[Federal Register Volume 59, Number 152 (Tuesday, August 9, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-19357]


[[Page Unknown]]

[Federal Register: August 9, 1994]


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Part VI





Department of Health and Human Services





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Food and Drug Administration



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International Conference on Harmonisation; Draft Document on Good 
Clinical Practices; Notices
DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 94N-0198]

 
International Conference on Harmonisation; Draft Document on Good 
Clinical Practices; Guideline for the Investigator's Brochure

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft 
document entitled ``Guideline for the Investigator's Brochure.'' The 
document describes the minimum information that should be included in 
an Investigator's Brochure and provides a suggested format. This 
document was prepared by the Efficacy Expert Working Group of the 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH). The draft document 
is intended to help ensure that the Investigator's Brochure contains 
information that will help clinical investigators understand the 
rationale for and comply with key features of a protocol and to help 
ensure that sponsors provide up-to-date Investigator's Brochures to 
their investigators. The concepts in this draft document will later be 
incorporated into a larger document on good clinical practices.
DATES: Written comments by October 11, 1994.

ADDRESSES: Submit written comments on the draft document to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23, 
12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: 
    Regarding the draft document: Bette L. Barton, Center for Drug 
Evaluation and Research (HFD-344), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1032.
    Regarding the ICH: Janet Showalter, Office of Health Affairs (HFY-
20), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-443-1382.
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives 
have been undertaken by regulatory authorities and industry 
associations to promote international harmonization of regulatory 
requirements. FDA has participated in many meetings designed to enhance 
harmonization and is committed to seeking scientifically based 
harmonized technical procedures for pharmaceutical development. One of 
the goals of harmonization is to identify and then reduce differences 
in technical requirements for drug development.
    ICH was organized to provide an opportunity for tripartite 
harmonization initiatives to be developed with input from both 
regulatory and industry representatives. FDA also seeks input from 
consumer representatives and others. ICH is concerned with 
harmonization of technical requirements for the registration of 
pharmaceutical products among three regions: The European Union, Japan, 
and the United States. The six ICH sponsors are the European 
Commission, the European Federation of Pharmaceutical Industry 
Associations, the Japanese Ministry of Health and Welfare, the Japanese 
Pharmaceutical Manufacturers Association, FDA, and the U.S. 
Pharmaceutical Research Manufacturers of America. The ICH Secretariat, 
which coordinates the preparation of documentation, is provided by the 
International Federation of Pharmaceutical Manufacturers Associations 
(IFPMA).
    The ICH Steering Committee includes representatives from each of 
the ICH sponsors and the IFPMA, as well as observers from the World 
Health Organization, the Canadian Health Protection Branch, and the 
European Free Trade Area.
    At a meeting held on October 27, 1993, the ICH Steering Committee 
agreed that the following draft document entitled ``Guideline for the 
Investigator's Brochure'' should be made available for public comment. 
The draft document is the product of the Efficacy Expert Working Group 
of the ICH. The draft document describes the minimum information that 
should be included in an Investigator's Brochure, such as information 
on physical, chemical, and pharmaceutical properties, and the drug's 
effect in humans; a suggested layout is also provided. Comments about 
this draft will be considered by FDA and the Expert Working Group. 
Modifications will appear in a larger draft document on good clinical 
practices. Ultimately, FDA intends to adopt the ICH Steering 
Committee's final guidelines and recommendations.
    Although not required, FDA would normally provide at least a 75-day 
comment period and preferably a 90-day comment period to provide 
interested persons with ample time to review and comment upon this type 
of an action. However, the comment period for this guideline has been 
shortened to 60 days so that comments may be received by FDA in time to 
be discussed at an October 1994 meeting involving this guideline.
    Guidelines are generally issued under Sec. 10.90(b) (21 CFR 
10.90(b)), which provides for the use of guidelines to state procedures 
or standards of general applicability that are not legal requirements 
but that are acceptable to FDA. The agency is now in the process of 
revising Sec. 10.90(b). Therefore, this document when made final would 
not be issued under current Sec. 10.90(b), and it would not create or 
confer any rights, privileges, or benefits for or on any person, nor 
would it operate to bind FDA in any way.
    Interested persons may, on or before October 11, 1994, submit to 
the Dockets Management Branch (address above) written comments on the 
draft document. Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. The draft document and received comments may be seen in the 
office above between 9 a.m. and 4 p.m., Monday through Friday.
    The text of the draft document follows:

Guideline for the Investigator's Brochure

1. Introduction

    The Investigator's Brochure (IB) is a compilation of the 
clinical and nonclinical data on the investigational product which 
is relevant to its study in human subjects. Its purpose is to 
provide the investigators and others involved in the study with the 
information to facilitate their understanding of the rationale for, 
and their compliance with, many key features of the protocol, such 
as the dose, dose frequency/interval, methods of administration and 
safety monitoring procedures. It also provides insight to support 
the clinical management of the study subjects during the course of 
the clinical trial. The data should be presented in a concise, 
simple, objective, balanced and nonpromotional form which enables a 
clinician, or potential investigator, to understand it and make his/
her own unbiased risk-benefit assessment of the appropriateness of 
the proposed trial. For this reason, the compilation of an 
Investigator's Brochure should generally be supervised by a 
medically qualified person, and the content should be approved by 
the disciplines that generated the described data.
    These guidelines delineate the minimum information to be 
included in an Investigator's Brochure and provide a suggestion for 
its layout. It is expected that the type and extent of information 
available will vary with the stage of development. Where the 
investigational product is marketed and the pharmacology is widely 
understood by medical practitioners, an extensive Investigator's 
Brochure may not be required. Where regulatory requirements permit, 
a current basic drug information brochure, package leaflet, or 
labelling may be an appropriate alternative, provided that it 
includes current, comprehensive detailed information on all aspects 
of the investigational product which might be of importance to the 
investigator. Where a new aspect is being studied in a marketed drug 
which may lead to new regulatory approval, an Investigator's 
Brochure specific to that aspect should be prepared. The 
Investigator's Brochure should be reviewed at least annually and 
revised as necessary in compliance with a sponsor's procedures. More 
frequent revision may be appropriate depending on the stage of 
development and generation of relevant new information. However, in 
accordance with Good Clinical Practice, relevant new information may 
be so important that it needs to be communicated to the 
investigators, and possible Ethics Committees (EthC's)/Institutional 
Review Boards (IRB's) and/or regulatory authorities prior to 
inclusion in a revision of the Investigator's Brochure.
    Generally, the sponsor is responsible for ensuring that an up-
to-date Investigator's Brochure is made available to the 
investigator. In the case of an investigator-sponsored study, that 
individual should determine whether a brochure is available from the 
commercial manufacturer. If the investigational product is being 
produced through an investigator-sponsor, he/she is responsible for 
providing the necessary information to the study personnel. In some 
such cases, preparation of a formal Investigator's Brochure is 
impractical. If so, an expanded background section in the study 
protocol, containing the minimum current information described in 
this guideline, may provide an acceptable substitute.

2. General Considerations

    The Investigator's Brochure should include:

2.1. A Title Page

    This should bear: The sponsor's name, the identity of the 
investigational product (i.e., research number, chemical or approved 
generic name; and trade name(s) where legally permissible and 
desired by the sponsor), and a dated statement of the formal 
release\1\ of the investigator's brochure. It is also suggested that 
an edition number and a reference to the number and date of the 
edition that it supersedes may prove useful. An example is given in 
Appendix 1.
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    \1\The sponsor should have a procedure for the approval and 
release of the document.

2.2. A Confidentiality Statement

    The sponsor may wish to include a statement requiring the 
investigator/recipients to treat the Brochure as a confidential 
document for the sole information of the Investigator's team.

3. Contents of the Investigator's Brochure

    The IB also contains the following sections, each with 
literature references where appropriate:

3.1. Table of Contents

    An example of the Table of Contents is to be found in Appendix 
2.

3.2. Summary

    A brief summary (preferably not exceeding two pages) should be 
given, highlighting the significant chemical, pharmaceutical, 
pharmacological, toxicological, pharmacokinetic, metabolic, and 
clinical information available which is relevant to the stage of 
clinical development of the investigational product.

3.3. Introduction

    A brief introductory statement containing the chemical name (and 
generic and trade name(s) when approved) of the investigational 
product, all active ingredients, the investigational product's 
pharmacological class and its expected position within this class 
(for example, advantages), the rationale for performing research 
with the investigational product, the anticipated prophylactic, 
therapeutic or diagnostic EFFICACY indication(s) and the general 
approach to be followed in evaluating the investigational product 
should be given.

3.4. Physical, Chemical, and Pharmaceutical Properties

    A description of the investigational product substance, 
including the chemical and/or structural formula(e) and a brief 
summary of relevant physical, chemical, and pharmaceutical 
properties should be given. Any structural similarities to other 
known compounds should also be mentioned.

3.5. Nonclinical Studies

    Introduction:
    The results of all nonclinical pharmacology, toxicology, 
pharmacokinetic, and drug metabolism studies should be provided in 
summary form. In each case, the methodology used, the results, and a 
discussion of the relevance of the findings in connection with the 
expected therapeutic and possible undesired effects in humans should 
be given.
    The information provided should include the following, as 
appropriate if known/available:
    Species and strain(s) tested.
    Number and sex of animals in each group.
    Unit dose (milligram/kilogram(mg/kg)).
    Dose interval.
    Route of administration.
    Duration of dosing.
    Information on systemic exposure.
    Duration of postexposure followup (recovery period).
    Results, including the following aspects:
    Nature and frequency of pharmacological or toxic effects.
    Severity or intensity of pharmacological or toxic effects.
    Time to onset.
    Reversibility.
    Duration.
    Dose response.
    Tabular format/listings should be used whenever possible to 
enhance the clarity of the presentation.
    A discussion should follow each section highlighting the most 
important findings from the studies including the dose response of 
observed effects, relevance to humans, and aspects to be studied in 
humans. If applicable, the effective and nontoxic dose findings in 
the same animal species should be compared or the therapeutic ratio 
should be discussed. The relevance of this information to the 
proposed human dosing should be addressed. Wherever possible, 
comparisons should be made in terms of systemic exposure rather than 
on a mg/kg basis.

3.5.1. Nonclinical Pharmacology

    A summary of the pharmacological aspects of the investigational 
product and, as far as possible, its significant metabolites studied 
in animals should be included. Such a summary should incorporate 
studies which assess potential therapeutic activity (for example, 
efficacy models, receptor binding and specificity) as well as those 
which assess safety (for example, special studies to assess 
pharmacological actions other than the intended therapeutic 
effect(s)).

3.5.2. Toxicology

    A summary of the toxicological effects found in studies 
conducted in different animal species should be described under the 
following headings where appropriate:
    Single dose.
    Repeated dose.
    Genotoxicity (mutagenicity).
    Reproductive toxicity.
    Carcinogenicity.
    Special studies, for example, irritancy and sensitization.

3.5.3. Pharmacokinetics and Drug Metabolism in Animals

    A summary of the pharmacokinetics and biological transformation 
and disposition of the investigational product in all species tested 
should be given. The discussion of the findings should address the 
local and systemic bioavailability of the investigational product 
and its metabolites and their relationship to the pharmacological 
and toxicological findings in animal species.

3.6. Effects in Humans

    Introduction:
    A thorough discussion of the known effects of the 
investigational product in humans should be provided, including 
information on pharmacokinetics, metabolism, pharmacodynamics, dose-
response, safety, therapeutic efficacy, and other pharmacological 
activities. Where possible, a summary of each completed clinical 
study should be provided, although if there is a large number of 
studies, an integrated summary may be more appropriate (see 3.6.3). 
Information should also be provided regarding results of any use of 
the investigational product other than from clinical trials, such as 
from experience after marketing.

3.6.1. Pharmacokinetics

    A summary of information on the pharmacokinetics of the 
investigational product should be presented, including the 
following, if available:
    Pharmacokinetics, including metabolism.
    Bioavailability of the investigational product (absolute where 
possible, and/or comparative) using a defined dosage form.
    Plasma protein binding studies.
    Population subgroups, for example, gender, age, impaired organ 
function.
    Interactions, for example, drug-drug interactions, effects of 
food.
    Other pharmacokinetic data, for example, derived from clinical 
trials, population studies.

3.6.2. Clinical Trials (Phases I-IV)

    A summary of information relating to investigational product 
safety, pharmacodynamics, efficacy, and dose-response obtained from 
preceding trials in humans, whether in healthy volunteers and/or 
patients, should be provided. If possible each trial should be 
summarized individually. Where the number of trials is large it may 
be appropriate to summarize them in groups by phase to facilitate 
discussion of the data and their implications. For each trial, the 
aim, design, methods, results (safety and efficacy) and conclusions 
should be described.
    A discussion of the implications of the results should be 
provided and recommendations for further investigation should be 
made, unless this has already been included in an integrated 
summary.

3.6.3. Integrated Summaries of Drug Safety and Therapeutic Efficacy

    In cases where a number of clinical studies have been completed, 
the use of integrated summaries on safety and efficacy by indication 
may provide a clearer and more informative presentation of the data. 
The summaries should describe the number of studies completed, the 
number of subjects enrolled, the dose and duration of therapy, the 
results in terms of safety, therapeutic efficacy and dose-response 
for each, any significant subject compliance problems noted, and any 
significant variations in investigational product effects in patient 
subgroups noted. Tabular summaries of adverse drug events for all 
study treatments in all clinical trials (including those from all 
studied indications) are strongly recommended. Where differences in 
adverse drug event patterns/incidences exist they should be listed 
by indication.

3.6.4. Other Human Use

    Countries should be identified in which the investigational 
product has been marketed or approved. The approved indications, 
dose, and labelling conditions including precautions, 
contraindications, warnings, and drug interactions should be 
mentioned. When the investigational product is marketed, the serious 
drug event profile should be included. Any uses, formulations, or 
routes of administration, other than those used in the study, should 
be summarized with emphasis on safety information.

3.7. Investigational Product

    The justification of a particular formulation and its stage of 
development (final or developmental) and of the dosage strength and 
the route(s) of administration should be stated. To permit 
appropriate safety measures to be taken in the course of the trial, 
a description of the formulation(s) to be used, including excipients 
and their proportions, should be provided. Instructions for the 
storage and handling of the dosage forms should also be given.

3.8. Overall Discussion of Data and Guidance for the Investigator

    This section should provide an overall discussion of the 
nonclinical and clinical data, integrating information from various 
sources on different aspects of the investigational product wherever 
possible. In this way the prospective investigator can be provided 
with the most informative interpretation of the available data and 
at the same time with an assessment of the implications of the 
information for future clinical trials.
For example:
     Information obtained from pharmacokinetic and metabolic 
studies in animals and in humans may be correlated with the safety 
and efficacy results in the same species to provide an understanding 
of the dose and concentration relationships of these effects.
     Pharmacokinetic and metabolic data in humans may be 
compared to those in animals to provide an insight into the 
suitability of the animal models for predicting toxic and other 
pharmacological effects in humans.
     Experience across clinical trials should be analyzed 
and any correlation of the investigational product's effects with 
the dose, duration of treatment, and/or patient population 
described.
     Where appropriate, the published results on related 
drugs should be discussed. This could help the Investigator to 
anticipate adverse drug events or other problems in clinical trials.
    The overall aim of this section is to provide the investigator 
with a clear understanding of the possible risks and adverse 
effects, and of the special patient observations and precautions 
that may be needed for a specific trial based on the available 
chemical, pharmaceutical, pharmacological, toxicological, and 
clinical information on the investigational product. Guidance should 
also be given on the surveillance and treatment of overdose and 
adverse drug events based on previous human experience and the 
pharmacology of the investigational product.

Appendix 1

TITLE PAGE: EXAMPLE

Sponsor's Name

Product:

Research Number:
Name(s): Chemical, Generic (if approved).
    Trade Name(s) (if legally permissible and desired by the sponsor).

INVESTIGATOR'S BROCHURE

Edition No.:
Release Date:
Replaces previous edition no. ---- dated:

Appendix 2

EXAMPLE

TABLE OF CONTENTS OF INVESTIGATOR'S BROCHURE

- Confidentiality Statement (optional)
- Signature Page (optional)
1. Table of Contents
2. Summary
3. Introduction
4. Physical, Chemical, and Pharmaceutical Properties
5. Nonclinical studies
    5.1. Nonclinical Pharmacology
    5.2. Toxicology
    5.3. Pharmacokinetics and Drug Metabolism in Animals
6. Effects in Humans
    6.1. Pharmacokinetics
    6.2. Clinical Trials (Phases I-IV)
    6.3. Integrated Summaries of Drug Safety and Therapeutic 
Efficacy
    6.4. Other Human Use
7. Investigational Product
8. Overall Discussion of Data and Guide for the Investigator
N.B. References on
    1. Publications
    2. Internal Reports

    These are to be found at the end of each chapter.

Appendix: e.g., Package Leaflet for Phase IV Trials
Supplement: e.g., Brochure/Summary Information of Product 
Characteristics

    Dated: August 3, 1994.
 William K. Hubbard,
 Acting Deputy Commissioner for Policy.
[FR Doc. 94-19357 Filed 8-8-94; 8:45 am]
BILLING CODE 4160-01-F