[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]]

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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                             
------------------------------------------------------------------------
                                      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\                     
------------------------------------------------------------------------
\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