S4A Duration of Chronic Toxicity Testing in Animals (Rodent and Nonrodent Toxicity Testing)

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

34259	Federal Register / Vol. 64, No. 122 / Friday, June 25, 1999 / Notices
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. 97D–0444]
International Conference on
Harmonisation; Guidance on the
Duration of Chronic Toxicity Testing in
Animals (Rodent and Nonrodent
Toxicity Testing); Availability
AGENCY: Food and Drug Administration,
HHS.
ACTION: Notice.
SUMMARY: The Food and Drug
Administration (FDA) is publishing a
guidance entitled ‘‘S4A Duration of
Chronic Toxicity Testing in Animals
(Rodent and Nonrodent Toxicity
Testing).’’ The guidance was prepared
under the auspices of the International
Conference on Harmonisation of
Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH)
and is intended to provide guidance on
the duration of chronic toxicity testing
in rodents and nonrodents as part of the
safety evaluation of a drug product. FDA
is also noting circumstances in which it
may accept durations of chronic toxicity
testing in nonrodents that differ from
the duration generally recommended by
ICH.
DATES: Effective June 25, 1999. Submit
written comments at any time.
ADDRESSES: Submit written comments
on the guidance to the Dockets
Management Branch (HFA–305), Food
and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852.
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: Joseph J.
DeGeorge, Center for Drug
Evaluation and Research (HFD–24),
Food and Drug Administration,
5600 Fishers Lane, Rockville, MD
20857, 301–594–6758.
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.
In the Federal Register of November
18, 1997 (62 FR 61513), FDA published
a draft tripartite guidance entitled ‘‘S4A
Duration of Chronic Toxicity Testing in
Animals (Rodent and Nonrodent
Toxicity Testing).’’ The notice gave
interested persons an opportunity to
submit comments by January 20, 1998.
There were no comments received
and no 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 September 2,
1998.
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 document provides guidance on
the duration of chronic toxicity testing
in rodents and nonrodents as part of the
safety evaluation of a drug product. The
guidance is intended to help eliminate
or reduce the need for pharmaceutical
companies to duplicate testing in
animals during the development of new
drug products. The guidance is based on
information currently available to the
agency, and this information is available
to the public in Docket No. 97D–0444.
This guidance represents the agency’s
current thinking on the duration of
chronic toxicity testing in animals
(rodent and nonrodent toxicity testing).
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.
For guidance on biotechnology-
derived pharmaceuticals, interested
parties are advised to consult the ICH
guidance ‘‘S6 Preclinical Safety
Evaluation of Biotechnology-Derived
Pharmaceuticals’’ (62 FR 61515,
November 18, 1997).
FDA note on duration of chronic
toxicity testing in nonrodents: The ICH
guidance recommends 9-month chronic
toxicity studies in nonrodents. FDA
considers 9-month studies in
nonrodents acceptable for most drug
development programs, shorter studies
may be equally acceptable in some
circumstances and longer studies may
be more appropriate in others, as
follows:
• Six-month studies may be
acceptable for indications of chronic
conditions associated with short-term,
intermittent drug exposure, such as
bacterial infections, migraine, erectile
dysfunction, and herpes.
• Six-month studies may be
acceptable for drugs intended for
indications for life-threatening diseases
for which substantial long-term human
clinical data are available, such as
cancer chemotherapy in advanced
disease or in adjuvant use.
• Twelve-month studies may be more
appropriate for chronically used drugs
to be approved on the basis of short-
term clinical trials employing efficacy
surrogate markers where safety data
from humans are limited to short-term
exposure, such as some acquired
immunodeficiency syndrome (AIDS)
therapies.

34260 	Federal Register / Vol. 64, No. 122 / Friday, June 25, 1999 / Notices
This guidance represents the agency’s current
thinking on the duration of chronic toxicity testing
in animals (rodent and nonrodent toxicity testing).
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 satisifes the requirements of the
applicable statute, regulations, or both.
• Twelve-month studies may be more
appropriate for new molecular entities
acting at new molecular targets where
postmarketing experience is not
available for the pharmacological class.
Thus, the therapeutic is the first in a
pharmacological class for which there is
limited human or animal experience on
its long-term toxic potential.
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 at ‘‘http://www.fda.gov/
cder/guidance/index.htm’’ or at CBER’s
World Wide Web site at ‘‘http://
www.fda.gov/cber/publications.htm’’.
The text of the guidance follows:
S4A Duration of Chronic Toxicity Testing in
Animals (Rodent and Nonrodent Toxicity
Testing)1
1. Objective
The objective of this guidance is to set out
the considerations that apply to chronic
toxicity testing in rodents and nonrodents as
part of the safety evaluation of a medicinal
product. Since guidance is not legally
binding, an applicant may submit
justification for an alternative approach.
2. Scope
This guidance has been prepared for the
development of medicinal products with the
exception of those already covered by the
ICH guidance ‘‘S6 Preclinical Safety
Evaluation of Biotechnology-Derived
Pharmaceuticals’’ (62 FR 61515, November
18, 1997), e.g., monoclonal antibodies,
recombinant DNA proteins.
3. Background
During the first International Conference
on Harmonisation in 1991, the practices for
the testing of chronic toxicity in the three
regions (the European Union, Japan, and the
United States) were reviewed. Arising from
this, it emerged that there was a scientific
consensus on the approach for chronic
testing in rodents, supporting the
harmonized duration of testing of 6 months.
However, for chronic toxicity testing in
nonrodents, there were different approaches
to the duration of testing.
The lack of harmonized duration led to the
need for pharmaceutical companies to
perform partially duplicative studies for both
6 and 12 months’ duration when developing
new medicinal products. As the objective of
ICH is to reduce or eliminate the need to
duplicate testing during development of
medicinal products and to ensure a more
economical use of material, animal, and
human resources, while at the same time
maintaining safeguards to protect public
health, further scientific evaluation was
undertaken.
Each of the regulatory authorities in the
European Union, Japan, and the United
States undertook a review to determine
whether a single duration for chronic toxicity
testing in nonrodents could be identified.
From this analysis, it emerged that in 16
cases a more detailed evaluation of 6 versus
12 months’ data should be undertaken.
This evaluation was conducted as a joint
exercise by the competent authorities in the
three regions.
In some of the cases analyzed at the
tripartite meetings, there were no additional
findings at 12 months. For some other cases,
there was not complete agreement among the
regulators with respect to the comparability
in study design and conduct to allow
assessment of whether there were differences
in the findings at 6 and 12 months due to
duration of treatment alone.
In a number of cases there were findings
observed by 12 months, but not by 6 months.
It was concluded that these would, or could,
have been detected in a study of 9 months’
duration. Varying degrees of concern for the
differences in findings detected between the
studies of different durations were expressed.
An agreement on the clinical relevance of
these findings could not be reached.
Studies of 12 months’ duration are usually
not necessary, and studies of shorter than 9
months’ duration may be sufficient.
In the European Union, studies of 6
months’ duration in nonrodents are
acceptable according to Council Directive 75/
318/EEC, as amended. To avoid duplication,
where studies with a longer duration have
been conducted, it would not be necessary to
conduct a study of 6 months.
4. Guidance on Duration of Chronic Toxicity
Testing for Tripartite Development Plan
Arising from the extensive analysis and
review of the above mentioned data in
nonrodents and based upon the
achievements of ICH 1 for testing in rodents,
and so as to avoid duplication and follow a
single development plan for chronic toxicity
testing of new medicinal products, the
following studies are considered acceptable
for submission in the three regions:
(1) Rodents:A study of 6 months’ duration;
(2) Nonrodents: A study of 9 months’
duration.
Dated: June 17, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy
Coordination.
[FR Doc. 99–16189 Filed 6–24–99; 8:45 am]
BILLING CODE 4160–01–F
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
Blood Donor Suitability Workshop:
Donor History of Hepatitis
AGENCY : Food and Drug Administration,
HHS.
ACTION: Notice.
The Food and Drug Administration
(FDA) is announcing the following
public workshop entitled ‘‘Blood Donor
Suitability Workshop: Donor History of
Hepatitis.’’ The purpose of the
workshop is to discuss whether
prospective blood donors with a history
of viral hepatitis should be deferred
from donating blood.
Date and Time: The workshop will be
held on Wednesday, July 21, 1999, 8:30
a.m. to 5 p.m.
Location: The workshop will be held
at Natcher Auditorium, Bldg. 45, 45
Center Dr., National Institutes of Health,
8800 Rockville Pike, Bethesda, MD.
Contact: Joseph Wilczek, Center for
Biologics Evaluation and Research
(HFM–350), Food and Drug
Administration, 1401 Rockville Pike,
Rockville, MD 20852–1448, 301–827–
6129, FAX 301–827–2843.
Registration: Early registration is
recommended. Mail or fax registration
information (including name, title, firm
name, address, telephone, and fax
number), to the contact person on or
before Friday, July 2, 1999.
Registration at the site will be done on
a space available basis on the day of the
workshop beginning at 7:30 a.m. There
is no registration fee for the workshop.
If you need special accommodations
due to disability, please contact Joseph
Wilczek at least 7 days in advance.
Agenda: The public workshop is
intended to discuss a variety of issues
concerning blood donor deferrals based
on a history of viral hepatitis. These
issues include, but are not limited to,
the following: (1) Definitions and
clarification of terms such as ‘‘history of
hepatitis’’ and ‘‘history of jaundice’’ in
the context of blood donation; (2)
whether a prospective blood donor with
a history of hepatitis A, who is anti-
HAV IgG positive, is an unacceptable
donor; (3) whether deferrals are
appropriate for individuals with a