[Federal Register Volume 61, Number 42 (Friday, March 1, 1996)]
[Notices]
[Pages 8154-8156]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-4791]




[[Page 8153]]

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Part III





Department of Health and Human Services





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Food and Drug Administration



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International Conference on Harmonisation; Notice

  Federal Register / Vol. 61, No. 42 / Friday, March 1, 1996 / 
Notices  
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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 95D-0217]


International Conference on Harmonisation; Final Guideline on the 
Need for Long-Term Rodent Carcinogenicity Studies of Pharmaceuticals; 
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a final 
guideline entitled ``Guideline on the Need for Long-Term Rodent 
Carcinogenicity Studies of Pharmaceuticals.'' The guideline was 
prepared under the auspices of the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). The guideline is intended to 
define the conditions for which carcinogenicity studies should be 
conducted, to provide guidance to avoid the unnecessary use of animals 
in testing, and to provide consistency in worldwide regulatory 
assessments of applications.

DATES: Effective March 1, 1996. Submit written comments at any time.

ADDRESSES: Submit written comments on the guideline to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guideline 
are available from the Division of Communications Management (HFD-210), 
Center for Drug Evaluation and Research, Food and Drug Administration, 
7500 Standish Pl., Rockville, MD 20855, 301-594-1012. An electronic 
version of this guideline is also available via Internet by connecting 
to the CDER file transfer protocol (FTP) server (CDVS2.CDER.FDA.GOV).

FOR FURTHER INFORMATION CONTACT:
    Regarding the guideline: -Joy A. Cavagnaro, Center for Biologics 
Evaluation and Research (HFM-500), Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852, 301-827-0379.
    Regarding ICH: Janet Showalter, Office of Health Affairs (HFY-1), 
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 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 August 21, 1995 (60 FR 43498), FDA 
published a draft tripartite guideline entitled ``Conditions Which 
Require Carcinogenicity Studies for Pharmaceuticals.'' The notice gave 
interested persons an opportunity to submit comments by October 5, 
1995.
    After consideration of the comments received and revisions to the 
guideline, a final draft of the guideline was submitted to the ICH 
Steering Committee and endorsed by the three participating regulatory 
agencies at the ICH meeting held on November 29, 1995.
    The guideline is intended to define the conditions for which 
carcinogenicity studies should be conducted, to provide guidance to 
avoid the unnecessary use of animals in testing, and to provide 
consistency in worldwide regulatory assessments of applications. The 
objectives of carcinogenicity studies are to identify a tumorigenic 
potential in animals and to understand the potential for such risk in 
humans. Any cause for concern derived from laboratory investigations, 
animal toxicity studies, and data in humans may lead to a need for 
carcinogenicity studies. The fundamental considerations in assessing 
the need for carcinogenicity studies are the maximum duration of 
patient treatment and any perceived cause for concern arising from 
other investigations. Other factors may also be considered such as the 
intended patient population, prior assessment of carcinogenic 
potential, the extent of systemic exposure, the (dis)similarity to 
endogenous substances, the appropriate study design, or the timing of 
study performance relative to clinical development.
    In the past, guidelines have generally been issued under 
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of 
guidelines to state procedures or standards of general applicability 
that are not legal requirements but are acceptable to FDA. The agency 
is now in the process of revising Sec. 10.90(b). Although this 
guideline does not create or confer any rights on or for any person and 
does not operate to bind FDA in any way, it does represent the agency's 
current thinking on long-term rodent carcinogenicity studies of 
pharmaceuticals.
    As with all of FDA's guidelines, the public is encouraged to submit 
written comments with new data or other new information pertinent to 
this guideline. The comments in the docket will be periodically 
reviewed, and, where appropriate, the guideline 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 guideline 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 guideline 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 guideline follows:

-Guideline on the Need for Long-Term Rodent Carcinogenicity Studies of 
Pharmaceuticals

 1. Introduction

    The objectives of carcinogenicity studies are to identify a 
tumorigenic potential in 

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animals and to assess the relevant risk in humans. Any cause for 
concern derived from laboratory investigations, animal toxicology 
studies, and data in humans may lead to a need for carcinogenicity 
studies. The practice of requiring carcinogenicity studies in 
rodents was instituted for pharmaceuticals that were expected to be 
administered regularly over a substantial part of a patient's 
lifetime. The design and interpretation of the results from these 
studies preceded much of the available current technology to test 
for genotoxic potential and the more recent advances in technologies 
to assess systemic exposure. These studies also preceded our current 
understanding of tumorigenesis with nongenotoxic agents. Results 
from genotoxicity studies, toxicokinetics, and mechanistic studies 
can now be routinely applied in preclinical safety assessment. These 
additional data are important not only in considering whether to 
perform carcinogenicity studies but for interpreting study outcomes 
with respect to relevance for human safety. Since carcinogenicity 
studies are time consuming and resource intensive, they should be 
performed only when human exposure warrants the need for information 
from life-time studies in animals in order to assess carcinogenic 
potential.

 2. Historical Background

    In Japan, according to the 1990 ``Guidelines for Toxicity 
Studies of Drugs Manual,'' carcinogenicity studies were needed if 
the clinical use was expected to be continuously for 6 months or 
longer. If there was cause for concern, pharmaceuticals generally 
used continuously for less than 6 months may have needed 
carcinogenicity studies. In the United States, most pharmaceuticals 
were tested in animals for their carcinogenic potential before 
widespread use in humans. According to the U.S. Food and Drug 
Administration, pharmaceuticals generally used for 3 months or more 
necessitated carcinogenicity studies. In Europe, the Rules Governing 
Medicinal Products in the European Community defined the 
circumstances when carcinogenicity studies were required. These 
circumstances included administration over a substantial period of 
life, i.e., continuously during a minimum period of 6 months or 
frequently in an intermittent manner so that the total exposure was 
similar.

3. Objective of the Guideline-

    The objective of this guideline is to define the conditions 
under which carcinogenicity studies should be conducted to avoid the 
unnecessary use of animals in testing, and to provide consistency in 
worldwide regulatory assessments of applications. It is expected 
that these studies will be performed in a manner that reflects 
currently accepted scientific standards.
    The fundamental considerations in assessing the need for 
carcinogenicity studies are the maximum duration of patient 
treatment and any perceived cause for concern arising from other 
investigations. Other factors may also be considered such as the 
intended patient population, prior assessment of carcinogenic 
potential, the extent of systemic exposure, the (dis)similarity to 
endogenous substances, the appropriate study design, or the timing 
of study performance relative to clinical development.

 4. Factors to Consider for Carcinogenicity Testing

 4.1 Duration and Exposure

     Carcinogenicity studies should be performed for any 
pharmaceutical whose expected clinical use is continuous for at 
least 6 months (see Note 1).
     Certain classes of compounds may not be used continuously over 
a minimum of 6 months but may be expected to be used repeatedly in 
an intermittent manner. It is difficult to determine and to justify 
scientifically what time represents a clinically relevant treatment 
period for frequent use with regard to carcinogenic potential, 
especially for discontinuous treatment periods. For pharmaceuticals 
used frequently in an intermittent manner in the treatment of 
chronic or recurrent conditions, carcinogenicity studies are 
generally needed. Examples of such conditions include allergic 
rhinitis, depression, and anxiety. Carcinogenicity studies may also 
need to be considered for certain delivery systems which may result 
in prolonged exposures. Pharmaceuticals administered infrequently or 
for short duration of exposure (e.g., anesthetics and radiolabeled 
imaging agents) do not need carcinogenicity studies unless there is 
cause for concern.

 4.2 Cause for Concern

    Carcinogenicity studies may be recommended for some 
pharmaceuticals if there is concern about their carcinogenic 
potential. Criteria for defining these cases should be very 
carefully considered because this is the most important reason to 
conduct carcinogenicity studies for most categories of 
pharmaceuticals. Several factors which could be considered may 
include: (1) Previous demonstration of carcinogenic potential in the 
product class that is considered relevant to humans; (2) structure-
activity relationship suggesting carcinogenic risk; (3) evidence of 
preneoplastic lesions in repeated dose toxicity studies; and (4) 
long-term tissue retention of parent compound or metabolite(s) 
resulting in local tissue reactions or other pathophysiological 
responses.

 4.3 Genotoxicity

     Unequivocally genotoxic compounds, in the absence of other 
data, are presumed to be transspecies carcinogens, implying a hazard 
to humans. Such compounds need not be subjected to long-term 
carcinogenicity studies. However, if such a drug is intended to be 
administered chronically to humans, a chronic toxicity study (up to 
1 year) may be necessary to detect early tumorigenic effects.
     Assessment of the genotoxic potential of a compound should take 
into account the totality of the findings and acknowledge the 
intrinsic value and limitations of both in vitro and in vivo tests. 
The test battery approach of in vitro and in vivo tests is designed 
to reduce the risk of false negative results for compounds with 
genotoxic potential. A single positive result in any assay for 
genotoxicity does not necessarily mean that the test compound poses 
a genotoxic hazard to humans (see the ICH Guideline on Specific 
Aspects of Regulatory Genotoxicity Tests).

 4.4 Indication and Patient Population

     When carcinogenicity studies are required they usually need to 
be completed before application for marketing approval. However, 
completed rodent carcinogenicity studies are not needed in advance 
of the conduct of large scale clinical trials unless there is 
special concern for the patient population.
     For pharmaceuticals developed to treat certain serious 
diseases, carcinogenicity testing need not be conducted before 
market approval although these studies should be conducted post-
approval. This speeds the availability of pharmaceuticals for life-
threatening or severely debilitating diseases, especially where no 
satisfactory alternative therapy exists.
     In instances where the life-expectancy in the indicated 
population is short (i.e., less than 2 to 3 years), no long-term 
carcinogenicity studies may be required. For example, oncolytic 
agents intended for treatment of advanced systemic disease do not 
generally need carcinogenicity studies. In cases where the 
therapeutic agent for cancer is generally successful and life is 
significantly prolonged, there may be later concerns regarding 
secondary cancers. When such pharmaceuticals are intended for 
adjuvant therapy in tumor free patients or for prolonged use in 
noncancer indications, carcinogenicity studies are usually needed.

 4.5 Route of Exposure

     The route of exposure in animals should be the same as the 
intended clinical route when feasible (see the ICH Guideline on Dose 
Selection for Carcinogenicity Studies of Pharmaceuticals). If 
similar metabolism and systemic exposure can be demonstrated by 
differing routes of administration, carcinogenicity studies should 
only be conducted by a single route, recognizing that it is 
important that relevant organs for the clinical route (e.g., lung 
for inhalational agents) be adequately exposed to the test material. 
Evidence of adequate exposure may be derived from pharmacokinetic 
data (see the ICH Guideline on Repeated Dose Tissue Distribution 
Studies).

 4.6 Extent of Systemic Exposure

     Pharmaceuticals applied topically (e.g., dermal and ocular 
routes of administration) may need carcinogenicity studies. 
Pharmaceuticals showing poor systemic exposure from topical routes 
in humans may not need studies by the oral route to assess the 
carcinogenic potential to internal organs. Where there is cause for 
concern for photocarcinogenic potential, carcinogenicity studies by 
dermal application (generally in mice) may be needed. 
Pharmaceuticals administered by the ocular route may not need 
carcinogenicity studies unless there is cause for concern or unless 
there is significant systemic exposure.
     For different salts, acids, or bases of the same therapeutic 
moiety, where prior carcinogenicity studies are available, evidence 
should be provided that there are 

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no significant changes in pharmacokinetics, pharmacodynamics, or 
toxicity. When changes in exposure and consequent toxicity are 
noted, additional bridging studies may be used to determine whether 
additional carcinogenicity studies are needed. For esters and 
complex derivatives, similar data would be valuable in assessing the 
need for an additional carcinogenicity study, but this should be 
considered on a case-by-case basis.

 4.7 Endogenous Peptides and Protein Substances or Their Analogs

     Endogenous peptides or proteins and their analogs produced by 
chemical synthesis, by extraction/purification from an animal/human 
source, or by biotechnological methods such as recombinant DNA 
technology, may require special considerations.
     Carcinogenicity studies are not generally needed for endogenous 
substances given essentially as replacement therapy (i.e., 
physiological levels), particularly where there is previous clinical 
experience with similar products (e.g., animal insulins, pituitary-
derived growth hormone, and calcitonin).
     Although not usually necessary, long-term carcinogenicity 
studies in rodent species should be considered for the other 
biotechnology products noted above if indicated by the treatment 
duration, clinical indication, or patient population (provided 
neutralizing antibodies are not elicited to such an extent in 
repeated dose studies as to invalidate the results). Conduct of 
carcinogenicity studies may be important in the following 
circumstances: (1) For products where there are significant 
differences in biological effects to the natural counterpart(s); (2) 
for products where modifications lead to significant changes in 
structure compared to the natural counterpart; and (3) for products 
resulting in humans in a significant increase over the existing 
local or systemic concentration (i.e., pharmacological levels).

 5. Need for Additional Testing

     The relevance of the results obtained from animal 
carcinogenicity studies for assessment of human safety are often 
cause for debate. Further research may be needed, investigating the 
mode of action, which may result in confirming the presence or the 
lack of carcinogenic potential for humans. Mechanistic studies are 
useful to evaluate the relevance of tumor findings in animals for 
human safety.
    Supplementary Note-
    Note 1: It is expected that most pharmaceuticals indicated for 
3-months treatment would also likely be used for 6 months. In an 
inquiry to a number of pharmaceutical research and regulatory 
groups, no cases were identified in which a pharmaceutical would be 
used only for 3 months.

    Dated: February 23, 1996
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-4791 Filed 2-29-96; 8:45 am]
BILLING CODE 4160-01-F