FDA drafts guidance on follow up testing for drug candidates with mutagenic potential
The US Food and Drug Administration (FDA) has detailed its thinking on how and when it is acceptable to conduct first-in-human (FIH) trials of drugs with mutagenic potential. The agency takes a risk-based approach to allow the development of certain mutagenic products if prior testing shows minimal risk to healthy trial subjects.On 26 November, FDA published a draft guidance on testing for Ames-positive drugs or metabolites used in FIH trials with healthy subjects and scenarios in which such drugs may be appropriate for further development.
As such, the agency recommends that sponsors conduct follow-up in vitro and in vivo mutagenicity testing of Ames-positive active ingredients.
FDA defines genotoxicity tests as in vitro and in vivo tests intended to identify compounds that induce genetic damage (mutagenicity or clastogenicity). The tests can help stakeholders understand a drug's potential to cause DNA damage and its fixation.
“Genotoxicity tests play a significant role in protecting clinical trial subjects from potential increased risk of genotoxic hazard and cancer during the investigational new drug application (IND) phase of drug development,” said the agency. “A standard battery of genetic toxicology studies has been accepted by industry and regulators through the ICH consultative process.”
The agency lists several International Council for Harmonization (ICH) guidelines, including ICH M3(R2), and recommends mutagenicity tests to protect trial subjects, often conducted before the start of phase I or at least before a phase II trial. Typically, most drugs found to be mutagenic are not developed further for FDA approval. However, due to their therapeutic mechanism of action, certain cancer drugs may be permitted by FDA to be developed further despite their mutagenic potential.
“This guidance makes recommendations on follow-up testing for Ames-positive active ingredients in those rare circumstances when a sponsor decides to continue development,” the guidance stated. “These recommendations are intended to potentially address and lower certain safety concerns before proceeding with FIH trials in healthy human subjects.”
“Follow-up testing cannot entirely mitigate the concerns raised by an Ames-positive finding, and some residual risk remains in the absence of an adequate carcinogenicity assessment,” the guidance added. “Thus, Ames-positive active ingredients that are further developed should be those targeting serious or life-threatening diseases with unmet medical needs.”
The guidance recommends how sponsors should analyze their Ames test data and conduct follow-up testing if their tests give positive results. It also details conducting weight-of-evidence (WoE) assessments of Ames-positive drugs or metabolites. The agency has drawn a decision tree that sponsors can use when conducting a WoE assessment where they are considering using an Ames-positive product on healthy trial subjects.
FDA said it might consider allowing Ames-positive active ingredients to be administered to healthy subjects only if the results of prior extensive follow-up testing lower the risk of cancer based on the WoE assessment.
“Both the in vitro mammalian cell gene mutation assay and in vivo gene mutation assay would need to be negative for considering a FIH trial with healthy subjects,” said the agency. “If either the in vitro mammalian cell gene mutation assay or the in vivo gene mutation assay was positive, a FIH trial with healthy subjects would not be supported.”
The guidance recommends that sponsors who want to use Ames-positive products in healthy clinical trial subjects should engage reviewers at the appropriate division at FDA's Center for Drug Evaluation and Research (CDER) through its pre-IND process. While the guidance applies to the development of small molecule active ingredients, the agency notes that biological products, drugs for patients with advanced cancer, and DNA-reactive (mutagenic) impurities are outside the scope of the guidance.
Stakeholders can comment on the draft guidance on www.regulations.gov under docket no. FDA-2024-D-4540 until 25 February.
Draft guidance
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