Bioequivalence and Bioavailability Forum

Hi John!

❝ I have a question. If there is a FDA a draft BE guidance for a product specifing the type of 2 way crossover studies that need to be conducted:

❝

❝ 1. 2-way crossover (Test vs Reference) fasting

❝ 2. 2-way crossover (Test vs Reference) fed

Sure, many. One example is our baby methylphenidate XR (+sprinkled, BTW).

❝ What if we end up running a 4-way crossover involving 3 test formulations vs 1 Reference for each study? Everything will be the same except for 2 extra arms. The reason we are doing this is because we want to bypass the pilot study.

❝

❝ Would that be doable?

In principle yes.

❝ The only issue I can see (beside the cost) is the ethical issue because we will (obviously) draw more blood samples per subject, and may have a larger sample size due to potential dropouts since the length of the study is doubled.

Right. But there’s another problem: In this type of higher-order XOver you obtain a common (pooled) variance from treatment variances. What if one of the formulations not only shows a PE far away from 100% (which would lead to dropping it from development), but performs ‘bad’ in terms of the CV? Especially if MR formulations are concerned, the differences sometimes are large. This formulation will inflate your CIs and require a larger sample size compared to simple XOvers. We had a similar debate in the EU where EMA in their drafted GL wanted to see a four-way XOver T and R (fed/fasting). In the final GL such a design is not required.

❝ I believe FDA allows the use of an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.

Sure.

❝ Do you think the agency will have an issue with the approach?

No idea. ^*

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• Edit: Thinking it over I would expect that the FDA will not like this approach. What if it’s the other way ’round? Three tests; T1 and T2 perform bad in terms of their PEs whilst T3 is fine. Now let’s assume that s²_WT1=s²_WT2=s²_WR ≪ s²_WT3. The pooled s²_W will be ‘dampened’ by the (later dropped) formulations T1 and T2. In other words you would never be able to demonstrate BE of T1 in a 2-way XOver of the same size. Though theses variances are not accessible in a nonreplicate design I think that the FDA wouldn’t like the idea of approving a product with a potential ‘variance-brake’ in the pivotal study.