The US Food and Drug Administration (FDA) on Monday issued updates related to two International Conference for Harmonization (ICH) guidelines, including a revised guideline on the efficacy portion of the common technical document (CTD) and changes to ICH's list for permitted daily exposure (PDE) to solvents.
For the first update, FDA issued a draft guidance for public comment in line with ICH's revised guideline on the efficacy portion of the CTD, M4E(R2) – Efficacy, which details the key benefit and risk information that should be included in the clinical overview portion of section 2.5.6 of the CTD.
The revised guideline was adopted by ICH and sent to its members for implementation in June 2016. So far the revision has been adopted by the European Medicines Agency (EMA) and Japan's Pharmaceuticals and Medical Devices Agency (PMDA).
According to FDA, the original version of M4E did not provide additional guidance on the structure of that information, which led to "a high degree of variability in the approaches taken by applicants in presenting this information."
However, FDA says the revision "provides more specific guidance regarding the format and structure of the benefit-risk assessment in section 2.5.6," which is further broken up into sections on therapeutic context, benefit, risk and the benefit-risk assessment.
But, while the revised guideline lays out key aspects that should be considered while discussing benefit and risk in an application, FDA says the revised guideline does not specify an approach to conducting the benefit-risk assessment.
FDA also announced two updates to the ICH Q3C Impurities: Residual Solvents guideline, including new recommendations for PDE to the residual solvent triethylamine, and a revised recommendation for PDE for the residual solvent methylisobutylketone.
FDA says the recommended PDE for triethylamine is 62.5 mg/day, which puts the solvent on the list of solvents with a low toxic potential (Class 3).
For methylisobutylketone, FDA says the recommended PDE has risen from 22.6 mg/day to 45 mg/day, "based on reconsideration of the severity of effects identified in rat studies and the human relevance of effects identified in mouse carcinogenicity study."
But despite the increased PDE, FDA says methylisobutylketone remains a moderate toxicity risk, and will stay on the list of Class 2 solvents.
M4E(R2): The CTD—Efficacy, Federal Register Notice
Q3C — Tables and List,PDE for Triethylamine and Methylisobutylketone, Federal Register Notice