[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]
[[Page 43933]]
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Part VI
Department of Health and Human Services
_______________________________________________________________________
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
[[Page 43934]]
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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
[[Page 43935]]
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