[Federal Register Volume 61, Number 166 (Monday, August 26, 1996)]
[Notices]
[Pages 43934-43935]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-21651]



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Part VI





Department of Health and Human Services





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Food and Drug Administration



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Single Dose Acute Toxicity Testing for Pharmaceuticals; Revised 
Guidance; Availability; Notice

  Federal Register / Vol. 61, No. 166 / Monday, August 26, 1996 / 
Notices  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 92N-0136]


Single Dose Acute Toxicity Testing for Pharmaceuticals; Revised 
Guidance; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a revised 
guidance entitled ``Single Dose Acute Toxicity Testing for 
Pharmacueticals.'' This guidance was originally published as part of a 
proposed implementation document entitled ``U.S. FDA's Proposed 
Implementation of ICH Safety Working Group Consensus Regarding New Drug 
Applications.'' The agency has revised the guidance based on comments 
it received on the proposed implementation document.

DATES: Written comments on the revised guidance may be submitted at any 
time.

ADDRESSES:  Submit written requests for single copies of the revised 
guidance entitled ``Single Dose Acute Toxicity Testing for 
Pharmaceuticals'' to the Division of Communications Management (HFD-
210), Center for Drug Evaluation and Research, Food and Drug 
Administration, 7500 Standish Pl., Rockville, MD 20855. Send two self-
addressed adhesive labels to assist that office in processing your 
requests. An electronic version of this guidance is also available via 
Internet using FTP, Gopher or the World Wide Web (WWW). For FTP, 
connect to the Center for Drug Evaluation and Research (CDER) anonymous 
FTP server at CDVS2.CDER.FDA.GOV and change to the ``guidance'' 
directory. For Gopher, connect to the CDER Gopher server at 
GOPHER.CDER.FDA.GOV and select the ``Industry Guidance'' menu option. 
For WWW, connect to the FDA Home Page at WWW.FDA.GOV and go to the CDER 
section. Submit written
comments on the revised guidance to the Dockets Management Branch (HFA-
305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Requests and comments should be identified with 
the docket number found in brackets in the heading of this document. A 
copy of the guidance and received comments are available for public 
examination in the Dockets Management Branch between 9 a.m. and 4 p.m., 
Monday through Friday.

FOR FURTHER INFORMATION CONTACT:
    Regarding the toxicity testing document: Joseph J. DeGeorge, Center 
for Drug Evaluation and Research (HFD-150), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-5758.
    Regarding the ICH: Janet Showalter, Office of Health Affairs (HFY-
20), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-443-1382.

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 Industry 
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 Association 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 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 April 15, 1992 (57 FR 13105), FDA 
published a notice of availability of a proposed implementation 
document entitled ``U.S. FDA's Proposed Implementation of ICH Safety 
Working Group Consensus Regarding New Drug Applications.'' The proposed 
implementation document was developed by the Safety Working Group of 
the ICH and described scientific and technical aspects of conducting 
pharmacology and toxicology studies, including single dose (acute 
toxicity studies), to be submitted to FDA. That notice gave interested 
persons an opportunity to submit written comments by June 15, 1992. In 
the Federal Register of July 31, 1992 (57 FR 33965), FDA reopened the 
comment period until August 14, 1992, in response to a request for an 
extension of the comment period.
    The FDA draft guidance on Single Dose (acute) Toxicity Studies 
placed in the docket (92N-0136) for comment was considered compatible 
with the ICH participant regulatory agencies policies and with the 
consensus opinion of ICH Safety Working Group members on single dose 
toxicity testing. The main intent of the guidance was to have all 
regulatory regions confirm that LD50 studies were not necessary as 
part of acute toxicity testing. The agency received 15 comments on the 
proposed implementation document. In response to comments on the draft 
guidance, FDA modified its proposed guidance to provide information 
that would allow for use of single-dose toxicity studies to support 
single dose studies in humans. This approach, designed to facilitate 
the early stages of pharmaceutical development, is not an ICH consensus 
position although it is considered to be in general agreement with the 
ICH position on acute toxicity testing. It is, however, an FDA specific 
modification of the Single Dose Toxicity guidance of regional 
applicability.
    Although this guidance does not create or confer any rights for or 
on any person and does not operate to bind FDA, it does represent the 
agency's current thinking on single dose acute toxicity testing for 
pharmaceuticals.
    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 
final 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

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document. The guidance and received comments may be seen in the office 
above between 9 a.m. and 4 p.m., Monday through Friday.
    The text of the revised guidance follows:
Single Dose Acute Toxicity Testing for Pharmaceuticals
 Introduction
    Acute toxicity studies in animals are usually necessary for any 
pharmaceutical intended for human use. The information obtained from 
these studies is useful in choosing doses for repeat-dose studies, 
providing preliminary identification of target organs of toxicity, 
and, occasionally, revealing delayed toxicity. Acute toxicity 
studies may also aid in the selection of starting doses for Phase 1 
human studies, and provide information relevant to acute overdosing 
in humans.
 Definition
    Acute toxicity is the toxicity produced by a pharmaceutical when 
it is administered in one or more doses during a period not 
exceeding 24 hours.
 Testing Procedures
    The test compound should be administered to animals to identify 
doses causing no adverse effect and doses causing major (life-
threatening) toxicity. The use of vehicle control groups should be 
considered. For compounds with low toxicity, the maximum feasible 
dose should be administered.
    Acute toxicity studies in animals should ordinarily be conducted 
using two routes of drug administration: (1) The route intended for 
human administration, and (2) intravenous administration, if 
feasible. When intravenous dosing is proposed in humans, use of this 
route alone in animal testing is sufficient.
    Studies should be conducted in at least two mammalian species, 
including a nonrodent species when reasonable. The objectives of 
acute studies can usually be achieved in rodents using small groups 
of animals (for instance, three to five rodents per sex per dose). 
Where nonrodent species are appropriate for investigation, use of 
fewer animals may be considered. Any data providing information on 
acute effects in nonrodent species, including preliminary dose-range 
finding data for repeat-dose toxicity studies, may be acceptable.
Observation
    Animals should be observed for 14 days after pharmaceutical 
administration. All mortalities, clinical signs, time of onset, 
duration, and reversibility of toxicity should be recorded. Gross 
necropsies should be performed on all animals, including those 
sacrificed moribund, found dead, or terminated at 14 days.
    In addition, if acute toxicity studies in animals are to provide 
the primary safety data supporting single dose safety/kinetic 
studies in humans (e.g., a study screening multiple analogs to aid 
in the selection of a lead compound for clinical development), the 
toxicity studies should be designed to assess dose-response 
relationships and pharmacokinetics. Clinical pathology and 
histopathology should be monitored at an early time and at 
termination (i.e., ideally, for maximum effect and recovery).
Note: Animal Protection
    Studies should be designed so that the maximum amount of 
information is obtained from the smallest number of animals. 
Calculating lethality parameters (e.g., LD50) using large 
numbers of animals, as was done previously, is not recommended (see 
the Federal Register of October 11, 1988, 53 FR 39650).
    To avoid causing excessive pain or tissue damage in the animals, 
pharmaceuticals with irritant or corrosive characteristics should 
not be administered in concentrations that produce severe toxicity 
solely from local effects.

    Dated: August 15, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-21651 Filed 8-23-96; 8:45 am]
BILLING CODE 4160-01-F