## Deep shit [RSABE / ABEL]

Dear Helmut,
You seem to strengthen my doubts.

» See above. You calculate the CI once. If you fail ABE (first assessment with a nominal α 0.05), you assess it for ABEL (second assessment with a nominal α 0.05). Is it clear now? Two tests, each performed at level 0.05. Inflated Type I Error. Full stop.

It has no practical sense for me. As I know trials frequently recalculated with some modifications, usually slight ones. I saw that the FDA did this, for example. I do not see that alpha levels were reduced in those recalculations. If we employ this approach (no recalculations or lower alpha level) we may paralyze the whole industry. There would be massive wastes of resources - a lot of studies would be rejected - and huge risks for patients - depriving, for example, them live-saving medications because trials should be repeated in some cases. Actually, we can ask people from the forum how many sponsors or CROs they know whose trials have never been recalculated?

» CV (%) n.ABE n.ABEL n.ABEL.Bonf n.ABEL.adj n.Molins
»     20    10     18          24         18       22
»     30    20     34          44         42       42
»     40    34     30          38         32       36
»     50    50     28          34         28       32

It seems that we have to multiple the ABE column by 2 to get full the sample size but not the ABEL column; otherwise, it has no much sense for me. I also wonder if the dropout rate has been considered in the calculations. Looking at your table and slides post, it is appears that in the region CV between 30 - 40% the sample size for ABEL and ABE trials may be very close to each other. If it is true, the ABEL trials (CV between 30-40) should not be allowed by ethic and regulatory bodies because of unnecessary risks for subjects. It invalidates the RABE/ABEL approach in this region.

» » Finally, I disagree that pharmacovigilance is senseless. If it is done properly, it should and can pick up bad players (drugs and companies).
»
» I don’t believe it.
» The only example I’m aware of was the formulation change of levothyroxine in France (passed ABE with narrower limits and the AEs went through the ceiling).

Actually, it works and even better the BE trials in some cases. Scotland is a good example. In 2015, it had a system, the GP system, that was well developed to spot safety signals. At that time it was not fully developed and tuned. It has some issues like privacy, it collects a lot of private data, complexity, not all doctors know how to operate the system to get full benefits. Also, it was not connected to the pharmacy and hospital systems yet.

Best regards