Between study variability common for HVDs [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2010-08-04 19:45 (4101 d 12:02 ago) – Posting: # 5717
Views: 14,311

Dear ElMaestro, Dan and all!

» […] did you receive a deficiency question from module 3 regarding the product's release specifications? After all, this is where the inter-batch variability comes into the picture.

Not necessarily. Dan stated in his post that the drug is highly variable. It’s a common property of HVDs that not only the variance is high, but also the location of the T/R-ratio may vary across studies. If would suggest to have a look at papers by the “Two Lászlós” for further explanations. Remember that the restriction of the point estimate of [0.8-1.25] was introduced by the FDA after long discussions for political reasons [sic!]* – and copypasted by the EMA. Such a restriction is questionable and not statistically justified. The pivotal studies demonstrated BE, but I would build an argument based on the natural property of the underlying distribution.

The concept of batch-to-batch in vivo BE is only of historical interest. It was discussed at the BioInternational 1994 in Munich and was dropped. Same participants even asked the heretic question whether a product would be still bioequivalent to itself at the end of the shelf-life (don’t ask me how we would store the reference batch for the final BE study: in liquid N2?).

BTW, I agree with D. Labes’ observations about ref. 1, which was employed in studies 1 & 3.


  1. There is no scientific basis or rationale for the point
    estimate recommendations
  2. There is no belief that addition of the point estimate
    criteria will improve the safety of approved generic
    drugs
  3. The point estimate recommendations are only
    “political” to give greater assurance to clinicians and
    patients who are not familiar (don’t understand) the
    statistics of highly variable drugs

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