[Federal Register Volume 60, Number 161 (Monday, August 21, 1995)]
[Notices]
[Pages 43498-43500]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-20610]



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[Docket No. 95D-0217]


International Conference on Harmonisation; Draft Guideline on 
Conditions Which Require Carcinogenicity Studies for Pharmaceuticals; 
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft 
guideline entitled ``Conditions Which Require Carcinogenicity Studies 
for Pharmaceuticals.'' This guideline was prepared under the auspices 
of the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH). 
The draft 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: Written comments by October 5, 1995.

ADDRESSES: Submit written comments on the draft guideline to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 
1-23, 12420 Parklawn Dr., Rockville, MD 20857. Copies of the draft 
guideline are available from the CDER Executive Secretariat Staff (HFD-
8), Center for Drug Evaluation and Research, Food and Drug 
Administration, 7500 Standish Pl., Rockville, MD 20855.

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 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.
    At a meeting held on March 29, 1995, the ICH Steering Committee 
agreed that a draft guideline entitled ``Conditions Which Require 
Carcinogenicity Studies for Pharmaceuticals'' should be made available 
for public comment. The draft guideline is the product of the Safety 
Expert Working Group of the ICH. Comments about this draft will be 
considered by FDA and the Expert Working Group. Ultimately, FDA intends 
to adopt the ICH Steering Committee's final guideline.
    The draft guideline is intended to define the conditions which 
require carcinogenicity studies, to provide guidance in order 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 any perceived cause for 
concern arising from other investigations and the maximum duration of 
patient treatment. Other factors may also be considered such as the 
appropriate study design, the timing of study performance relative to 
clinical development, the intended patient population, prior assessment 
of carcinogenic potential, the extent of systemic exposure, or the 
(dis)similarity to endogenous substances.
    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). Therefore, this 
guideline is not being issued under the authority of Sec. 10.90(b), and 
it does not create or confer any rights, privileges, or benefits for or 
on any person, nor does it operate to bind FDA in any way.
    Interested persons may, on or before October 5, 1995, submit to the 
Dockets Management Branch (address above) written comments on the draft 
guideline. 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 
draft guideline and received comments may be seen in the office above 
between 9 

[[Page 43499]]
a.m. and 4 p.m., Monday through Friday.
    The text of the draft guideline follows:

Conditions Which Require Carcinogenicity Studies for Pharmaceuticals

Purpose

    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 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 only be 
performed when human exposure warrants the need for information from 
life-time studies in animals in order to assess carcinogenic 
potential.

Historical Background

    In Japan, according to the 1990 ``Guidelines for Toxicity 
Studies of Drugs Manual,'' carcinogenicity studies are needed if the 
clinical use is expected to be continuously for 6 months or longer. 
If there is cause for concern, pharmaceuticals generally used 
continuously for less than 6 months may need carcinogenicity 
studies. In the United States, most pharmaceuticals are tested in 
animals for their carcinogenic potential before widespread use in 
humans. According to the U.S. Food and Drug Administration, 
pharmaceuticals generally used 3 months or more require 
carcinogenicity studies. In Europe, the Rules Governing Medicinal 
Products in the European Community define the circumstances when 
carcinogenicity studies are required. These circumstances include 
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 is similar.

Introduction

    The objective of this guideline is to define the conditions that 
require carcinogenicity studies, to provide the appropriate guidance 
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 any perceived cause for concern arising 
from other investigations and the maximum duration of patient 
treatment. Other factors may also be considered such as the 
appropriate study design, the timing of study performance relative 
to clinical development, the intended patient population, prior 
assessment of carcinogenic potential, the extent of systemic 
exposure, or the (dis)similarity to endogenous substances.
    For novel compounds, for which the pharmacologic profile or 
spectrum of biological effects is poorly understood, mechanistic 
studies may be particularly appropriate. Important research 
initiatives over the next decade will include optimization of study 
designs, modifications in diet, and development of new animal 
models, such as the newborn mouse, partially hepatectomized rats, 
and transgenic animals.

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) Findings in genotoxicity studies (Note 1); (2) previous 
demonstration of carcinogenic potential in the product class that is 
considered relevant to humans; (3) structure-activity relationship 
suggesting genotoxic or carcinogenic risk; (4) evidence of 
preneoplastic toxicity in repeated dose toxicity studies; and (5) 
long-term tissue retention of parent compound or metabolite(s) 
resulting in local tissue reactions or other pathophysiological 
responses.

Duration and Exposure

    Carcinogenicity studies should be performed for any 
pharmaceutical whose expected clinical use is continuous for at 
least 6 months. It is expected that most pharmaceuticals indicated 
for 3-months treatment would also likely be used for 6 months.
    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 clinically relevant treatment 
periods 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. Some 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 durations of exposure (e.g., anesthetics and radiolabeled 
imaging agents) do not need carcinogenicity studies unless there is 
cause for concern.

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 diseases it is 
not considered appropriate to require carcinogenicity testing before 
market approval. 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. In other cases to speed 
the availability of pharmaceuticals for life-threatening or severely 
debilitating diseases, especially where no satisfactory alternative 
therapy exists, carcinogenicity studies may be completed 
postapproval.

Route of Exposure

    The route of exposure in animals should be the same as the 
intended clinical route when feasible (reference ICH Safety Topic 
S1C). If similar metabolism and systemic exposure can be 
demonstrated by differing routes of administration, then it is only 
necessary to conduct carcinogenicity studies by a single route. It 
is important that relevant organs for the clinical effect be 
adequately exposed to the test material. Evidence of adequate 
exposure may be derived from pharmacokinetic data (reference ICH 
Safety Topic S3B).

Extent of Systemic Exposure

    Pharmaceuticals applied topically (e.g., dermal and ocular 
routes of administration) may need carcinogenicity studies. Where 
there is cause for concern for photocarcinogenic potential or if 
chronic irritation occurs, carcinogenicity studies by dermal 
application (generally in mice) may be needed. Pharmaceuticals 
showing poor systemic exposure from topical routes may not need 
studies by the oral route to assess the carcinogenic potential to 
internal organs.
    For different salts, acids, or bases of the same therapeutic 
moiety, where prior carcinogenicity studies are available, evidence 
should be provided that there are no significant changes in 
pharmacokinetics, pharmacodynamics, or toxicity. When changes in 
exposure and consequent toxicity are noted, then the results of 
additional bridging studies may be necessary 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.

[[Page 43500]]


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 (for example, animal insulins, 
pituitary-derived growth hormone, and calcitonin).
    The need for carcinogenicity studies in rodent species should be 
considered if indicated by the treatment duration, clinical 
indication, or patient population (providing neutralizing antibodies 
are not elicited to such an extent in repeated dose studies as to 
invalidate the results). Carcinogenicity studies may be needed 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).

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. When it is considered 
important to evaluate the relevance of tumor findings in animals for 
human safety, mechanistic studies are essential.

Supplementary Notes

    Note 1: Assessment of the genotoxic potential of a compound must 
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 positive result in any assay for genotoxicity 
does not necessarily mean that the test compound poses a genotoxic 
hazard to humans (reference ICH Safety Topic S2A).

    Dated: August 14, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-20610 Filed 8-18-95; 8:45 am]
BILLING CODE 4160-01-F