Drug mutagenicity, proarrhythmic potential addressed in pair of FDA guidances

Regulatory NewsRegulatory News | 29 September 2020 |  By 

The US Food and Drug Administration (FDA) has issued two new draft International Council on Harmonisation (ICH) guidelines for public consultation.
A question-and-answer (Q&A) guidance on clinical and nonclinical evaluation of QT/QTc interval prolongation and proarrhythmic potential of medicines was published in draft form by FDA on 29 September; the guidance is currently in ICH Step 2b, awaiting consultation from the Council's participating countries. The draft guidelines contain Q&As addressing the ICH E14 guidance on clinical evaluation of delayed ventricular repolarization and proarrhythmic potential of non-antiarrhythmic drugs; it also includes answers to new questions regarding the ICH S7B guidance addressing nonclinical evaluation of drugs that have the potential to cause delayed ventricular repolarization.
The Q & A guides members of industry through considerations for conducting an integrated nonclinical-clinical risk assessment, “in particular, at later stages of drug development when clinical data are available,” said FDA. The Q&A also addresses such scenarios as assessing proarrhythmic and QT prolongation potential of drugs that cannot be safely administered to healthy individuals at supratherapeutic levels, and what strategies to take when placebo control is not possible.
“The draft guidance is intended to provide a harmonized approach to integrate nonclinical and clinical information for proarrhythmia risk assessment to streamline drug development and provide clarity on regulatory decision making,” said FDA, noting that comment is particularly sought on how to define the lack of clinically relevant QT prolongation in the context of cases where a “conventional thorough QT study” may not be feasible.
A second Step 2b ICH guidance was made available by FDA for public consultation on 28 September after its June 2020 ICH Assembly endorsement. “The draft Q&A guidance is intended to clarify, promote the convergence of, and improve the harmonization of the considerations for assessment and control of DNA reactive (mutagenic) impurities and of the information that should be provided when developing drugs, completing marketing authorization applications, and using drug master files,” said FDA in its notice of the draft guidance availability.
The guidance follows the ICH M7 guideline on considerations for control of mutagenic impurities; it clarifies expectation for evaluation of mutagenic potential of impurities, situations where more extensive genetic toxicity testing are recommended, and which drug products are included in the scope of ICH M7. The draft guidance also specifies that carcinogenic but non-mutagenic impurities lie outside the M7 scope.
Various scenarios involving Ames-positive impurities are also addressed by the draft guidance, as is guidance on which control strategies are appropriate under what circumstances.
Both draft guidances are open for public comment in the US for 60 days from the date of publication; ICH will gather consultation results from FDA and other international regulators before finalization and eventual implementation by individual participating countries. 

E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrythmic Potential—Questions and Answers

M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk—Questions and Answers


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