Guideline for Industry

The Need for Long-term Rodent

Carcinogenicity Studies of

Pharmaceuticals

March 1996

ICH S1A
i

Table of Contents

I. INFORMATION (1) ................................................... 1

II. HISTORICAL BACKGROUND (2) ....................................... 1

III. OBJECTIVE OF THE GUIDELINE (3) .................................... 2

IV. FACTORS TO CONSIDER FOR CARCINOGENICITY TESTING (4) ............ 2

A. Duration and Exposure (4.1) ....................................... 2

B. Cause for Concern (4.2) ........................................... 3

C. Genotoxicity (4.3) ............................................... 3

D. Indication and Patient Population (4.4) ................................ 3

E. Route of Exposure (4.5) ........................................... 4

F. Extent of Systemic Exposure (4.6) ................................... 4

G. Endogenous Peptides and Protein Substances or Their Analogs (4.7) ......... 5

V. NEED FOR ADDITIONAL TESTING (5) .................................. 5
This guideline was developed within the Expert Working Group (Safety) of the International Conference on 1

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been

subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed

by the ICH Steering Committee at Step 4 of the ICH process, November 29, 1995. At Step 4 of the process, the final

draft is recommended for adoption to the regulatory bodies of the European Union, Japan and the USA. This guideline

was published in the Federal Register on March 1, 1996 (61 FR 8153) and is applicable to drug and biological

products. Although this guideline does not create or confer any rights for or on any person and does not operate to bind

FDA or the industry, it does represent the Agency’s current thinking on long-term rodent carcinogenicity studies of

pharmaceuticals. For additional copies of this guideline, contact the Drug Information Branch, HFD-210, CDER, FDA,

5600 Fishers Lane, Rockville, MD 20857 (Phone: 301-827-4573) or the Manufacturers Assistance and Communication

Staff (HFM-42), CBER, FDA, 1401 Rockville Pike, Rockville, MD 20852-1448. Send one self-addressed adhesive

label to assist the offices in processing your request. An electronic version of this guidance is also available via Internet

using the World Wide Web (WWW) (connect to the CDER Home Page at WWW.FDA.GOV/CDER and go to the

“Regulatory Guidance” section).

GUIDELINE FOR INDUSTRY1

THE NEED FOR LONG-TERM 

RODENT CARCINOGENICITY STUDIES OF

PHARMACEUTICALS

I. INFORMATION (1)

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

II. HISTORICAL BACKGROUND (2)

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
It is expected that most pharmaceuticals indicated for 3-months treatment would also likely be used for 6 2

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.

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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.

III. OBJECTIVE OF THE GUIDELINE (3)

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.

IV. FACTORS TO CONSIDER FOR CARCINOGENICITY TESTING (4)

A. Duration and Exposure (4.1)

Carcinogenicity studies should be performed for any pharmaceutical whose expected

clinical use is continuous for at least 6 months.2

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
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duration of exposure (e.g., anesthetics and radiolabeled imaging agents) do not need

carcinogenicity studies unless there is cause for concern.

B. Cause for Concern (4.2)

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.

C. Genotoxicity (4.3)

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).

D. Indication and Patient Population (4.4)

When carcinogenicity studies are required they usually need to be completed before

application for marketing approval. However, completed rodent carcinogenicity studies
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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.

E. Route of Exposure (4.5)

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).

F. Extent of Systemic Exposure (4.6)

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 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
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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.

G. Endogenous Peptides and Protein Substances or Their Analogs (4.7)

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).

V. NEED FOR ADDITIONAL TESTING (5)

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.