Hot topic at GBHI: Narrow Therapeutic Index (NTI) Drugs and Highly Variable Drugs (HVDs)
Ralph-Steven Wedemeyer from SocraTec R&D and SocraMetrics provides insight into the discussion of bioequivalence studies for Narrow Therapeutic Index (NTI) Drugs and Highly Variable Drugs (HVDs) at the Global Bioequivalence Harmonisation Initiative (GBHI) 2024 conference.
What is the current situation in demonstrating bioequivalence of narrow therapeutic index drugs?
Narrow therapeutic index drugs are critical regarding dose – too high or too low concentrations can be dangerous. Therefore, the criteria for showing bioequivalence are stricter: Nowadays, they include either narrower acceptance criteria or reference scaling (according to FDA guidance) with narrowed acceptance criteria and additional assessment of intra-individual variability. Despite a global disunity in handling narrow therapeutic index drugs, there is general agreement on the need to tighten the acceptance criteria for demonstrating bioequivalence. Adapting the acceptance limits to a fixed value results in straightforward outcomes, but also in in larger sample sizes and thus a higher time and resource burden.
What will be discussed at the GBHI conference for narrow therapeutic index drugs?
Paulo Paix?o from Infarmed in Portugal will present approaches to evaluation of bioequivalence studies focusing on ways to control type-1-errors. Assuming that these approaches also include a scaling for the narrowing of acceptance criteria, these will contribute to the discussion of harmonized standards at the conference. Wanjie Sun from FDA will also give a perspective on alternative bioequivalence criteria and approaches for narrow therapeutic index products, and Wenlei Jiang from FDA will discuss data-driven harmonization of bioequivalence criteria. Differences in the written guidelines may, thus, vary more than the current mindset at the authorities, which makes unification of standards more likely.
What is the current practice for bioequivalence studies with highly variable drugs?
Highly variable drug products are defined by a within-subject variability of 30% or more. To show bioequivalence for these, guidelines allow to widen the acceptance limits. However, implementation of the approach in guidelines differ in relevant details, with upper limits for widening and/or restriction to specific parameters in some regions and details in the actual calculation. The approach itself is still under discussion due to an increased risk of false positive results (type 1 error, patients’ risk). This is a recurrent topic at the GBHI, and Helmut Schütz from BEBAC in Austria will resume the discussion on highly variable drug products.
Acceptance criteria may be scaled for both, narrow therapeutic index drugs and highly variable drugs - what are the challenges of this approach?
Consideration of the intra-individual variability of the Reference plays a central role for both approaches. The challenge for both is: observed variability in the trial comes from a sample itself and may appear larger than it actually is. In specific situations this could lead to more than appropriate widening of acceptance criteria for highly variable drugs, or less than necessary tightening for drugs with a narrow therapeutic index. Either of these may make falsely positive trial results more likely than they should be in the regions of switching from fixed criteria to a scaling approach.
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What else to be said in this context about GBHI 2024?
Another expert talk at the conference will be on two-stage designs and their acceptability in the EC area given by Susanne Urach from AGES. The insights into the current practice and situation will be very interesting to discuss.
It is important to mention, that these topics are certainly not new topics at GBHI and have been discussed at previous conferences [e.g., 1]. It is very promising, that some of the invited speakers have already been part of previous discussions and provide a continued presentation of the current status and potential developments. European and US authorities as well as industry and academia will be represented at GBHI 2024 and we expect lively discussions, driven by a lot of hands-on-experience and exchange on difficulties in applying (alternative) approaches.
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Stay with us – we will keep you informed about this important conference also in future articles.
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Sources
[1] M. Mehta et al., European Journal of Pharmaceutical Sciences, 2023