Health Canada’s Proposed Modification for Multiphasic Modified Release DrugsPublished on September 18, 2017
The guidance on Comparative Bioavailability Standards: Formulations Used for Systemic Effects provides sponsors with standards and parameters to consider for pharmacodynamics studies and comparative bioavailability studies against the reference product. It applies to comparative bioavailability studies for subsequent entry products, studies for line extensions or post-approval changes, bridging studies, and studies to support a Drug Identification Number Application (DINA), among others. Information from this guidance can be applied to various formulations such as oral dosage forms and non-injectable forms such as inhalers and transdermal patches for delivery into systemic circulation. However, the guidance does not include specific requirements for comparative studies of drug products with multiphasic plasma concentration vs. time profiles. It was acknowledged that the general standard for modified-release products may not be enough for such products. As a result, on July 27th 2017, Health Canada issued the Notice on Proposed Modification to Bioequivalence Standards for Multiphasic Modified-Release Drug Products.
From the notice we learn that Health Canada proposes additional information to the guidance on Comparative Bioavailability Standards: Formulations Used for Systemic Effects to better serve drug products with multiphasic plasma concentration verses time profiles. Section 188.8.131.52 of the guidance on Modified-release dosage forms will be amended to include the following information for multiphasic plasma concentration profiles:
· “Modified-release products with multiphasic plasma concentration profiles demonstrated to be integral to their therapeutic effect will be subject to standards on the partial area under the concentration versus time curve (pAUC), defined over a restricted time interval(s) after drug administration. These standards will be applied in addition to those normally applied in the assessment of bioequivalence (i.e. AUC and Cmax).
· The requirement for pAUC assessment metrics for multiphasic modified-release formulations will be based on data available from various sources, including but not limited to peer-reviewed scientific literature and the approved Canadian labelling, as applicable. The time course of changes in the rate of drug delivery throughout the day should be reconciled with generally accepted and clinically relevant response data generated from a well-designed randomized clinical trial program. Specifically, standards based on the 90% confidence interval of pAUC metrics should be met. The specific pAUC time intervals to be considered will be based on clinical data showing the therapeutic relevance of the particular time interval (e.g. early onset, maintenance, dose clearance, fasted versus fed state). Selected time intervals should be justified, specified a priori and applied to all study subjects for both the test and reference products.”
Source: Health Canada’s Notice on Proposed Modification to Bioequivalence Standards for Multiphasic Modified-Release Drug Products
The notice informs the industry that this modification to the guidance is up for comments which are to be sent to the Therapeutic Products Directorate in Health Canada. The comment period will last for 60 days (Notice was issued on July 27th 2017). Detailed information is provided in the Notice listed in the reference section below.
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Notice: Proposed Modification to Bioequivalence Standards for Multiphasic Modified-Release Drug Products
Guidance Document - Comparative Bioavailability Standards: Formulations Used for Systemic Effects
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