Notice: Proposed Modification to Bioequivalence Standards for Multiphasic Modified-Release Drug Products

July 27, 2017
Our file number: 17-108014-918

This Notice serves to inform sponsors of drug submissions pursuant to Division C.08 of the Food and Drug Regulations (i.e., new drug and abbreviated new drug submissions), of proposed modifications to Health Canada’s comparative bioavailability requirements when multiphasic plasma concentration profiles have been demonstrated to be integral to the product’s therapeutic effect.

Health Canada’s current guidance document, entitled Comparative Bioavailability Standards: Formulations Used for Systemic Effects, does not include special requirements for comparison of drug products which exhibit multiphasic concentration versus time profiles. Health Canada recognises that for some such products, the general standards for modified-release products may not be sufficient.

In order to address this, in keeping with recommendations from Health Canada’s Scientific Advisory Panel on Bioequivalence Requirements for Modified-Release Dosage Forms, Health Canada is proposing to add the following to Section 2.1.1.1 of the above-mentioned guidance document:

• 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 C_max).

• 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.

Health Canada is posting this Notice for a 60-day comment period. Please send comments to:

Bureau of Policy, Science and International Programs
Therapeutic Products Directorate
Health Canada
Holland Cross, Tower B, 2^nd Floor
Address Locator: 3102C3
1600 Scott Street
Ottawa, Ontario
K1A 0K9

Email: Policy Bureau Enquiries/HC-SC/GC/CA
Telephone: 613-948-4623
Fax: 613-941-1812