This document provides guidelines on when carcinogenicity studies of pharmaceuticals are needed. It outlines several factors to consider, including the maximum duration of patient treatment, intended patient population, prior assessment of carcinogenic potential, extent of systemic exposure, and similarity to endogenous substances. The guidelines specify that carcinogenicity studies are generally needed for continuous patient exposures of 6 months or longer, or intermittent exposures equivalent to 6 months, but may not be needed for short-term exposures or if there is no cause for concern about carcinogenic potential.

1. S1A
GUIDELINE ON THE NEED FOR CARCINOGENICITY STUDIES OF
PHARMACEUTICALS

2. Introduction – Carcinogenicity Studies
• To identify a tumorigenic potential in animals
• Performed only when human exposure is a concern
History
Carcinogenic tests are mandated for pharmaceuticals
• In Japan – continuous use of 6 months or longer
• In USA (FDA) – use for 3 months or more
• In Europe – use of 6 months or total exposure is same as 6 months

3. OBJECTIVE OF THE GUIDELINE
• When and Which carcinogenicity test should be done
• Factors to be considered
1. maximum duration of patient treatment
2. intended patient population
3. prior assessment of carcinogenic potential
4. extent of systemic exposure
5. (dis)similarity to endogenous substances
6. appropriate study design or
7. the timing of study performance relative to clinical development.

4. 1) Duration and Exposure
• Continuous for at least 6 months
• Intermittent manner in 6 months ( Eg: allergic rhinitis, depression,
and anxiety.) requires carcinogenicity studies
• Delivery systems that prolonged exposures
• Short duration of exposure (e.g., anaesthetics and radiolabelled
imaging agents) do not need UNLESS there is cause of concern

5. 2) Cause for Concern
(1) previous demonstration of same class;
(2) structure-activity relationship;
(3) evidence of preneoplastic lesions in repeated dose toxicity studies;
(4) long-term tissue retention of parent compound or metabolite

6. 3) Genotoxicity
• Genotoxic compounds (in absence of other data) are trans-species
carcinogens. (So no need of any carcinogenicity test).
• Unless it is used in humans (Chronic toxicity -1 year test needed)
• -----------------x------------------------x------------------------x------------------
• ICH Guidance on Specific Aspects of Regulatory Genotoxicity Tests
• Single positive – non necessarily genotoxic
• ICH test battery reduce only false negatives ( i.e real cancer getting
negative test)

7. 4) Indication and Patient Population
• Need to be done before marketing
• Rodent carcinogenicity studies are not needed to conduct of large
scale clinical trials approval
• Life threatening diseases – no carcinogenicity test needed – post
approval

8. 5) Route of Exposure
• Animals need to tested in the same route as patients (ICH Dose
Selection)
• Test conducted only in single route, if relevant organ/similar
metabolism exist (Eg: Lung for Inhalation)
• Evidence of Exposure from ICH Guidance on Repeated Dose

9. 6) Extent of Systemic Exposure
• Drugs through dermal and ocular routes need testing.
• Poor absorption by dermal do not need carcinogenicity test by oral route,
unless there is a concern
• Ocular in general do not need carcinogenicity unless there is a concern.
• Change in Functional Groups
• No change in PDPK evidence should be provided for Different salt, acid, base
• Additional bridging studies determine the Carcinogenicity testing
• Ester and complex derivative – case by case basis

10. 7) Endogenous Peptides and Protein
Substances or Their Analogs
• Not needed for endogenous products such as replacement therapy
(upto physiological level)
• Previous clinical experience (animal insulin, hormone and calcitonin)
• Biotech Requires special considerations
• Endogeneous peptides or analogous
• Extracted/purified
• Recombinant DNA technology
significant biological changes, change in structure and different than
physiological level(systemic or local) need CT testing