Hot topic at GBHI: single dose vs. multiple dose studies and strength waivers

Barbara Schug from SocraTec R&D gives insight into the discussion of single dose vs. multiple dose studies and strength waivers in bioequivalence considerations for modified release drug products at the Global Bioequivalence Harmonisation Initiative (GBHI) 2024 conference.

Why is the discussion of single dose vs. multiple dose studies important?

Although this has been discussed at previous GBHI conferences, there is currently no global standard on whether single dose studies are sufficient or multiple dose studies are required to demonstrate bioequivalence for modified release drug products. Opinions differ on the need for multiple dose studies: voices from European regulatory agencies advocate multiple dose studies as essential in case of accumulation, while FDA supports single dose trials in healthy subjects, whenever possible. The main argument of those who see multiple dose studies as essential comes back to patient safety, while the main argument against multiple dose studies is cost and time efficiency, resulting in beneficial use of limited resources and lower drug prices. Modelling and simulation approaches could help covering both aspects. In this tension, we expect fruitful discussions at GBHI 2024. Although we are confronted with conflicting views on the need for multiple dose studies, we see potential for global harmonisation of regulatory standards. For instance, this scientific exchange will lay the foundation of potential future ICH guidelines.

What are the opposing positions in the discussion of single dose vs. multiple dose studies?

If we compare the US and Europe, we find two main views: the opinion of the US regulatory agencies comes back to the assumption that the accumulation of active substances should be the same if the administered dose is the same. On the other hand, European regulators argue that equal accumulation is not to be expected and emphasize the need for multiple dose studies in addition to single dose studies. This allows comparison of the drug profile after single dosing and under accumulation after multiple dosing. European agencies accept a waiver of multiple dose studies, if the AUC in the dosing interval covers more than 90% of the total area. In general, we find a here more progressive approach on the US side and a more conservative approach on the European side.

On the other hand, in those cases when studies cannot be realized in healthy subjects, both regions are already quite close by accepting MD trials in the patient population – however as we see for example with the 1-months paliperidone palmitate EU may ask for a low-dose single dose study in healthy subjects in addition.

What methods could be used to avoid multiple dose studies?

Model informed drug development (MIDD) and model-integrated evidence (MIE) approaches specifically for long-acting injectables (LAI) can demonstrate bioequivalence and could therefore replace multiple dose studies. These methods use mathematical modeling and simulation to assess bioequivalence. The authors state that this can accurately and precisely identify relative differences in bioavailability and absorption rates between treatments, even in situations where traditional methods may fail [1]. If these models are validated and shown to accurately represent drug behavior, they could indeed avoid the necessity for multiple dose studies. This would be particularly valuable for bioequivalence studies of long-acting injectables, as multiple dose studies for those are extremely time-consuming and costly. We are very happy that we have experienced speakers invited: Vivek Purohit from Pfizer will present examples for oral MR forms, transdermal therapeutic systems and long-acting injectables and Yuqing Gong from FDA will present the MIE approach for LAIs.

GBHI 2024 will also focus on strength waivers - what will be discussed?

The discussion will concentrate on the use of strength waivers in solid oral modified release drug products to demonstrate bioequivalence. When discussing this, it is important to distinguish between single and multiple unit dosage forms. The criteria discussed for considering the implementation of strength waivers cover excipients including proportionality of formulations, pharmacokinetics including proportionality of exposure and dissolution. This scientific discussion may also support the ICH M13B part of the series, as these criteria are also considered in case of Immediate Release products.

What are the key differences in the standards for considering strength waivers?

The criteria for the use of strength waivers vary around the world, including different standards in the US and Europe. Roughly speaking (and it can be complex), testing of the highest strength under fasting and fed conditions is often sufficient for US regulatory authorities, while European regulatory authorities require a more complex decision tree including - after consideration of the label - testing of all strengths (or justifying a bracket approach) under the recommended food condition and the most sensitive strength plus waiver option under the alternative condition. However, the concept of a “bracketing approach” is also to be considered. As an example of minor differences, we also find different standards for the prolonged release formulation regarding the in vitro dissolution: for US regulatory authorities, the dissolution performance of the reference product is mentioned as criterion for the decision to use a strength waiver, whereas for European authorities the reference product is basically not relevant. This shows that approaches to waive trials to demonstrate bioequivalence with additional strengths vary between authorities in different parts of the world. Harmonised standards for the use of strength waivers that take into account patient safety and cost-effectiveness would be highly desirable. This is what we are pushing for at GBHI 2024.

Stay with us – we will keep you informed about this important conference also in future articles.

[1] Gong et al., Establishing the suitability of model-integrated evidence to demonstrate bioequivalence for long-acting injectable and implantable drug products: Summary of workshop, CPT Pharmacometrics Syst Pharmacol., 2023