ICH M12: Pharma industry wants clarity on rifampin dosing, more information on biomarkers

Regulatory NewsRegulatory News | 07 October 2022 |  By 

The pharmaceutical industry would like the International Council for Harmonization (ICH) to clarify dosing information for rifampin and requests additional information on the use of biomarkers as a type of drug-drug interaction study (DDI), while the Pharmaceutical Research and Manufacturers of America (PhRMA) and Pfizer want more flexibility in developing a DDI strategy.
The comments were made in response to the US Food and Drug Administration’s (FDA) call for feedback on the ICH M12 guidance on DDI studies. The European Medicines Agency (EMA) released the guidance for comment in July (RELATED: EMA consults on ICH M12 guideline for drug-drug interactions studies, Regulatory Focus, 25 July 2022).
The guidance recommends designing, conducting and interpreting DDI studies mediated by enzymes and/or transporters that occur in vitro during the development of an investigational therapeutic drug.
In its comments, PhRMA said it “applauds” the guideline as it will “facilitate harmonized approaches for the design, conduct, and interpretations of enzyme- or transporter-mediated in vitro and clinical drug-drug interactions (DDI) studies during the development of a therapeutic product. The guidance will help facilitate the use of globally accepted approaches and reduce uncertainty for the pharmaceutical industry in meeting the requirements of multiple regulatory agencies and lead to more efficient utilization of resources and increased patient access to medicines.”
Yet PhRMA and other companies said there is room for improvement.
Pfizer and PhRMA say they would like more dosage information on the use of rifampin, and in an identical set of comments, wrote that “FDA has indicated that use of rifampin products with MNP impurity (nitrosamine impurities) above 0.16 ppm in healthy subjects or patients who do not have tuberculosis may result in a clinical hold. If no acceptable rifampicin products identified, FDA recommends use of carbamazepine in clinical DDI studies. Due to the importance of rifampin, we suggest adding text in the general principles on this subject. The EWG may also consider footnoting all tables listing rifampin.”
Both PhRMA and Pfizer urged ICH to be flexible in specifying how DDI studies are designed.
The guidance, said PhRMA, “implies that a clinical mass balance study is recommended prior to developing a DDI strategy; however, knowledge of metabolism and routes of elimination are typically obtained prior to conducting the study. In many cases, there is sufficient knowledge to adequately proceed with DDI strategies before conducting a clinical mass balance study. Therefore, PhRMA recommends that the guidance explicitly allow for flexibility in developing a DDI strategy based on in vitro results and the metabolite identity prior to being obtained in early development and prior to completion of the clinical mass balance study.”
Pfizer also requested flexibility in developing a draft DDI strategy.
PhRMA also would like more information on the use of biomarkers. “While the guidance mentions biomarkers throughout the document, PhRMA recommends including a specific paragraph on this topic and including associated references.”
Pfizer and Bristol Myers Squibb also would like additional information on biomarkers.
BMS wrote that “although biomarker has been mentioned throughout the guidance, it would be useful to have a specific subsection on the topic with recommendations and references.”
Comments on M12 drug-drug interaction guidance


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