical trials organizations have
devised model protocols, the content
of whose elements can be altered to
suit the needs of a particular study.

The use of model documents is an
effective way of ensuring a complete
protocol. Those who use such models,
however, should make certain that
inappropriate ‘‘boiler-plate’ text does
not get carried over to protocols
where it makes little or no sense. Our
experience is that disease-oriented
background information and statistical
sections (sample size estimates and
stopping rules) are at greatest risk for
the ‘“‘word-processor syndrome?’
 

8. Protocol Review and
Approval at CTEP

 

= 8.1 The Protocol and
Information Office

= 8.2 How to Submit a
Protocol

Within CTEP, the PIO manages the
review process and maintains the offi-
cial record of all CTEP sponsored
protocols, amendments, results, publi-
cations, and protocol-related com-
munications as well as all protocol
submissions for PDQ. More than 7000
protocols are maintained in the PIO.

All protocols and related correspon-
dence should be addressed directly to
the Head, PIO, Landow Building,
Room 4C-33, Bethesda, Maryland
20892. The PIO will distribute all mail
to the appropriate CTEP physician
staff. Please do not direct protocol-
related materials to any other CTEP
staff member. Doing otherwise will
lengthen the time required for
resolution.

Please accompany the materials
relating to a single protocol with a
Protocol Submission Checklist (see
Appendix VIII) indicating the type of
enclosure, i.e., new protocol, revised
protocol awaiting approval, study
status notice, amendment, and
“‘other’” (special communications,
study summaries, publications). All
telephone calls regarding status of
protocol and amendment reviews
should be directed to the PIO at
301-496-1367.

Each new protocol should be sent
directly to the PIO. You must include
in the submission:

8.2.1 - The appropriate Protocol
Submission Checklist. (There are two
separate forms: one for cooperative
group trials, one for all other studies.
See Appendix VIII for samples; please
duplicate as needed.)

8.2.2 - Two copies of a paginated,
legible protocol, including a local
protocol number. Please be certain the
protocol document contains informa-
tion about each of the topics listed in
Sections 7.1 and 7.2.

8.2.3 - An informed consent document
which addresses the elements required
by FDA regulation (Appendix VII).

If these items are missing or
incomplete, the submission will be
returned to the protocol source
without review.

Upon receipt by the PIO, each proto-
col is assigned an NCI protocol
number. You will receive an acknowl-
edgment of your protocol submission
with the NCI assigned protocol
number. This NCI protocol number
must be referenced in all subsequent
communications with the CTEP
regarding this study. The assignment
of this number does not imply
approval; only the final approval letter
signifies approval and the authoriza-
tion to order drugs.

43
 

 

= 8.3 IRB Approval

= 8.4 Protocol Review

44

Each investigator must meet the
requirements of the Federal regula-
tions for informed consent (45 CFR
46) and for IRB review and approval.
See Sections 12.1.1 and 12.1.2.

Except for cooperative group
protocols, each protocol must have
documentation of IRB approval prior
to CTEP approval. Evidence of IRB
approval may be submitted to CTEP
at any time in the review process. If
multiple IRBs are involved, only the
approval from the coordinating
research base need be submitted for
CTEP records; of course, each investi-
gator must meet Federal regulations
for informed consent (45 CFR 46)
and IRB review.

Failure of investigators to submit
evidence of IRB approval is a major
cause of delay in protocol approval.
The documentation requirements are
satisfied by completion of Form 596,
or by specifying:

a The study title.

a The protocol chairman. The
institution’s assurance number, i.e.,
the assurance number issued by the
OPRR, NIH.

= Date of IRB review.

s The dated signature of an
institutional official, usually the
IRB chairman.

CTEP must review and approve every
protocol involving DCT investigational
drugs. Each protocol is reviewed for
scientific merit, duplication of existing
studies, patient safety and adequacy
of the informed consent.

8.4.1 Receipt of the Protocol by
CTEP - Upon receipt, the protocol is
checked for completeness (including
legibility, complete pages, presence of
required sections, and the informed

consent). Each protocol is also ex-
amined to verify that the investiga-
tor/institution is eligible to conduct a
DCT-sponsored study, i.e., has an
approved mechanism of sponsorship
by NCI (cooperative group, cancer
center, contract, new drug study
group, RO1/PO01, etc.). Investigator
eligibility is explained more fully in
Sections 4.2, 4.3, 4.4, 5.2, 5.3, and 6.2.
If the protocol is incomplete, or the
investigator/institution is not eligible
under the proposed category of spon-
sorship, then the protocol source is so
informed and the study is not
reviewed for scientific content. CTEP
sends the protocol source an acknowl-
edgment of studies that are complete
and eligible at submission.

8.4.2 Scheduling the protocol for
Review - The PIO schedules the pro-
tocol for review by the PRC within 2
to 3 weeks of receipt. Studies are
registered, scheduled for review (the
second Thursday thereafter), and
distributed to reviewers on Friday.

Therefore, a protocol arriving
Thursday afternoon will be scheduled
for review in 14 days; if that same
protocol arrives Friday afternoon, it
will wait another week for registration
and distribution, and require 20 days
to reach the review committee.

8.4.3 Review by the CTEP Protocol
Review Committee - All protocols are
reviewed by the PRC. This committee,
composed of the professional staff of
the CTEP and chaired by the Asso-
ciate Director, CTEP, meets weekly
and usually reviews 10 to 20 protocols
at each session. Each protocol is
assigned a minimum of three
reviewers; as many as 4 to 6 may be
required for complex multimodality
protocols. One of the reviewers is
always a biostatistician. The informed
consent document is also reviewed by
a separate professional reviewer.
 

 

8.4.3.1 The Review of the Protocol -
The PRC discusses the protocol after
hearing the reviews of each assigned
reviewer and makes a decision that the
science of the study is either:

wu Accepted as written.

un Accepted with recommendations -
The investigator is requested to
consider the points raised in the
consensus review but is not obli-
gated to amend the study. If
changes are made prior to activa-
tion of the study, the investigator
must send CTEP an activation
amendment which details any
changes in the CTEP-approved
document.

mn Acceptance deferred pending
revisions - The PRC has significant
questions about the proposed study.
It cannot be accepted unless the
investigators satisfactorily address
the concerns of the written consen-
Sus review.

s Disapproved - In the judgment of
the PRC the protocol cannot be
approved even with major revisions.

The PRC disapproves relatively few
studies and only does so when it
feels that a proposal is unneces-
sarily duplicative or fatally flawed
in concept, design, or feasibility.

8.4.3.2 The Review of the Informed
Consent - The PRC also reviews the
informed consent document to be
certain that:

as The document includes all required
elements of informed consent as
mandated by Federal regulation (see
Appendix VII).

= The description of potential benefits
and toxicities for IND drug studies
is complete and accurate.

Any changes made to the consent
document resulting from a CTEP
review should be made known to the
IRB.

It is not the intent of the CTEP
informed consent review to supplant
the review of the IRB. Provided the
consent document meets the require-
ments of the regulation and law and
contains sufficient information to
enable an individual to make an in-
formed choice, the local IRB approval
of the contents of an informed con-
sent document generally is to be
regarded as determinative.

8.4.3.3 The Consensus Review - After
the PRC meeting the primary reviewer
generates a ‘‘Consensus Review,’
which states the collective concerns of
the PRC. This consensus review,
together with a cover letter stating the
summary PRC decision, is sent to the
protocol source within 40 days of the
receipt of a complete protocol.

8.4.3.4. Responding to CTEP
Consensus Review - If revisions are
required in the protocol or the
informed consent, the investigator
should send a revised protocol and/or
informed consent document to the
PIO. The revised documents should be
accompanied by a cover letter which
details the responses to the points
raised in the consensus review. If the
consensus reviewer finds the response
satisfactory, then the protocol goes
forward for final approval.

The consensus reviewer may, and
often does, choose to send the revised
protocol back to the full PRC for
further consideration. In any case, if
the protocol is still not accepted, then
a letter is sent to the investigator
detailing any remaining CTEP con-
cerns. This process continues until the
science and informed consent are each
accepted or the study is withdrawn or

45
 

 

= 8.5 Protocol Approval

= 8.6 Amendments

46

disapproved. Each evaluation of a
revised study requires 10-30 days on
average.

Upon final acceptance of the science
and the informed consent, as indi-
cated by the concurrence of the
consensus reviewer and appropriate
CTEP officials, a letter of protocol
approval is sent to the protocol source
(requires 7-10 days average).

Please note that no protocol approvals
will be given by telephone. Although
CTEP staff may discuss the study
with the protocol chairman, he/she
should consider nothing official until
receiving written notice. After written
approval is sent, orders for inves-
tigational drugs will be honored.
Approved protocols using DCT-spon-
sored drugs are submitted to the FDA
as part of the IND file.

Any change to the approved protocol
document must be documented point
by point and submitted to the PIO
(see Protocol Submission Checklist,
Appendix VIII). Please reference the
NCI protocol number, date each
amendment, and number sequentially
for each study. Upon receipt, each
amendment is reviewed by a CTEP
physician.

8.6.1 Activation Amendment - Any
change in the protocol which occurs
between CTEP approval and activa-
tion by the research base should be
submitted to CTEP as an ‘‘Activation
Amendment’. Such amendments are
often used when the CTEP approval
letter conveys recommendations that
the investigator wishes to implement.

8.6.2 Scientific and Participant
Amendments:

» Each amendment which modifies
the science, the statistics or the par-
ticipants of the approved protocol
must be submitted to CTEP for
approval prior to implementation.

a For those rare studies where an
immediate change is imperative for
patient safety, the IDB staff physi-
cian for that drug may be contacted
by telephone and the written
amendment must be sent to the
PIO within 3 working days.

8.6.3 Administrative Amendments:

» Each amendment which clarifies the
study by editorial corrections,
changes in administrative informa-
tion, changes in protocol chairman,
or changes in the informed consent
must be submitted to the CTEP for
recordkeeping purposes and will be
acknowledged in writing.

Each amendment is recorded in the
official PIO protocol file, the drug
distribution file, the IND file, PDQ,
and by the CTEP Clinical Trials
Monitoring Service (CTMS) (where
applicable).

N.B. Cooperative Group Protocols:
Amendments to these studies are
handled in accord with procedures
arranged directly between CTEP and
the Group. The review procedures
stated above do not apply to the
Cooperative Groups.
 

 

= 8.7 Reactivation of
Studies

= 8.8 Study Status

8.7.1. - Protocols which are tem-
porarily closed require written CTEP
approval prior to reactivating if they
are:

= temporarily closed for reasons of
patient safety

= closed for reasons of peer review,
site visit, or other NClI-initiated
reasons.

8.7.2 - Protocols which are tem-
porarily closed to accrual by the
research base based on early stopping
rules do not require CTEP approval
to be reactivated.

Changes in study status should be
communicated immediately to the
CTEP PIO. Changes can be easily
reported on the Protocol Submission
Checklist (see Appendix VIII). The
following list includes the categories
of study status recognized by CTEP
and PDQ:

us Approved - CTEP approves the
protocol in writing when the science
and informed consent are accept-
able, the IRB documentation is on
file (not applicable to Cooperative
Groups), there are adequate supplies
of the requested investigational
drug, and when the investigator has
a current signed FDA-1573 on file
with CTEP.

If the approval includes recommen-
dations, and they are adopted by
the research base, then an ‘‘Acti-
vation Amendment’’ should be
submitted to indicate any changes
to the CTEP approved document.

mn Active - After CTEP approval the
decision by a Group or Institution
to open a study for patient entry.

Temporarily Closed - The decision
by a Group or Institution to stop
patient entry pending study
evaluation.

Reactivated - Patient entry resumes.

Closed - The decision by a Group
or Institution to close a study to
new patient entries; previously
entered patients will continue
treatment.

Completed - The study is closed

and no patients are being treated or
followed for data collection.

47
 

9. Ordering
Investigational
Drugs

From NCI

 

= 9.1 How to Place
Drug Orders

48

The DCT will provide investigational
drugs for use in CTEP-approved
protocols, as well as for Special
Exception and Group C guideline
requests (See Section 18) to registered
investigators with a current FDA-1573
(see Section 12.1). Drugs will not be
sent to assistant investigators who are
not named on the protocol or who
have not filed an FDA-1573.

INVESTIGATIONAL DRUGS
SUPPLIED BY DCT WILL BE
USED ONLY FOR TREATMENT OF
PATIENTS ENTERED ONTO CTEP-
APPROVED PROTOCOLS.

Complete the Clinical Drug Request
Form (NIH-986) (see Appendix X)
which provides the following
information:

= Investigator name, and NCI
assigned investigator number.

» Telephone number of investigator
and/or individual preparing form.

a NCl-assigned protocol number,
cooperative group number, or IND
number.

as NSC number; current inventory as
indicated on Drug Accountability
Record of drug name, strength and
dose form, and quantity.

» The investigator or his/her designee
must date and sign the drug request
form. No matter who may be
delegated to sign this form (e.g. the
pharmacist) the investigator is
responsible for the disposition of all
investigational drug shipped under
his/her name.

If the requester is at an affiliate
institution of a research base, then
the request should also be signed by
an authorized individual at the
research base.

Specify your affiliation, such as
cooperative group, cancer center,
CCOP, etc.

Only one drug item may be entered
on each line on the form.

If there is more than one protocol
per drug, use a separate line for
each protocol.

Indicate the official mailing address
to which drug is to be sent.

Orders should be submitted to the
Drug Management and
Authorization Section, IDB. The
address is listed in Appendix III.
 

 

= 9.2 Particular Points to
Note

= 9.3 Routing of Drug
Requests

wu The clinical drug request form
should be completed in full and
typed. If it is not complete, the
form will be returned.

a All clinical drug requests should use
this form including those for
Special Exception and Group C use.

us Allow three weeks from time of
mailing the drug order until receipt.

= Do not order more than a 2-month
supply at a time.

= Avoid ordering excessive quantities.
CTEP will reduce the quantity
shipped if the order is excessive in
relation to protocol requirements, or
if the inventory at CTEP is
insufficient at that time.

ns Telephone requests will be honored
only for genuine medical emergen-
cies in which a drug is needed
immediately for a patient on a
protocol. However, we recommend
that rush orders be sent via over-
night delivery service, which greatly
expedites your receipt of drug
supplies. All such orders are filled
the same day if the order arrives
before 12 noon.

In general, investigators should submit
drug requests directly to the Drug
Management and Authorization
Section (see Appendix III). There are,
however, three special circumstances:

9.3.1 Cooperative Groups - Most
cooperative groups require that drug
requests be routed through the opera-
tions office. Check with your coopera-
tive group operations offfice to deter-
mine its policies.

9.3.2 CCOPs - Drug orders must be
submitted to CTEP through the
research base which is conducting the
study (i.e., cooperative group or cancer
center).

9.3.3 Biologic Agents - Drug orders
for biologic agents on Phase I trials
sponsored by the BRMP should be
sent to the Biologics Distribution
Desk, Biologic Resources Branch,
BRMP, NCI-FCRF, Building 426,
Frederick, Maryland 21701.

49
 

 

= 9.4 Affiliates and Drug
Orders

50

CTEP strongly prefers to ship investi-
gational drugs to the most distal site
in order to simplify as much as pos-
sible the procedures of drug account-
ability. Therefore, investigators at
satellites or affiliates of a research
base should obtain investigational
drugs by submitting a request to
CTEP. As noted above in most cases
this order should be routed through
the research base for verification and
authorization. CTEP policy does not
permit the transfer of drugs between
institutions. CTEP intends that IND
drugs be distributed directly to
investigators. If under exceptional
circumstances emergency transfer
seems justified, explicit approval by
CTEP is required. In addition,
investigators who are involved in late
Phase II or Phase III drug studies but
who only see a small number (five or
fewer) of patients each year may
receive drug directly from a protocol
chairman or from a member principal
investigator in the Cooperative Group.
There should be no secondary
distribution (i.e., provision of drug
from one physician to another) of
drugs received for Phase I studies,
Group C or Special Exceptions.
Finally, CTEP may approve a special
distribution arrangement for certain
unusual circumstances.
 

 

= 9.5 Requests for Non-
Protocol Use of
Investigational Drugs

= 9.6 THC Orders

= 9.7 Requests for Non-
Clinical Use of
Investigational Drugs

Requests for use of DCT investiga-
tional drugs under Group C or
Special Exception categories must
satisfy certain requirements. These
considerations are detailed in Section
18 of this Handbook.

Please remember that these requests
originate from participating pharma-
cies rather than investigators, and
must be accompanied by a fully
completed Schedule I and a DEA
Form 222. DCT anticipates cessation
of its THC distribution program in
late 1986, as soon as a commercial
sponsor is prepared to assume the
responsibility.

Requests for use of these drugs for
laboratory experiments should be
directed to the Pharmaceutical
Resources Branch, NCI (See Appendix
III for address).
 

10. Responsibility
for Reporting of
Results to CTEP

 

= 10.1 Introduction

52

The timely and accurate reporting of
data from investigational drug trials to
the sponsor is an important responsi-
bility of investigators testing IND
drugs. The receipt of these reports in
a timely fashion is not an arbitrary
requirement. The information con-
tained in them is the material which
informs CTEP of the progress of the
development of the drug and suggests
promising new directions. In addition,
the material is required by CTEP to
meet its obligations under FDA regu-
lations to (a) monitor the study and
(b) submit an annual report of current
findings to that agency. Failure to
comply with these reporting require-
ments is a serious breach of the
agreement that each investigator
makes in signing the FDA-1573 and
may result in suspension or termina-
tion of investigator privileges.

For all trials, the reporting of two
types of data is important: individual
patient data and study summaries.
Each is briefly discussed in the
following two paragraphs. Following
that, specific reporting requirements
for Phase I trials are detailed in
Section 10.2, and for Phase II and III
trials in Section 10.3.

nu Case Report Forms - Information
about patients is recorded on case
report forms which incorporate all
patient data stipulated in the
protocol.

The case report document should
not be the same as the patient’s
primary medical record. The former
ultimately serves as the formal and
fixed data base on which the study
is reported. A well-designed case
report form will assist the investi-
gator and assistants in collecting
and recording all data called for in
the protocol. The patient’s chart,
although the primary medical
record, is generally not organized

for purposes of research and does
not reliably contain the judgments
of the treating physician on the
effects of the protocol treatment.
For these reasons a separate
research record (i.e., case report
form) should be maintained on
each protocol patient. Case report
forms are best maintained concur-
rently with the medical record.

A case record should include not
only the actual data, but the re-
sponsible physician’s assessment of
the treatment effect (e.g., response
category) and judgment as to
whether any medical events in the
patient’s course were treatment-
induced (i.e., drug toxicity).
Unfortunately toxicities are probably
often underreported, particularly if
the effect is well-described.

Study Summary Forms - The study
summary is a tabulation and
analysis of the collated individual
patient data. It includes not only
objective tabulations of data, but
the assessment of the protocol
chairman concerning each case,
with particular attention to
eligibility, evaluability, and
interpretation of the observations.

In addition to data recording and
reporting, investigators and protocol
chairmen have several other respon-
sibilities for the reporting of per-
tinent protocol information to
CTEP. Procedures for reporting
study data vary according to the
type of study and category of
sponsorship. They are outlined
below for the three phases of
clinical drug development.
 

 

= 10.2 Reporting
Requirements of
Phase 1 Trials

10.2.1 Individual Patient Data - For
each patient on trial, data are record-
ed on a CTEP case report form. This
form is specific for Phase I/11/phar-
macokinetic trials. All information
specified in the protocol should be
recorded on this form. It must be
maintained prospectively. These forms
are submitted biweekly to the CTMS
of CTEP. The biweekly submission
should include case report forms on
patients actively on study and all new
patients entered since the last update.
At the end of each course, the
investigator should indicate which
medical events in the patient’s course
were in his judgment drug induced.

All evaluations regarding toxicity
should be reported according to the
CTEP toxicity criteria scale. This is a
standard format which has been
adopted by all CTEP Phase |
investigators.

These reporting requirements apply to
all Phase I trials of drugs newly
entering clinical trial, including both
adult and pediatric studies. Investi-
gators will receive a full report of
their study from the CTMS each
month. They should review the
printout for accuracy and report any
discrepancies to CTMS. The CTMS
provides CTEP with summary infor-
mation on all trials in the data base
with each drug. Investigators may, if
they wish, receive this summary
information for any drug they are
studying. The CTMS analyzes the
data from Phase I trials for timeliness
of submission and completeness and
provides monthly reports of this
analysis to CTEP investigators.

A microcomputer based software
package (ACES) is now available from
CTEP which emulates the case report
form. Data from Phase I trials may
be entered directly in a PC; the
software contains a facility for direct
transmission via telephone to CTMS.

10.2.2 Study Summaries - CTEP has
developed a study summary form
which contains the protocol chair-
man’s tabulation of results and
assessment of the results. This
document is designed to be main-
tained prospectively. It should be
submitted to the CTEP PIO every 6
months and at study completion.

10.2.3 Adverse Drug Reactions - Phase
I investigators should be acutely aware
of the need to maintain close tele-
phone contact with the CTEP drug
monitor responsible for the study and
inform the drug monitor of any signi-
ficant new findings. Since the defini-
tion of an adverse drug reaction in
Phase I is not clearcut, an investigator
should regard any severe, life-threaten-
ing, or fatal event as potentially
reportable immediately by telephone
(See Section 11 for full details).

10.2.4. Study Status - Changes in
study status must be promptly com-
municated in writing to the CTEP
PIO (See Section 8.8). Telephone dis-
cussions with CTEP Physician staff
are not considered formal notice of
status changes.

10.2.5 Amendments - All amendments
to a Phase I protocol must be sub-
mitted and approved by CTEP prior
to implementation (see Section 8.6).

10.2.6 Presentations - A progress
report of the study is presented by the
protocol chairman at meetings of the
Phase I Working Group, held at NCI,
usually three times per year. Minutes
of the meeting are circulated to Phase
I investigators and other interested
parties.

10.2.7 Publications - Any publication
resulting from a DCT-sponsored study
should be sent to the Protocol and
Information Office, CTEP, identifying
the protocol by the NCI protocol
number.

53
 

 

= 10.3 Reporting
Requirements of
Phase II and
Phase III Studies

54

Reporting requirements for these
studies differ from Phase I in the
frequency of reporting and in other
respects depending on whether the
clinical trials organization is a single
institution or a cooperative group.
The following apply to all Phase II
and Phase III trials.

10.3.1 Individual Patient Data -
Currently CTEP is exploring the
feasibility of using individual case
report forms for experimental drug
studies performed in cancer centers
and other single institutions. These
case report forms are being field-
tested by the Phase II-III drug devel-
opment contractors. If, as we expect,
these forms prove feasible and useful,
we shall later widen implementation at
single center studies. Where these
forms are used, each participating
investigator is responsible for assuring
that the data from patients under
his/her direction will be maintained
on these forms. He/she also bears
final responsibility for their content,
whoever else may assist in the
recordkeeping. These documents will
then be submitted to the protocol
chairman or his assistant for further
review. These forms may be audited
during a site visit (see Section 16).

N.B. Cooperative Groups - Each
cooperative group has specific record
keeping procedures for its investiga-
tors. Each group also has its own
specific case report form(s), which
must be used on all of its trials. The
group’s procedures should be followed
in all its trials.

10.3.2 Study Summaries - CTEP is
implementing a standard Study
Summary Form for Phase II trials
which will be maintained prospectively
and submitted to the CTEP every 6
months and at study completion. For
non-cooperative group studies, this
task is the responsibility of the
protocol chairman. The Study

Summary Form should be signed by
the protocol chairman, indicating
he/she has reviewed it and is in accord
with the assessments in the document.
It should be sent to CTEP PIO. If
these study summaries prove useful,
they will be implemented widely
among clinical trials organization
performing new drug studies under
DCT sponsorship. Their use in Phase
III studies is also being explored.

10.3.3 Study Status - Changes in study
status must be promptly communi-
cated in writing to the CTEP PIO
(see Section 8.8). Telephone discus-
sions with CTEP physician staff are
not considered formal notice of status
changes.

10.3.4 Adverse Drug Reactions - The
importance of reporting adverse drug
reactions (ADR) cannot be overstated.
Section 11 discusses these requirements
in detail. You are reminded that some
types of reactions must be telephoned
immediately. IDB maintains a 24-hour
line at 301-496-7957 to record these
messages. You are urged to call if in
doubt concerning the need to report
any particular reaction.

N.B. Cooperative Groups - Most
cooperative groups have established
procedures for the reporting of ADRs,
which are usually reported to an indi-
vidual in the group who is in turn
responsible for relaying the informa-
tion to others in the group and to
CTEP. If you are in doubt, contact
the operations office of your group. If
you are still in doubt or cannot reach
that office, contact the IDB at the
number listed above.
 

 

 

= 10.4 Retention of
Records

= 10.5 Reporting to IRBs

10.3.5 Amendments - For investiga-
tional drug trials, any change in the
approved protocol document must be
submitted to CTEP for review. Speci-
fic procedures for the submission of
amendments and a description of the
review of amendments of CTEP are
outlined in Section 8.6

10.3.6 Presentations - CTEP usually
sponsors two meetings annually at
which protocol chairmen present the
findings of current Phase II trials.
These usually focus on results of
single-agent Phase II trials.

10.3.7 Publications - Any publication
resulting from an investigational drug
study sponsored by DCT should be
sent to the CTEP Protocol and
Information Office, identifying the
protocol by the NCI protocol number.

FDA regulations require that all case
report records must be kept by the
investigator for at least 2 years after
an NDA has been approved or the
IND has been closed. CTEP will
notify investigators when these events
occur. This requirement is an explicit
part of the FDA-1573 (see Appendix
IV).

Each investigator must report to
his/her IRB any problems, serious
adverse drug reactions, or proposed
changes in the protocol which may
affect the status of the investigation
and the willingness of patients to par-
ticipate in it. The investigator must
also give a report to the IRB at inter-
vals appropriate to the degree of risk
in the study, but no less frequently
than once a year, or at study closure.

55
 

 

11. Adverse Drug
Reactions

 

56

Because most antineoplastic agents
have a very narrow therapeutic index,
toxic effects of treatment commonly
accompany drug administration. Since
cancer patients often exhibit signs and
symptoms referable to cancer or its
complications, both the definition and
identification of a medical event as an
adverse reaction to a cancer drug
present special problems for the
investigator and sponsor. We have
developed operational definitions of
ADRs which apply to anticancer drug
trials; these definitions are described
in Sections 11.1 and 11.2 below. The
prompt reporting of ADRs to the
CTEP is the responsibility of each
investigator engaged in clinical
research with investigational drugs
supplied by the DCT. Investigators are
encouraged to submit reports even if
there is only a suspicion of a drug
effect. Timely and accurate reporting
of ADRs is necessary because only
the sponsor can collate information
from diverse sources and quickly
disseminate the information to
investigators working with the drug.
The centralization of information on
real or suspected ADRs makes
possible a much more accurate
determination of the degree to which
a suspected reaction is in fact drug-
induced. Finally, regulations require
DCT to report to FDA all findings
regarding ADRs occurring in trials
under its sponsorship.

N.B. Investigators should apply the
toxicity scales as defined by their
research base in meeting the reporting
requirements set forth in the following
paragraphs.
 

 

= 11.1 Phase I Studies

« 11.2 Phase II and III
Studies

11.1.1 Report by phone to IDB within
24 hours:
= All life-threatening reactions
(Grade 4) which may be due
to drug administration

= All fatal events

A written report should be submitted
within 10 working days.

11.1.2 Report the first occurrence of
any toxicity of any grade by telephone
within 24 hours. An ADR report may
be required. For aplasia in leukemia
patients: Grade 4 unknown and
known reactions not to be reported.
Grade 5 unknown and known
reactions reported with 10 working
days if clearly related to experimental
drug (ie., single agent therapy).
Otherwise do not report.

Adverse reactions in these studies
should be handled according to
whether the reaction is known or
unknown. The list of known toxicities
includes those found in the protocol.
If in doubt, consider the reaction
unknown.

11.2.1 Unknown Reactions:

Grades 2 - 3 should be reported in
writing to the address listed in Section
11.3 within 10 working days.

Grades 4-5 should be reported within
24 hours to the telephone number
listed in Section 11.3. A written report
should follow within 10 working days.

11.2.2 Known Reactions:

Grades 1-3 should not be submitted as
an ADR. They should be included in

the routine report of the study by the
protocol chairman.

Grades 4-5 should be submitted as a
written report within 10 working days
to the address listed below. Grade 4
myelosuppression need not be reported
as an ADR.

For aplasia in leukemia patients:
Grade 4 unknown and known
reactions not to be reported. Grade 5
unknown and known reactions
reported within 10 working days if
clearly related to experimental drug
(i.e., single agent therapy). Otherwise
do not report.

57
 

 

= 11.3 Where to Report

= 11.4 Adverse Drug
Reactions with Non-
Investigational Drugs

= 11.5 Adverse Drug
Reactions and Routine
Reporting of Toxic
Effects

= 11.6 Actions Taken by
CTEP on ADR
Reports

58

By Phone: 301-496-7957
Available 24
hours.

By Mail: This address is for ADRs
only. Do not send other
correspondence to this location.

Investigational Drug Branch
P.O. Box 30012
Bethesda, Maryland 20814

Use NCI designated ADR form
(Appendix XI).

Cooperative group investigators should
check with the Operations Office
and/or the Chairmen of the New
Agents Committee about group
practices for handling these reports.

For studies sponsored or funded by
NCI involving commercially available
drugs, ADRs should be reported
promptly in writing using the standard
FDA ADR reporting form (FD-1639),
if that type of side effect has not
previously been reported in the
package insert and/or the literature. A
clear description of the suspected
reaction should be provided along
with an assessment as to whether the
event is drug- or disease-related. The
report should be sent to:

Investigational Drug Branch,
PO. Box 30012,
Bethesda, Maryland 20814

The reporting of ADRs is in addition
to and does not supplant the report-
ing of toxicities as part of the regular
scientific report of the results of the
research protocol. Reporting of toxi-
city should be in accord with the
procedures for reporting of results
described in Section 10.

CTEP physicians review each sub-
mitted report, including the investiga-
tor’s assessment. This review may
result in a request for further
information from the investigator.

Each submitted ADR report is
classified according to its likely
relation to the drug, and to the
patient’s underlying disease. Based on
this assessment, a decision is made
concerning the need for further
action.
 

 

The prime consideration is whether
the new findings affect the safety of
patients enrolled in ongoing trials. If
so, CTEP takes immediate steps to
notify the investigator community and
the FDA simultaneously.

In addition other measures may be
taken, including:

= Communicating the new informa-
tion by:

— Sending written notice directly to
investigators.

— Publishing findings in the
“CTEP Letter.”

» Altering existing research:
— Modification of protocols.

— Discontinuation or suspension of
one or more trials.

= Investigating the reaction:

— Initiate special clinical or
preclinical studies.

= Altering the process of informed
consent:

— Modification of existing
informed consent forms.

— Inform patients of new findings.

59
 

Part D

The Organization
of a Clinical Trial

The following six sections
provide a detailed descrip-
tion of NCI policies and
procedures for the respon-
sibilities of individuals and
institutions, including the
research base. It includes a
discussion of affiliates,
accountability and storage
of investigational drugs,
and monitoring and
quality assurance.

 
 

12. The Investigator
and Protocol
Chairman: Roles
and Responsibilities

 

= 12.1 The Investigator

62

An investigator is any physician who
assumes full responsibility for the
treatment and evaluation of patients
on research protocols, as well as the
integrity of the research data. The
term distinguishes physicians acting
as investigators from those who
assume the more limited role of
simply administering investigational
drugs. The investigator is responsible
to see that the protocol is followed,
and the data are collected promptly
and accurately, even if he delegates
the administration of the drug to
another physician. Most cancer trials
involve collaboration among many
investigators, one or more of whom
is designated a protocol chairman as
distinct from that of the participating
investigators.

There are about 5000 physicians
eligible to receive DCT-sponsored
investigational cancer drugs. Most are
eligible because they are investigators
supported by a peer-reviewed NCI-
funded grant, contract, or cooperative
agreement. Each investigator agrees to
certain essential principles of partici-
pation in clinical drug research. These
principles are contained in an agree-
ment, the FDA-1573, which is defined
by FDA regulation (see Appendix IV).

12.1.1 The FDA-1573

In signing the FDA-1573, the
investigator assures CTEP that the
clinical trial will be conducted
according to ethically and
scientifically sound principles. More
specifically, a signed FDA-1573
commits the investigator to the
following obligations or tasks:

s The investigator provides on the
FDA-1573 a statement of the
education and experience which
qualify him/her to perform the
study.

= The investigator assures that a

properly constituted IRB will be
responsible for the initial and
continuing review and approval of
the study. Any changes in the
research protocol will require IRB
approval, and all unanticipated
problems involving risks to human
subjects must be reported to the
IRB.

The investigator is required to
maintain adequate drug account-
ability records (See Section 15).

The investigator is required to
prepare and maintain adequate and
accurate case histories designed to
record all observations and other
data pertinent to each patient
(Section 10).

The investigator is required to
furnish reports to the CTEP. (See
Section 10). In the case of
multicenter studies, it is actually
the coordinating statistical center
and the protocol chairman who are
responsible for the generation of
these reports.

The investigator is responsible for
promptly reporting any ADR
reasonably regarded as caused by,
or probably caused by the drug and
if the ADR is alarming, it shall be
reported immediately.

CTEP devised a detailed policy
statement which adapts this
necessarily ambiguous language to
the setting of cancer clinical trials,
so that an investigation may more
easily determine when a medical
event needs to be reported to
CTEP. (See Section 11).
 

 

s The investigator shall maintain the
records of drug accountabililty and
case histories for two years
following the date a NDA is
approved or if an application is not
approved, until 2 years after the
IND or study is discontinued.

Upon the request of a scientifically
trained and properly authorized
employee of the DHHS (either
FDA or NCI), the investigator will
make records available for
inspection and copying.

The investigator certifies that the
drug will be administered only to
subjects under his/her personal
supervision or under the supervision
of physicians responsible to him/
her. A list of these investigators
should be provided on the
FDA-1573. The drug will not be
supplied to any other investigator
or to any clinic for administration
to subjects. (See Section 14, Who
May Administer Experimental
Drugs).

The investigator certifies that
he/she will inform subjects or their
representatives that drugs are being
used for investigational purposes
and will obtain the consent of the
subjects or their locally authorized
representatives.

The investigator assures CTEP that
the study will not be initiated until
the IRB has reviewed and approved
the study.

12.1.2 Responsibilities of an
Investigator for Human Subjects
Protection - The responsibilities of an
investigator for IRB review deserve
special mention. Each investigator
who participates in NCI sponsored
clinical research must have the
research approved by an IRB. The
procedures followed by the inves-
tigator and his institution for the
protection of human subjects,
including IRB composition and
function, as well as the basic
elements of the informed consent
document are specified in regulations
of the DHHS. All clinical research
sponsored by the DHHS must be in
compliance with these regulations
(Title 45, Code of Federal
Regulations, Part 46). Within the
DHHS, the Office for Protection
from Research Risks (OPRR) at the
NIH administers these regulations
with each institution. The OPRR
negotiates assurances of compliance
with HHS regulations for the
protection of human subjects. Under
an assurance the IRB is authorized to
review and approve research. Each
investigator who participates in NCI
sponsored research must conduct the
research at an institution with an
OPRR approved assurance. If this
assurance is lacking a single page
agreement may be filed with OPRR.
Further information about this may
be obtained by contacting OPRR at
(301)-496-7005.

63
 

 

= 12.2 The Protocol

64

Chairman

12.2.1. Responsibilities - The
chairman of a clinical trial assumes
certain responsibilities in addition to
those of the participating investigator.
Specifically these include:

= Writing the protocol document.

= Assuring that necessary approvals
are obtained, including those of
the IRB, the sponsor (DCT), and
any others for the protocol and
subsequent amendments.

= Monitoring the study during its
execution, which includes:
— Reviewing each case record to
confirm eligibility.

— Reviewing each case, record to
determine compliance with the
protocol.

— Reporting of adverse drug
reactions.

— Determining any necessary
changes in the protocol and
the informed consent docu-
ments and submitting them as
protocol amendments to the
research base and to CTEP.

— Monitoring accrual to the
study and stopping the study
when the requirements of the
study design have been
fulfilled.

— Reporting study status changes
to CTEP (see 8.8).

= Analyzing Results - The protocol
chairman should make an assess-
ment of each case to determine
eligibility, evaluability, toxicity,
protocol compliance, and out-
come. This assessment should be
independent of that of the
treating investigator.

= Reporting Results - The results
should be analyzed and tabulated
for submission to CTEP. The
protocol chairman bears the
primary responsibility for this
task. In multicenter trials, of
course, the statistical center is the
protocol chairman’s most impor-
tant collaborator in fulfillment of
reporting requirements.

12.2.2. Who May Serve as a Protocol
Chairman - Since the protocol
chairman is responsible for meeting
all NCI requirements for IND drug
research, as stated in this manual, the
protocol chairman must be at the
faculty level. Trainees may not serve
as protocol chairmen. The only
exception is that a trainee may be a
co-protocol chairman provided that a
faculty member is also co-protocol
chairman. In all cases the faculty
member is responsible to NCI for
meeting all requirements stated in this
manual.
 

13. Affiliate
Investigators

 

= 13.1 Definition

The participation of physicians who
collaborate with major institutions in
clinical trials is an important compo-
nent of the NCI program. The contri-
butions of these participants is
recognized by NCI, the clinical
cooperative groups, and many cancer
centers. In order to assure and main-
tain the high quality of clinical
research and patient care conducted
by the clinical trials organizations, it
is important to maintain a strong
relationship between these affiliate
investigators and the research base.

To accomplish this objective, methods
of organization are needed that
permit all participating investigators
to have easy access to accurate and
timely information on matters of
scientific importance and to conduct
treatment research in compliance with
Federal regulations. The following
guidelines have been provided to
assist research bases in formulating
specific policies for strengthening the
relationship between affiliate
investigators consistent with these
guidelines. The content of the
guidelines applies to affiliates of any
research base.

We recommend that each research
base develop an affiliate policy
consistent with these guidelines.

An affiliate investigator of a research
base is a physician who:

= Participates in research clinical
trials organized by the research
base, and

s Has satisfied all criteria for
affiliate membership as defined by
the research base.

65
 

 

= 13.2 Requirements
of an Affiliate
Investigator

= 13.3 Responsibilities
of Affiliate
Investigators

66

Must have demonstrated
competence in the treatment of
cancer patients as defined by the
research base.

Must have the ability to accrue a
minimum number of patients as
set by the research base.

Must have established a close
cooperative professional relation-
ship with the research base
through regular participation in
group meetings and/or educa-
tional sessions sponsored by the
research base.

Must have successfully passed a
probation period during which
time the affiliate investigator has
demonstrated:

— Ability to enter patients on
protocol.

— Ability to comply with the
protocol.

— Ability to adhere to the
procedures and standards of
the research base and the
CTEP.

Must have an OPRR assurance
for the protection of human
subjects (See Section 12.1.2).

The affiliate investigator must adhere
to the procedures of the research base
and CTEP for the conduct of clinical
research by:

Meeting the recordkeeping policies
of the research base.

Making certain that each protocol
is approved by an authorized IRB
prior to involvement of human
subjects.

= Making certain that each patient

signs and is given a copy of the
IRB-approved consent form. The
consent forms should be main-
tained on file by the affiliate
investigator.

Complying with the policies of
CTEP and the FDA concerning the
use of investigational drugs which
include as a minimum the
following:

— Filing a signed FDA-1573 with
the CTEP.

— Observing DCT procedures for
the use of investigational drugs,
including maintaining NCI Drug
Accountability Records (Appen-
dix XII).

— Agreeing that primary medical
records of patients may be au-
dited in accordance with the
policies of the research base, the
CTEP, and the FDA (See Sec-
tion 16).
 

 

= 13.4 Responsibilities
of Research Bases
for Affiliates

13.4.1 The Cooperative Groups

The cooperative groups have the
following responsibilities for their
affiliate investigators:

= Maintaining an accurate and up-to-
date list of all member institutions
and affiliate investigators.

s Informing CTEP of important
actions regarding membership
status of its member institutions
and affiliate investigators.

= Reviewing performance of all
members in periodic and timely
fashion.

= Assuring that all members, full and
affiliate, are in compliance with
CTEP policies and HHS
regulations.

13.4.2 The Principal Investigator
Responsibilities for Affiliate
Investigators in Cooperative Group
Protocols

The principal investigator in coopera-
tive groups has the following respon-
sibilities for affiliate investigators:

= Assuring the cooperative group
that the affiliate member’s per-
formance meets the procedures and
standards of the research base.

= Informing the cooperative group of
important changes in affiliate-
member relationships.

= Agreeing to site-visit the affiliate as
deemed necessary by the
cooperative group.

s Providing the affiliate with
accurate and timely information on
matters of scientific importance.

= Communicating to affiliates in a
timely manner all policies (and any
changes in policy) on the conduct
of clinical research. .

13.4.3 Cancer Centers

The cancer centers have the following
responsibilities for their physician
members and for their affiliate
institutions:

= Maintaining an accurate and up-to-
date list of all members and
affiliates.

s Informing CTEP of important
actions taken regarding membership
status of its members and affiliate
investigators.

» Conducting periodic and timely
review of the performance of all
members and affiliate investigators.

» Agreeing to site-visit the affiliate
investigator in accord with CTEP
policies.

= Assuring that all members and
affiliate investigators are in
compliance with CTEP policies
and FDA regulations.

« Communicating to affiliate
investigators in a timely manner all
policies and changes in policy on
the conduct of clinical research.

67
 

14. Who May
Administer
Experimental
Drugs

 

= 14.1 Restrictions to
Physicians Registered
as Investigators with
CTEP

68

The distribution of investigational
drugs is restricted to physicians who
are registered as investigators with
CTEP. Specifically, the secondary
distribution of investigational drugs
from registered investigators to
unregistered physicians is prohibited
except for the clearly defined
circumstances outlined below. All
patients on clinical trials involving
the use of investigational drugs must
receive all treatments with these drugs
from a registered investigator, except
as stipulated explicitly by the protocol
that is approved by CTEP.

The reason for this policy is clear.
Physicians who treat patients as part
of a clinical trial must have a com-
mitment to the goals of the trial and
to the methodologic requirements of
clinical research. They must be
experienced in the evaluation of
therapeutic results and of the toxic
manifestations of anticancer therapy.
The major issue, therefore, in the
conduct of a clinical trial is: Who is
making the observations and the
decisions? For example, who is
deciding on the dose modifications
and the laboratory tests to be
obtained? Who is interpreting the
response data? Who is observing the
patient for toxicities of the inves-
tigational drugs? A physician per-
forming these tasks with investiga-
tional drugs must have the training
and experience to function effectively
as a clincial investigator, and
acknowledge his commitment to
those principles.

All investigators participating in trials
sponsored by CTEP must be formally
registered with their research base
(i.e. cooperative group or cancer
center) and with CTEP. Such
registration signifies that the
physician-investigator meets certain
requirements for participation in
clinical trials. Investigators register
with CTEP by completing a Form
FDA-1573. (Appendix IV).

Physicians in training may administer
investigational drugs under the direct
supervision of a registered investiga-
tor holding a current FDA-1573. They
need not submit a FDA-1573 under
their own signature. In such cases the
registered investigator assumes com-
plete responsibility for the use of
these drugs.

CTEP recognizes that it is often
convenient for a cooperating group
member or cancer center physician to
ask a local physician to adminster
protocol treatment to a patient who
may have traveled long distances to
the research base for initial con-
sultation. We believe that this
approach is ultimately detrimental to
the clinical research effort unless very
careful surveillance is maintained by
the investigator. If close monitoring is
impossible, it seems much more
sensible to require that all treatments
be administered by registered
investigators. Physicians will have to
carefully consider whether a patient
being evaluated for study will be able
to receive each treatment at the hands
of a registered physician. We are
confident, however, that the benefits
of this policy, in terms of both
patient safety and integrity of the
research data, far outweigh the
disadvantages and are in the long-
term best interests of both patients
on clinical trials and the drug
development program of the DCT.
 

 

 

»« 14.2 Administration of
Investigational Drugs
by Non-registered
Physicans

For trials involving certain agents
which are at advanced stages of
development and for which the
clinical toxicities are well charac-
terized, it may occasionally be
appropriate for investigators to seek
the assistance of local physicians in
the patient’s community to adminis-
ter portions of protocol treatment.
CTEP will consider this practice to
be in compliance with its drug dis-
tribution policies provided that all of
the following stipulations are met:

14.2.1 - The registered investigator
remains responsible to the DCT and
the FDA for meeting all investigator
obligations listed in this handbook.
Remember that you, and not the
local physician, are the investigator.
You are responsible legally and
scientifically for all treatments,
whether you administer them yourself
or whether they are administered
under your direction by an oncology
nurse, an oncology fellow, or a
referring physician.

14.2.2 - The local physician
administers treatment only under
explicit instructions from the
registered investigator.

14.2.3 - Decisions about dose
modification are made only by the
registered investigator.

14.2.4 - Observations concerning
response status, toxicities, and the
decisions on whether to continue or
terminate therapy are to be made
only by the registered investigator.

14.2.5 - If non-registered physicians
are to administer any portion of
protocol treatment involving
experimental drugs, the protocol
document, when submitted to CTEP
for review, must state:

» Precisely what responsibilities
non-registered physicians will
assume in drug administration.

» The intervals at which a patient

will be evaluated by a physician-
investigator at the research base.

69
 

15. Accountability
and Storage of
Investigational Drugs

 

= 15.1 Procedures for
Drug Accountability
and Storage

70

The investigator is responsible for the
physical storage and recordkeeping of
investigational drugs received from
CTEP. Specifically, the investigator
must:

= Maintain a careful record of the
disposition of all drug received from
CTEP, using the NCI Drug Account-
ability Record Form (DARF)
(Appendix XII).

= Store the drug in a secure location,
accessible to only authorized person-
nel, preferably in the pharmacy.

The intent of the drug accountability
procedures described in this section is
to assist the investigator in making
certain that drugs received from DCT
are used only for patients entered
onto an approved protocol. The
recordkeeping described in this
section is required under FDA
regulation.

Investigators are responsible for the
use of investigational drugs shipped
in their name. Even if a pharmacist
or chemotherapy nurse has the actual
task of handling these agents upon
receipt, the investigator is the respon-
sible individual and has agreed to
accept this responsibility by signing
the FDA-1573.

15.1.1 - Each drug should be stored
separately for each protocol. If a
drug is used for more than one
protocol, there should be separate
physical storage for each protocol.
(Remember that CTEP provides
drugs on a protocol-by-protocol basis
and maintains for each investigator
distinct records of drug shipments on
each protocol).

15.1.2 - In parallel with the physical
storage of drug by protocol, there
should be a separate DARF for each
drug in the protocol. If there is more
than one protocol using a particular
drug, there should be a separate
DAREF for each protocol.

15.1.3 - Separate accountability forms
should be maintained for each
different strength or dosage form of
a particular drug (e.g., a drug with a
1 mg vial and a 5 mg vial would
require a different DARF for the 1
mg vial than for the 5 mg vial).

15.1.4 - The DARF has been designed
for use at each location where drugs
are stored, e.g., main pharmacy,
satellite pharmacy, physician’s office,
or other dispensing areas.

15.1.5 - The DARF is also designed
to accommodate both dispensing
records and other drug transaction
documentation (e.g., receipt of drug,
internal transfers, returns, broken
vials, etc.).

A full explanation, as well as a copy
of the DARF may be found in
Appendix XII.
 

 

= 15.2 Drug Returns

= 15.3 Verification of
Compliance

= 15.4 Handling of
Antineoplastic Agents

Many investigators are not aware that
drugs should be returned to the
sponsor (DCT). Investigators are
required to return drugs if:

= The study is completed or
discontinued

ms Drugs are outdated

= There is an obvious excess in
inventory

ms The drug is damaged (i.e., loss of
refrigeration)

To return drug to DCT: (1) package
the drugs securely to prevent
breakage, (2) complete the Return
Drug List Form, which can be found
on the reverse of the Clinical Drug
Request Form (NIH-986) (Appendix
X), and (3) send to the NCI Clinical
Drug Repository at the address
indicated on the Return Drug Form.

Investigators are reminded that
compliance with procedures to ensure
proper drug usage will be reviewed
during site visits conducted under the
monitoring program. Specifically, site
visitors will check that the drug
accountability system is being
maintained, and will spot check the
drug accountability records by
comparing them with the patients’
medical records to verify that the
drugs were administered to a patient
entered onto the recorded protocol.

There has been considerable concern
about the potential risk of chronic
exposure to low-level concentrations
of antineoplastic agents among health
care workers routinely handling these
agents. The potential mutagenic

activity of antineoplastic agents has
been examined in vitro and in vivo.
Urinary alkylating and anthracycline
agents have shown mutagenic activity
in experimental systems, whereas this
has not been demonstrated for most
of the antimetabolities and vinca
alkaloids. Recent reports indicate that
antineoplastic agents may be
absorbed by workers who are
handling them. In addition, some of
the compounds are carcinogenic in
animals and are suspected of being so
in humans, but only in patients
receiving the drug at therapeutic
levels.

However, there is no clear evidence at
this time that chronic exposure to low
level concentrations of antineoplastic
agents has been carcinogenic in
health care workers. Nevertheless, it
would seem prudent to consider the
adoption of certain precautions in the
procedures of workers handling these
agents.

Several professional organizations
have reviewed the data on this subject
in an attempt to develop guidelines
for safe handling. While there are
now several published sets of guide-
lines, they do not differ significantly.

We have reproduced in Appendix
XIII the Recommendations for
Handling Cytotoxic Agents by the
National Study Commission on
Cytotoxic Exposure. Please note that
these are guidelines and do not have
regulatory or legal force. They are
included for your consideration and
information.

71
 

16. Monitoring and
Quality Assurance

 

= 16.1 Introduction

= 16.2 Protocol
Compliance

72

Sponsors and research bases must
monitor their clinical trials. In
assuring the quality of data,
monitoring is a key component of
any clinical trials program. Quality
assurance and monitoring are
concerned with the execution of a
trial, rather than its conception, and
with the quality of the data which
support the scientific conclusions.

Many individual activities are part of
quality assurance, and investigators
have recognized some of them as
vital to the integrity of clinical trials
for years. In particular the quality
control of pathology and radio-
therapy has been part of the coopera-
tive group program for a long time.
More recently, investigators have
increasingly recognized the impor-
tance of verifying the accuracy of
other classes of data.

We shall now discuss in more detail
the items which form the major focus
of the DCT-sponsored quality
assurance effort. Note that the first
two classes of concern (protocol
compliance and data accuracy) are
really central problems in clinical
trials methodology. The fact that they
are assessed intensively by the site
visit monitoring program should in
no way divert attention from their
essential importance to the scientific
content of clinical trials.

16.2.1 Cooperative Groups - The
groups have recognized the
importance of assessing extent of
protocol compliance for many years.
One of the first areas to receive
attention was the confirmation of
diagnosis. Today virtually all groups
have Pathology Committees or
Reference Panels for selected studies;
central pathology review reduces one
important source of variability in
trial results. Furthermore, most
cooperative groups have quality
control in radiotherapy, which

consists at least of reviews of port
films by group radiotherapists. These
reviews are best done prospectively, so
that errors can be detected in time to
alter subsequent treatment. In the
cooperative groups the medical
oncology committee or the protocol
chairman reviews case report forms to
establish whether dose adjustments
have followed protocol guidelines,
and whether appropriate study tests
have been obtained.

In most cooperative groups, the
protocol chairman also reviews each
case to determine eligibility, evalu-
ability, and validity of response and
toxicity assessment. In some cases,
the statistical office accomplishes one
or more of these tasks. All of these
assessments are performed through
review of submitted case report
forms.

16.2.2 Cancer Centers - Few cancer
centers have organized procedures to
assess protocol compliance centrally
and systemically (see Section 3,
Research Bases). However, the CTEP
site visit monitoring program evalu-
ates protocol compliance as part of
its monitoring site visits. Indeed, this
is the major focus of a monitoring
site visit to a cancer center.

16.2.3 CTEP Clinical Drug Develop-
ment Contractors - Protocol compli-
ance is assessed by the CTMS. Phase
I and Phase 11/111 contractors submit
data to CTMS, which reviews it
carefully for extent of compliance
with the protocol. Reports of these
evaluations are provided monthly to
the investigator and to CTEP.
 

 

= 16.3 Data Accuracy

= 16.4 Procedural
Requirements

The importance of verifying the
accuracy of the basic data elements
used in the analysis of treatment
effects is obvious. Data accuracy is
assessed in site visits by comparison
of the research record (e.g., flow
sheets) with the primary patient
record. Response assessment may be
evaluated by examination of radio-
graphs or scintiscans, where relevant.

In many of the site visits performed
thus far, CTEP has been concerned
about the absence of formalized
procedures within many centers for
assessing these important issues inter-
nally. Many institutions lack central
registration mechanisms to enlist
patients on trials. Centralized systems
of data management are often not
available. Some institutions lack clear
procedures for certifying the accuracy
of research data. Formal procedures
for evaluating the accuracy of
response assessment, for example by
second party review, are commonly
lacking. As institutions recognize the
importance of these tools for the
conduct of clinical trials and bring
them “‘on line)’ the quality of data
will improve commensurately.

As an IND sponsor, the DCT must
verify that its investigators adhere to
the various procedural requirements
of investigational drug trials. The
specific procedural activities checked
at the time of the site visit are:

s Informed Consent - Investigators
must be certain that the patient
signs the IRB-approved version of
the informed consent. Please note
that the consent form must be the
document specifically written for
the protocol.

= IRB Approval - Each protocol
must be approved by the IRB
responsible for the institution
where the patient is treated. There
should be written verification of
this action and of at least annual
review. Substantive protocol
amendments must also be approved
by the IRB.

= Drug Accountability - Each
investigator must assure that:

— All IND drugs supplied by DCT
are used only for patients on
the specific protocol for which
CTEP has approved the drugs.

— Logs are maintained which
record the disposition of each
unit of drug received from
CTEP for the protocol.

Site visitors may also review the
completeness of reporting adverse
drug reactions and the quality of
recordkeeping with particular
reference to the completeness of the
source documentation.

Each of these areas is reviewed at the
time of site visit. In addition, many
cooperative groups and cancer centers
maintain internal procedures to assure
that IRB approvals are obtained prior
to patient accession.

73
 

 

= 16.5 Components of
the Quality Assurance
Program Implemented
by CTEP

74

16.5.1 Monitoring

Monitoring includes following the
overall progress of the study to
ensure that projected accrual goals
are met in a timely fashion and
excessive accrual is avoided, that
eligibility and evaluability rates do
not fall below acceptable standards,
and that risks of the study do not
outweigh benefits. Poor performance
in any of these areas is cause for
concern. Because these activities are
performed during study execution,
they may lead directly to improved
conduct of the trial.

The cooperative groups are perform-
ing these tasks according to systema-
tic, formalized procedures. For Phase
I studies, the CTMS performs these
duties.

Cancer center studies are monitored
by CTEP physicians through review
of semiannual study summary
reports.

16.5.2 The Site Visit Auditing
Program

16.5.2.1 Purpose of Site Visit Audits

= Verification of data accuracy - By
comparison of the primary medical
record with the case report form
maintained by the research base for
analysis.

= Verification of the presence of an
IRB approved consent form signed
by the patient.

= Verification of IRB approval of
each sponsored study.

= Verification that procedures for
drug accountability, including NCI
Drug Accountability Records, are
being maintained in accord with
DCT procedures.

16.5.2.2 Outline of Audit Procedures

= Trials to be audited are those
involving DCT investigational
drugs.

= All site visits to be conducted by
teams of peers.

s Site visits will be randomly timed.

= Site visits will be conducted at an
average rate of once every three
years (except Phase I trials).

16.5.2.3 Adaptions of Basic
Procedures to Specific Needs

These basic procedures have been
adapted to the several types of
clinical trials organizations supported
by NCI in the following way:

a Cooperative Groups - Each group
will perform its own program of
site visits, to be conducted by its
members. CTEP will attend a
reasonable percentage as observers.

a Clinical Drug Development
Contractors - Site visit audits are
made to the Phase I contractors
three times each year and to the
Phase 11/111 contractors once
annually. All are site visited by the
CTMS.

a Others - This category comprises
all others performing DCT IND
drug studies, including cancer
centers, RO1/POI1 holders (con-
ducting clinical IND drug trials as
part of grant-related activity) and
new drug studies groups. Site
visitors will be drawn from a pool
formed by investigators at all the
institutions to be site visited.
 

 

Table 1 summarizes the relationship
between the content of the site visit
audits and the type of clinical trials

 

 

 

organization.
Table 1 Components of the Quality Assurance Program
Protocol Compliance Data Accuracy Procedural
Contract CTMS SVAP CTMS
Cancer Centers SVAP SVAP SVAP
Cooperative Groups Group * Group* Group *

* Conducted as part of the site visit auditing SVAP = Site Visit Auditing Program (periodic
program of the cooperative groups, and co- site visits for the purposes described
site visited by NCI. in the text).

+ Protocol compliance is verified by each CTMS = Clinical Trials Monitoring Service
cooperative group through its own quality (CTEP monitoring organization,
assurance program. Most of this is which monitors Phase I and some
accomplished through a central review of Phase II trials, and coordinates Site
case report forms. However, protocol Visit Auditing Program).

compliance may also be checked at the time
of site visits to review patient charts, since
information pertinent to the eligibility and
evaluability of a patient may be discovered
which was not included on the case report
form.

75
 

 

= 16.6 Informed Consent
and the Monitoring
Program

76

Many have asked about the legality
of review of a patient’s primary
medical record by outside individuals.
The answer is straightforward. No
Federal law prohibits external review
of a patient’s medical record. The
regulations of informed consent do
require, however, that the patient be
informed of ‘‘the extent to which
confidentiality of records will be
maintained!” This means that there is
no rule against chart review by
outsiders, but that the patient must
be told what will be done. For this
reason, CTEP requires that each
informed consent document for
investigational drug trials include a
statement with the following language
“A qualified representative of FDA
and NCI may review my medical
records?’

Also please note that medical records
are protected from inquiries under
the Freedom of Information Act
(FOIA). Even if the study is per-
formed under government sponsor-
ship, any records on the premises of
the investigator are not subject to
FOIA requests. Furthermore, any
patient-related records in government
files are protected from FOIA
requests by the Privacy Act. As an
additional measure of safeguarding,
CTEP removes patient names from
any documents in its possession.
 

 

= 16.7 Dealing with
Problems Identified
at Site Visits

CTEP and the cooperative groups
have a full range of options in
dealing with problems identified at
the site visit. In a great majority of
cases, the measures are intended to be
constructive, educational, and
corrective rather than punitive. The
actions that are taken vary with the
individual case.

All site visit reports are sent to
CTEP. The reports are assessed by
CTEP staff on a regular basis. When
major problems are identified by the
audit team on a cooperative group
trial, this information is immediately
conveyed to the group chairman and
CTEP for further action and investi-
gations. After requesting a written
clarification, and following review of
the case by the cooperative group
and/or CTEP, appropriate measures
will be applied if the original assess-
ment is confirmed. The options for
action include:

— Letter of Warning
— Probationary status

— Suspension of patient entry
privileges

— Immediate repeat site visit

— Removal of access to
investigational drugs

— Notification of FDA if
investigational drugs are involved.
FDA may conduct its own
investigation.

The following actions are taken only
in instances of fraud or severe
misconduct:

— Replacement of principal
investigator

— Termination of grant or contract

— Reanalysis or retraction of
published results

— Formal NIH investigation

— Debarrment of investigator from
future participation in NIH
clinical trials

77
 

 

 

 
 

17. Group C

 

« 17.1 Definition

= 17.2 Placement of a
Drug Into Group C

« 17.3 Current Group C
Drugs

« 17.4 Use of a Group
C Drug

80

Investigational drugs which have been
given Group C designation by FDA
have reproducible efficacy in one or
more specific tumor types. Such a
drug has altered or is likely to alter
the pattern of treatment of the
disease and can be safely
administered by properly trained
physicians without specialized
supportive care facilities.

If a drug meets the criteria in the
preceding paragraph, CTEP may
initiate a formal application to the
FDA to authorize Group C distribu-
tion for the specific indication. Such
authorization is not equivalent to
formal FDA approval of effectiveness
for this indication.

A physician should request drugs
under Group C if he/she wishes to
treat a patient with an indication
specifically authorized for the
requested drug, as listed in Table 2.
All other non-research requests for
clinical use are considered a ‘‘Special
Exception’ (see Section 18).

The usage of a drug for a Group C
approved indication is fully described
in the GUIDELINE PROTOCOL.
This document is written by CTEP
and approved by FDA. It describes

the indications, dosage, precautions,
warning, and known adverse effects
of the drug for the specific indica-
tion(s). It also contains an FDA-
approved informed consent which
must be used if there has been no
local IRB review.

Guideline protocols may be obtained
by sending a written request to the
Drug Management and Authorization
Section, IDB, at the address listed in
Appendix IV. Additional information,
is available by phone at the number
listed in Appendix III.

Please note that:

a Patients treated under Group C
guidelines are not part of a clinical
trial at the time of the treatment
with the Group C drug.

= A drug classified in Group C for a
certain indication may still be
under active clinical investigation
for the same or other indications.

a Group C must not be used to
obtain drug to conduct clinical
trials.
 

 

= 17.5 Requesting a
Group C Drug

= 17.6 Responsibilities
When Using Group C
Drugs

= You may request a Group C drug
by contacting the Drug
Management and Authorization
section, IDB, by telephone or in
writing. (See Appendix III for
number and address.)

= You should indicate the diagnosis
of the patient.

= You must have a current FDA-1573
on file with CTEP (i.e. signed
within the last 12 months).

» If your request is approved you will
receive a supply of drug, and under
separate cover, an approval letter, a
copy of the Guidelines Protocol,
and a copy of the ADR Reporting
Form.

uw Drug Accountability: You should
record the disposition of drug
received on the Drug Account-
ability Record Form (see Section 15
and Appendix XII).

mn Adverse Drug Reactions: Since
Group C drugs are still investiga-

tional agents, physicians using
them are obligated to report
adverse drug reactions to CTEP
(see Section 11).

wu Informed Consent: You must obtain
written consent from the patient.
The Guidelines Protocol contains
the required consent form.

ms IRB Review: Since administration
of a drug under Group C guide-
lines is not done with research
intent, there is no CTEP require-
ment that IRB approval must be
obtained. CTEP has obtained an
exemption from this requirment
from FDA. You should, however,
check with your IRB to determine
whether its local policies require
approval.

In the future, CTEP will consider
Group C classification only for those
agents whose activity is well enough
established that NDA approval in the
relatively near future is considered
likely.

 

Table 2

*There are special requirements for
ordering THC. If you are not
familiar with these program, contact
the Drug Management and
Authorization Section, IDB.

Current Group C Drugs

 

 

Drug Indication

Azacytidine Refractory Acute Leukemia Single
Agent Treatment

AMSA Refractory Acute Leukemia Single

Agent Treatment

 

Erwinia Asparaginase

Patients Allergic to E. coli
Asparaginase

 

 

Hexamethylmelamine Refractory Ovarian Cancer Single
Agent Treatment
THC* Chemotherapy-induced nausea and

vomiting refractory to standard
antiemetics

 

81
 

18. Special Exceptions

 

= 18.1 Definition

= 18.2 Criteria for
Approval Of A Special
Exception Request

82

Physicians with patients who are
refractory to standard measures, who
are not eligible for an ongoing
research protocol, and who have a
cancer diagnosis for which an inves-
tigational drug has demonstrated
activity may receive the drug from
CTEP as a ‘‘Special Exception” to
the policy of administering investi-
gational drugs only under a research
protocol. If the requested drug is
approved for Group C for that
indication it should be requested
under the Group C Guidelines.

(see Section 17.)

The Special Exception mechanism is
the functional equivalent of a com-
passionate IND but differs from it in
that the investigator may obtain
drugs directly from CTEP, instead of
having to obtain an IND from FDA.
CTEP provides this mechanism as a
service to the oncologic community
and to cancer patients. Substantial
effort on the part of CTEP profes-
sional and support staff is commited
to maintaining it.

We expect that patients treated under
the Special Exception mechanism are
not eligible for established research
protocols. Drugs available for Special
Exception are always in Phase II or
Phase 111 trials. Special Exceptions
are not granted for Phase I drugs.

The purpose of the Special Exception
mechanism is to make non-approved
agents which have a significant
activity against specific malignancies
available to cancer patients and
investigators.

Physician staff members of the IDB
review each Special Exception request
and make the decision on a patient-
by-patient basis, based on the
following considerations:

» Is there a research protocol for
which the patient is eligible?

= Have standard therapies been
exhausted?

» Is there objective evidence that the
investigational drug is active in the
disease for which the request is
being made?

A review of the experience with
Special Exception Protocols in the
past indicated that patients experi-
enced considerable toxicity with
little significant benefit. As a
result, CTEP has attempted to
improve the selection criteria for
patients treated under Special
Exception. Considerable evidence
must attest to the activity of the
agent for the requested indication.
There should be sufficient data
available to provide a reasonable
expectation that the agent will
prolong survival or improve the
quality of life in a cohort of
similar patients so treated. Reports
of low response rates, or responses
of brief duration, or anecdotal
reports of an occasional response
are not sufficient to justify
approval.
 

 

= 18.3 Requesting A
Special Exception
Drug:

= 18.4 Responsibilities
of Physicians
Administering Special
Exception Drugs

= Is the drug likely to benefit this
patient?

Even if the drug has been reported
to be active in the disease, the
specific circumstances of the
patient must be weighed by both
his/her physicians and CTEP
physicians.

Please note that the Special
Exception service may not be used
as a means to obtain drugs to treat
a series of patients on protocol, or
to do pilot work for an intended
study. CTEP tracks these requests
and will take whatever measures are
necessary to discontinue such
practices by an investigator.
(Similar considerations apply to
Group C). Drugs distributed under
the Special Exception service
remain investigational and are
subject to FDA regulation and
CTEP policy.

Requests for Special Exceptions may
be made in writing or by telephone
to the Special Exception Coordinator,
Drug Management and Authorization
Section, IDB (See Appendix III). You
should indicate the patient’s
diagnosis, previous cancer therapy,
current clinical status, intended dose
and schedule of the requested drug
and any proposed concomitant cancer
drugs or other therapies.

You should explain why the proposed
use of the investigational drug is a
better selection than a commercially
available drug. In addition, the age,
sex, and date of diagnosis should be
included.

(see Appendix XIV).

83
 
 

 

i

x

 

 
 

 

 
 

Policy Statement:

 

Relationships Between
Pharmaceutical Industry
and Therapeutic Trials in
the Clinical Cooperative
Groups Supported by the
National Cancer Institute

I. Introduction

This policy statement pertains to trials
involving new drugs or biologicals
conducted by the clinical cooperative
groups supported by the National
Cancer Institute (NCI). It gives
general guidelines for the three-way
collaboration between clinical investi-
gators in the cooperative groups, the
pharmaceutical companies, and the
NCI. Its contents rest upon the
following premises:

A. The NCI recognizes the impor-
tance of the pharmaceutical indus-
try in the clinical development of
new anticancer agents. NCI wishes
to foster collaboration with indus-
try wherever possible. As part of
its mission to improve cancer care,
NCI shares with industry the im-
portant goal of defining the
precise contribution of a new drug
or biologic in the treatment of
cancer. NCI therefore recognizes
and supports the need of a private
sponsor to focus at the appropri-
ate time on clinical trials which
lead to a New Drug Application
(NDA), since an NDA is the vehi-
cle through which new drug
therapies become widely available
to cancer patients. Thus NCI feels
that it is appropriate for the
cooperative groups to do clinical
trials of interest to, and partially
supported by a pharmaceutical
firm, provided that the trials have
scientific merit and are consistent
with the overall goals of the
group. The primary consideration
for the group in choosing to per-
form a trial will be the scientific
merit of the proposal and not the
availability of additional funds
from private sponsors.

. Inasmuch as NCI functions as a

coordinator of a large volume of
clinical research in new drugs and
biologics, industry recognizes
NCI’s need to be aware of in-
dustry’s plans for the clinical
development of new agents of
mutual interest, particularly if a
pharmaceutical firm plans to
utilize the resources of the NCI-
supported clinical trials
mechanism. Industry also
recognizes the necessity of preserv-
ing the spirit of free and open in-
quiry among clinical investigators.

. The Clinical Cooperative Groups

recognize that their operating pro-
cedures remain as defined by the
Terms of Award of their
cooperative agreements with the
NCI. The Groups also recognize
that industry may have special
needs for data acquisition over
and above those of trials not sup-
ported by industry.

89
 

 

90

II. Planning of Clinical Trials
When there is a private sponsor, if
the drug to be developed is also of
interest to NCI, then the overall plan
for its clinical development shall be a
collaborative undertaking by the phar-
maceutical firm and the NCI; such a
plan shall be formulated and/or
discussed in joint meeting(s) before
the implementation of large-scale
clinical testing. In addition to areas of
mutual interest, NCI and the pharma-
ceutical firm may independently pur-
sue clinical studies of particular inter-
est to each. Because such studies have
implications for commitment of
resources by both NCI and the phar-
maceutical firm, they shall also be the
subject of joint discussion and plan-
ning between the NCI and the private
sponsor. There should be frequent
and full interchange between staff
members of the Cancer Therapy
Evaluation Program and the private
sponsor. Furthermore, whenever
possible, the planning of a particular
clinical trial, particularly large-scale
studies and/or trials of pivotal impor-
tance, should be a joint venture in-
volving the cooperative group, the
pharmaceutical firm, and the NCI.

III. Clinical Protocols

Protocols involving investigational
drugs or biologics in the cooperative
groups, regardless of the IND spon-
sor, will be activated only after review
and approval by the Protocol Review
Committee of the Cancer Therapy
Evaluation Program. Protocols
developed under NCI-IND will be sent
to the appropriate private sponsor for
scientific review and comment; review
by the private sponsor will take place
before activation of the study and the
comments by the firm will be sent to
the investigators along with the CTEP
Consensus Review. In addition, large-
scale trials will be examined carefully
by NCI and the firm for appropriate-
ness of resource allocation.

IV. INDs

Generally the needs of both NCI and
the pharmaceutical firm are best
served where each holds an IND. We
therefore expect that in most cases
either NCI or the pharmaceutical firm
will file an IND which references an
IND or master file held by the other.
In certain instances, when agreeable to
both the NCI and the pharmaceutical
firm, clinical trials within cooperative
groups may be conducted under the
IND of the pharmaceutical firm. As a
general rule, all information in INDs
will be fully shared between the
National Cancer Institute and the
pharmaceutical firm. However, certain
information pertaining to manufac-
turing processes may be held in
confidence by the private sponsor.
Nevertheless, all quality assurance data
concerning the manufacturing process
will be shared.

NCI and the pharmaceutical firm will
exchange all information submitted to
its IND including but not restricted to
protocols, adverse drugs reactions,
toxicology findings, and other
materials. The primary data relating
to certain sensitive laboratory studies
will, upon request by the pharmaceu-
tical firm, be returned to the company
by the NCI. NCI files will, however,
contain summaries of all such studies.
 

 

V. Resources Provided to
Cooperative Group by Private
Sector

In principle, the NCI encourages
support of clinical research from the
pharmaceutical industry. Funds,
support personnel to perform
additional monitoring, computer
resources, etc. may be provided
directly to the cooperative group.
Funds provided to a cooperative group
for additional monitoring beyond the
standard practices of the group will be
regarded as supplementary funding.
As is the case with NCI support, all
resources, financial or otherwise,
provided to a cooperative group by a
pharmaceutical firm should be a
matter of record.

VI. Data Rights, Confidentiality,
and Publications

All data derived from clinical trials
done by an NCI sponsored group will
be made fully available to the NCI.
Similarly, data generated in trials
directly supported by a pharmaceutical
firm will be available to the firm in a
manner to be decided upon jointly by
the group and the firm. Such data
may include case report forms as well
as summary data. Data arising from
cooperative group trials involving
drugs or biologics supplied by a firm
but for which the firm has not
committed other resources may be
made available to the firm by the
cooperative group; if there are
additional costs to the group for
providing such data, the group may
be reimbursed by the firm in a
manner to be negotiated by the group
and the firm. A firm supporting a
clinical trial with drugs, biologics, or
financial resources committed
specifically to that trial shall
ordinarily be the only frim to which
the group will provide data generated

in the trial. The firm may, if it
wishes, release the group from this
obligation; such a release must be in
writing and would permit the group
to provide data from the trial to
another company.

As is the case with all the clinical
trials data of a cooperative group, the
data generated in trials supported by a
pharmaceutical firm are the property
of the cooperative group. As stated
above, however, these data are to be
fully available to the firm and may be
used by the firm for its own analyses
and in its applications for registration.

The cooperative group maintains the
full right to present and publish the
data at such time and place as its
membership sees fit. Manuscripts
from pivotal trials or those to which
industry has specifically committed
financial resources should have
advisory review and comment by the
private sponsor a meaningful length
of time prior to submission for
publication.

VII. Cooperative Agreement
Clinical trials conducted with agents
from a pharmaceutical firm irrespec-
tive of IND sponsorship or funding
arrangements should be included in
the progress reports and competitive
renewal application of the group.

Progress reports and renewal
applications should clearly indicate the
IND sponsor, if other than NCI, and
the resources (funding, personnel, etc.)
which have been provided by private
SpONSOT.

91
i

 
 

Policy Statement:

 

The Conduct of
Phase 1 Trials
in Children

In a Phase I trial it is important that
each treatment of an individual
patient with the new agent be based
on full knowledge of the toxicities
encountered by other patients at the
dosage to be employed. The principal
investigator should have access to all
clinical data, and has the final
responsibility for the conduct of the
study. For these reasons, it is NCI
policy that Phase I trials should be
conducted within a single institution
under the direct supervision of a
single investigator.

Because of the rarity of cancer in
children, most pediatric Phase I trials
cannot be done efficiently by a single
institution. For this reason, the NCI
recognizes the appropriateness of
conducting multi-institutional Phase I
trials in pediatric populations.
However, the principles noted in the
first paragraph impose special
responsibilities on investigators
conducting multi-institution Phase I
trials. The protocol chairperson must
have complete up-to-the-minute
knowledge of entire toxicity data set
(all patients) in order to most safely
and appropriately administer each
course of drug. This should be true
not only for decisions to escalate
doses but also for each retreatment.
Obviously, the flow of information
between the participating institutions,
the protocol chairman and the NCI
must be timely, accurate, and
accessible.

Based on these precepts, the following
general policies apply to the conduct
of Phase I trials under NCI sponsor-
ship in pediatric populations:

1. Selection of Cooperative Group
Institutions for Participation in
Phase I Trials:

Participation should be limited to
institutions as follows:

¢ Intensive care and blood bank
facilities must be available on site.

e Must have at least two full time
investigators both willing and
judged capable by the New Agents
Committee of doing Phase I
studies.

e Patient entry only at investigator’s
institutions; cancer control, CCOP,
and satellite institutions may not
participate.

® Must have PI approval.

e Must have data manager available
to collect data as is generated, i.e.
daily.

2. Protocol Development and
Approval:

Drugs to be studied in Phase I trials
will be agreed to by the Group and
Investigational Drug Branch in the
framework of the Phase I Working
Group. It is recommended that a
Letter of Intent be submitted before
developing a full protocol.

Protocol authorship, group review and
submission to NCI will proceed
according to normal group procedures.

D3
 

 

96

3. Study Chairperson:

A protocol chairperson shall be
appointed by the Group’s New Agents
Committee for each study. Protocol
chairpersons should be experienced in
the conduct of Phase I trials. Inexpe-
rienced investigators interested in
Phase I trials may enter the system as
participants provided their institutions
meet the criteria in (1) above.

The Protocol Chairperson is
responsible for:

— approving each patient entry onto
the trial as well as to subsequent
levels of dose escalation,

— approving each course of treatment
for each patient,

— deciding when to escalate dose
levels, and to what dose,

— establishing that the MTD and a
Phase II dose have been
satisfactorily defined,

— terminating the study in a timely
manner,

— keeping all investigators informed
of possible toxicities,

— keeping NCI informed of the
progress of the trial,

— the timely review of data,

— the analysis of trial results,

— informing NCI of Adverse Drug
Reactions.

4. Participating Investigators are

Responsible for:

— obtaining approval from the
protocol chairperson for each
course,

— assuring that all drugs will be
administered at the approved
institution,

— reporting toxicities and data

5. Data Flow:

a) The protocol chairperson must
have direct and immediate access
to current patient information.
Each Group will decide how to
triage the flow of data from the
investigators to the Group
Operations Office and to NCI. The
raw patient data should be
submitted in the NCI/CTMS data
base by posting at biweekly
intervals, irrespective of the source
of the submission to CTMS.

b) Flow Sheets, Criteria for Toxicity
and Response
Group flow sheets will be
transcribed onto standard Phase I
case report forms and submitted to
CTMS.

Criteria for toxicity and response
should be the same used by the
adult Phase I contractors with any
necessary modification for the
pediatric population.
 

 

6. Adverse Drug Reaction (ADR)
Reporting:

The responsibilities of reporting ADRs
to NCI will rest with the protocol
chairperson. Severe life-threatening or
fatal toxicities should be reported
immediately by telephone to NCI as
per the NCI/ADRC reporting
guidelines.

7. Site Visit Monitoring

The Clinical Trials Monitoring Service
(CTMS) will be employed by NCI to
audit the data collected in Phase I
trials. Periodic site visits will be
conducted to compare the patient
records with submitted data. This is
the standard for adult Phase I studies,
and is a reflection of NCI’s
obligations as a sponsor of new
agents. Because of the number of
institutions involved in pediatric Phase
I trials a modified site visit schedule
will be employed.

8. Drug Distribution

Although it is an NCI policy to ship
drugs directly to each registered
investigator under any specific
protocol an exception will be made in
this case. The Protocol Chairperson
will be solely responsible for drug
dispensing and should order directly
from NCI. He/she will subsequently
re-distribute the drugs to the partici-
pating institutions. This increase in
authority of the Protocol Chairperson
is intended to assist him/her in
meeting the increased responsibilities
under this policy for Phase I trials.
Drug accountability logs should be
maintained by each participating
investigator.

97
 

 

 

 
 

 

 

 

Cancer Therapy
Evaluation Program
Office of the Director

 

 

 

 

 

 

 

 

 

 

 

 

Dr. Wittes
- 9 )
Program Management Protocol and
and Analysis Office Information Office
Ms. Carpenter Ms. Hogan
Z

 

(

]

 

 

Investigational Drug

 

 

Regulatory Affairs

 

 

1

1

 

 

Biometric Research

 

 

Clinical Investigation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Branch Branch Branch Branch
Dr. Hoth Dr. Shoemaker Dr. Simon Dr. Friedman
Biologics
| Evaluation Drug Regulatory Medicine Section
Section Affairs Section — Dr. Killen
; Dr. Shoemaker :
Dr. Hawkins
Developmental Quality Assurance Nutrition and
- Chemotherapy and Compliance A Supportive Care
Section Section Section
Dr. Leyland-Jones Dr. Macfarlane (Vacant)
Drug Management
_ and Authorization ~ Surgery Section
Section Dr. Avis
Mr. Fortner

 

 

 

 

 

 

 

 

_ Pediatric Section
Dr. Ungerleider

 

 

 

101
 

 

List of Key Addresses and
Telephone Numbers

102

FOR ADMINISTRATIVE INQUIRIES

Protocols and Amendments:
Protocol and Information Office
Cancer Therapy Evaluation Program
Landow Building, Room 4C-33
Bethesda, Maryland 20892
Telephone: (301)-496-1367

Use this address only for Express Mail:

Protocol and Information Office
Cancer Therapy Evaluation Program
Landow Building, Room 4C-33
7910 Woodmont Avenue

Bethesda, Maryland 20814

Letters of Intent:

LOI Coordinator

Protocol and Information Office
Cancer Therapy Evaluation Program
Landow Building, Room 4C-33
Bethesda, Maryland 20892
Telephone (301)-496-7957

Adverse Drug Reactions:
Investigational Drug Branch
P.O. Box 30012

Bethesda, Maryland 20814
Telephone (301)-496-7957

Clinical Brochures:

Regulatory Affairs Branch, CTEP
Landow Building, Room 4C-17
Bethesda, Maryland 20892
Telephone: (301)-496-7912

Clinical Drug Orders, Group C
Drugs, and Special Exceptions:

Drug Management and Authorization
Section

Investigational Drug Branch, CTEP

Landow Building, Room 1304

Bethesda, Maryland 20892

Telephone: (301)496-5725

Requests for Non-Clinical Use of
Investigational Drugs:

Chief, Pharmaceutical Resources
Branch

Developmental Therapeutics Program

Landow Building, Room 5C-25

Bethesda, Maryland 20892

Telephone: (301)-496-8774

Quality Assurance, Site Visits,
Monitoring, and Informed Consent
Issues:

Quality Assurance and Compliance

Section

Regulatory Affairs Branch, CTEP

Landow Building, Room 4C-19

Bethesda, Maryland 20892

Telephone: (301)-496-8798

Regulatory Questions:

Chief, Regulatory Affairs Branch
Cancer Therapy Evaluation Program
Landow Building, Room 4C-19
Bethesda, Maryland 20892
Telephone: (301)-496-7912

FOR SCIENTIFIC INQUIRIES:

Biologics Related Questions:

Senior Investigator

Biologics Evaluation Section
Investigational Drug Branch, CTEP
Landow Building, Room 4C-19
Bethesda, Maryland 20892
Telephone: (301)-496-8798

Chemotherapy Drug Related
Questions:

Senior Investigator

Developmental Chemotherapy Section

Investigational Drug Branch, CTEP

Landow Building, Room 4C-09

Bethesda, Maryland 20892

Telephone: (301)-496-1196

Disease Related Questions:
Disease Coordinator

Clinical Investigations Branch
Landow Building, Room 4A-04A
Bethesda, Maryland 20892
Telephone (301)-496-6056
 

 

 
 

DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE Form approved OMB No. 0910-0013
FOOD AND DRUG ADMINISTRATION

 

STATEMENT OF INVESTIGATOR Note: No drug may be shipped or study initiated unless
a completed statement has been received
(21 CFR 312.1(a)(12)).

 

TO: SUPPLIER OF DRUG (Name, address, and Zip Code) NAME OF INVESTIGATOR (Print or Type)

 

DATE

 

NAME OF DRUG

 

 

Dear Sir:
The undersigned,

submits this statement as required by section 505(i) of the Federal Food, Drug, and Cosmetic Act and §312.1 of Title 21 of the Code of

Federal Regulations as a condition for receiving and conducting clinical investigations with a new drug limited by Federal (or United States)
law to investigational use.

 

 

1. THE FOLLOWING IS ASTATEMENT OF MY EDUCATION AND EXPERIENCE:

 

a. COLLEGES, UNIVERSITIES, AND MEDICAL OR OTHER PROFESSIONAL SCHOOLS ATTENDED, WITH DATES OF ATTENDANCE, DEGREES,
AND DATES DEGREES WERE AWARDED

 

b. POSTGRADUATE MEDICAL OR OTHER PROFESSIONAL TRAINING. GIVE DATES, NAMES OF INSTITUTIONS, AND NATURE OF TRAINING.

 

c. TEACHING OR RESEARCH EXPERIENCE. GIVE DATES, INSTITUTIONS, AND BRIEF DESCRIPTION OF EXPERIENCE.

 

d. EXPERIENCE IN MEDICAL PRACTICE OR OTHER PROFESSIONAL EXPERIENCE, GIVE DATES, INSTITUTIONAL AFFILIATIONS, NATURE
OF PRACTICE, OR OTHER PROFESSIONAL EXPERIENCE.

 

e. REPRESENTATIVE LIST OF PERTINENT MEDICAL OR OTHER SCIENTIFIC PUBLICATIONS. GIVE TITLES OF ARTICLES, NAME OF
PUBLICATIONS AND VOLUME, PAGE NUMBER, AND DATE.

IF THIS INFORMATION HAS PREVIOUSLY BEEN SUBMITTED TO THE SPONSOR, IT MAY BE REFERRED TO AND ANY ADDITIONS
MADE TO BRING IT UP-TO-DATE.

FORM FDA 1573 (10/82) PREVIOUS EDITIONS ARE OBSOLETE.

105

 
 

2a. The investigator assures that an IRB that complies with
the requirements set forth in Part 56 of this chapter will be
responsible for the initial and continuing review and approval
of the proposed clinical study. The investigator also assures
that he/she will report to the IRB all changes in the research
activity and all unanticipated problems involving risks to
human subjects or others, and that he/she will not make any
changes in the research that would increase the risks to human
subjects without IRB approval. FDA will regard the signing
of the Form FDA 1573 as providing the necessary assurances
stated above.

b. A description of any clinical laboratory facilities that will
be used. (If this information has been submitted to the spon-
sor and reported by him on Form FDA 1571, reference to the
previous submission will be adequate).

2. he investigational drug will be used by the undersigned
or under his supervision in accordance with the plan of investi-
gation described as follows: (Outline the plan of investigation
including approximation of the number of subjects to be
treated with the drug and the number to be employed as con-
trols, if any, clinical uses to be investigated; characteristics of
subjects by age, sex and condition; the kind of clinical obser-
vations and laboratory tests to be undertaken prior to, during,
and after administration of the drug, the estimated duration
of the investigation; and a description or copies of report
forms to be used to maintain an adequate record of the obser-
vations and test results obtained. This plan may include rea-
sonable alternates and variations and should be supplemented
or amended when any significant change in direction or scope
of the investigation is undertaken.)

4. THE UNDERSIGNED UNDERSTANDS THAT THE FOL-
LOWING CONDITIONS, GENERALLY APPLICABLE TO
NEW DRUGS FOR INVESTIGATIONAL USE, GOVERN
HIS RECEIPTS AND USE OF THIS INVESTIGATIONAL
DRUG:

a. The sponsor is required to supply the investigator with full
information concerning the preclinical investigations that
justify clinical trials, together with fully informative material
describing any prior investigations and experience and any
possible hazards, contraindications, side-effects, and precau-
tions to be taken into account in the course of the investiga-
tion.

b. The investigator is required to maintain adequate records
of the disposition of all receipts of the drug, including dates,
quantities, and use by subjects, and if the investigation is
terminated, suspended, discontinued, or completed, to return
to the sponsor any unused supply of the drug. If the investi-
gational drug is subject to the Comprehensive Drug Abuse
Prevention and Control Act of 1970, adequate precautions
must be taken including storage of the investigational drug
in a securely locked, substantially constructed cabinet, or
other securely locked substantially constructed enclosure,
access to which is limited, to prevent theft or diversion of the
substance into illegal channels of distribution.

 

c. The investigator is required to prepare and maintain ade-
quate and accurate case histories designed to record all obser-
vations and other data pertinent to the investigation on each
individual treated with the drug or employed as a control in
the investigation.

d. The investigator is required to furnish his reports to the
sponsor of the drug who is responsible for collecting and eval-
uating the results obtained by various investigators. The spon-
sor is required to present progress reports to the Food and
Drug Administration at appropriate intervals not exceeding
1 year. Any adverse effect that may reasonably be regarded
as caused by, or probably caused by, the new drug shall be
reported to the sponsor promptly, and if the adverse effect
is alarming, it shall be reported immediately. An adequate
report of the investigation should be furnished to the sponsor
shortly after completion of the investigation.

e. The investigator shall maintain the records of disposition
of the drug and the case histories described above for a period
of 2 years following the date a new-drug application is ap-
proved for the drug; or if the application is not approved,
until 2 years after the investigation is discontinued. Upon the
request of a scientifically trained and properly authorized
employee of the Department, at reasonable times, the investi-
gator will make such records available for inspection and
copying. The subjects’ names need not be divulged unless the
records of particular individuals require a more detailed study
of the cases, or unless there is reason to believe that the rec-
ords do not represent actual cases studied, or do not represent
actual results obtained.

f. The investigator certifies that the drug will be administered
only to subjects under his personal supervision or under the
supervision of the following investigators responsible to him,

 

 

 

and that the drug will not be supplied to any other investi-
gator or to any clinic for administration to subjects.

g. The investigator certifies that he will inform any subjects
including subjects used as controls, or their representatives,
that drugs are being used for investigational purposes, and
will obtain the consent of the subjects, or their representatives,
except where this is not feasible or, in the investigator’s pro-
fessional judgment, is contrary to the best interests of the
subjects.

h. The investigator is required to assure the sponsor that for
investigations subject to an institutional review requirement
under Part 56 of this chapter the studies will not be initiated
until the institutional review board has reviewed and approved
the study. (The organization and procedure requirements for
such a board as set forth in Part 56 should be explained to
the investigator by the sponsor.)

 

Name of Investigator

Very truly yours,

 

Address.

Telephone ( )

 

 

(This form should be supplemented or amended from time to time if new subjects are added or if significant changes are made in the plan of investigation.)

106
 

 

New Drug Studies Group
Application Guidelines

I. Introduction

The Division of Cancer Treatment of
the National Cancer Institute has
established the New Drug Studies
Group mechanism in order to provide
NCI Investigational New Drugs for
study by clinical investigators who are
not members of NCI approved Cancer
Centers. Since DCT policy restricts
eligibility to test its drugs to investiga-
tors approved by peer review, either
under contract, PO1/ROI holders,
cooperative group grantees, or who
are staff of NCI approved (CORE)
Cancer Centers, this mechanism
permits other highly qualified clinical
researchers to test NCI drugs.

It is anticipated that studies conducted
by NDSG will be Phase II trials.
Under exceptional circumstances Phase
III trials may be conducted (See
Section 6 of Investigators Handbook).
No Phase I trials will be permitted.

II. Application Requirements
Investigational groups seeking
designation as a New Drug Studies
Group should indicate in their appli-
cation, according to the following
outline:

a. The proposed Leader of the Group
for evaluation of Investigational
New Drugs and his qualifications,
with particular reference to experi-
ence in conducting clinical trials
with investigational anticancer
drugs.

b. Prior experience of participating
investigators with the evaluation of
investigational drugs.

¢. Prior experience of the group/insti-
tution in conducting clinical cancer
research.

d. The proposed tumor types to be
studied, and evidence that
sufficient numbers of patients are
available to conduct the proposed
studies.

. An applicant who is a member of

an NCI sponsored Cooperative
Group must document that the
trials under the NDSG will not
conflict with commitments to
Cooperative Groups.

. If any affiliate investigators or in-

stitutions are intended, then there
should be a written policy for
qualifications and standards for
affiliates (see Section 13 of the
Investigator Handbook) as well as
mechanisms for assuring the qual-
ity of clinical research by these
affiliates (see Section 16 of the
Investigator Handbook).

. Procedures for data management

and assurance of protocol
compliance.

. A description of:

1) facilities available for in and out
patient treatment,

2) institutional programs relating to
cancer, including a description
of organizational entities and
staff which will be responsible
for these studies (eg. divisions,
departments, sections, etc.),

3) statistical support for evaluation
of the results of protocol studies
of Investigational New Drugs,
and

4) institutional procedures and
facilities for storage, dispensing,
handling and account of investi-
gational drugs, in accord with
NCI policies.

i. A description of the Institutional

Review Board (as defined by Public
Law 93-348, Title 2, Section 212(a)
of the Code of Federal Regulations
and FD Form 1571, Section 10,
Part C).

j. A signed FD-1573 for each

investigator.

109
 

 

110

III. Review of Applications

1. The application will be reviewed by
staff of the Cancer Therapy
Evaluation Program (CTEP).

2. The review will focus on three
broad areas:

a. The qualifications of the investi-
gators and merits of the
proposal, as outlined in the
application.

b. The demonstrated ability of
proposer to perform clinical
research and the existence of
procedures to assure the quality
of work.

c. The extent to which the pro-
posed NDSG provides DCT with
a needed resource (e.g.,
particular scientific expertise or
an unusual patient population)
which does not duplicate that
which is available through
already supported mechanisms.

IV. Instructions to Applicants
1. The applicant should submit 5
copies of the application to:

Head, Protocol and Information
Office

Cancer Therapy Evaluation
Program

Division of Cancer Treatment,
NCI

Landow Building, Room 4C-33

Bethesda, Maryland 20892

2. Written notification of the receipt
of the application will be made.

3. The application will be reviewed by
the Cancer Therapy Evaluation
Program (CTEP) Staff.

V. Responsibilities of NDSG
Approved applicants are expected to
follow all DCT IND drug procedures
as outlined in the Investigator’s
Handbook. Please pay particular
attention to Section 12. Responsibilities
of the Protocol Chairman and Clinical
Investigators
Letter of Intent
Investigational Drug Trial
National Cancer Institute
Cancer Therapy Evaluation Program

Drug

 

Dose

 

Schedule

 

Tumor Type

 

Group or Institution

 

Performance Status of Patients

 

Prior Treatment Status of Patients

 

 

Experimental Design

 

 

 

 

When Would Trial Begin Estimated Annual Accrual

 

Accrual Documented by Prior Trials (include breakdown by P.S. and prior treatment)

 

 

Proposed Sample Size

 

Projected Date of Completion of Accrual

 

List Competing Studies in the Selected Tumor Type

 

 

List Competing Studies for Which the Proposed Patient Population will be Eligible

 

 

 

Date Protocol Chairman

 

Group Chairman/Contract PI

(If applicable)
10/85

113
Informed Consent Checklist

I. Required Elements - Must be present in the informed consent document.

IL.

III.

L

Clearly state that the study involves research.
State which drug(s), treatment(s) or delivery technique(s) is experimental.
Clarify the study purpose(s) in layman’s terms.

State the patient’s expected duration of participation in study (e.g., the patient will be treated until there
is evidence that therapy is no longer effective).

Give a brief description of the procedure(s) to be performed to monitor the patient during study (e.g.,
X-rays, lab evaluations, etc.). An exhaustive list is not necessary.

Give a description of the experimental aspect(s) or new delivery technique(s) of the study.
State in specific terms the route of administration of each drug (e.g., IV, oral, continuous infusion, etc.).

State estimated time of delivery of each drug or time of procedure (e.g., 5 minutes, 30 minutes, 24 hours,
etc.).

. State which risks are attributed to specific drug(s) or procedures(s).

. Clarify and describe expected benefit(s) to be derived from participation in this study (e.g., tumor

shrinkage, quality of life, etc.).

. In general terms, discuss alternative treatment(s) to participation in this study (e.g., conventional

chemotherapy, irradiation, hormonal therapy, surgery, etc.).

. State the extent to which confidentiality of records will be maintained.

State that a qualified representative of the FDA may inspect patient/study records.

State that a qualified representative of the NCI may inspect patient/study records.

State if compensation for study related injury will be provided by the institution or other insurer.
State if emergency treatment of injury will or will not be provided by the institution.

Provide space in the form or list the name(s) and number(s) of contact person(s) for research related
questions.

Provide space in the form or list name(s) and number(s) of the contact person(s) (not involved in the
research) for patient rights related questions.

. Clearly state participation is voluntary.

State that refusal to participate will involve no loss of benefits or penalize the patient’s care.

State that discontinuation of participation in the study will involve no loss of benefits to which the
patient is entitled.

Additional Elements - May be appropriate for some studies

1.
2

3.
4.
5.
6.

State that unforseeable or unexpected risk(s) may be involved.

State the circumstances under which the patient’s participation may be terminated by the investigator
without the patient’s consent.

State that additional costs may be incurred by the patient’s participation in the study.
State the consequences of the patient’s decision to withdraw from the study.
State that significant new findings that relate to the patient’s treatment will be discussed with the patient.

State the approximate number of patients involved in the study.

Suggested Elements

I:
2.
3.

State that a copy of the informed consent form shall be given to the patient.
The form should be written in layman’s terms.

Reference to approval by the IRB, NCI or Cooperative Group may be misleading to the patient.

117
NAME OF INSTITUTION

Protocol Submission Checklist
National Cancer Institute
Cancer Therapy Evaluation Program

 

INSTITUTION PROTOCOL #: = NCI PROTOCOL #:

PROTOCOL CHAIRMAN: PHONE NUMBER:
LIST NCI SUPPLIED DRUGS:

 

 

Please indicate type of material enclosed and fill in blanks:

[J New Protocol [J Revised Protocol [J] Amendment [J Status Notice

I

IL.

IIL.

IV.

NEW PROTOCOL ENTITLED:

 

 

 

 

[J [J HAVE YOU SUBMITTED A LETTER OF INTENT FOR THIS PROTOCOL?

Y N IF YES, LOI #

[J [0 ARE YOU ENCLOSING A SIGNED AND DATED IRB APPROVAL (Form 596)?

Y N IF NO, EXPLAIN

[J [J ARE YOU SUBMITTING THIS PROTOCOL FOR APPROVAL FOR CCOP?

Y N

[J [J IS THIS PROTOCOL PART OF A ROl OR POI? GRANT #

Y N

[J [J DO YOU WISH THIS PROTOCOL TO BE CONSIDERED A CONTRACT FUNDED STUDY?
Y N CONTRACT #

PROJECTED DATE OF ACTIVATION. (If already opened, provide activation date ___ ~~)

REVISIONS: RESPONSE TO CTEP QUESTIONS FOR PROTOCOL AWAITING CTEP APPROVAL
AMENDMENT TO APPROVED PROTOCOL:

[J] ACTIVATION AMENDMENT (List of changes between CTEP approval & local activation)
[J Activation Amendment Only (list changes)
[J Activation Amendment plus replacement pages
[J Activation Amendment plus replacement document

[Ll AMENDMENT FOR ACTIVE STUDY
[J] Editorial, Administrative changes [J] Change of participants
[J Scientific changes [J Change of Protocol Chairman

OFFICIAL NOTICE OF CHANGE IN PROTOCOL STATUS:

 

 

 

 

 

[J] ACTIVATION Date:
[J TEMPORARY CLOSURE Date:
[] REACTIVATION Date:
[J] CLOSURE Date:
[J COMPLETION Date:
OTHER:

 

 

 

 

SIGNATURE OF PERSON COMPLETING THE FORM/TELEPHONE NUMBER/DATE 7/85

121
Group Protocol Submission Checklist
National Cancer Institute
Cancer Therapy Evaluation Program

NAME OF GROUP:
GROUP PROTOCOL #: ~~ NCI PROTOCOL # (if different):
PROTOCOL CHAIRMAN: PHONE #:
LIST NCI SUPPLIED DRUGS:

 

 

 

Please indicate type of material enclosed and fill in blanks:

[] New Protocol [] Revised Protocol [J Amendment [] Status Notice

I. NEW PROTOCOL ENTITLED:

[J] [J HAVE YOU SUBMITTED A LETTER OF INTENT OR A CONCEPT REVIEW FOR THIS
Y PROTOCOL? IFYES, Lo1#__ = orCR#

[J [J IS THIS A PILOT STUDY SUBMITTED FOR “INFORMATION & FILING ONLY” (No IND
Y N drugs and <100 patients)?

[J [J DOES THIS PROTOCOL INCLUDE A NEW MASTER PROTOCOL?

Y N

(J [J IS THIS AN INTERGROUP STUDY?

Y N

(J [J WILL THIS PROTOCOL BE OPEN TO ANY CCOP(S)?

Y N

PROJECTED DATE OF ACTIVATION (Month/Year)

 

II. REVISIONS: RESPONSE TO CTEP QUESTIONS FOR PROTOCOL AWAITING CTEP APPROVAL
III. AMENDMENT TO APPROVED PROTOCOL: [] REQUEST FOR PRIOR APPROVAL

[J ACTIVATION AMENDMENT (List of changes between CTEP approval & Group activation)
[J Activation Amendment Only (list of changes)
[J Activation Amendment plus replacement pages
[J Activation Amendment plus replacement document

[J AMENDMENT FOR ACTIVE STUDY
[J Editorial, administrative changes [J Change of participants
[J Scientific changes [J Change of Protocol Chairman

IV. OFFICIAL NOTICE OF CHANGE IN PROTOCOL STATUS:

 

 

 

 

 

[J ACTIVATION Date:

[J TEMPORARY CLOSURE Date:

[J REACTIVATION Date:

[J CLOSURE Date:

[J COMPLETION Date:
V. OTHER:

 

 

 

 

SIGNATURE OF PERSON COMPLETING THE FORM/TELEPHONE NUMBER/DATE

7/86

122
 

 

CTEP Glossary

ACTIVATION: The decision by a
Group/Institution to open an IND
study for patient entry (which occurs
after CTEP approval).

ACTIVATION AMENDMENT: Any
protocol change which occurs after
CTEP approval and prior to local
activation. Examples: the study is
approved by CTEP with recommen-
dations which are incorporated prior
to activation; these changes must be
listed and submitted to CTEP as an
Activation Amendment.

ADR: Adverse Drug Reaction - An
‘alarming’ ADR is any serious, fatal,
or life-threatening clinical experience
in a patient which is thought to be
drug related. It must be reported
immediately to the drug sponsor.
“Other” ADR’s are reported if that
effect has not been described
previously.

AMENDMENT: Any protocol change
which occurs after activation.

APPROVAL: CTEP approves the
protocol in writing when the science
and informed consent are acceptable,
the IRB documentation is on file (not
applicable to Groups), and the drugs
to be supplied are specified by the
Drug Management and Authorization
Section. If recommendations are
specified, CTEP expects an ‘‘Activa-
tion Amendment’’ to indicate any
changes to the approved document.

BES: Biologics Evaluation Section,
IDB, CTEP, DCT, NCI.

BRB: Biometric Research Branch,
CTEP, DCT, NCI.

BRMP: Biological Response Modifiers
Program, DCT, NCI.

CANCER CENTER: An institution
which is designated by NCI as a
comprehensive or clinical cancer
center and is eligible to conduct IND
drug studies.

CCOP: Community Clinical Oncology
Program - CCOP is a cooperative
agreement supported program which
provides support to community-based
oncologists to participate in clinical
trials sponsored by the clinical
cooperative groups and/or cancer
centers. Each CCOP is expected to
enter a minimum of 50 patients per
year on NCl-approved research
protocols.

CIB: Clinical Investigations Branch,
CTEP, DCT, NCI

CLINICAL BROCHURE: This
document contains all relevant
information about the drug, including
animal screening, preclinical toxi-
cology, and detailed pharmaceutical
data. Also included, if available is a
summary of current knowledge about
pharmacology and mechanism of
action and a full description of the
clinical toxicities.

CLINICAL COOPERATIVE
GROUPS: Cancer clinical cooperative
groups are composed of investigators
who join together to develop and
implement common protocols. The
distinguishing characteristic of
cooperative groups is the central
operations and statistical offices which
support the administrative require-
ments of the research and perform
central data collection and analysis.

CLINICAL TRIALS MONITORING
SERVICE: An organization which
receives, reviews, and performs data
management tasks on individual
patient case report forms for Phase I
and some Phase II NCI investiga-
tional drug studies.

125
 

 

126

CLOSED: The decision by a Group,
Institution, or NCI to close a study to
new patient entries; previously entered
patients will continue treatment.

COMPLETED: The study is closed
and no patients are being treated or
followed for data collection.

COOPERATIVE ONCOLOGY
GROUP ASSURANCE. An
agreement for the protection of
human research subjects filed with the
OPRR by an institution participating
in cooperative group trials.

CTEP: Cancer Therapy Evaluation
Program, DCT, NCI.

CTEP LETTER: Newsletter which
announces the approval of new drugs
for clinical trials and other drug
development information.

DCPC: Division of Cancer Prevention
and Control, NCI.

DCS: Developmental Chemotherapy
Section, IDB, CTEP, NCI.

DCT: Division of Cancer Treatment,
NCI.

DHHS: Department of Health and
Human Services.

DRUG ACCOUNTABILITY
RECORD FORM: Form used to
maintain records of disposition of
NCI investigational drugs. NIH
Form-2564.

DMAS: Drug Management and
Authorization Section, IDB, CTEP.

DRAS: Drug Regulatory Affairs
Section, RAB, CTEP, DCT, NCI.

DRUG MONITOR: A physician in
IDB is assigned to each IND drug to
coordinate its clinical development.

DTP: Developmental Therapeutics
Program, DCT, NCI.

FDA: Food and Drug Administration,
DHHS.

FDA-1573: Also referred to as a
“Statement of Investigator;” it is a
requirement of section 505(i) of the
Food, Drug, and Cosmetic Act and
{312.1 of Title 21 CFR, that an
investigator complete this form as a
condition for receiving and conducting
clinical studies involving investiga-
tional drug(s). It includes the
investigator’s training and experience
and provides for legal certifications.

FORM NIH-986: Clinical Drug
Request Form.

IDB: Investigational Drug Branch,
CTEP, DCT, NCI

IND: Investigational New Drug Appli-
cation - The IND is the legal
mechanism under which experimental
drug research is performed in the
United States. An IND is submitted to
the Food and Drug Administration in
order to receive an exception from
premarketing approval requirements so
that experimental clinical trials may be
conducted.

INVESTIGATOR: Any physician who
assumes full responsibility for the
treatment and evaluation of patients
on research protocols as well as the
integrity of the research data.

LOI: The Letter of Intent is an in-
vestigator’s declaration of interest in
conducting a Phase II trial with a
specific investigational drug in a
particular disease. Approval of the
LOI by CTEP commits an investigator
to submit a protocol within a
specified timeframe.
 

 

MULTIPLE PROJECT
ASSURANCE (MPA): Is a formal
written agreement with the Office of
Protection from Research Risks (on
behalf of the Secretary of DHHS)
and an institution which conducts or
supports a large amount of DHHS
sponsored research involving human
subjects, the MPA specifies how the
institution will implement the DHHS
regulations at 45 CFR 46.

NCI: National Cancer Institute, NIH,
DHHS.

NDA: New Drug Application is the
formal process by which the FDA
makes the drug generally available to
patients and physicians for specific
medications.

NEW DRUG STUDY GROUP:
Highly qualified clinical researchers at
an institution specifically approved by
IDB to participate in NCI’s drug
development program.

NIH: National Institutes of Health,
DHHS.

OPRR: Office for Protection from
Research Risks, NIH.

OFFICIALLY FILED: At the time of
CTEP approval, the protocol docu-
ment, the informed consent, or
amendment is placed in the
“approved” PIO file and is distrib-
uted to the Drug Management and
Authorization Section, the Clinical
Trials Monitoring Services, the Food
and Drug Administration, and/or
PDQ.

PDQ: The Physician Data Query is an
on-line data base which makes state-
of-the-art treatment information,
directory information, and protocol
information available to primary care
physicians. This data base is main-
tained by the International Cancer
Research Data Base Branch,
International Cancer Information
Center, NCI.

PIO: The Protocol and Information
Office, CTEP, DCT manages the
protocol and amendment review
process and maintains the official
record of all NCI sponsored protocols
as well as voluntary protocols for
PDQ.

PHS: Public Health Service, DHHS.

PRB: Pharmaceutical Resources
Branch, DTP, DCT, NCI, NIH,
DHHS.

PRC: The CTEP Protocol Review
Committee reviews and approves all
studies involving DCT investigational
drugs, cooperative group, or CCOP
credit.

PRINCIPAL INVESTIGATOR (PI):
Name of physician who has organiza-
tional and fiscal responsibility for the
use of federal funds to conduct a plan
of research which frequently includes
several clinical trials, i.., Contract PI,
Group Chairman, ROI or POI, PI,
etc.

PROTOCOL CHAIRMAN: The
scientific coordinator of the study
who is responsible for developing and
monitoring the study as well as
analyzing, reporting, and publishing
its results.

QACS: Quality Assurance and
Compliance Section, RAB, CTEP,
DCT, NCI.

127
 

 

128

QUALITY ASSURANCE: The
monitoring of a clinical trial to assure
the quality of the data that supports
scientific conclusions.

RAB: Regulatory Affairs Branch,
CTEP, DCT, NCI, NIH.

RESEARCH BASE: An institution or
cooperative group which assumes a
broad range of responsibilities and
functions for the support of clinical
trials conducted under its name. It
supports the investigator in develop-
ing, organizing, implementing, and
analyzing clinical trials. It assumes
responsibility for the quality of the
research, both in concept and execu-
tion, and has an important role in
assuring patient safety.

REVISIONS: Any protocol change
which occurs between initial submis-
sion and CTEP approval and official
filing.

SINGLE PROJECT ASSURANCE
(SPA): Is a formal written agreement
with the Office of Protection from
Research (on behalf of the Secretary
of DHHS) and an institution which
has a Multiple Project Assurance and
conducts a DHHS - sponsored
research project. The SPA specifies
how the institution will implement the
DHHS regulations a 45 CFR 46.

SPONSOR: An organization or indi-
vidual who assumes legal responsi-
bility for supervising or overseeing
clinical trials with investigational
agents.

TEMPORARILY CLOSED: The
decision by a Group, Institution, or
NCI to stop patient entry pending
study evaluation.
I€1

"U.S. GOVERNMENT PRINTING OFF ICE: 1984—446-045

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

NIH-986
REV. 6-84 The drugs listed below are requested for the use of: FOR NCI USE ONLY
RETURN COMPLETED FORM TO: ORDER NUMBER oa7E
NATIONAL INSTITUTES OF HEALTH Drug Management and Authorization Dr. oo No.
NATIONAL CANCER INSTITUTE gation Caner Fraalment, NC) Requester (if other than investigator): SIGNATURE OF AUTHORIZING OFFICIAL
Landow Building, Room 222
CLINICAL DRUG REQUEST 7910 Woodmont Avenue oo
Bethesda, Maryland 20205, U.S.A. me
Title: Tel.
STRENGTH & QUANTITY
PROTOCOL NO. YOUR
NSC DOSE FORM ORDERED MANUFACTURER
OR IND PT. CURRENT DRUG NAME
NUMBER (Specify vials, tablets, (Specity vials & LOT NUMBER COMMENTS
NUMBER * INVENTORY capsules) or bottles)
A
B
C
D
E
F
G
H
INSTRUCTIONS ‘Number of patients currently on study. IPPING INFORMATION
1. Dre ALL INFORMATION — One item or protocol per P ™
line. Investigator Signature Date: DATE SHIPPED:
2 fir in all sections completely including the shipping
address.
3. DO NOT cross the double line into the shaded area Operations Office/ Research Base Verification Date
marked FOR NCI USE ONLY. How Shipped: Pulled ty:
4. Limit drug request to an eight (8) week supply :
5. Sign and date the order y 1. [J Room Temperature
6. Return the completed form to the address indicated: PLEASE SPECIFY AFFILIATION BELOW: 2. [J Refrigerate On
above. Ark
1. [J Study Group 6. [J International Agreement al
. : In 7
Shipping Address Must Be Typed in Space Below. 7. [J Group C (Guidelines) 3. [J Packed In Dry Ice Checked by:
4. [7] Priority Mail
2. [J Contract 8. [J ccop 5. [J GBL
3. [J Phase | Working Group 6. [J Other (Specify)
4. [J Cancer Center 9. [] Special Exception Packaged by,
10. [J Nonclinical Use
5. [J NCI Intramural 11. [J Other (Specify)

 

 

 

1. PHARMACEUTICAL RESOURCES BRANCH
ERVIC,
NS Es vs

\
ed

A»

Ty

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

 

National Institutes of Health
National Cancer Institute
Bethesda, Maryland 20892

Revised Guidelines
Reporting of Adverse Drug Reactions

October 1985

TO  : Clinical Investigators
FROM: Investigational Drug Branch, CTEP, DCT, NCI

Enclosed are revised guidelines for the reporting of adverse drug reactions (ADRS)
in patients treated with investigational agents supplied under an IND sponsored by
the Division of Cancer Treatment, NCI.

The timely reporting of ADRs is required by the Food and Drug Administration
(FDA) regulations and such reporting improves both patient care and scientific
communication by allowing the NCI to rapidly disseminate the new findings to the
investigator community studying the drug. The requirement for timely reporting is
clearly stated in the investigator registration form FD-1573 (see Attachment I). In
signing the FD-1573 you accept the responsibility for conducting investigational
drug trials which includes reporting ADRs to the Division of Cancer Treatment,
NCI.

Please note that changes and clarification in the reporting requirements have been
made for Phase I studies as well as for Phase II and III studies. In addition, a new
form for reporting ADRs to NCI is included. The additional attachments include
the following:

Attachment 2: An outline and discussion of the requirements for reporting ADRs
Attachment 3: NCI form for reporting ADRs occurring with investigational agents

Attachment 4: FDA Form 1639 to be used to report ADRs occurring with
commercial agents.

135
 

 

Attachment 1
October 1985

Adverse Drug Reactions
FDA Regulations

NCI RESPONSIBILITY

“The sponsor shall promptly
investigate and report to the FDA
and to all investigators any findings
associated with the use of the drug
that may suggest significant
hazards, contraindications, side
effects and precautions pertaining
to the safety of the drug. If the
finding is alarming, it shall be
reported immediately and the
clinical investigation discontinued
until the finding is adequately
evaluated and a decision is reached
that it is safe to proceed”.

Form FD-1571

INVESTIGATOR
RESPONSIBILITY

“‘Any adverse effect that may
reasonably be regarded as caused
by, or probably caused by, the new
drug shall be reported to the spon-
sor promptly, and, if alarming, it
shall be reported immediately’.

Form FD-1573

136

Attachment 2
October 1985

NCI
Division of Cancer Treatment

Adverse Drug Reactions
with Investigational Agents

RESPONSIBILITIES OF
INVESTIGATORS

The prompt reporting of adverse
drug reactions (ADRs) to DCT is
the responsibility of each investiga-
tor engaged in clinical research with
investigational drugs supplied by
NCI. It is the policy of the DCT
that investigators are encouraged to
submit such reports even if there is
only a suspicion of a drug effect.
Procedures for reporting ADRs are
outlined in the attached chart.

In all instances investigators should
be prepared to provide additional
information to NCI if requested.

Any investigator who is dubious
about whether a particular adverse
reaction needs to be reported
should call the IDB at
301-496-7957.

Failure to report adverse reactions
in a timely manner may result in
discontination of the study, and, in
some cases, revocation or suspen-
sion of the investigator’s permission
to perform clinical research using
investigational drugs under the
Division of Cancer Treatment, NCI
sponsored IND.

This reporting of adverse reactions
is in addition to and does not
supplant the reporting of toxicities
as part of the report of the results
of the research protocol, e.g.,
cooperative group minutes. All
adverse reactions should also be
reported to your local Institutional
Review Board.

Adverse Drug Reactions Occurring
on Phase I Trials

Life-threatening reactions which
may be due to drug administration
and all fatal reactions occurring on
Phase I studies should be reported
immediately by phone. A written
report should be submitted within
ten (10) working days. The first
occurrence of any toxicity, regard-
less of grade, should be reported by
phone within 24 hours to the
appropriate Drug Monitor in IDB.
An ADR report may be required.

Adverse Drug Reactions Occuring
on Cooperative Group Studies
Investigators on protocols of
Cooperative Groups should check
with the Operations Office and/or
the Chairman of the New Agents
Committee about their practices for
handling these reports, which may
be routed through them if a
mechanism is in place to do that
on an emergency basis.

Adverse Drug Reactions Occurring
with Commercial Drugs

These toxicities should be reported
promptly in writing (ATTACH-
MENT 5, Form 1639) if that type
of effect has not previously been
reported in the package insert
and/or the literature. A clear
description of the suspected
reaction should be provided along
with an assessment as to whether
the event is drug- or disease-related.
The report should be sent to the
IDB within ten (10) working days
of its occurrence.
 

 

Attachment 2 (continued)

Investigational Agent Adverse Drug Reaction
Reporting Chart
National Cancer Institute,
Division of Cancer Treatment

Phase 1 Studies

Reaction Reporting Obligation
a. ALL LIFETHREATENING EVENTS REPORT BY PHONE TO IDB WITHIN
(Grade 4)> WHICH MAY BE DUE TO 24 HOURS.!

DRUG ADMINISTRATION.

b. ALL FATAL EVENTS. REPORT BY PHONE TO IDB WITHIN 24
HOURS.! (written report to follow within 10
working days?)

¢. FIRST OCCURRENCE OF ANY TOXICITY. REPORT TO THE DRUG MONITOR WITHIN 24

(regardless of grade) HOURS. (an ADR report may be required)

Phase II and III Studies

UNKNOWN REACTION*? KNOWN REACTION*?
GRADES 2-32 GRADES 4 AND 5 GRADES 1-3 GRADES 4 AND 5
Written report Report by phone to Not to be reported Written Report to
to IDB within IDB within 24 hrs.!. as ADRs. These IDB within 10
10 working days. Written report to toxicities should be working days.
follow within 10 be submitted as (grade 4 myelo-
working days. part of study suppression not to
summary. be reported.)

‘“‘Aplasia in leu-
kemia patients®”’

USE ATTACHMENT 4 TO REPORT ADRs WITH DCT SPONSORED DRUGS.

Telephone number available 24 hours daily: 301-496-7957
Use protocol designated toxicity grading scale.
3Report to: Investigational Drug Branch
P.O. Box 30012
Bethesda, Maryland 20814.
4A list of all known toxicities can be found in the protocol or informed consent form of the protocol.
Reactions definitely felt not to be treatment related should not be reported. However, a report should be
submitted if there is only a suspicion of drug effect.
Grade 4 unknown and known reactions not to be reported. Report Grade 5 unknown and known reactions
within 10 working days if clearly related to experimental drug (i.., single agent therapy). Otherwise do not
report.

137
138
Attachment 3
ADR #
(Assigned at NCI)

NCI Adverse Reaction Form for Investigational Agents

Person Completing this Form Date
Data Supplied by Phone Call Other
(For use by NCI) (Specify)

I. DEMOGRAPHICS
A. Patient Information

 

 

PT LD. # Age Sex Date of Initial DX
Malignancy
Site of Primary PS (At start of study)

 

Site(s) of Metastatic Disease

Concurrent Non-Malignant Disease and Non-Protocol Medications

B. Drug Information

 

 

 

 

 

 

 

Drug Name

Source of Drug: NCI ___ ~~ Other _____ (specify )
Type of Reaction Toxicity Grade

Date of Reaction Date IRB Notified

NCI Protocol # Investigator

Phase of Study Institution Phone ( )

 

Protocol Treatment (include all agents)

 

Drug Dose Schedule Route
Date of First Course Number of Courses
Date Last Course Started __ ~~ Date of Therapy Associated with ADR

Prior Therapy (Drug, radiation, relevant surgery: Include dates of therapy)

II. DOCUMENTATION OF REACTION
A. Non-Myelosuppressive Toxicity and Previously Unknown Myelosuppression
1. Description of Reaction and Temporal Relationship to Investigational Drug Administration

2. Physical Findings and Laboratory Data Documenting Toxicity

3. Treatment of Adverse Reaction

139
4. Complications and Sequelae (If death, was an autopsy obtained?) Attachment 3 (continued)

5. Past History of Organ Dysfunction

6. Rechallenge with Agent _ No __ Yes
If yes, describe:

Myelosuppression (Previously known or unknown)
1. Laboratory Data Documenting Myelosuppression
Recovery or

 

 

 

Baseline Nadir Latest Value

Date/ Value Date/ Value Date/ Value
WBC or PMN / / /
Platelets / / /
Hgb or Hct / / 7

 

 

2. Complications, Treatment and Sequelae (e.g. infections/hemorrhage)

Grade of Toxicity and Reporting Requirements (Check one)
1. Previously Unknown Toxicities:

 

 

a. Fatal or Life Threatening __ (Report by Telephone in
24 hours: 301-496-7957) Date _____ NCI Contact
b. Grade I II 11 (Send form within 10 days)
2. Previously Known Non-Myelosuppressive Toxicities:
a. Fatal or Life Threatening (Send form within 10 days)
3. Previously Known Myelosuppressive Toxicities:
a. Fatal (Send form within 10 days)

Send Forms to: Investigational Drug Branch, NCI
P.O. Box 30012
Bethesda, Maryland 20814

Investigator’s Assessment (If more than 1 investigational agent was used, give an assessment for each by
writing the drug names on the appropriate lines)
IND Non-IND

 

 

 

 

 

Drug Drug Disease Action Taken: Therapy Required:
Unrelated None None
Unlikely Dose Reduced __ Symptomatic
Possible Dose Withheld Supportive
Probable Drug Discontinued __ Intensive
Definite
N/A

E. Additional narrative may be sent on separate page if required

140
Attachment 4

 

EPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION (HFN-730)
ROCKVILLE, MD 20857

ADVERSE REACTION REPORT
(Drugs and Biologics)

Form Approved: OMB No. 0910-0230.

 

FDA

CONTROL NO.

 

 

ACCESSION
NO.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

REACTION INFORMATION

 

PATIENT ID/INITIALS (In Confidence)

2. AGE 3. SEX

4.-6.

REACTION ONSET

 

YRS.

 

 

 

MO.

 

DA.

 

YR.

 

DESCRIBE REACTION(S)

[]

 

RELEVANT TESTS/LABORATORY DATA

OJ

8.-12. CHECK ALL

APPROPRIATE:

PATIENT DIED

REACTION TREATED
WITH Rx DRUG

RESULTED IN, OR
PROLONGED, INPATIENT
HOSPITALIZATION

RESULTED IN
PERMANENT DISABILITY

NONE OF THE ABOVE

 

SUSPECT DRUG(S) INFORMATION

 

SUSPECT DRUG(S) (Give manufacturer and lot no. for vaccines/biologics)

 

. DAILY DOSE

 

16 ROUTE OF ADMINISTRATION

20. DID REACTION ABATE AFTER
STOPPING DRUG?

[] ves

(Jno [OO na

 

 

. INDICATION(S) FOR USE

 

. DATES OF ADMINISTRATION (From/To)

 

19 DURATION OF ADMINISTRATION

 

J YES

21. DID REACTION REAPPEAR
AFTER REINTRODUCTION?

[Aw [J VW

 

CONCOMITANT DRUGS AND HISTORY

_ CONCOMITANT DRUGS AND DATES OF ADMINISTRATION (Exclude those used to treat reaction)

 

_ OTHER RELEVANT HISTORY (e.g. diagnoses, allergies, pregnancy with LMP, etc.)

 

ONLY FOR REPORTS SUBMITTED BY MANUFACTURER

V.

INITIAL REPORTER (In confidence)

 

. NAME AND ADDRESS OF MANUFACTURER (Include Zip Code)

26.-26a. NAME AND ADDRESS OF REPORTER (Include Zip Code)

 

a. IND/NDA. NO. FOR SUSPECT
DRUG

 

24b MFR. CONTROL NO.

26b. TELEPHONE NO. (Include area code)

 

c. DATE RECEIVED BY
MANUFACTURER

 

24d. REPORT SOURCE (Check all that apply)

[Jroreicn [] sTuov [JuTERATURE

[[JHeALTH PROFESSIONAL [Jconsumer

[Ino

26¢. HAVE YOU ALSO REPORTED THIS REACTION TO THE
MANUFACTURER?

[] ves

 

 

i 15 DAY REPORT?

Clves [no

 

25a. REPORT TYPE

[1] wimac [J rorcowue

 

26d. ARE YOU AHEALTH
PROFESSIONAL?

C1 ves

[no

 

OTE: Required of manufacturers by 21 CFR 314.80

 

Submission of a report
does not necessarily
constitute an admission
that the drug caused the
adverse reaction.

 

IM FDA 1639 G 86)

PREVIOUS EDITION MAY BE USED

141

 
INSTRUCTIONS FOR COMPLETING FORM FDA 1639 Attachment 4 (continued)

!Jse a separate report form for each case. If more space is needed, additional pages may be attached.

1s

® NOOO, WN

10.

11.

12.

13.

14.

15.
16.
17.
18.
19.

20.

21.

22.

23.

24.

25.
26.

142

I. Patient/Reaction Information (Items 1-12)

Patient ID/Initials: Record patient's identification (i.e. medical record number, initials, etc). (This information is kept in confi-
dence by the FDA.)

. Age: Racord the age of the patient. When reporting a congenital malformation, record the age of the mother.

. Sex: Record the sex of the patient. When reporting a congenital malformation, record the sex of the baby.

. Weight: Record the weight of the patient in pounds. When reporting a congenital malformation, record the weight of t! : mother.
. Height: Record the height of the patient in inches. When reporting a congenital malformation, record the height of the mother.
. Reporting Date: Record the date when the report was initially communicated to the manufacturer.

. Reacticn Onset Date: Record the date on which the reaction was first observed or detected.

. Suspected Reaction(s): Describe the signs, symptoms and course of the drug related event in the terminology used by the original

observer of the reaction. (Coding terms e.g. COSTART, SNOMED, etc. may also be noted, but only in addition to original
description.)

. Outcome of Reaction: Indicate the status of the patient as of date indicated in Item 23. If the patient died, give the cause and

date of death. Include discharge summary and/or autopsy findings, if available.

Tests/l.aboratory Data: Describe the results of all diagnostic tests and exams (e.g. biochemical tests, x-rays, endoscopy, biopsy,
etc.) which were done as a result of the event described in Item 8. Pertinent base line values and laboratory normals should be
included with each test or exam reported. If this information is not available at the time of the initial report, a follow up report
should be submitted.

Treatn.ent Required: If “yes”, a short description of treatment should be included in Item 8.
Hospitalization Required: If ““yes’’, a short description of the treatment should be included in Item 8.

Il. Suspect Drug Information (Items 13-20)

Suspect Drug(s): Record the trade name. The generic name should be used only when the trade name is not known. Include
IND/NDA number of the drug as well as the lot number, when available.

Total Daily Dose: Record the total daily dose as of the date recorded in Item 7. If drug(s) was given in a different dose or form oi
a previous occasion, include dates and total daily dose for each drug exposure.

Route of Administration: Record the route of administration (i.e. po, IM, IV) as of the date recorded in Item 7.
Indication(s) for use: Record intended use in accepted medical terminology.

Therapy Dates: Give starting and stopping dates of administration for each drug listed in Item 13.

Therapy Duration: Give duration of therapy in days.

Dechallenge:
(a) Applicable if the suspect drug(s) was either reduced in dosage or discontinued.
(b) If 19(a) is checked, indicate whether the reaction subsided upon reduced dosage or discontinuation of the drug.

Rechallenge:
(a) Applicable if the suspect drug was reintroduced to the patient's therapy after dechallenge.
(b) If 20(a) is “'yes”, indicate whether or not the reaction reappeared upon rechallenge with the drug.

Il. Recent/Concomitant Drugs and Medical Problems (Items 21-22)

List all recent or concomitant drugs. Include the total daily dose(s), indication(s) for use, route(s) of administration and dates of
administration and/or duration of therapy for each drug.

Describe other relevant medical conditions or problems which could have contributed to the reaction. Include pertinent medical
history such as allergies, occupation, industrial hazards, diet, smoking, climate, ethnic origin, cosmetics and biologicals. When re-
porting a congenital malformation, include the date of the last menstrual period of the mother, gravidity, parity and previous
abortions.

IV. Other Information (Items 23-26)

Manufacturers Information: Include manufacturer's name, address, control number and date report is sent to FDA. This control
number is the identifying number assigned by the manufacturer to the report for internal record control.

Indicate if this is an initial submission to FDA or a follow-up of a previously submitted Form FDA 1639. If this is a follow-up
attach copy of initial report.

Record the name, title and address of the practitioner originating the report. (This information is kept in confidence by the FDA.)

Check “yes or “no”, if the source of this report may or may not be released to the Armed Forces Institute of Pathology for
further study and follow-up. This is encouraged whenever possible.
 

 

OS oo A Ee BE rr ® — a oo Ey 9 gd

 

.
 

OMB NO. 0925-0240
EXPIRES: 9/30/87

National Institutes of Health
National Cancer Institute

Investigational Drug Accountability Record

PAGE NO.

 

CONTROL RECORD O

 

 

SATELLITE RECORD O

 

Name of Institution

Protocol No. (NCI)

 

Drug Name, Dose Form and Strength

 

Protocol Title

 

Dispensing Area

 

Investigator

 

Date
Line Patient's
No. Initials

Patient's
|.D. Number Dose

Quantity
Dispensed
or
Received

Balance Forward

 

Balance

Recorder's
Initials

Manufacturer
and Lot No.

 

 

 

 

 

 

 

 

 

 

10.

 

11.

 

12.

 

13.

 

14.

 

15.

 

16.

 

17.

 

18.

 

19.

 

20.

 

21,

 

22.

 

23.

 

24.

 

 

 

 

 

 

 

 

 

NIH-2564
9-85

145
FE

 
 

         

 
National Study Recommendations
Commission on for Handling
Cytotoxic Exposure Cytotoxic Agents

Preamble The increasing use of cytotoxic agents and the growing awareness of potential hazards
requires special attention to the procedures utilized in the handling, preparation and
administration of these drugs. Equally important is the proper disposal of chemical
residues and wastes. These recommendations are intended to provide information for the
protection of personnel participating in the clinical process of chemotherapy. The
mutagenic and carcinogenic potential of many cytotoxic agents is well established and is a
possible hazard to the health of exposed individuals. It is the responsibility of institutional
and private health care providers to adopt and use appropriate procedures for protection
and safety.

|. Environmental Protection 1. All mixing of cytotoxic agents should be performed in a Class II, biological safety
cabinet. Type A cabinets are the minimal requirement. Type A cabinets which are
vented (some now classified as Type B3) are preferred.

2. Special techniques and precautions must be utilized because of the vertical (down-
ward) laminar airflow (see Supplement I).

3. The biological safety cabinet must be certified by qualified personnel annually or any
time the cabinet is physically moved.

4. The biological safety cabinet should be operated with the blower on, 24 hours per day
— seven days per week.

5. Drug preparations must be performed only with the view screen at the recommended
access opening. Professionally accepted practices concerning the aseptic preparation
of injectable products should be followed.

Il. Operator Protection 1. Disposable surgical latex gloves are recommended for all procedures involving
cytotoxic drugs. Polyvinyl chloride (PVC) gloves should not be worn while handling
cytotoxic agents. Several types of PVC gloves are permeable to a variety of drugs.

2. Gloves should routinely be changed approximately every 30 minutes when working
steadily with cytotoxic agents. Gloves should be removed immediately after overt
contamination.

3. Double gloving is reccommended for cleaning up of spills.

4. Protective barrier garments should be wom for all procedures involving the prepara-
tion and disposal of cytotoxic agents. These garments should have a closed front, long
sleeves and closed cuff (either elastic or knit).

wn

. All potentially contaminated garments must not be worn outside the work area.

lll. Compounding Procedures 1. Hands must be washed thoroughly before gloving and after gloves are removed.

and Techniques . . ; ; :
q _ Care must be taken to avoid puncturing of gloves and possible self-inoculation.

. Syringes and LV. sets with Luer-lock fittings should be used whenever possible.

HH Wo

_ Vials should be vented with a hydrophobic filter to eliminate internal pressure or
vacuum.

wn

. Before opening ampules, care should be taken to insure that no liquid remains in the
tip of the ampule. A sterile, disposable alcohol dampened gauze sponge should be
wrapped around the neck of the ampule to reduce aerosolization.

6. For sealed vials, final drug measurement should be performed prior to removing the
needle from the stopper of the vial and after the pressure has been equalized.

7. A closed collection vessel should be available in the biological safety cabinet or
the original vial may be used to hold discarded excess drug solutions.

8. Special procedures should be followed for acute exposure or spills (Supplement II).

9. Cytotoxic agents which are handled within the treatment area should be properly
labeled (e.g. “Chemotherapy: Dispose of Properly”).
PR ST ST LS Er

Approved by the National Study Commission on Cytotoxic Exposure March 1984

149
IV. Precautions for
Medication Administration

»

V. Disposal Procedures

VI. Personnel Policy
Recommendations

VII. Monitoring Procedures

No

Appendix XIII (continued)

- Disposable surgical latex gloves should be worn during all cytotoxic drug administra-

tion activities.

- Syringes and LV. sets with Luer-lock fittings should be used whenever possible.

- Special care must be taken in priming LV. sets. The distal tip cover must be removed

before priming. Priming should be performed into a sterile, alcohol-dampened gauze
sponge, which then is disposed of appropriately.

. Place contaminated materials in a leakproof, puncture-proof container appropriately

marked as hazardous waste.

- Cytotoxic drug waste should be transported according to the institutional procedures

for contaminated material.

- There is insufficient information to recommend any single preferred method for

disposal of cytotoxic drug waste.

3.1 One method for disposal of hazardous waste is by incineration at a temperature
considered sufficient by the Environmental Protection Agency (EPA) to destroy
organic compounds. Incineration should be done in an EPA permitted hazardous
waste incinerator.

3.2 Another method of disposal is by burial at an EPA permitted hazardous
waste site.

3.3 A licensed hazardous waste disposal company may be consulted for information
concerning available methods of disposal in the local area.

- All personnel working with cytotoxic agents must receive special training.

- Access to the compounding area must be limited to only necessary authorized

personnel.

. The personnel working with these agents should be observed regularly by supervisory

personnel to insure compliance with procedures.

- Acute exposure episodes must be documented. The employee must be referred for

professional medical examination.

- Procedures to monitor the equipment and operating techniques of the personnel

should be performed on a regular basis and documented. Specific methods of
monitoring should be developed to meet the complexities of the function.

- Itisrecommended that personnel involved in the preparation of cytotoxic agents on a

full time basis be given periodic health examinations in accordance with institutional
policy.

Supplement |

150

Special Techniques and Precautions for Use In the Class II Biological Safety Cabinet

- All equipment needed to complete the procedure in the Class IT Biological Safety

Cabinet should be placed into the cabinet before beginning and the view screen
should be placed at the recommended operating position. A wait of at least two to
three minutes before beginning work to allow the unit time to purge itself of airborne
contaminants is recommended.

. The proper procedures for use in the Biological Safety Cabinet are not the same as

those used in the horizontal laminar hood. In many cases they seem contradictory,
although in theory they are not. This is because of the nature of the airflow pattern in
the Biological Safety Cabinet. Clean air descends through the work zone from the top
of the cabinet toward the work surface. As it descends, the air is split, with some
leaving through the rear perforation and some leaving through the front perforation.
9.

10.

Supplement Il

Appendix XIII (continued)

The region where the airflow splits is known as the “smoke split” because smoke
introduced into this area appears to split into two directions.

. It is recommended that the smoke split be determined and marked on each cabinet

after it is purchased even if the manufacturer states its location. This can be easily
done by using an incense stick to generate smoke and moving it gently from front to
rear laterally along the work surface of the cabinet near the center.

. Routinely used large equipment should be placed in the cabinet in its normal position

when the determination of the smoke split is made. The equipment should then be
placed in the same position every time the cabinet is used.

. Personnel should refrain from applying any face powder, eye make-up, rouge, finger-

nail polish, hairspray or other cosmetics in the work area. These cosmetics may
provide a source of prolonged exposure if contaminated.

. Eating, drinking, chewing of gum, storage of food or smoking in, around or near the

Biological Safety Cabinet should be prohibited. Each of these are sources of ingestion
if they are accidentally contaminated by the cytotoxic agent or other hazardous
products.

. Sterile products should be arranged in the cabinet so as to minimize the possibility of

contamination. This may mean locating them in the immediate vicinity of the
smoke split. If appropriate, due to quantity or configuration, the sterile items should
be kept only in the center and nonsterile items on either side.

. For additional operator protection, it is reccommended that the area behind the smoke

split be used whenever possible since the airflow direction in that area is away from
the operator, lessening the chance of accidental exposure.

The least efficient area of the cabinet in terms of product and personnel protection
is within three inches of the sides near the front opening. Therefore, you should
not work within three inches of the sides of the cabinet.

Periodic evaluation of the smoke split should be performed on a routine basis. A
constantly changing smoke split location may be indicative of problems with the
operation of the cabinet.

. Entry into and exit from the cabinet should be in a direct manner perpendicular to the

face of the cabinet. Rapid movements of the hands in the cabinet and laterally
through the protective air barrier should be avoided.

Special Procedures for Acute Exposure or Spills

ACUTE EXPOSURE

1.1 Overtly contaminated gloves or outer garments should be removed and replaced
immediately after an exposure.

1.2 Hands should be washed after removing gloves. Gloves are not a substitute for
handwashing.

1.3 In case of skin contact with a cytotoxic drug product, the affected area should be
washed thoroughly with soap and water as soon as possible. Refer to professional
medical attention as soon as possible.

1.4 For eye exposure, flush affected eye with copious amounts of water. Refer to
professional medical attention immediately.

2.0 SPILLS

2.1 All personnel involved in the clean-up of a spill should wear protective clothing
(e.g. gloves, gowns, etc.). All clothes and other material used in the process should
be treated or disposed of properly.

2.2 Double gloving should be used in the cleaning up of spills.

151
 

Appendix XIII (continued)

National Study Commission
on Cytotoxic Exposure

Louis P. Jeffrey, Sc.D., Chairman
Director of Pharmacy Services
Rhode Island Hospital

Roger W. Anderson, M.S.
Director of Pharmacy
University of Texas
M.D. Anderson Hospital

Clarence L. Fortner, M.S.

Head, Drug Management and
Authorization Section

IDB Cancer Therapy Evaluation
Program

Division of Cancer Treatment

National Cancer Institute

Joseph F. Gallelli, Ph.D.
Chief, Pharmacy Department
The Clinical Center
National Institutes of Health
Dennis M. Hoffman, Pharm.D.
Director of Pharmacy Services
University of New York

at Stony Brook

For additional information contact:

Louis P. Jeffrey, Sc.D., Chairman

Louis A. Leone, M.D.
Director of Medical Oncology
Rhode Island Hospital

Robert M. O'Bryan, M.D.
Division Head, Medical Oncology
Henry Ford Hospital

Jeffrey C. Theiss, Ph.D.

Associate Professor and Convenor
of Environmental Services

University of Texas

School of Public Health

Joseph N. Gallina, Pharm.D. Secretariat
Director of Pharmacy Services
University of Maryland

Medical System/Hospital

National Study Commission on Cytotoxic Exposure

Rhode Island Hospital
Department of Pharmacy

Providence, Rhode Island ~~ 02902

EC EE TS)

Supported by a grant from | BRISTOL | [ LABORATORIES |

152
Selected Bibliography

Handling Cancer Chemotherapy Agents

Adamson, R. H. and Sieber, S. M., “Carcinogenic Po-
tential of Cancer Chemotherapeutic Agents in Man,”
The Cancer Bulletin 29:179 (6) 1977.

* American Society of Hospital Pharmacists, ‘Disposal
of Unused Anticancer Drugs,” The Signal May, 1979.

Ames, B. N,, et al, “Methods for Detecting Carcino-
gens and Mutagens with the Salmonella
Mammalian-Microsome Mutagenicity Test,” Muta-
tion Research 31:347-364 (December) 1975.

** Anderson, M,, et al., “Development and Operation of
a Pharmacy-Based Intravenous Cytotoxic Recon-
stitution Service.” B. Med. |. 286:32-36 (Jan. 1) 1983.

Anderson, R. W., et al., “Risk of Handling Injectable
Antineoplastic Agents,” Am. J. Hosp. Pharm.
39:1881-7 (Dec.) 1982.

** Avis, K. E. and Levchuk, |]. W., “Special Considera-
tions in the Use of Vertical Laminar-Flow Work-
benches.” Am. |. Hosp. Pharm. 41:81-87 (Jan.) 1984

Ballentine, Ron, “Cancerphobia — or Whatever Hap-
pened to Red M&M's?” (editorial) Drug Intell. Clini-
cal Pharmacy 16:60-61 (Jan.) 1982.

** Bergemann, D. A., "Handling Antineoplastic
Agents.” Am. |. IV Therapy and Clin. Nutrition
10:13-17 (Jan.) 1983

** Bledsoe, L., “Antineoplastic Agents — Management
of Health Risks for the LV. Nurse.” NITA 6:332-333,
1983.

Brier, Kenneth L., et al., “Effect of Laminar Air Flow
and Clean-Room Dress on Contamination Rates of
Intravenous Admixtures,”” Am. |. Hosp. Pharm
38:1144-47 (Aug) 1981

Carrano, A. V,, et al., “Sister Chromatid Exchange as
an Indicator of Mutagenesis,” Nature 271:551-553
(Feb. 9) 1978.

Clayson, D. B., “Principles Underlying Testing for
Carcinogenicity,” Cancer Bulletin 29:161-166 (6)
1977

Crudi, C. B,, “A Compounding Dilemma: I've Kept
the Drug Sterile But Have I Contaminated Myself?”
NITA 3:77-8, 1980.

** D'Arcy, P. F,, “Reactions and Interactions in Han-
dling Anticancer Drugs.” Drug Intell. Clinical Phar
macy 17:532-538 (July/Aug.) 1983

* Davis, M. R., “Guidelines for Safe Handling of
Cytotoxic Drugs in Pharmacy Department and Hos-
pital Wards (The Society of Hospital Pharmacists of
Australia),” Hosp. Pharm. 16:17-20 (Jan.) 1981.
Donner, A. L., “Possible Risk of Working with An-
tineoplastic Drugs in Horizontal Laminar Flow
Hoods (letter),”” Am. |. Hosp. Pharm. 35:900 (Aug.
1978.

Falck, K., et al, “Mutagenicity in Urine of Nurses
Handling Cytostatic Drugs (letter),”” Lancet 1:1250-1
(June 9) 1979
Farber, E., “Chemical Carcinogenesis,” New Engl. |
Med. 305:1379-89 (Dec. 3) 1981

** Gibson, |. F., et al, “Mutagenicity of Urine From
Nurses Handling Cytotoxic Drugs” (letter), Lancet
1:100-107 (Jan. 14) 1984

* Gousse, G. C., et al, “Biological Safety Cabinets for

Chemotherapy Preparation (letter),” Am. |. Hosp
Pharm. 38:967 (July) 1981

Gross, Jody, et al., “Possible Hazards of Working with
Cytotoxic Agents,” Oncology Nursing Forum
8(4):10-12, 1981.

Hamilton, C. W., “Risk to Personnel Admixing
Cancer Chemothrapy,” US Pharm. 7:H1-H8 (July)
1982.

Harris, C. C., “A Delayed Complication of Cancer
Therapy — Cancer,” [NCI 63:275-7, 1979.

* Harrison, Bruce R., “Developing Guidelines for
Working with Antineoplastic Drugs,” Am. J. Hosp.
Pharm. 38:1686-1693 (Nov.) 1981

** Hennessy, K. and Duval, A. “Chemotherapy Waste
Disposal: A Safe and Practical Method.” NITA
5:311-312, 1982.

** Hirst, M., “Occupational Exposure to Cyclophos-
phamide.” Lancet 1:186-188 (Jan. 28) 1984

* Hoffman, D. M., “The Handling of Antineoplastic
Drugs in a Major Cancer Center,” Hosp. Pharm
15:302-304 (June) 1980.

Hoffman, D. M., “Handling Cytotoxic Drugs (let-
ter),” Am. |. Hosp. Pharm. 38:1284-86 (Sept.) 1981.

Honda, D., Ignoffo, R. J., and Power, L. A., “Safety
Consideration in the Preparation of Parenteral An-
tineoplastics,” CSH? Voice 8:94-96 (Winter) 1981.
Hoover, R. and Fraumeni, J. D., “Drug-Induced
Cancer,” Cancer 47:1071-80 (March 1) 1981 (Sup-
plement).

** Johnson, B. L. and Gross, |., “Handling Methotrexate
— A Safety Problem,” Am. J. Nursing 82:1531 (Oct.)
1982.

Kleinberg, M. L. and Quinn, M. |, “Airborne Drug
Levels in a Laminar-Flow Hood,” Am. |. Hosp.
Pharm. 38:1301-13 (Sept.) 1981.

* Knowles, R. S. and Virden, J. E., “Handling of Injecta-
ble Antineoplastic Agents,” Brit. Med. |. 281:589-91
(August 30) 1980.

Ladik, C. F, et al, “Precautionary Measures in the
Preparation of Antineoplastics (letter),” Am. |. Hosp.
Pharm. 37:1184-86 (Sept.) 1980

**LeRoy, M. L., et al, “Procedures for Handling
Antineoplastic Injections in Comprehensive Cancer
Centers.” Am. |. Hosp. Pharm. 40:601-603 (April)
1983.

Marquardt, H. and Marquardt, H. “Induction of
Malignant Transformation and Mutagenesis in Cell
Cultures by Cancer Chemotherapy Agents,” Cancer
40:1930-34 (Oct.) 1977 (Supplement)

** Mattia, M. A. and Blake S. L., “Hospital Hazards:
Cancer Drugs,” Am. |. Nursing 83:758-762 (May)
1983.

** Neal, A. et al, “Exposure of Hospital Workers to
Airborne Antineoplastic Agents,” Am. |. Hosp
Pharm. 40: 597-601 (April) 1983

** Nevasaari, K., “Handling Cytostatic Drugs” (letter)
Lancet 1:247-248 (Jan. 29) 1983
Ng, L. M., “Possible Hazards of Handling Antineop-
lastic Drugs (letter),”” Pediatrics 46:648-49, 1970.
Norppa, H., et al, “Increased Sister Chromatid Ex-
change Frequencies in Lymphocytes of Nurses Han-
dling Cytostatic Drugs,” Scand. |. Work Environ
Health 6(4):299-301 (Dec.) 1980.

Perlman, M. and Walker, R., “Acute Leukemia Fol-
lowing Cytotoxic Chemotherapy (letter),” JAMA
224:250 (April 9) 1973.

Redfearn, |J., ‘Safety’ Cabinets are not safe, Says UK
Study,” Nature 278:384 (March 29) 1979.

Reich, Steven D., “Antineoplastic Agents as Poten-
tial Carcinogens: Are Nurses and Pharmacists at
Risk?,” Cancer Nursing 4:500-502 (Dec.) 1981.
Reimer, R. R. et al, “Acute Leukemia After Alkylat-

ing Agent Therapy of Ovarian Cancer,” N. Engl. |
Med. 297:177-81, 1977

*References containing handling guidelines

** Additional references since March 1983

Appendix XIII (continued)

Rosner, F., “Acute Leukemia as a Delayed Conse-
quence of Cancer Chemotherapy,” Cancer 37:1033-6,
1976.

Sieber, S. M., “Cancer Chemotherapeutic Agents and
Carcinogenesis,” Cancer Chemo. Reports. 59:915-18
(Sept./Oct.) 1975.

** Solimando, D. A. “Preparation of Antineoplastic

Drugs: A Review.” Am./. IV Therapy and Clin. Nutri
tion 10:16-27 (Sept.) 1983.

** Sotaniemi, E. A., “Liver Damage in Nurses Handling

Cytotoxic Agents,” Acta. Med. Scand. 214:181-189,
1983.

Staiano, N,, et al, “Lack of Mutagenic Activity in
Urine from Hospital Pharmacists Admixing An-
titumour Drugs,” Lancet 1:615-16 1981.

Stolar, M. H,, et al, “Recommendations for Handling
Cytotoxic Drugs in Hospitals,” Am. |. Hosp. Pharm
40:1163-1171 (July) 1983

Stuart, D. G., et al, “Survey, Use, and Performance of

Biological Safety Cabinets,” Am. Ind. Hygiene Assoc
J. 43:264-670 (April) 1982.

Theiss, J. C., “Detection of Carcinogens,”’ in
Cancer-Achievements, Challenges, and Prospects for
the 1980's, Vol. 1, Burchenal, J. H. and Oettgen, H. F.,
Editors, Grune and Stratton, New York, 1981, pp
281-90.
Thomsen, K. and Mikkelsen, H. I., “Protective
Capacity of Gloves Used for Handling of Nitrogen
Mustard,” Contact Dermatitis 1:268-69 (Aug.) 1975.
* Tortorici, M. P., “Precautions Followed by Personnel
Involved with the Preparation of Parenteral Antineo-
plastic Medications,” Hosp. Pharm. 15:293-301
June) 1980.

”"

 

** Vaccari, P. L., et al, “Disposal of Antineoplastic

Wastes at the National Institutes of Health,” Am. |
Hosp. Pharm. 41:87-93 (Jan.) 1984.

** Venitt, S., et al, “Monitoring Exposure of Nursing

and Pharmacy Personnel to Cytotoxic Drugs: Urinary
Mutation Assays and Urinary Platinum as Markers of
Absorption,” Lancet 1:74-77 (Jan. 19) 1984
Waksvik, H., et al, “Chromosome Analyses of
Nurses Handling Cytostatic Agents,” Cancer Treat
Rep. 65:607-10 (July/Aug.) 1981.

Weisburger, J. H., etal., “The Carcinogenic Properties
of Some of the Principal Drugs Used in Clinical
Cancer Chemotherapy,” Recent Results Cancer Res.
52:1-17, 1975.

Wilson, |. P. and Solimando, D. A., “Antineoplastics
A Safety Hazard? (letter),”” Am. |. Hosp. Pharm
38:624 (May) 1981

Wilson, James P., et al, “Aseptic Technique as a

Safety Precaution in the Preparation of Antineoplas-
tic Agents,” Hosp. Pharm. 16:575-81 (Nov.) 1981
Zellmer, William A., “Reducing Occupational Expo-
sure to Potential Carcinogens in Hospitals (edito-
rial)” Am. |. Hosp. Pharm. 38:1679 (Nov.) 1981

* Zimmerman, Paul F,, et al, “Recommendations for
the Safe Handling of Injectable Antineoplastic Drug
Products,” Am. |. Hosp. Pharm. 38:1693-95 (Nov.)
1981

©c opyright 1984
National Study Commission on Cytotoxic Exposure

153
 

 

National Cancer Institute
Procedure for
Management of
Investigational Drugs
Acquired for
Compassionate Treatment
of Individual Patients

Food and Drug Administration (FDA)
regulations and National Cancer Insti-
tute (NCI) policy require the following
steps to be completed as indicated:

1)

2

~~

3)

4)

Statement of Investigator (FDA
1573): Since you are not registered
as an investigator, it is required
that you complete and sign the
enclosed FDA 1573 form and
return it within 10 working days in
order to receive additional drug.
We would suggest that you read
this form very carefully since it
outlines your responsibilities as a
physician receiving investigational
drugs.

Protocol: A brief protocol must be
submitted for each patient which
describes the treatment plan,
toxicity, efficacy, and monitoring
procedures. For your convenience
we have devised a standard
protocol form which is included
and must be completed. The
original and three copies must be
returned within 10 working days.

Please return this document to the

following address:

Drug Management and Authoriza-
tion Section, IDB, CTEP

Division of Cancer Treatment, NCI

Landow Building, Room 1304-A

7910 Woodmont Avenue

Bethesda, MD 20892

Institutional Review Board
Approval: You must obtain Institu-
tional Review Board approval prior
to treatment of the patient and
retain documentation of this
approval in the patient’s medical
record.

Informed Consent: You must write
an informed consent form which
must be signed by the patient and
retained in the patient’s medical
record. The consent should include
a reasonable statement about the
side effects of the drug. The
informed consent must address
each of the eight elements required
under FDA regulations.

5)

6)

7)

8)

9)

Adverse Drug Reactions:
Unexpected toxicity must be
reported directly to the NCI. Lethal
or life-threatening toxicity must be
telephoned to the NCI within 24
hours of its occurrence
(301-496-7957, available 24
hours/day). All other toxicities
must be reported in writing within
10 days to the Investigational Drug
Branch, CTEP, DCT, National
Cancer Institute, Landow Bldg.,
Rm. 4C09, 7910 Woodmont
Avenue, Bethesda, MD, 20892.
Please read the guidelines for
reporting and use the ‘‘Adverse
Reaction Form for Investigational
Agents’ when reporting adverse
drug reactions.

Final Patient Report: Upon
completion of therapy, you must
provide NCI a report of the
treatment experience, which
describes toxicity and efficacy. We
have enclosed the form to be used.
Please return this form to the
above address.

Investigational Drug
Accountability: The enclosed
investigational drug accountability
record must be maintained and
retained in your records. These
records may be inspected upon
request by an authorized
representative of the FDA or the
NCI.

Failure to submit items 1, 2 and 5
in a timely manner will prevent any
further drug shipments, and may
result in recall of drug.

Drug Reorders: Additional drug
may be requested only for the
same patient previously treated.
The patient’s first name and ini-
tials of last name should be
indicated on the Clinical Drug
Request. Telephone orders will not
be accepted.

December 1985

157
Protocol Amendment No.

 

DEPARTMENT OF HEALTH & HUMAN SERVICES INSTRUCTIONS: 1. Use only this form for Special Exception Protocol.
Public Health Service
National Institutes of Health 2. Please type.

National Cancer Institute

SPECIAL EXCEPTION PROTOCOL

 

FOR THE USE OF

 

 

 

 

 

 

Investigational Drug(s) NCI Protocol Number
Physician’s Name
Address Investigator No.
PATIENT INFORMATION:
Identification
(Initials or Identification Number) Age Sex
Disease

 

Date of Diagnosis

 

Prior Therapy:

JUSTIFICATION FOR SELECTING PLAN OF TREATMENT:

158
Page 2
Special Exception Protocol for use of

 

PLANNED DOSAGE REGIMEN: (Include all chemotherapeutic agents and how often course will be repeated.)

DOSAGE MODIFICATION:

EXPECTED TOXICITIES:

MONITORING CRITERIA:

RESPONSIBLE PHYSICIAN Date
(Signature)

My signature indicates that:
1. Informed consent will be obtained.
2. This protocol will be followed.

3. A report on the patient’s progress will be submitted to the Investigational Drug Branch of the National
Cancer Institute after completion of therapy.

4. Any adverse drug reaction encountered will be reported to the Investigational Drug Branch of the National
Cancer Institute immediately.

159
 
 

 

Subject Index

Adverse Drug Reactions (ADRs)

Commercial Drugs and, 11.4
Group C Drugs and, 17.6
Phase I Trials and, 11.1
Phase 11/111 Trials and, 11.2
Protocol Chairman and, 122
Reporting of, 10.2, 10.3. 11,
Appendix XI
Where to Report 11.3
Affiliate Program
Affiliate Investigator Responsibilities 13.3
Drug Ordering by, 9.4
Phase II Trials and, 5.2, Appendix IV
Research Base and, 32, 134
Amendments

(See Protocol and Information Office)

Cancer Therapy Evaluation Program (CTEP)

CTEP Letter 45,54,55.,56
as Investigator Drug Sponsor 2
and Phase I Trials 4.1
and Phase II Trials 5.1
and Phase III Trials 6.3
and Protocol Review and Approval 8
Responsibilities for Clinical Trials 2
Scientific Policies of, 4.1, 5.1, 6.1
Clinical Trials Monitoring Service (CTMS)

Drug Accountability and Storage 15
Phase I Results Reporting and, 10.2
Phase I and II/III Contractors and, 16.2
Protocol Amendments and, 8.6
Quality Assurance and Monitoring 16, Table 1
Site Visits by, 15,16

Community Clinical Oncology Program
(CCOPs)

Drug Orders from, 9.3
CTEP Letter

and Letters of Intent (LOIs) 5.6
and Phase I Trials 4.5
and Phase II Trials 54,55
Cancer Centers

Affiliate Members and, 13.4
Clinical Drug Trials by, 2
Phase II Trials by, 52
as Research Base 3.1

Case Report Forms
(See Results Reporting)

Centralized Data Management

Research Base in 32
Clinical Brochures

Phase I Drugs in, 4.5
Phase II Drugs in, 5.5

Clinical Investigations Branch (CIB)
Phase III Planning 6.3, Appendix III

Clinical Drug Trials

Cancer Centers in, 2
Cooperative Groups in, 2, Appendix I
Investigator Responsibilities 12.1, 14,

Appendix IV
New Drug Development Contractors in, 2
Non-Registered Physicians in, 7.2, 14.2
Phase | 4
Phase II 5

Phase 111 6
Pharmaceutical Industry Support of, 24,25,

Appendix |
Protocol Chairman Responsibilities 12.2
Quality Assurance and monitoring in 16
Sponsors of, 2
University Hospitals in, 2

Compassionate Use of Investigational Drugs
(see Group C Drugs, Special Exception Drugs)

Cooperative Groups

Affiliate Investigators and, 13.4
Clinical Drug Trials by, 2
Letters of Intent (LOIs) from, 5.6
and Pharmaceutical Industry 2.3, Appendix I
Phase II Trials by, 52
Phase III Trials by, 6.2
Pharmaceutical Industry and, 2.4
Protocol Compliance and, 16.2
as Research Base 3.1
Drug Ordering

Biologic Agents 9.3
Clinical Drug Request Form 9.1, Appendix X
Group C 9.2, 95, 17.5
for Non-Clinical Use 9.7
Procedures for, 9,93
Special Exception 9.2, 95, 18.3

Drug Accountability and Storage
Drug Returns 15.2, Appendix X
NCI Drug Accountability

Record Form 15, Appendix XII
Procedures for, 15
Research Base in, 3.2
Safe Handling 15.4, Appendix XIII
Site Visits and, 15.3, 16.4
Drug Distribution
and Protocol Face Sheet 71
to Registered Investigators 14.1,

Appendix IV

Drug Accountability Record Form (DARF)
Accountability and Storage 15, Appendix XII
and Group C Drugs 17.6

Funding Clinical Trials
National Cancer Advisory

Board (NCAB) and, 21
Peer Review and, 2.1
Food and Drug Administration (FDA)

INDs and, 2.6
NDAs and, 27
Oncologic Drugs Advisory Committee of, 2.7
Regulations and NCI 2
Regulations and Pharmaceutical Industry 2
Regulations and Clinical Investigators 2
Results Reporting Requirements of, 10, 10.4
Statement of Investigator (FDA-1573) 12.1,

13.3, 14.1, 17.5, Appendix IV

161
 

 

162

FDA-1573
(Statement of Investigator, see above)

Freedom of Information Act

and Patient Medical Records 16.6
Group C Drugs
Guideline Protocols for, 17.4
Ordering of 9.2, 17.5
Responsibilities for use, 17.6
Informed Consent Document
and Affiliate Investigators 13.3
Checklist Appendix VII
and Group C Drugs 17.6
and Investigator Responsibilities 121
and Monitoring Program 16.4, 16.6
and Protocol Review Committee (PRC) 8.4
and Protocol Specificity 7.3
Institutional Review Board (IRB)
and Affiliate Investigators 13.3
and Group C Drugs 17.6
in Monitoring and Quality Assurance 16.4
Protocol Chairman and, 12.2
and Protocol Review and
Approval Process 32,33
and Results Reporting 10.5
Investigational Drug Administration
by Non-Registered Physicians 7.2, 14.2
by Registered Physicians 14.1, Appendix IV
Investigational Drug Branch (IDB)
as Drug Information Source 45, 5.5,
Appendix III
and Drug Ordering 9.1, Appendix III
and Letters of Intent (LOIs) 5.6, Appendix III
and Phase III Planning 6.3, Appendix III
Investigational New Drug (IND) Applications
FDA and, 2,26
Sponsor Responsibilities for, 2.6
Investigator Responsibilities
in Clinical Trials 12.1, Appendix IV
for Affiliate Investigators 13.4
Drug Accountability and Storage 15,
Appendix XII
Research Base and, 3.1
Results Reporting to CTEP 10
Results Reporting to IRBs 10.5
Letters of Intent (LOIs) 5.6, Appendix VI
Monitoring and Quality Assurance
Informed Consent Document and, 16.6
Multicenter Trials, and, 72
Research Base in, 3.2, 16
Site Visit Auditing Program 16.5
Multicenter Trials
Phase 11 52, 5.3
Phase 111 6.2
and Protocol Development 72
New Drug Application (NDA)
Commercial Drug Availability and, 27
FDA and, 2,27
Private Sponsor Responsibility for, 27

New Drug Study Groups
and Phase II Trials 5.2, Appendix V

Office of Protection from Research Risks

(OPRR)

Affiliate Investigators and, 13.2
Human Subjects and, 2
Investigator Responsibilities and, 12.1

Pharmaceutical Industry

Cooperative Groups and, 24
Federally Funded Trials and, 24
Federally Sponsored Unfunded Trials and, 2.5
NDA Submissions and, 27
Phase I Contractors and, 24
Phase 11/111 Contractors and, 24
Phase I Trials

Ad Hoc Investigators and, 42
Children in, 4.3, Appendix II
Contract Programs for, 4.2
CTEP Scientific Policies for, 4.1
Drug Information for, 4.5, Appendix III
Institutional Eligibility for, 43
Planning 4.1
Reporting Adverse Drug Reactiosn (ADRs) 11.1
Results Reporting 10.2
Phase II Trials

Cancer Centers and, 5.2
Cooperative Groups and, 5.2
CTEP Scientific Policies for, 54
Drug Combinations in, 5]
Institutional Eligibility for, 52
Letters of Intent (LOIs) in, 5.6
Multicenter Conduct of, 52
Phase 11/111 Contractors for, 52
Planning 5.1
Prior Therapy and Patient Eligibility 5.1
Reporting Adverse Drug Reactions

(ADRs) 11.2
Results Reporting 10.3
Single Drugs in, 5.1
Phase III Trials

Control Groups in, 6.1
Cooperative Groups and, 6.2
CTEP Scientific Policies for, 6.1
Multicenter Approach to, 6.2
Planning 6.3
Reporting Adverse Drug Reactions

(ADRs) 11.2
Results Reporting 10.3

Preclinical Drug Development
Biological Response Modifiers Program and, 2.2

DCT and, 22
Protocol Chairman

Clinical Trials Responsibilities 12.2
Protocol Data Query (PDQ)

and Protocol Face Sheet 7.1

and Protocol and Information Office
 

 

Protocol Development

Consensus Review 8.4
Drafting of Protocols 7
Essential Protocol Elements 7.2
Informed Consent and, 7.3, Appendix VII
and Multicenter Trials 7.2
and Phase I Trials 4.1
and Phase II Trials 5.1
Protocol Submission Checklist 8.1, 8.2,

Appendix VIII
Protocol Face Sheet Zl
Research Base and, 3.2
Review and Approval Process 8
Statistical Considerations in, 51,61, 72

Protocol and Information Office
and Letters of Intent (LOI) 5.6 Appendix VI

and Protocol Amendments 8.6, 10.3
and Protocol Face Sheet 7.1
and Protocol Review and Approval 8
and Protocol Study Status 8.7, 8.8, 10.3
Appendix VIII
and Results Reporting 10.3.2
and Publications 10.2.7
Protocol Review Committee
and Letters of Intent (LOIs) 5.6
in Protocol Review and Approval 8.4
Records Retention
FDA Requirements for, 10.4

Referring Physicians
and Investigational Drug

Administration 7.2, 14.1
Research Base
Clinical Trials Support by, 32
Definition and Responsibilities 3.1
Drug Ordering and, 9.1
Monitoring and Quality Assurance by, 16
Responsibility for Affiliates 13.4
Results Reporting by, 32
Results Reporting
Case Report Forms 10.1, 10.2, 10.3
Phase I Trials 10.2
Phase 11/111 Trials 10.3
Publications 10.2, 10.3
Research Base and, 3.2
Study Summary Forms 10.1, 10.2, 10.3
Site Visits
Drug Accountability and Storage 15
Quality Assurance and Monitoring 16.5,
Table 1
Special Exception Drugs
Ordering 9.2, 18.3
Responsibilities of use Appendix XIV
Sponsor of Drug Trials
Collaborative Efforts 2.3, Appendix I
Defined 2
Division of Cancer Treatment (DCT) as, 23
IND Submission by 2.6
Monitoring and Quality Assurance 16
Pharmaceutical Firms as, 23

Study Summary Forms (see Results Reporting)

163
U.C. BERKELEY LIBRARIES

TA

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