4.2.3.4.1 — Carcinogenicity Long-Term

2-year carcinogenicity bioassay in rodents. Required if drug intended for chronic use (≥6 months)

Requirements by Phase

IND Phase 3: required NDA: required

Content Requirements

• Long-term carcinogenicity studies by species
• Include range-finding studies
• Brief rationale for study choice and high-dose selection
• Supportive toxicokinetics
• 2-year rodent bioassay
• GLP required

Expected Deliverables

• 2-year carcinogenicity bioassay report (GLP)
• Range-finding study report
• Dose selection rationale document
• Toxicokinetic data tables

ICH Guidelines: S1A, S1B(R1)

Regulatory Requirements (ICH M3R2)

• [marketing] If carcinogenicity studies are recommended for the clinical indication, they should be conducted to support the marketing application.
• Carcinogenicity study results should only be submitted to support clinical trials if there is a significant cause for concern for carcinogenic risk.
• [post-approval] For pharmaceuticals treating serious diseases (adults or pediatric), carcinogenicity testing, if recommended, can be concluded post-approval.
• The appropriateness of carcinogenicity testing should be addressed before long-term exposure in pediatric clinical trials.
• Carcinogenicity studies are not recommended to support pediatric clinical trials unless there is a significant cause for concern (e.g., genotoxicity evidence, pro-carcinogenic risk).
• Combination genotoxicity, safety pharmacology, or carcinogenicity studies are generally not recommended if individual agents have been tested according to current standards.

Regulatory Requirements (ICH S1A)

• [Pre-marketing approval] Carcinogenicity studies should only be performed when human exposure warrants the need for information from life-time studies in animals in order to assess carcinogenic potential.
• [Pre-marketing approval] Carcinogenicity studies should be conducted to avoid the unnecessary use of animals in testing and to provide consistency in worldwide regulatory assessments of applications.
• [Pre-marketing approval] Carcinogenicity studies should be performed for any pharmaceutical whose expected clinical use is continuous for at least 6 months.
• [Pre-marketing approval] For pharmaceuticals used frequently in an intermittent manner in the treatment of chronic or recurrent conditions, carcinogenicity studies are generally needed.
• [Pre-marketing approval] Carcinogenicity studies may also need to be considered for certain delivery systems which may result in prolonged exposures.
• [Pre-marketing approval] Pharmaceuticals administered infrequently or for short duration of exposure (e.g., anaesthetics and radiolabelled imaging agents) do not need carcinogenicity studies unless there is cause for concern.
• [Pre-marketing approval] Carcinogenicity studies may be recommended for some pharmaceuticals if there is concern about their carcinogenic potential.
• [Pre-marketing approval] Unequivocally genotoxic compounds need not be subjected to long-term carcinogenicity studies.
• [Pre-marketing approval] When carcinogenicity studies are required, they usually need to be completed before application for marketing approval.
• [Clinical development] 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.
• [Pre-marketing approval] 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.
• [Pre-marketing approval] In instances where the life-expectancy in the indicated population is short (i.e., less than 2 - 3 years), no long-term carcinogenicity studies may be required.
• [Pre-marketing approval] Oncolytic agents intended for treatment of advanced systemic disease do not generally need carcinogenicity studies.
• [Pre-marketing approval] When pharmaceuticals (therapeutic agents for cancer) are intended for adjuvant therapy in tumour free patients or for prolonged use in noncancer indications, carcinogenicity studies are usually needed.
• [Pre-marketing approval] If similar metabolism and systemic exposure can be demonstrated by differing routes of administration, then carcinogenicity studies should only be conducted by a single route.

Note: 2-year rodent studies. Required if drug used ≥6 months

Source: ICH S1A; ICH S1B