[Federal Register Volume 62, Number 227 (Tuesday, November 25, 1997)]
[Notices]
[Pages 62922-62925]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-30913]
[[Page 62921]]
_______________________________________________________________________
Part VII
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Guidance on Nonclinical
Safety Studies for the Conduct of Human Clinical Trials for
Pharmaceuticals; Notice
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 /
Notices
[[Page 62922]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97D-0147]
International Conference on Harmonisation; Guidance on
Nonclinical Safety 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
guidance entitled ``M3 Nonclinical Safety Studies for the Conduct of
Human Clinical Trials for Pharmaceuticals.'' The guidance was prepared
under the auspices of the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH). The guidance 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: Effective November 25, 1997. Submit written comments at any
time.
ADDRESSES: Submit written comments on the guidance to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guidance 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 guidance
may be obtained by mail from the Office of Communication, Training and
Manufacturers Assistance (HFM-40), Center for Biologics Evaluation and
Research (CBER), 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 guidance: Robert E. Osterberg, Center for Drug
Evaluation and Research (HFD-520), Food and Drug Administration, 9201
Corporate Blvd., Rockville, MD 20850, 301-827-2123.
Regarding 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 (EU),
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.
In the Federal Register of May 2, 1997 (62 FR 24320), FDA published
a draft tripartite guideline entitled ``Guideline on the Timing of
Nonclinical Studies for the Conduct of Human Clinical Trials for
Pharmaceuticals'' (M3). The notice gave interested persons an
opportunity to submit comments by June 16, 1997.
After consideration of the comments received and revisions to the
guidance, a final draft of the guidance was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies on July 16, 1997.
In accordance with FDA's Good Guidance Practices (62 FR 8961,
February 27, 1997), this document has been designated a guidance,
rather than a guideline.
The guidance 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
pharmacology studies, and pharmacokinetic studies. The guidance
discusses these types of studies, their duration, and their relation to
the conduct of human clinical trials. The guidance should facilitate
the conduct of clinical trials and reduce the unnecessary use of
animals and other resources, which in turn should promote safe and
ethical development of drugs and the availability of new
pharmaceuticals.
This guidance represents the agency's current thinking on
nonclinical safety 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.
As with all of FDA's guidances, the public is encouraged to submit
written comments with new data or other new information pertinent to
this guidance. The comments in the docket will be periodically
reviewed, and, where appropriate, the guidance will be amended. The
public will be notified of any such amendments through a notice in the
Federal Register.
Interested persons may, at any time, submit written comments on the
guidance to the Dockets Management Branch (address above). 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 guidance 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 guidance is
available on the Internet (http://www.fda.gov/cder/guidance.htm) or
through the CBER home page (http://www.fda.gov/cber/cberftp.html).
[[Page 62923]]
The text of the guidance follows:
M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials
for Pharmaceuticals\1\
---------------------------------------------------------------------------
\1\ This guidance represents the agency's current thinking on
nonclinical safety 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.
---------------------------------------------------------------------------
1. Introduction
1.1 Objectives of the Guidance
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 facilitate the timely conduct of clinical
trials and reduce the unnecessary use of animals and other
resources. This should promote safe and ethical development and
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 scientific justification for
these differences and whether it would be possible to develop a
mutually acceptable guidance.
The present guidance 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 Guidance
The nonclinical safety study recommendations for the marketing
approval of a pharmaceutical usually include single and repeated
dose toxicity studies, reproduction toxicity studies, genotoxicity
studies, local tolerance studies, and for drugs that have special
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 (absorption, distribution,
metabolism, and excretion (ADME)) studies. These types of studies
and their relation to the conduct of human clinical trials are
presented in this guidance.
This guidance applies to the situations usually encountered
during the conventional development of pharmaceuticals and should be
viewed as providing general guidance for drug development. Animal
safety studies and human clinical trials should be planned and
designed to represent an approach that is scientifically and
ethically appropriate for the pharmaceutical under development.
There have been marked changes in the kinds of therapeutic
agents being developed (e.g., biotechnology-derived products), and
the existing paradigms for safety evaluation may not always be
appropriate or relevant. The safety evaluation in such cases should
be considered on a case-by-case basis as described in the ICH
guidance ``Safety Studies in Biotechnological Products'' (Ref. 1).
Similarly, pharmaceuticals under development for indications in
life-threatening or serious diseases without current effective
therapy may also warrant a case-by-case approach to both the
toxicological evaluation and clinical development to optimize and
expedite drug development. In these cases, particular studies may be
abbreviated, deferred, or omitted.
1.4 General Principles
The development of a pharmaceutical 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 under the conditions of the
supported clinical trial.
Human clinical trials are conducted to demonstrate the efficacy
and safety 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 guidance ``General
Considerations for 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 exploratory efficacy and safety studies in patients
(Phase II studies--Therapeutic Exploratory studies). This is
followed by confirmatory clinical trials for efficacy and safety 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 ADME in animals
should be made available to compare human and animal metabolic
pathways. Appropriate information should usually be available by the
time the 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 considered an acceptable
alternative to the single dose design.
5. Repeated Dose Toxicity Studies
The recommended duration of the repeated dose toxicity studies
is usually related to the duration, therapeutic indication, 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 up to the maximum recommended duration of the
repeated dose toxicity studies (Tables 1 and 2).
In certain circumstances, where significant therapeutic gain has
been shown, trials may be extended beyond the duration of supportive
repeated dose toxicity studies on a case-by-case basis.
5.1 Phase I and II Studies
A repeated dose toxicity study in two species (one nonrodent)
for a minimum duration of 2 to 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. Six-month rodent and
chronic nonrodent studies (Ref. 11) would support clinical trials of
longer duration than 6 months.
[[Page 62924]]
Table 1.--Duration of Repeated Dose Toxicity Studies to Support Phase I
and II Trials in the EU and Phase I, II, and III Trials in the United
States and Japan1
------------------------------------------------------------------------
Minimum Duration of Repeated Dose Toxicity
Duration of Clinical Studies
Trials ------------------------------------------------
Rodents Nonrodents
------------------------------------------------------------------------
Single Dose 2-4 Weeks\2\ 2 Weeks
Up to 2 Weeks 2-4 Weeks\2\ 2 Weeks
Up to 1 Month 1 Month 1 Month
Up to 3 Months 3 Months 3 Months
Up to 6 Months 6 Months 6 Months\3\
> 6 Months 6 Months Chronic\3\
------------------------------------------------------------------------
\1\ In Japan, if there are no Phase II clinical trials of equivalent
duration to the planned Phase III trials, conduct of longer duration
toxicity studies should be considered as given in Table 2.
\2\ In the EU and the 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, as an alternative to 2-
week studies, single dose toxicity studies with extended examinations
can support single dose human trials (Ref. 4).
\3\ See Ref. 11. Data from 6 months of administration in nonrodents
should be available before the initiation of clinical trials longer
than 3 months. Alternatively, if applicable, data from a 9-month
nonrodent study should be available before the treatment duration
exceeds that which is supported by the available toxicity studies.
5.2 Phase III Studies
For the Phase III (Therapeutic Confirmatory) studies, the
recommendations for the United States and Japan are the same as
those in Table 1. In the EU, a 1-month toxicity study in two species
(one nonrodent) would support clinical trials of up to 2 weeks
duration (Table 2). Three-month toxicity studies would support
clinical trials for up to 1 month duration, while 6-month toxicity
studies in rodents and 3-month studies in nonrodents would support
clinical trials of a duration up to 3 months. For longer term
clinical trials, a 6-month study in rodents and a chronic study in
nonrodents are recommended.
Table 2.--Duration of Repeated Dose Toxicity Studies to Support Phase
III Trials in the EU and Marketing in All Regions1
------------------------------------------------------------------------
Minimum Duration of Repeated Dose Toxicity
Duration of Clinical Studies
Trials ------------------------------------------------
Rodents Nonrodents
------------------------------------------------------------------------
Up to 2 Weeks 1 Month 1 Month
Up to 1 Month 3 Months 3 Months
Up to 3 Months 6 Months 3 Months
> 3 Months 6 Months Chronic\2\
------------------------------------------------------------------------
\1\ The above table also reflects the marketing recommendations in the
three regions except that a chronic nonrodent study is recommended for
clinical use > 1 month.
\2\ See Ref. 11.
6. Local Tolerance Studies
Local tolerance should be studied in animals using routes
relevant to the proposed clinical administration. 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 the ICH document (Ref. 7).
For pharmaceuticals developed to treat certain serious diseases,
carcinogenicity testing, if needed, may be concluded postapproval.
9. Reproduction Toxicity Studies
Reproduction 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 reproduction 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 reproduction toxicity studies to support the inclusion of
women of childbearing potential in clinical trials.
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. In the EU, assessment of embryo-fetal development should be
completed prior to Phase I trials in women of childbearing potential
and female fertility studies prior to Phase III trials.
In the United States, women of childbearing potential may be
included in early, carefully monitored studies without reproduction
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 3), 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 of 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.
In the three regions, the pre- and postnatal development study
should be submitted for marketing approval or earlier if there is
cause for concern. For all regions, all female reproduction 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 3) or whose pregnancy status is unknown.
9.4 Pregnant Women
Prior to the inclusion of pregnant women in clinical trials, all
the reproduction 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 Studies
Additional nonclinical studies may be needed if previous
nonclinical or clinical findings with the product or related
products have indicated special safety concerns.
[[Page 62925]]
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 information and should generally be available before
pediatric clinical trials. The necessity for adult human data would
be determined on a case-by-case basis.
In addition to appropriate repeated dose toxicity studies, all
reproduction 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
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 guidance. However, differences remain in a few
areas. These include toxicity studies to support first entry into
man and the recommendations for reproduction toxicity studies for
women of childbearing potential. 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 guidances.
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 has usually been conducted prior to the inclusion of
men in clinical trials. However, an assessment of male fertility by
careful histopathological examination in the rodent 4-week repeated
dose toxicity study has been found to be more sensitive in detecting
effects on male reproductive organs than fertility studies (Ref. 9),
and is now recommended to be performed prior to the first clinical
trial in 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 A highly effective method of birth control is defined as
one that results in a low failure rate (i.e., less than 1 percent
per year) when used consistently and correctly, such as implants,
injectables, combined oral contraceptives, some intrauterine
contraceptive devices (IUD's), sexual abstinence, or a vasectomized
partner. For subjects using a hormonal contraceptive method,
information regarding the product under evaluation and its potential
effect on the contraceptive should be addressed.
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: The Assessment of Systemic Exposure in Toxicity
Studies.''
4. FDA, ``Single Dose Acute Toxicity Testing for
Pharmaceuticals; Revised Guidance,'' 61 FR 43934 to 43935, August
26, 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 Carcinogenicity Studies for 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.
11. ICH Topic S4 Document ``Duration of Chronic Toxicity Testing
in Animals (Rodent and Nonrodent Toxicity Testing).''
Dated: November 18, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-30913 Filed 11-24-97; 8:45 am]
BILLING CODE 4160-01-F
