Guidance for Industry and Review Staff: Recommended Approaches to Integration of Genetic Toxicology Study Results

Status of Guidance: Final

Release Date: 3 January 2006

Link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079257.pdf

Target Audience: Individuals/companies developing clinical safety evaluation plans and reviewers for the Center for Drug Evaluation and Research for drug products that had positive genotoxic study results.

Laws and Regulations Referenced: No laws or regulations were referenced. This guidance is considered an additional reference for genetic toxicology studies presented in the ICH guidances for industry: M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, S2A Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals, and S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals.

Summary: The S2B standard genotoxicity battery of genotoxicity studies are needed to provide information about the genotoxic potential of new drugs before they are used in clinical trials. A positive result from any of these studies needs to be explained or evaluated further to ensure the safety in humans. Statistically significant in vitro positive results may not be biologically and/or clinically relevant. All of the evidence collected from the core studies, additional tests, and mechanism of action should be considered together when determining the safety risk of potentially genotoxic drugs. The specific patient population should also be taken into consideration as well. Some potentially genotoxic drugs may be suitable in terminally ill patients or those with life threatening diseases but not healthy volunteers.

Rationale: The 3 core genotoxicity studies recommended before human clinical trials are performed are: bacterial gene mutation, chromosomal damage in mammalian cells, and chromosomal damage in rodent hematopoietic cells. Clinical trials can proceed if there are no positive results in any of these core studies. For positive results, it needs to be determined if the drug product is interacting directly with the DNA. If the drug is not interacting directly with DNA there may not be a significant risk for genotoxicity in living organisms. If the drug is determined to be directly damaging DNA, it may still be suitable for use in terminally ill patients or those with life-threatening disease, but not healthy volunteers.

Resulting Recommendations: There are three approaches to determining the biologic genotoxic potential of a drug if positive results are observed in any of the core genotoxicity studies.

The first is a weight of evidence approach. This approach compares the exposure levels used in the in vitro studies against the desired clinical exposure. If positive results are only seen at the highest doses studied in vitro and this dose is not to be used in vivo then the genotoxic potential may not be clinically relevant. Similarly, if positive results are seen in the in vitro studies but not in the in vivo mouse lymphoma study, there may not be clinical relevance. The level of cytotoxicity should also be considered.

A thorough understanding of the mechanism of action is another way to explain positive results and demonstrate no biological relevance. For example, some drugs that test positive in the core tests induce genotoxic effects indirectly below the biologic threshold. Also, positive results from tests with high osmolarity or low pH are not relevant to in vivo exposure due to the nonphysiologic conditions.

The third approach is to perform additional tests. Micronucleus induction can be evaluated from peripheral blood smears of mice in repeat-dose toxicity studies. Chromosomal damage can be evaluated in peripheral blood lymphocytes of rats or monkeys in repeat-dose toxicity studies. Transgenic mouse models are also a viable option for evaluating short-term carcinogenicity potential. These additional studies should be considered with all previous studies in a weight of evidence approach.

Impact: A full understanding of the genotoxic potential of a drug is important to ensure the safety of all clinical trial patients. If the drug is not intended to treat terminally ill patients or those with life threatening diseases, then unexplained positive genotoxic results from non clinical studies may provide evidence that the drug is not safe for humans. Alternatively, if positive results are not fully understood, they could not be clinically relevant and delay or prevent the availability of a potentially useful new drug.