History [BE/BA News]

posted by Helmut Homepage – Vienna, Austria, 2016-04-14 14:41 (1830 d 18:13 ago) – Posting: # 16201
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Hi cbertoncini,

» ANMAT regulatory requirements are crystal clear, also with several amendments made during the last few years, and are applied to newly registered products. However, according to ANMAT, complying with the BE regulations has somehow proven difficult for products already authorized and manufactured by the local pharma industry. This planned waiver of BE requirements is tailored to such products that lack a proper BE assessment and have been in the local market for more than 5 years.

Politics protecting the local manufacturers?

» According to this ANMAT proposal, if a product that lacks BE has been marketed in Argentina for more than 5 years before the new ruling, renewal of the marketing authorization would only require an in vitro head to head comparison of test and reference, and not anymore a proper BE study. To my knowledge there is no international precedent to such a ruling.

The current BE-requirements might be more strict than necessary for some drugs (see here). The 20% acceptable difference was an ad-hoc solution (lacking a scientific justification) to a real problem. Over the years different approaches were applied:
  1. Content uniformity. Maybe (!) dissolution – sometimes only liberation. No in vivo testing at all.
  2. The FDA’s 75/75 rule: ≥75% of subjects must show a T/R-ratio within 0.75–1.25. Consequently studies with <25% of subjects with even extreme T/R-ratios still passed BE. Looks weird from our current perspective but many products approved according to this rule.
  3. Testing for a significant difference: Leads to approval of products with high variability (no significant difference) and failing of ones with low variability (significant difference). That’s actually the opposite of what we want. For one of my early sins see here (all three generics were marketed; phenytoin is a NTID…).
  4. The FDA’s 80/20 rule: As above but the test must have ≥80% post-hoc power to detect a 20% difference.
  5. ABE & confidence interval inclusion. Generally the acceptance range (AR) is set to 80–125% but exceptions exist (narrower for NTIDs).
  6. As above but assess BE based on an (active) metabolite or only in steady state. For many drugs closer to the clinical situation and a means to deal with high variability of the parent after a single dose.
  7. Population and Individual BE: Comparison not only of the means but of the variances (for ”prescribability” PBE and for “switchability” IBE). Great concept but was never seriously implemented.
  8. Assessing only the T/R-ratio of Cmax – not the CI (Canada since 1991).
  9. Pre-specify a wider AR for HVDs. 70–143% was not uncommon in the EU and later limited to 75–133%. Implemented in many jurisdictions following EMA’s GLs (Australia, ASEAN-states).
  10. Reference-scaling: Wider (HVDS: FDA, EMA) or narrower (NTIDs: FDA) AR based on the variability of the reference product estimated in a replicate design study.
  11. BCS-based biowaivers (i.e., substitute in-vivo BE by in-vitro similarity for certain classes of drugs + risk assessment).
We’ve come a long way. All (!) these approaches lead to approval of products. It might be possible that some of them would never pass current requirements. At least since #5 is the common method we have empiric evidence that it “works” despite its statistical shortcomings – only the means are assessed.
I don’t think that agencies asked for BE-studies of approved products if requirements were updated towards more strict conditions.
History lesson: In Germany there was an official “positive list” of drugs/formulations which were considered “uncomplicated” and do not possess a risk of inequivalence. For these products no study (not even an in-vitro comparison) was required. Poland happily adopted this list only when it wanted to join the EU to learn that in the meantime Germany dropped this list. Until recently a similar (but shorter) list existed in The Netherlands for national market authorizations only. Must have been a schizophrenic situation for assessors of the MEB: In the morning a dossier for national MA without a BE-study – stamp “approved”. After a coffee break another dossier of the same product in the course of a European submission. BE-study performed, but lower 90% CI 79.99%. Stamp “rejected”. Bizarre.

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Helmut Schütz

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