ICH Harmonized Tripartite Guideline: Guideline on the Need for Carcinogenicity Studies if Pharmaceuticals, S1A

Status of Guidance: Step 4

Release Date: 29 November 1995

Link: http://www.ich.org/LOB/media/MEDIA489.pdf

Target Audience: Individuals/companies developing non-clinical safety evaluation plans for drug products expected for chronic use in humans.

Laws and Regulations Referenced: No laws or regulations are referenced in this guidance.

Summary: Carcinogenicity studies assess the potential for new drugs to induce tumors can and can be an important part of non clinical safety evaluations. The old rationale required carcinogenicity tests to be performed before drugs were administered to humans. However, this requirement no longer applies to all classes of drugs. Drugs intended for short term use, use in terminally ill or deep salvage patients, or those that do not induce systemic exposure may not need carcinogenicity studies performed. Data collected from in vivo and in vitro genotoxicity tests, repeat dose toxicity tests, and chronic toxicity tests can be used to evaluate the need for resource and time intensive carcinogenicity tests.

Rationale: Carcinogenicity studies assess the potential for new drugs to induce tumors can and can be an important part of non clinical safety evaluations. However, these studies are time consuming and resource intensive and may not be beneficial to the overall safety assessment if there is no prior concern for carcinogenetic effects.

Guidances for when a carcinogenicity study is needed for a new drug previously differed widely between Japan, the US, and Europe. The main point of contention was how long a drug was expected to be administered to patients. Other considerations for carcinogenicity studies include: other similar drugs that have previously demonstrated carcinogenic potential; molecular structure similar to those known to pose a carcinogenetic risk; pre-cancerous indications in repeat-dose toxicity studies; and long-term retention of the drug or metabolites in specific organs.

A standard battery of in vivo and in vitro genotoxicity tests can either indicate risk or limited risk for carcinogenetic potential. The life expectancy of the intended patient population should also be considered when deciding if long term carcinogenicity studies are needed. A lack of systemic exposure to dermal or ocularly adminsted drugs as established in other non clinical safety studies can also indicate that additional oral carcinogenicity studies are not needed.

Resulting Recommendations: Drugs that are expected to be chronically administered for 6 or more months or administered intermittently for chronic conditions should include carcinogenicity studies in their safety assessment plan.

Drugs that have positive findings from in vivo and in vitro genotoxicity testing and are considered to be genotoxic do not require carcinogenicity studies. However, a 1 year chronic toxicity study should be performed if these drugs are intended for chronic use in humans.

Carcinogenicity studies are not needed if the life expectancy of the intended patient population is less than 3 years. If the drug is intended to treat life threatening diseases that currently do not have an effective treatment available, carcinogenicity studies do not need to be completed until after marketing approval. Carcinogenicity studies are generally not needed for dermal or ocularly adminsitered drugs, except if there is concern for photocarcinogenic risk.
Impact: These recommendations indicate that costly and time consuming carcinogenicity studies that were previously required before the drug could be administered to humans may not be needed for all new drugs. Companies and regulating agencies can use data from other required studies to make determinations about the risk of carcinogenecity and potentially reduce the number of animals used and reduce the time drugs can reach the intended population.