Bioequivalence and Bioavailability Forum

Hi K Vishal,

please answer Ohlbe’s question:

❝ ❝ Any outlier / subject with "strange" results in the pivotal study ?

❝ […] what are the potential causes

As ElMaestro’s wrote above: “a ton of reasons”. Please answer his questions:

❝ ❝ check […] if the right randomization code was applied in the pilot (i.e. was the (single) generated code used for dispensing?

❝ ❝ Was the code used for stats?

❝ and in this even i can not change formulation …

Why not? But in your case I suspect bad study conduct rather than formulation problems.

❝ … whether study on more subjects i.e 40 + will solve this issue.

No. The intra-subject coefficient of variation (CV) in the pilot was 25% and in the pivotal 84% (the ratio of standard deviations was 3). If you assume that you will get exactly the same CV and geometric means ratio (GMR 110%) in the next study, you would need ~400 (‼) subjects for 80% power (π). Since the probability of a Type II Error (β) is 1 – π the chance of failing to demonstrate bioequivalence for a product which is BE is 20%. Forget it.
Try to find out why the variabilities in the two studies differed so much (as advised by Ohlbe and ElMaestro already).

❝ Since i am purely from formulation development dont know much about statistical bio designs.

I strongly suggest to get some training if you want to design further studies. Without sufficient knowledge (GCP, GLP, bioanalytical method validation, medical ethics, and – yes, biostatistics) you place yourself entirely in the hands of greedy CROs which are always eager to repeat studies – especially with high sample sizes. Increases their profits. And Indian CROs are not the best on the planet. Sorry to say.

Remember that administering drugs to volunteers always carries some risk. Before you plan the next study, ask yourself these questions:

1. Would I take the drug myself?
   
2. Would I give it to my wife/husband/spouse?
   
3. Would I give it to my children?

If the answer to any is “No!” reconsider what you are doing. Humans ≠ guinea pigs.