Bioequivalence and Bioavailability Forum

Hi Lucas,

❝ ❝ The origin of these limits lies in the dark ages.

❝ ❝ • Reference-scaling for HVDPs is dependent on the CV_WR estimated in particular studies. That’s completely different from the “one size fits all” 80/125-concept. Sooner or later we will have generics of HVDPs on the market which were approved according to different rules.

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❝ I would love to see studies showing that the 80-125% and also Reference-scaling are actually good.

There were very few prospective studies where the null-hypothesis was inequivalence and the study’s primary endpoint was clinical effect. BE was secondary. As you can imagine these studies were quite large. Innovators tried to challenge the BE concept and loved to see was sumfink like: BE shown in the PK study, but not equivalent in effect(s). All studies failed to show that. At the end innovators gave up. The last one was performed at UCSF. The company tried to prevent the investigator from publishing the study. Was a big story.
See Les Benet: http://www.youtube.com/watch?v=UjgE39CUlSw (navigate to 35:49).

ABE was never developed as a scientific theory (construction and testing of falsifiable hypo­theses). The ±20% entered the scene in an ad-hoc manner because there were serious pro­blems in the late 1970 indeed and something had to be done – quick. If my house is on fire I’d rather not discuss whether the water pressure of the pump might be sufficient, etc. I want the fire brigade to act – now.
Retrospectively the ABE-concept seems to work. But since it was never seriously challenged the – arbitrary – 20% might be more restrictive than necessary for some drugs. Before reference-scaling we had in some regulations three dichotomous acceptance ranges: 90–111% (NTIDs), 80–125% (well), and 75–133%/70–143% (HVDPs).

❝ […] I think that this is a very strong statement when you say that some drugs does not show difference in efficacy/safety when the 80-125% criteria is applied.

Not sure whether I wrote that. Are you reading in between the lines? It would be worthwhile to go back in time when – apart from ABE – prescrib­ability (by population BE) and switchability (by individual BE) was discussed. For PBE and IBE we need fully replicated designs because not only the GMR (which is accessible in a 2×2 cross-over) is compared, but also the variances. In PBE the total variance and in IBE the variances of T and R (+ the magic subject-by-formulation interaction).
The ideas was that – based on PBE – the physician could chose a product for a drug-naïve (!) patient and – based on IBE – patients could switch products while already under treatment. The entire concept went down the drain.
Strictly speaking ABE does not allow switching under therapy. But it happens all the time. In some countries the pharmacist has to switch to a generic even if the physician stated the innovator on the prescription. It would not make sense to switch between two generic NTIDs anyway. Even stated on Denmark’s website.

One option would be to run all BE studies in a full replicate design and scale according to the references CV. But then we would face alpha-inflation (as discussed somewhere else in the forum) and products which were approved to different rules. It’s very, very tricky.

❝ Even worst may be for HVDPs. It is scientifically proved that higher the CV wider is the therapeutic index? Do all drugs, regardless of class or indication, have similar PBPK/PD relation?

José used the word “proof” sloppily. We can’t prove anything in science. We can only make a statement like “All swans are white”. This is a working hypothesis awaiting rejection – which actually was done in 1790 when the first black swan was described. My personal working hypothesis “No swans are red” still holds.

Seriously: The statement “highly variable drugs are safe drugs” is observational, but well founded. The innovator explored the dose-response­ curve in development and if it would not be flat, there would have been efficacy/safety problems in phase III. If we have a steep dose-response curve high variability would lead to lacking efficacy or toxicity from day-to-day. If we are talking about generics it is even more clear. The innovator has a database of hundreds–thousands of patients before he gets the approval. If a generic comes in we have a database of millions of patient-years. In other words I would worry less about a RSABE-study of a generic than about a similar study of the innovator going from clinical batches to full production.