Safety Testing of Drug Metabolites

Status: Final

Date: February 2008

Target Audience:

Drug trial sponsors, contract research organizations, and individuals charged with designing non-clinical safety evaluations and clinical safety evaluations

Laws and Regulations:

  1. 21 CFR part 58- Good Laboratory Practices
  2. ICH Guidance for Industry M3 (R1)- Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals
  3. ICH Guidance for Industry S2A- Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals
  4. ICH Guidance for Industry S2B- Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals
  5. ICH Guidance for Industry S5 (R2)- Detection of Toxicity to Reproduction for Medicinal Products and Toxicity to Male Fertility

Summary and Rationale
Generally in drug development, metabolites have not been evaluated during non-clinical safety trials. However, sometimes clinically relevant, and possibly toxic, metabolites are not formed in animals but are formed in humans. Or certain metabolites are formed in higher concentrations in human plasma than in that of animals. Unfortunately in these cases, not until clinical trials do researchers identify metabolites’ contribution to the toxicity of the drug.

As a result of the toxicity profile of the drug in humans, clinical trials can be halted and time lost in drug development. To avoid this, metabolites should be identified as soon as possible during drug development. In this final guidance, the FDA recommends safety testing for metabolites, both in vitro and in vivo, during the non-clinical period.

Recommendations
The FDA encourages metabolite identification as soon as possible during drug development. In vitro studies can be performed using liver cells and slices from humans and animals. Later, in vivo tests can be used to determine whether the drug has the same metabolite profile in both animals and humans. Once the metabolites have been identified, toxicity, embryo-fetal development, and carcinogenicity studies of the metabolites should be performed as soon as possible. During the clinical safety testing process, metabolite identification should be done as early as possible, as well. The toxicity studies should be performed according to ICH guidances for industry and good laboratory practice guidelines.

Impact
Sponsors developing new drugs will need to plan the non-clinical phases to include metabolite identification and toxicity testing on the identified metabolites. They will also need to allow enough time for testing and analyzing the results of their tests before moving on to the clinical phases of the drug development process.

The guidance will surely add more time to the pre-clinical process, but it can later save time if identifying possibly toxic metabolites saves research teams from having to stop clinical trials after recruitment.

For more information on this issue, contact the Kulkarni Law Firm.