[Federal Register Volume 62, Number 85 (Friday, May 2, 1997)]
[Notices]
[Pages 24320-24323]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-11496]
[[Page 24319]]
_______________________________________________________________________
Part X
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Draft Guideline on the
Timing of Nonclinical Studies for the Conduct of Human Clinical Trials
for Pharmaceuticals; Notice
Federal Register / Vol. 62, No. 85 / Friday, May 2, 1997 / Notices
[[Page 24320]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97D-0147]
International Conference on Harmonisation; Draft Guideline on the
Timing of Nonclinical Studies for the Conduct of Human Clinical Trials
for Pharmaceuticals
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is publishing a draft
guideline entitled ``Guideline for the Timing of Nonclinical Studies
for the Conduct of Human Clinical Trials for Pharmaceuticals.'' The
draft guideline was prepared under the auspices of the International
Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH). The draft guideline is intended
to recommend international standards for and to promote harmonization
of the nonclinical safety studies needed to support human clinical
trials of a given scope and duration.
DATES: Written comments by June 16, 1997.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the draft
guideline are available from the Drug Information Branch (HFD-210),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, 301-827-4573. Single copies of
the draft guideline may be obtained by mail from the Office of
Communication, Training and Manufacturers Assistance (HFM-40), Center
for Biologics Evaluation and Research, 1401 Rockville Pike, Rockville,
MD 20852-1448, or by calling the CBER Voice Information System at 1-
800-835-4709 or 301-827-1800. Copies may be obtained from CBER's FAX
Information System at 1-888-CBER-FAX or 301-827-3844.
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Lisa D. Rarick, Center for Drug Evaluation
and Research (HFD-580), Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-827-4260.
Regarding the ICH: Janet J. Showalter, Office of Health Affairs
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, 301-827-0864.
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 among regulatory
agencies.
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 Industries
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research, FDA, and
the Pharmaceutical Research and 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 November 7, 1996, the ICH Steering Committee
agreed that a draft guideline entitled ``Guideline for the Timing of
Nonclinical Studies for the Conduct of Human Clinical Trials for
Pharmaceuticals'' should be made available for public comment. The
draft guideline is the product of the Multidisciplinary (Safety/
Efficacy) Expert Working Group of the ICH. Comments about this draft
will be considered by FDA and the Multidisciplinary (Safety/Efficacy)
Expert Working Group.
The draft guideline is intended to recommend international
standards for and to promote harmonization of the nonclinical safety
studies needed to support human clinical trials of a given scope and
duration. The nonclinical safety study requirements for the marketing
approval of pharmaceuticals usually include single and repeat dose
toxicity studies, reproductive toxicity studies, genotoxicity studies,
local tolerance studies, an assessment of carcinogenic potential,
safety pharmocology studies, and pharmacokinetic studies. The draft
guideline discusses these types of studies, their duration, and their
relation to the conduct of human clinical trials. The draft guideline
should minimize delays in the conduct of clinical trials and reduce the
unnecessary use of animals and other resources, which in turn should
expedite the ethical development of drugs and facilitate the
availability of new pharmaceuticals.
In publishing this draft guideline, a note from a prior draft (Note
4) has been deleted because it could have been read to suggest,
incorrectly, that FDA lacks the authority to require the inclusion of
certain populations in particular clinical trials. FDA has such
authority under the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 301
et seq., and the Public Health Service Act, 42 U.S.C. 201 et seq. The
note was deleted because it was subject to misinterpretation and was
unnecessary.
This guideline represents the agency's current thinking on the
timing of nonclinical studies for the conduct of human clinical trials
for pharmaceuticals. It does not create or confer any rights for or on
any person and does not operate to bind FDA or the public. An
alternative approach may be used if such approach satisfies the
requirements of the applicable statute, regulations, or both.
Interested persons may, on or before June 16, 1997, submit to the
Dockets Management Branch (address above) written comments on the draft
guideline. 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 guideline and received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday. An electronic version
of this guideline is available via Internet using the World Wide Web
(WWW)(http://www.fda.gov/cder/guidance.htm). To connect to CBER's WWW
site, type http://www.fda.gov/cber/cberftp.html.
The text of the draft guideline follows:
[[Page 24321]]
Draft Guideline for the Timing of Nonclinical Studies for the Conduct
of Human Clinical Trials for Pharmaceuticals
1. Introduction
1.1 Objectives of the Guideline
The purpose of this document is to recommend international
standards for and to promote harmonization of the nonclinical safety
studies needed to support human clinical trials of a given scope and
duration.
Harmonization of the guidance for nonclinical safety studies
will help to define the current recommendations and reduce the
likelihood that substantial differences will exist between regions.
This guidance should minimize delays in the conduct of clinical
trials and reduce the unnecessary use of animals and other
resources. This should expedite the ethical development of drugs and
facilitate the availability of new pharmaceuticals.
1.2 Background
The recommendations for the extent of nonclinical safety studies
to support the various stages of clinical development differ among
the regions of Europe, the United States, and Japan. This raises the
important question of whether there is any scientific justification
for these differences and whether it would be possible to develop a
mutually acceptable guidance.
The present guideline represents the consensus that exists among
the ICH regions regarding the scope and duration of nonclinical
safety studies to support the conduct of human clinical trials for
pharmaceuticals.
1.3 Scope of the Guideline
The nonclinical safety study requirements for the marketing
approval of a pharmaceutical agent usually include single and
repeated dose toxicity studies, reproductive toxicity studies,
genotoxicity studies, local tolerance studies, and for drugs which
have cause for concern or are intended for a long duration of use,
an assessment of carcinogenic potential. Other nonclinical studies
include pharmacology studies for safety assessment (safety
pharmacology) and pharmacokinetic (ADME) studies. These various
types of studies, their duration, and the relation to the conduct of
human clinical trials are presented in this guideline.
This guideline applies to the situations usually encountered
during the development of conventional pharmaceutical agents and
should be viewed as providing general guidance for drug development
and not rigid requirements. The animal safety study and human
clinical trial plans should be designed to represent that approach
which is the most scientifically and ethically appropriate for the
pharmaceutical agent under development.
There have been marked advances in the innovation of therapeutic
agents (e.g., biotechnology-derived products) for which the existing
paradigms for safety evaluation may not always be appropriate or
relevant and they should therefore be evaluated on a case-by-case
basis (Ref. 1). Similarly, pharmaceuticals in development for
indications in life-threatening diseases or diseases without current
effective therapy may also warrant a case-by-case approach to both
the toxicological evaluation and clinical development to optimize or
expedite drug development. In certain cases, studies may be
abbreviated, deferred, or omitted.
1.4 General Principles
The development of a pharmaceutical agent is a stepwise process
involving an evaluation of both the animal and human safety
information. The goals of the nonclinical safety evaluation include:
A characterization of toxic effects with respect to target organs,
dose dependence, relationship to exposure, and potential
reversibility. This information is important for the estimation of
an initial safe starting dose for the human trials and the
identification of parameters for clinical monitoring for potential
adverse effects. The nonclinical safety studies, although limited at
the beginning of clinical development, should be adequate to
characterize potential toxic effects.
Human clinical trials are conducted to demonstrate the safety
and efficacy of a pharmaceutical, starting with a relatively low
exposure in a small number of subjects. This is followed by clinical
trials in which exposure usually increases by dose, duration and/or
size of the exposed patient population. Clinical trials are extended
based on the demonstration of adequate safety in the previous
clinical trial(s) as well as additional nonclinical safety
information that is available as the clinical trials proceed.
Serious adverse clinical or nonclinical findings may influence the
continuation of clinical trials and/or suggest the need for
additional nonclinical studies and a reevaluation of previous
clinical adverse events to resolve the issue.
Clinical trials are conducted in phases for which different
terminology has been utilized in the various regions. This document
uses the terminology as defined in the ICH guideline ``General
Considerations for the Clinical Trials'' (Ref. 2). Clinical trials
may be grouped by their purpose and objectives. The first human
exposure studies are generally single dose studies, followed by dose
escalation and short-term repeated dose studies to evaluate
pharmacokinetic parameters and tolerance (Phase I studies--Human
Pharmacology studies). These studies are often conducted in healthy
volunteers but may also include patients. The next phase of trials
consists of small scale studies for additional safety and clinical
pharmacology as well as preliminary efficacy studies in patients
(Phase II studies--Therapeutic Exploratory studies). This is
followed by large scale clinical trials for safety and efficacy in
patient populations (Phase III studies--Therapeutic Confirmatory
studies).
2. Safety Pharmacology
Safety pharmacology includes the assessment of effects on vital
functions (such as cardiovascular, central nervous, and respiratory
systems) and these should be evaluated prior to human exposure.
These evaluations may be conducted as additions to toxicity studies
or as separate studies.
3. Toxicokinetic and Pharmacokinetic Studies
Exposure data in animals should be evaluated prior to human
clinical trials (Ref. 3). Further information on absorption,
distribution, metabolism, and excretion in animals should be made
available to compare human and animal metabolic pathways.
Appropriate information should usually be available by the time the
early Phase I (Human Pharmacology) studies have been completed.
4. Single Dose Toxicity Studies
The single dose (acute) toxicity for a pharmaceutical should be
evaluated in two mammalian species prior to the first human exposure
(Note 1). A dose escalation study is an acceptable alternative to
the single dose design.
5. Repeated Dose Toxicity Studies
The recommended duration of the repeated dose toxicity studies
is related to the duration and scale of the proposed clinical trial.
In principle, the duration of the animal toxicity studies conducted
in two mammalian species (one nonrodent) should be equal to or
exceed the duration of the human clinical trials (Table 1).
5.1 Phase I and II Studies
A repeated dose toxicity study in two species (one nonrodent)
for a minimum duration of 2-4 weeks (Table 1) would support Phase I
(Human Pharmacology) and Phase II (Therapeutic Exploratory) studies
up to 2 weeks in duration. Beyond this, 1-, 3-, or 6-month toxicity
studies would support these types of human clinical trials for up to
1, 3, or 6 months, respectively.
Table 1.--Duration of Repeated Dose Toxicity Studies to Support Phase I
and II Trials in EU and Japan and Phase I, II, and III Trials in the
United States
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Duration of Repeated Dose Toxicity
Duration of Clinical Trials\1\ Studies
------------------------------------------------------------------------
Single Dose 2-4 Weeks\2\
Up to 2 Weeks 2-4 Weeks\2\
Up to 1 Month 1 Month
Up to 3 Months 3 Months
Up to 6 Months 6 Months
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>6 Months 6-12 Months\3\
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\1\ In special circumstances, trials may be extended beyond the duration
of completed repeat dose toxicity studies on a case-by-case basis.
\2\ EU and United States: 2-week studies are the minimum duration. In
Japan: 2-week nonrodent and 4-week rodent studies are needed (Also,
see Note 2). In the United States, single dose toxicity studies with
extended examinations can support single dose human studies (Ref. 4).
\3\ In EU and Japan, 6-month studies are adequate. In the United States,
a 12-month nonrodent study is usually needed (See Note 3).
5.2 Phase III Studies
For the Phase III (Therapeutic Confirmatory) studies, a 1-month
toxicity study in two species (one nonrodent) would support clinical
trials of up to 2 weeks in duration (Table 2). Three-month toxicity
studies would support clinical trials for up to 1-month duration,
while 6-month toxicity studies would support clinical trials for a
longer duration.
Table 2.--Duration of Repeated Dose Toxicity Studies to Support Phase
III Trials in the EU and Japan\1\
------------------------------------------------------------------------
Duration of Repeated Dose Toxicity
Duration of Clinical Trials\2\ Studies
------------------------------------------------------------------------
Up to 2 Weeks 1 Month
Up to 1 Month 3 Months
> 1 Month 6 Months
------------------------------------------------------------------------
\1\ The durations in this table also indicate the marketing requirements
in the United States and EU. In addition, in the United States, for
drugs used for duration in excess of 6 months, a 12-month nonrodent
study is generally considered an important part of the safety
evaluation for marketing.
\2\ In special circumstances, trials may be extended beyond the duration
of completed repeat dose toxicity studies on a case-by-case basis.
6. Local Tolerance Studies
Local tolerance should be studied in animals using a route which
is relevant to the proposed clinical administration site. The
evaluation of local tolerance should be performed prior to human
exposure. The assessment of local tolerance may be part of other
toxicity studies.
7. Genotoxicity Studies
Prior to first human exposure, in vitro tests for the evaluation
of mutations and chromosomal damage are generally needed. If an
equivocal or positive finding occurs, additional testing should be
performed (Ref. 5).
The standard battery of tests for genotoxicity (Ref. 6) should
be completed prior to the initiation of Phase II studies.
8. Carcinogenicity Studies
Completed carcinogenicity studies are not usually needed in
advance of the conduct of clinical trials unless there is cause for
concern. Conditions relevant for carcinogenicity testing are
discussed in ICH document ``Guideline on the Need for Long-Term
Rodent Carcinogenicity Studies of Pharmaceuticals'' (Ref. 7).
For pharmaceuticals developed to treat certain serious diseases,
carcinogenicity testing, if needed, may be conducted postapproval.
9. Reproductive Toxicity Studies
Reproductive toxicity studies (Refs. 8 and 9) should be
conducted as is appropriate for the population that is to be
exposed.
9.1 Men
Men may be included in Phase I and II trials prior to the
conduct of the male fertility study since an evaluation of the male
reproductive organs is performed in the repeated dose toxicity
studies (Note 2).
A male fertility study should be completed prior to the
initiation of Phase III trials (Refs. 8 and 9).
9.2 Women Not of Childbearing Potential
Women not of childbearing potential (i.e., permanently
sterilized, postmenopausal) may be included in clinical trials
without reproductive toxicity studies provided the relevant repeated
dose toxicity studies (which include an evaluation of the female
reproductive organs) have been conducted.
9.3 Women of Childbearing Potential
For women of childbearing potential there is a high level of
concern for the unintentional exposure of an embryo/fetus before
information is available concerning the potential benefits versus
potential risks. There are currently regional differences in the
timing of reproductive toxicity studies to support the inclusion of
women of childbearing potential in clinical trials.
In the EU and in Japan, assessment of female fertility and
embryo-fetal development should be completed prior to the inclusion
of women of childbearing potential using birth control in any type
of clinical trial. The pre- and postnatal development study should
be submitted for marketing approval.
In the United States, women of childbearing potential may be
included in early, carefully monitored studies without reproductive
toxicity studies provided appropriate precautions are taken to
minimize risk. These precautions include pregnancy testing (for
example, based on the b-subunit of HCG), use of a highly effective
method of birth control (Note 5), and entry after a confirmed
menstrual period. Continued testing and monitoring during the trial
should be sufficient to ensure compliance with the measures not to
become pregnant during the period of drug exposure (which may exceed
the length of study). To support this approach, informed consent
should include any known pertinent information related to
reproductive toxicity, such as a general assessment of potential
toxicity in pharmaceuticals with related structures or
pharmacological effects. If no relevant information is available,
the informed consent should clearly note the potential for risk.
In the United States, assessment of female fertility and embryo-
fetal development should be completed before women of childbearing
potential using birth control are enrolled in Phase III trials.
Unless there is cause for concern, the pre- and postnatal
development study should be submitted for marketing approval. For
all regions, all female reproductive toxicity studies (Ref. 8) and
the standard battery of genotoxicity tests (Ref. 6) should be
completed prior to the inclusion, in any clinical trial, of women of
childbearing potential not using highly effective birth control
(Note 5) or whose pregnancy status is unknown.
9.4 Pregnant Women
Prior to the inclusion of pregnant women in clinical trials, all
the reproductive toxicity studies (Refs. 8 and 9) and the standard
battery of genotoxicity tests (Ref. 6) should be conducted. In
addition, safety data from previous human exposure are generally
needed.
10. Supplementary Toxicity Studies
Special toxicity studies may be needed if previous nonclinical
or clinical findings with the study product or related product have
indicated special toxicological concerns.
11. Clinical Trials in Pediatric Populations
When pediatric patients are included in clinical trials, safety
data from previous adult human exposure would usually represent the
most relevant safety data and should
[[Page 24323]]
generally be available before pediatric clinical trials (Note 6).
In addition to appropriate repeated dose toxicity studies, all
reproductive toxicity studies (Ref. 8) and the standard battery of
genotoxicity tests (Ref. 6) should be available prior to the
initiation of trials in pediatric populations. Juvenile animal
safety studies should be considered on an individual basis when
previous animal data and human safety data are insufficient.
The need for carcinogenicity testing should be addressed prior
to long-term exposure in pediatric clinical trials considering the
length of treatment or cause for concern (Ref. 7).
12. Continuing Efforts to Improve Harmonization
It is recognized that significant advances in harmonization of
the timing of nonclinical safety studies for the conduct of human
clinical trials for pharmaceuticals have already been achieved and
are detailed in this guideline. However, differences remain in a few
areas. These include toxicity studies to support first entry into
man, the recommendations for reproductive toxicity studies for women
of childbearing potential, and the duration of nonclinical safety
studies for trials and marketing of drugs intended for greater than
6 months clinical use. Regulators and industry will continue to
consider these differences and work towards further improving the
drug development process.
13. Endnotes
Note 1 For the conduct of single dose toxicity studies, refer to the
ICH-1 recommendations (Ref. 10) and the regional guidelines (e.g.,
Ref. 4).
Note 2 There are currently regional differences for the minimum
duration of repeated dose toxicity studies: 2 weeks in the EU and
the United States, and 2-weeks nonrodent and 4-weeks rodent in
Japan. In Japan, unlike the EU and the United States, the male
fertility study is expected prior to the inclusion of men in
clinical trials. As an alternative, an assessment of male fertility
by careful histopathological examination in rodents can be made in
the 4-week repeated dose toxicity study (Ref. 9) and thus fulfills
this requirement for Japan. In the EU and the United States, 2-week
repeated dose studies are considered adequate for an overall
assessment of the potential toxicity of a drug to support clinical
trials for a short duration.
Note 3 In the United States, if the 12-month nonrodent study will
not be completed before clinical trials exceed 6 months, the U.S.
Food and Drug Administration should be consulted. The nature of the
pharmaceutical being developed, the patient population being
treated, and the available nonclinical toxicity information should
be considered. If, for example, 6-month studies in two species (one
rodent and one nonrodent) have been completed and there is no cause
for concern for the safety of the subjects being studied, the 12-
month nonrodent study should be ongoing such that it exceeds the
duration of the clinical trial. This lead should be sufficient to
allow application of the findings from the nonclinical study to
influence monitoring and conduct of the clinical study if additional
unexpected hazards are identified to ensure patient safety and
efficient evaluation of potential clinical hazards.
Note 4 Deleted.
Note 5 A highly effective method of birth control is defined as one
which results in a low failure rate when used consistently and
correctly (i.e., less than 1 percent per year), such as implants,
injectables, combined oral contraceptives, some IUD's, sexual
abstinence, or vasectomized partner. For subjects using hormonal
contraceptive method, information regarding the product under
evaluation and its potential effect on the contraceptive should be
addressed.
Note 6 The necessity for adult human data would be determined on a
case-by-case basis.
14. References
1. ICH Topic S6 Document ``Preclinical Testing of Biotechnology-
Derived Pharmaceuticals.''
2. ICH Topic E8 Document ``General Considerations for Clinical
Trials.''
3. ICH Harmonised Tripartite Guideline (S3A) Note for
``Toxicokinetics--Guidance on the Assessment of Systemic Exposure in
Toxicity Studies.''
4. Food and Drug Administration, ``Single Dose Acute Toxicity
Testing for Pharmaceuticals,'' Guidance for Industry, August 1996.
5. ICH Harmonised Tripartite Guideline (S2A) ``Guidance on
Specific Aspects of Regulatory Genotoxicity Tests.''
6. ICH Topic S2B Document ``Standard Battery of Genotoxicity
Tests.''
7. ICH Harmonised Tripartite Guideline (S1A) ``Guideline on the
Need for Long-Term Rodent Carcinogenicity Studies of
Pharmaceuticals.''
8. ICH Harmonised Tripartite Guideline (S5A) ``Detection of
Toxicity to Reproduction for Medicinal Products.''
9. ICH Harmonised Tripartite Guideline (S5B) ``Toxicity to Male
Fertility.''
10. Arcy, P. F., and D. W. G. Harron, ``Proceeding of The First
International Conference on Harmonisation, Brussels 1991,'' Queen's
University of Belfast, pp. 183-184, 1992.
Dated: April 25, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-11496 Filed 5-1-97; 8:45 am]
BILLING CODE 4160-01-F