Notice to Industry - Bioequivalence Requirements for Drugs for Which an Early Time of Onset or Rapid Rate of Absorption Is Important (rapid onset drugs)

2005-06-22
Our file number: 05-113913-859

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Notice

This notice is the fourth in a series of notices which the Therapeutic Products Directorate is issuing to update its guidelines on the assessment of bioavailability and bioequivalence (Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part A: Oral Dosage Formulations used for Systemic Effects, 1992 (Guideline A); and Part B: Oral Modified Release Formulations, 1996 (Guideline B)). Some of the issues identified in Expert Advisory Committee on Bioavailability Report C: Report on Bioavailability of Oral Dosage Formulations, not in Modified Release Form, of Drugs used for Systemic Effects, having Complicated or Variable Pharmacokinetics December 1992 (Report C) which have not been finalised will also be handled this way.

The purpose of this communication is to state the Therapeutic Products Directorate's (TPD) bioequivalence requirements specific to rapid onset drugs.

Section 1.3 of Guideline A mentions drugs with an important time of onset of effect or rate of absorption as one of several possible exceptions that may require modification to the guideline.

Report C defined drugs in this category as those for which the time of onset of effect is important because of therapeutic or toxic effects, for example, an analgesic for rapid relief of pain. In addition to the 90% confidence interval criterion for AUC, the following standards were recommended for this group.

1. The 90% confidence interval of the relative mean measured C_max of the test to reference formulation should be between 80% and 125%.
2. The relative mean AUC_Reftmax of the test to reference formulation should be within 80 to 125%, where AUC_Reftmax for a test product is defined as the area under the curve to the time of the maximum concentration of the reference product, calculated for each study subject.

Given the current increased precision of analytical methodologies and better methodologies to collect more frequent blood samples, it has been decided that bioequivalence requirements for these drug products need no longer be as stringent as recommended in Report C. To date this standard has only been applied to two drugs, gel formulations of ibuprofen and tablet formulations of sumatriptan.

This notice serves to clarify that bioequivalence standards for drugs for which an early time of onset or rapid rate of absorption is important because of therapeutic or toxic effects (for example, an analgesic for rapid relief of pain) are as described in current TPD guidelines and policy statements. In addition, the relative mean AUC_Reftmax of the test to reference formulation should be within 80 to 125%, where AUC_Reftmax for a test product is defined as the area under the curve to the time of the maximum concentration of the reference product, calculated for each study subject.

We reiterate that this notice applies to comparative bioavailability (bioequivalence) studies only. Submissions in support of comparative (superiority) claims, such that time to onset of effect is important, may need additional pharmacokinetic-pharmacodynamic or clinical data.

Should you have any questions or require further clarification relating to this Notice, please contact:

Policy Bureau Enquiries
E-mail: policy_bureau_enquiries@hc-sc.gc.ca
Telephone: (613) 946-9491
Fax: (613) 941-1812