62922 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices

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).
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 62923

1This 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.

The text of the guidance follows:

M3 Nonclinical Safety Studies for the

Conduct of Human Clinical Trials for

Pharmaceuticals1

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 lifethreatening 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.
62924 Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices

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

Duration of

Clinical Trials

Minimum Duration of Repeated Dose Toxicity Studies

Rodents Nonrodents

Single Dose 2–4 Weeks2 2 Weeks

Up to 2

Weeks

2–4 Weeks2 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 Months3

> 6 Months 6 Months Chronic3

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). 3See 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

Duration of

Clinical Trials

Minimum Duration of Repeated Dose Toxicity Studies

Rodents Nonrodents

Up to 2

Weeks

1 Month 1 Month

Up to 1

Month

3 Months 3 Months

TABLE 2.—DURATION OF REPEATED

DOSE TOXICITY STUDIES TO SUPPORT PHASE III TRIALS IN THE EU

AND MARKETING IN ALL REGIONS1—

Continued

Duration of

Clinical Trials

Minimum Duration of Repeated Dose Toxicity Studies

Rodents Nonrodents

Up to 3

Months

6 Months 3 Months

> 3 Months 6 Months Chronic2

1The above table also reflects the marketing recommendations in the three regions except that a chronic nonrodent study is recommended for clinical use > 1 month. 2See 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.
Federal Register / Vol. 62, No. 227 / Tuesday, November 25, 1997 / Notices 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