[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.

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 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 Japan<SUP>1                           
------------------------------------------------------------------------
                            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 Regions<SUP>1           
------------------------------------------------------------------------
                            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