International Conference on Harmonisation; Draft Guideline on the Timing of Nonclinical Studies for the Conduct of Human Clinical Trials for Pharmaceuticals

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

[[Page 24322]]

>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