Health Canada on Monday unveiled new comparative bioavailability requirements for drugs exhibiting large pharmacokinetic within-subject variation in terms of absorption.
Although highly variable drugs are generally safe, the Canadian regulator says, the bioequivalence of their formulations is a problem because high variability means that large numbers of subjects are required to give adequate statistical power.
In addition, highly variable drugs are poor quality formulations where high within-formulation variability (e.g. tablet to tablet variability) poses a problem, according to at least one study.
Health Canada's view has evolved with ongoing consultations and it now recognizes 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 in which the 90% confidence interval should fall within the bioequivalence interval of 80.0-125.0%.
Other regulatory agencies have also recognized this issue and developed approaches to reduce the number of subjects required to meet regulatory standards.
In draft guidance from 2013, the US Food and Drug Administration (FDA) made clear: “For highly variable drugs (intrasubject variability > 30%), applicants can conduct BE [bioequivalence] studies using a replicate design approach. Alternatively, a single-dose, randomized, three-period reference-scaled, average BE approach is also appropriate. The reference-scaled average BE approach adjusts the BE limits of highly variable drugs by scaling to the within-subject variability of the RLD in the study and imposes a limit of 0.8 to 1.25 on the geometric mean ratio.”
That guidance followed a 2006 advisory panel at FDA where the limit was discussed, as well as a proposal for a minimum sample size of 36 subjects when evaluating the bioequivalence of highly variable drugs.
Following recommendations made by Health Canada's Scientific Advisory Committee on Pharmaceutical Sciences and Clinical Pharmacology in June 2014, the agency says it has reviewed various approaches and has adopted an average bioequivalence approach to highly variable drugs with expanding limits "based on the within-subject variability of the reference product (reference scaling).”
The agency clarifies: “A drug product may be considered a HVDP [highly variable drug product] if the within-subject coefficient of variation (CV) of the AUC [area under the concentration versus time curve] for the reference product is greater than 30.0%. Critical dose drugs 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, Health Canada says, noting that the new scaled approach applies to new drug and abbreviated drug submissions but does not apply to veterinary or biological drug products.
“A scientific rationale should be provided to support that the high variability in exposure is not clinically significant,” Health Canada says. “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.”
Health Canada also lays out comparative bioavailability standards for drugs that should be met:
- The 90% confidence interval of the relative mean AUC of the test to reference product should be within the following limits:
- 80.0%-125.0%, if (sWR) [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)] ≤0.294 (i.e., CV ≤30.0%);
- [exp(-0.76(sWR)) × 100.0%]-[exp(0.76(sWR)) × 100.0%] if 0.294 <(sWR) ≤0.534 (i.e., 30.0% <CV ≤57.40%); or,
- 66.7%-150.0%, if (sWR) >0.534 (i.e., CV >57.4%).
- The relative mean AUC of the test to reference product should be within 80.0% and 125.0% inclusive;
- The relative mean maximum concentration (Cmax) of the test to reference product should be between 80.0% and 125.0% inclusive.
Health Canada Notice: Policy on Bioequivalence Standards for Highly Variable Drug Products