Notice: Policy on Bioequivalence Standards for Highly Variable Drug Products

April 18, 2016
Our file number: 16-104293-140

This Notice serves to inform sponsors of drug submissions pursuant to Division C.08 of the Food and Drug Regulations (that is [i.e.], new drug and abbreviated new drug submissions) of changes in Health Canada's comparative bioavailability requirements for drug products which exhibit large pharmacokinetic within-subject variation in extent of absorption, as measured by area under the concentration versus time curve (AUC). The scaled approached defined below does not apply to veterinary or biological drug products.

Previous Health Canada guidance has emphasized study design to address the challenges presented by highly variable drug products (HVDPs). Nevertheless, Health Canada's view has continued to evolve with ongoing external consultations on this issue. Health Canada recognises that when the within-subject variation of a pharmacokinetic parameter is high, a larger number of subjects must be recruited in order to meet the usual bioequivalence standard of where the 90% confidence interval should fall within the bioequivalence interval of 80.0-125.0%. Other regulatory agencies have also recognised the issue with HVDPs and have developed approaches to reduce the number of subjects required to meet their regulatory standards.

Further to recommendations made by Health Canada's Scientific Advisory Committee on Pharmaceutical Sciences and Clinical Pharmacology, in June 2014, Health Canada has reviewed various approaches and has adopted an average bioequivalence approach to HVDP with expanding limits based on the within-subject variability of the reference product (reference scaling). The approach permits expansion of the bioequivalence interval for AUC, with a point estimate constraint. A drug product may be considered a HVDP if the within-subject coefficient of variation (CV) of the AUCFootnote 1 for the reference product is greater than 30.0%. Critical dose drugsFootnote 2 are not eligible for the application of this approach of expanding the bioequivalence intervals.

Evidence from the literature, or the results of well conducted studies, should be provided to indicate that the AUC is highly variable. The proposal for expanding the bioequivalence interval should be defined a priori in the study protocol. A scientific rationale should be provided to support that the high variability in exposure is not clinically significant. Submissions for HVDPs should also be supported by a justification to demonstrate that the CV estimates are reliable and not subject to the influence of outliers.

For HVDPs, replicate design comparative bioavailability studies must be conducted with the reference product administered at least twice to determine the within-subject variability for the reference product. The test product (T) should be administered either once in a 3-period design (RTR, TRR, RRT) or twice in a 4-period design (TRTR, RTRT).  The lower and upper limits of the expanded bioequivalence interval should be calculated using the within-subject standard deviation of the log-transformed values of AUC of the reference product (sWR). Expansion of the bioequivalence interval may be permitted up to a maximum of 66.7% to 150.0% (equivalent to a scaled criterion for CV = 57.4%).

For human pharmaceutical drugs the following comparative bioavailability standards should be met:

  1. The 90% confidence interval of the relative mean AUC of the test to reference product should be within the following limits:
    1. 80.0%-125.0%, if sWR ≤0.294 (i.e., CV ≤30.0%);
    2. [exp(-0.76sWR) × 100.0%]-[exp(0.76sWR) × 100.0%] if 0.294 <sWR ≤0.534 (i.e., 30.0% <CV ≤57.40%); or,
    3. 66.7%-150.0%, if sWR >0.534 (i.e., CV >57.4%).
  2. The relative mean AUC of the test to reference product should be within 80.0% and 125.0% inclusive;
  3. The relative mean maximum concentration (Cmax) of the test to reference product should be between 80.0% and 125.0% inclusive.

References

Endrenyi L. and Tothfalusi L. (2009). Regulatory conditions for the determination of bioequivalence of highly variable drugs. J. Pharm. Pharmaceut. Sci. 12: 138-149.

Tothfalusi L. and Endrenyi L. (2012). Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs.  J. Pharm. Pharmaceut. Sci. 15(1) 73-84.

A request for a copy of the consultation results and enquires with regard to this Notice can be sent to:

Bureau of Policy, Science and International Programs
Therapeutic Products Directorate
Health Canada
Holland Cross, Tower B, 2nd Floor
Address Locator: 3102C1
1600 Scott Street
Ottawa, Ontario
K1A 0K9

Telephone: 613-948-4623
Facsimile: 613-941-1812
E-mail: Policy_Bureau_Enquiries@hc-sc.gc.ca

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