Stakeholders take issue with FDA’s guidance on drugs with mutagenic potential

Stakeholders are concerned that a recent US Food and Drug Administration (FDA) draft guidance on developing drug with Ames-positive active ingredients may be contradictory in certain instances. They argue that the agency’s thinking on minimizing risk is impractical and should better align with current international standards.

In November, FDA published a draft guidance outlining recommendations for when it is acceptable to conduct first-in-human (FIH) trials of drugs with mutagenic potential. The agency proposed a risk-based approach to allow the development of certain mutagenic products if prior testing shows minimal risk to healthy trial subjects. (RELATED: FDA drafts guidance on follow up testing for drug candidates with mutagenic potential, Regulatory Focus 27 November 2024)

More specifically, FDA addresses 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. It 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.

The International Consortium for Innovation and Quality in Pharmaceutical Development asked FDA to remove the phrase "first-in-human" from the title. It argued that clinical trials in health volunteers can occur at any time, though they typically tend to be conducted as the first trials in humans.

“Often in the development of anti-cancer drugs, which initiate in patients, development teams may wish to conduct a single dose trial in healthy subjects,” said the consortium. “This can occur much later in clinical development.”

“Therefore, removal of the term ‘first in human’ in the title will make it clearer the intent is to discuss dosing healthy subjects, no matter the timing, with an Ames positive active ingredient or metabolite,” the group added.

The draft guidance states that there are significant safety concerns about whether it is appropriate to administer even one dose of an Ames-positive active ingredient to healthy subjects since even a single dose of such drugs has a "nonzero probability of increasing the subject’s cancer risk."

The consortium took issue with the statement and said it is "impractical to achieve zero probability of risks" in clinical trials, whether a sponsor is developing a cancer drug or another molecule.

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 the agency to be developed further despite such potential. In such cases, the guidance proposes recommendations on follow-up testing for Ames-positive active ingredients.

FDA cautions that follow-up testing can’t entirely mitigate the concerns raised by an Ames-positive finding, and some residual risk remains without adequate carcinogenicity assessments. The consortium again took issue with that perspective and said it was inconsistent with the agency’s position on circumstances where Ames positive findings are irrelevant in in vivo testing.

Drugmaker Eli Lilly raised concerns about FDA’s position as well. The company said the statement was inconsistent with the National Academy of Sciences (NRC) Principles of Risk Assessment and core concepts of the International Council for Harmonisation (ICH) M7(R2) guideline.

“The Ames assay identifies a hazard, which is then contextualized by additional data including those mentioned in ICH M7 as follow-up tests to Investigate the in vivo Relevance of in vitro Mutagens (Positive Bacterial Mutagenicity),” said Lilly “The present guidance language suggests that there is no definitive in vivo [genetic toxicology] assay or [weight-of-evidence] to address mutagenicity concern raised by an Ames positive [finding]”

“Is the guidance intended to state that no definitive in vivo [genetic toxicology] assay, even a [transgenic rodent mutation] assay and [weight-of-evidence] can de-risk/qualify an Ames positive result for either the API or a metabolite?” asked the company.

More broadly, Lilly said FDA’s positions in the guidance question the validity of the approaches it lays out to develop drugs with Ames-positive active ingredients.

“Presumably the inclusion of in vitro mammalian mutagenicity assays to screen out positive molecules prior to in vivo studies is due to [replace, reduce and refine (3Rs)] considerations and is appreciated,” said Lilly. “However, there are numerous opportunities for clarification and optimization of this draft guidance, including harmonization of concepts within the document as to whether an in vivo mutagenicity study can qualify one or more in vitro positives.”

“As written, it is unclear whether a negative in vivo mutagenicity study would be accepted as qualifying an Ames-positive API or metabolite, which conflicts with accepted in vivo genetic toxicity qualification practices core to ICH M7,” the company added. “Uncertainty remains around which recommendations pertain to API vs metabolites, and the suggestions based on relative abundance of metabolites which should align with FDA's MIST guidance.”

Lilly also said the guidance seems to argue that a positive Ames and positive mammalian in vitro assay means the in vivo mutagenicity study cannot be used to supersede a positive result which contradicts current practice and cross-industry position that a negative transgenic rodent mutation assay should supersede both in vitro responses.

Lilly said the proposed guidance indicates that it does not cover active pharmaceutical ingredients (API) intended to treat patients with advanced cancer even though it cites ICH S9, which addresses nonclinical evaluation for anticancer drugs. The company asked if the guidance would apply to anticancer drugs only if given to healthy volunteers in a first-in-human study.

"This could be clearer," said Lilly. "If guidance is not intended to cover advanced cancer, then suggest limiting reference to ICH S9 throughout."

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Stakeholders take issue with FDA’s guidance on drugs with mutagenic potential

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