Notice to industry Bioequivalence requirements for combination drug products

2004-06-03
Our file number: 04-111053-848

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Contact: Bureau of Policy, Science and International Programs Enquiries

Notice

This notice is the second in a series of notices which the Therapeutic Products Directorate (TPD) 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 TPD's bioequivalence requirements specific to combination drug products.

Section 1.3 of Guideline A mentions combination products as one of several possible exceptions that require modification to the guideline.

Report C defined a combination drug product as a product containing two or more active ingredients. It differentiated between products in which the drugs were intended to act independently (Type 1) and those that were intended to act synergistically (Type 2).

For Type 1 combinations, the recommended standards to be met were those which would normally be required of each drug if it were in the formulation as a single entity.

For Type 2 combinations, additional criteria were recommended, based on ratios of the concentrations of each drug and on ratios of AUC of the drugs.

This notice serves to clarify that for all combination products requiring comparative bioavailability studies, the pharmacokinetic parameters to be reported and assessed are those which would normally be required of each drug if it were in the formulation as a single entity, as described in current TPD guidelines and policy statements.

We reiterate that this notice applies to comparative bioavailability (bioequivalence) studies involving combination products. Further work is being done on requirements for fixed dose combinations, particularly in New Drug Submissions.

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

Bioavailability and Bioequivalence