[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
_______________________________________________________________________
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
