Kent’s #2 Blog Post: Safety Testing of Drug Metabolites

Name of Guidance
Guidance for Industry: Safety Testing of Drug Metabolites

Status of Guidance
Final

Release Date
February 2008

Link to Guidance
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf

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

Laws and Regulations Referenced
Code of Federal Regulations (21 CFR part 58) Good Laboratory Practices

ICH Guidance for Industry M3 (R1) Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals

ICH Guidance for Industry S2A Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals

ICH Guidance for Industry S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals

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 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.

Resulting 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 FDA 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.

Guidance for Industry: Postmarketing Studies and Clinical Trials -- Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act

This draft guidance was released in July 2009 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM172001.pdf for applicants of new prescription drugs or biological products.

Laws and regulations referenced:

Authorization for the FDA to require certain postmarketing studies and clincial trials for prescription drugs including biological products approved under the new section 505(0) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(0)), which was added by section 901 of the Food and Drug Administration Amendments Act of 2007, or under section 351 of the Public Health Service Act (PHS Act, 42 U.S.C. 262).

Rationale: The new section 505(0) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(0)) authorizes the FDA to require postmarketing studies or clinical trials to access a known/potential new serious risk associated with a prescription drug or biological product at or after approval if the FDA aware of such a risk. Under the same section, applicants required to conduct postmarketing studies or clinical trials must also provide periodic status reports with specific required information on these studies, trials, or any other studies or trials undertaken to investigate a safety issue.

Summary: This guidance describes the requirements for postmarketing studies and clinical trials under 21 U.S.C. 355(0) and the types of postmarketing studies and clinical trials that will generally either be

• required (i.e., a postmarketing requirement) under the new law


• agreed-upon as a commitment (i.e., a postmarketing commitment)
  

Resulting Recommendations:

The FDA requires a postmarketing study or clinical trial as a postmarketing requirement if the following conditions are met:

1. 
   the FDA has appropriate scientific data (including data on chemically- or pharmacologically-related drugs) as evidence
2. before requiring a postmarketing study, the FDA has found (a) adverse event reporting under section 505(k)(1) and the new pharmacovigilance system to be established under section 505(k)(3) of 21 U.S.C. 355(0) or (b) a postmarketing study will be insufficient to meet condition 3 below
3. when a study or clinical proposes to (a) access a known serious risk related to the drug, (b) access signals of (a), and/or (c) identify unexpected serious risk when available data suggests a potential serious risk

Postmarketing requirements may include but are not limited to:

• observational pharmacoepidemiology studies evaluating a serious risk related to drug exposure or to access/quantify factors (e.g., drug dose, time of exposure, or patient characteristics) that may influence the risk of serious toxicity)
• clinical trials with a safety primary endpoint with prespecified assessments
• animal safety studies acessing specific end-organ toxicities (e.g., carcinogenicity, reproductive toxicity)
• in vitro laboratory safety studies
• pharmacokinetic studies or clinical trials in the patient population specified in the drug label or in a subpopulation potentially at risk for toxicity from high drug exposure
• drug interaction or bioavailability studies or clinical trials when scientific data indicate a potential sereious safety risk

A postmarketing study or clinical trial that an applicant of a prescription drug or biological product agrees to undertake without a postmarketing requirement from the FDA is a postmarketing commitment.

Postmarketing commitments may include:

• drug and biologic quality studies (e.g., manufacturing, stability, immunogenecity) without a safety endpoint
• pharmacoepidemiology studies accessing the natural disease history or background adverse event rates
• clinical trials with a primary efficacy endpoint
  

Impact: Whenever a marketing application for a new prescription drug (including biological products) is filed to the FDA, the FDA will send to the applicant a list of possible postmarketing requirements and postmarketing commitments to be discussed and finalized with the FDA review team. Once the applicant agrees to conduct the agreed upon postmarketing requirements and/or commitments under an agreed upon timetable, the applicant must periodically report on the status of these studies or clinical trials. If an applicant does not comply with the timetable, periodic reporting, or other requirements in section 505(o)(3)(E)(ii), the FDA will be able to enforce these requirements by issuing an unapproved drug charge, a misbranding charge (21 U.S.C. 332(z)), or civil monetary penalties (21 U.S.C. 333(f)(4)(A)).

With applicants of new prescription drugs being required to conduct postmarketing safety studies and clinical trials, the FDA will have more data to identify and access potential safety risks and consequently the patient population taking these new prescription drugs will be better protected from these potential safety risks.