Federal Register/Vol. 64, No. 122/Friday, June 25, 1999/Notices 34259
DEPARTMENT OF HEALTH AND Office of Health Affairs (HFY20), In accordance with FDAs Good
HUMAN SERVICES Food and Drug Administration, Guidance Practices (62 FR 8961,
5600 Fishers Lane, Rockville, MD February 27, 1997), this document has
Food and Drug Administration 20857, 3018270864. been designated a guidance, rather than
[Docket No. 97D0444] SUPPLEMENTARYINFORMATION: In recent a guideline.
years, many important initiatives have The document provides guidance on
International Conference on been undertaken by regulatory the duration of chronic toxicity testing
Harmonisation; Guidance on the authorities and industry associations to in rodents and nonrodents as part of the
Duration of Chronic Toxicity Testing in promote international harmonization of safety evaluation of a drug product. The
Animals (Rodent and Nonrodent regulatory requirements. FDA has guidance is intended to help eliminate
Toxicity Testing); Availability participated in many meetings designed or reduce the need for pharmaceutical
to enhance harmonization and is companies to duplicate testing in
AGENCY: Food and Drug Administration, committed to seeking scientifically animals during the development of new
HHS. based harmonized technical procedures drug products. The guidance is based on
ACTION: Notice. for pharmaceutical development. One of information currently available to the
the goals of harmonization is to identify agency, and this information is available
SUMMARY: The Food and Drug and then reduce differences in technical to the public in Docket No. 97D0444.
Administration (FDA) is publishing a
requirements for drug development This guidance represents the agencys
guidance entitled S4A Duration of
among regulatory agencies. current thinking on the duration of
Chronic Toxicity Testing in Animals
ICH was organized to provide an chronic toxicity testing in animals
(Rodent and Nonrodent Toxicity
opportunity for tripartite harmonization (rodent and nonrodent toxicity testing).
Testing). The guidance was prepared
initiatives to be developed with input It does not create or confer any rights for
under the auspices of the International
from both regulatory and industry or on any person and does not operate
Conference on Harmonisation of
representatives. FDA also seeks input to bind FDA or the public. An
Technical Requirements for Registration
from consumer representatives and alternative approach may be used if
of Pharmaceuticals for Human Use (ICH)
others. ICH is concerned with such approach satisfies the
and is intended to provide guidance on
harmonization of technical requirements of the applicable statute,
the duration of chronic toxicity testing
requirements for the registration of regulations, or both.
in rodents and nonrodents as part of the
pharmaceutical products among three For guidance on biotechnology-
safety evaluation of a drug product. FDA
regions: The European Union, Japan, derived pharmaceuticals, interested
is also noting circumstances in which it
and the United States. The six ICH parties are advised to consult the ICH
may accept durations of chronic toxicity
sponsors are the European Commission, guidance S6 Preclinical Safety
testing in nonrodents that differ from
the European Federation of Evaluation of Biotechnology-Derived
the duration generally recommended by
Pharmaceutical Industries Associations, Pharmaceuticals (62 FR 61515,
ICH.
the Japanese Ministry of Health and November 18, 1997).
DATES: Effective June 25, 1999. Submit Welfare, the Japanese Pharmaceutical FDA note on duration of chronic
written comments at any time. Manufacturers Association, the Centers toxicity testing in nonrodents: The ICH
ADDRESSES: Submit written comments for Drug Evaluation and Research and guidance recommends 9-month chronic
on the guidance to the Dockets Biologics Evaluation and Research, toxicity studies in nonrodents. FDA
Management Branch (HFA305), Food FDA, and the Pharmaceutical Research considers 9-month studies in
and Drug Administration, 5630 Fishers and Manufacturers of America. The ICH nonrodents acceptable for most drug
Lane, rm. 1061, Rockville, MD 20852. Secretariat, which coordinates the development programs, shorter studies
Copies of the guidance are available preparation of documentation, is may be equally acceptable in some
from the Drug Information Branch provided by the International circumstances and longer studies may
(HFD210), Center for Drug Evaluation Federation of Pharmaceutical be more appropriate in others, as
and Research, Food and Drug Manufacturers Associations (IFPMA). follows:
Administration, 5600 Fishers Lane, The ICH Steering Committee includes  Six-month studies may be
Rockville, MD 20857, 3018274573. representatives from each of the ICH acceptable for indications of chronic
Single copies of the guidance may be sponsors and the IFPMA, as well as conditions associated with short-term,
obtained by mail from the Office of observers from the World Health intermittent drug exposure, such as
Communication, Training and Organization, the Canadian Health bacterial infections, migraine, erectile
Manufacturers Assistance (HFM40), Protection Branch, and the European dysfunction, and herpes.
Center for Biologics Evaluation and Free Trade Area.  Six-month studies may be
Research (CBER), 1401 Rockville Pike, In the Federal Register of November acceptable for drugs intended for
Rockville, MD 208521448, or by calling 18, 1997 (62 FR 61513), FDA published indications for life-threatening diseases
the CBER Voice Information System at a draft tripartite guidance entitled S4A for which substantial long-term human
18008354709 or 3018271800. Duration of Chronic Toxicity Testing in clinical data are available, such as
Copies may be obtained from CBERs Animals (Rodent and Nonrodent cancer chemotherapy in advanced
FAX Information System at 1888 Toxicity Testing). The notice gave disease or in adjuvant use.
CBERFAX or 3018273844. interested persons an opportunity to  Twelve-month studies may be more
FORFURTHERINFORMATIONCONTACT: submit comments by January 20, 1998. appropriate for chronically used drugs
Regarding the guidance: Joseph J. There were no comments received to be approved on the basis of short-
DeGeorge, Center for Drug and no revisions to the guidance. A final term clinical trials employing efficacy
Evaluation and Research (HFD24), draft of the guidance was submitted to surrogate markers where safety data
Food and Drug Administration, the ICH Steering Committee and from humans are limited to short-term
5600 Fishers Lane, Rockville, MD endorsed by the three participating exposure, such as some acquired
20857, 3015946758. regulatory agencies on September 2, immunodeficiency syndrome (AIDS)
Regarding the ICH: Janet J. Showalter, 1998. therapies.
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 Twelve-month studies may be more the testing of chronic toxicity in the three Dated: June 17, 1999.
appropriate for new molecular entities regions (the European Union, Japan, and the Margaret M. Dotzel,
acting at new molecular targets where United States) were reviewed. Arising from Acting Associate Commissioner for Policy
this, it emerged that there was a scientific
postmarketing experience is not Coordination.
consensus on the approach for chronic
available for the pharmacological class. testing in rodents, supporting the [FR Doc. 9916189 Filed 62499; 8:45 am]
Thus, the therapeutic is the first in a
harmonized duration of testing of 6 months. BILLING CODE 416001F
pharmacological class for which there is However, for chronic toxicity testing in
limited human or animal experience on nonrodents, there were different approaches
its long-term toxic potential. to the duration of testing. DEPARTMENT OF HEALTH AND
As with all of FDAs guidances, the The lack of harmonized duration led to the HUMAN SERVICES
public is encouraged to submit written need for pharmaceutical companies to
comments with new data or other new perform partially duplicative studies for both Food and Drug Administration
6 and 12 months duration when developing
information pertinent to this guidance.
The comments in the docket will be new medicinal products. As the objective of Blood Donor Suitability Workshop:
ICH is to reduce or eliminate the need to
periodically reviewed, and, where duplicate testing during development of Donor History of Hepatitis
appropriate, the guidance will be medicinal products and to ensure a more
amended. The public will be notified of economical use of material, animal, and AGENCY: Food and Drug Administration,
any such amendments through a notice human resources, while at the same time HHS.
in the Federal Register. maintaining safeguards to protect public ACTION: Notice.
Interested persons may, at any time, health, further scientific evaluation was
undertaken. The Food and Drug Administration
submit written comments on the
Each of the regulatory authorities in the (FDA) is announcing the following
guidance to the Dockets Management
European Union, Japan, and the United public workshop entitled Blood Donor
Branch (address above). Two copies of
States undertook a review to determine
Suitability Workshop: Donor History of
any comments are to be submitted, whether a single duration for chronic toxicity
Hepatitis. The purpose of the
except that individuals may submit one testing in nonrodents could be identified.
workshop is to discuss whether
copy. Comments are to be identified From this analysis, it emerged that in 16
with the docket number found in cases a more detailed evaluation of 6 versus prospective blood donors with a history
brackets in the heading of this 12 months data should be undertaken. of viral hepatitis should be deferred
document. The guidance and received This evaluation was conducted as a joint from donating blood.
comments may be seen in the office exercise by the competent authorities in the Date and Time: The workshop will be
above between 9 a.m. and 4 p.m., three regions. held on Wednesday, July 21, 1999, 8:30
In some of the cases analyzed at the
Monday through Friday. An electronic a.m. to 5 p.m.
tripartite meetings, there were no additional
version of this guidance is available on findings at 12 months. For some other cases, Location: The workshop will be held
the Internet at http://www.fda.gov/ there was not complete agreement among the at Natcher Auditorium, Bldg. 45, 45
cder/guidance/index.htm or at CBERs regulators with respect to the comparability Center Dr., National Institutes of Health,
World Wide Web site at http:// in study design and conduct to allow 8800 Rockville Pike, Bethesda, MD.
www.fda.gov/cber/publications.htm. assessment of whether there were differences Contact: Joseph Wilczek, Center for
The text of the guidance follows: in the findings at 6 and 12 months due to Biologics Evaluation and Research
duration of treatment alone. (HFM350), Food and Drug
S4A Duration of Chronic Toxicity Testing in In a number of cases there were findings Administration, 1401 Rockville Pike,
Animals (Rodent and Nonrodent Toxicity observed by 12 months, but not by 6 months.
Rockville, MD 208521448, 301827
Testing)1 It was concluded that these would, or could,
6129, FAX 3018272843.
have been detected in a study of 9 months
1. Objective Registration: Early registration is
duration. Varying degrees of concern for the
The objective of this guidance is to set out differences in findings detected between the recommended. Mail or fax registration
the considerations that apply to chronic studies of different durations were expressed. information (including name, title, firm
toxicity testing in rodents and nonrodents as An agreement on the clinical relevance of name, address, telephone, and fax
part of the safety evaluation of a medicinal these findings could not be reached. number), to the contact person on or
product. Since guidance is not legally Studies of 12 months duration are usually before Friday, July 2, 1999.
binding, an applicant may submit not necessary, and studies of shorter than 9
Registration at the site will be done on
justification for an alternative approach. months duration may be sufficient.
a space available basis on the day of the
2. Scope In the European Union, studies of 6 workshop beginning at 7:30 a.m. There
months duration in nonrodents are
This guidance has been prepared for the acceptable according to Council Directive 75/ is no registration fee for the workshop.
development of medicinal products with the 318/EEC, as amended. To avoid duplication, If you need special accommodations
exception of those already covered by the
where studies with a longer duration have due to disability, please contact Joseph
ICH guidance S6 Preclinical Safety
been conducted, it would not be necessary to Wilczek at least 7 days in advance.
Evaluation of Biotechnology-Derived
conduct a study of 6 months. Agenda: The public workshop is
Pharmaceuticals (62 FR 61515, November
18, 1997), e.g., monoclonal antibodies, 4. Guidance on Duration of Chronic Toxicity intended to discuss a variety of issues
recombinant DNA proteins. Testing for Tripartite Development Plan concerning blood donor deferrals based
3. Background Arising from the extensive analysis and on a history of viral hepatitis. These
review of the above mentioned data in issues include, but are not limited to,
During the first International Conference
nonrodents and based upon the the following: (1) Definitions and
on Harmonisation in 1991, the practices for
achievements of ICH 1 for testing in rodents, clarification of terms such as history of
and so as to avoid duplication and follow a hepatitis and history of jaundice in
This guidance represents the agencys current single development plan for chronic toxicity the context of blood donation; (2)
thinking on the duration of chronic toxicity testing testing of new medicinal products, the
in animals (rodent and nonrodent toxicity testing). whether a prospective blood donor with
following studies are considered acceptable
It does not create or confer any rights for or on any a history of hepatitis A, who is anti-
for submission in the three regions:
ppeurbsloicn.  aAnnd  adloteersn natoitv oe paeprparteo atcoh b minady F bDeA u soerd t hife such (1) Rodents:A study of 6 months duration; HAV IgG positive, is an unacceptable
approach satisifes the requirements of the (2) Nonrodents: A study of 9 months donor; (3) whether deferrals are
applicable statute, regulations, or both. duration. appropriate for individuals with a
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