Bioequivalence and Bioavailability Forum

Dear Ohlbe & Amira,

❝ But if you run two separate studies I would not make it a strict requirement that it should only be the same subjects participating in both: there would be a higher risk of drop-out. Helmut would explain you that the loss of power due to a couple of drop-outs is minimal,…

❝ … but if there are many subjects missing you could get in trouble.

OK, OK.

❝ If you insist on having the same subjects in both trials: you should make it clear in the protocol of the second study, so that the Ethics Committee can check the time between studies and the cumulative blood loss.

I submitted a comment (which never will be published) to the drafted MR-GL. We should keep in mind that only T vs. R in fasting and fed state are required. The assessment of food effects of T and R is only “nice to know”.^a
If you run two separate studies there are two issues:

1. The evaluation (with different subjects) as a parallel designs lacks power.
   
2. If you have the same subjects you can evaluate the study as a paired design but have to assume lacking period effects.

What I prefer – and which was accepted in some studies already: One study with four periods and two sequences. No full randomization but only within the fasting/fed-parts, e.g.,

T_fed – R_fed – T_fasting – R_fasting
R_fed – T_fed – R_fasting – T_fasting

Since for many drugs the fed state is more demanding, I prefer to have it first.^b
In one study (where I expected higher variability in fed state) I opted for a TSD. In the interim assess the CVs (separate for the fed and fasting parts) and initiate the second stage with potentially different sample sizes.
The fed and fasting parts are simple 2×2×2 crossovers. The evaluation of the food effect follows #2 above. Assuming lacking period effects is common practice in assessing linear PK of new drugs (MD AUC_0–τ vs. SD AUC_0–∞). We gave that as a justification in the protocol, which was accepted by the German BfArM in 2015.

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1. If T shows a substantially lower food effect than R that’s good for the patients. However, if you want to state that in the label/SmPC (“can be taken with or without food”) you have to switch from a generic to a hybrid application. The EMA welcomes that. Whether the additional clinical studies are worth the efforts is another story.
   
2. It is beyond my intellectual reach why many companies perform the fasting study first, only to discover that the fed study failed later. Reformulation plus costs of two studies instead of one if the fed study would have been performed first.