Notice to industry

2003-09-24

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Contact: Policy Bureau Enquiries

Removal of Requirement for 15% Random Replicate Samples

The Therapeutic Products Directorate is beginning 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; and Part B: Oral Modified Release Formulations, 1996). A series of notices and policy consultations will be forthcoming in the next year on specific issues that have been identified over the years. We believe this method of modernising the guidelines will be more efficient that rewriting the guidelines all at once. Dealing with specific issues will allow a more focussed consultation. Also some issues can be implemented very quickly while others will need some in-depth research, analysis and consultation. It is also proposed that some of the issues identified in Report C of the Expert Advisory Committee on Bioavailability and Bioequivalence which have not been finalised can be handled this way.

This notice is the first in a series.

The purpose of this communication is to inform stakeholders of a change to the Therapeutic Products Directorate's (TPD) criteria for the validation of bioanalytical methods. This notice serves to remove the current requirement that fifteen percent of the subject samples be randomly selected and re-assayed when single assays are performed.

The determination of bioavailability is dependent upon the reliable, precise, and accurate measurement of the analyte. The analytical methods used must be reproducible, specific, and sufficiently sensitive, precise, and accurate. When these operating parameters have been shown to be adequate in the hands of the test laboratory, the investigators can then undertake the bioavailability study.

Current TPD criteria are enunciated in several guidances (Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part A: Oral Dosage Formulations used for Systemic Effects, 1992; and Part B: Oral Modified Release Formulations, 1996). These provide guidance regarding the validation of bioanalytical methods for comparative bioavailability studies undertaken to demonstrate the bioequivalence of two oral dosage forms. Sections 6.8.1 and 9.8.1 (Replicate Samples) of these guidances, respectively, state, in part:

"In general, single sample analysis will suffice. When single assays are performed, 15 percent of the incurred samples must be randomly selected and re-assayed."

As of the date this Notice is posted on the TPD website, for the analysis of samples for comparative bioavailability studies undertaken to demonstrate the bioequivalence of two formulations, the random selection and re-analysis of 15% of clinical (incurred) samples will no longer be required. This does not, however, detract in any way from the importance of adequately validating the analytical method used.

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