Notice to Industry - Bioequivalence Requirements for Long Half-life Drugs

2005-06-22
Our file number: 05-113899-750

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Notice

This notice is the third 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 long half-life drugs.

Section 1.3 of Guideline A mentions drugs with effective half-lives greater than 24 hours as one of several possible exceptions that require modification to the guideline. Report C defined a category of drugs with effective half-lives greater than 12 hours. The effective half-life was defined as that half-life which is determined by the disposition rate constant which predominantly affects the dosing regimen. For these drugs Report C recommended the use of the same standards as in Guideline A with the exception that AUC_0-72h was to be employed. It was also recommended that when the effective half-life of the drug exceeds 72 hours, parallel studies, steady-state studies or the use of stable isotopes should be considered.

Information on terminal elimination half-lives of drugs is more readily available than information on effective half-lives. The terminal elimination half-life is longer than the effective half-life. Measurement of more than 80% of the expected AUC_inf for a drug with a terminal elimination half-life greater than 24 hours may require an unreasonably long sampling duration. Furthermore, absorption from the formulation generally occurs within 24 hours post-ingestion such that formulation differences should be detectable well before the drug is completely eliminated. It is therefore appropriate to shorten the time over which the drug is to be measured.

This notice serves to clarify that for drugs which exhibit a terminal elimination half-life greater than 24 hours, bioequivalence standards in comparative bioavailability studies will be applied to AUC_0-72h. For the purpose of bioequivalence assessment, it will not be necessary to sample for more than 72 hours post-dose, regardless of the half-life. Alternate designs such as parallel studies could be considered.

Other requirements are as described in current TPD guidance documents.

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