cbertoncini
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Argentina,
2016-04-12 14:17

Posting: # 16189
Views: 4,726
 

 ANMAT – Bioquivalence requirements under consultation [BE/BA News]

Dear all,
I’m writing from Argentina. Bioequivalence has been historically under debate and tough scrutiny in this country. Despite several regulations issued by the local health authority (ANMAT) there are just a few bioequivalent products available in the local market.
Recently ANMAT issued a new document for consultation (ANMAT-MED-BIO-006-00, only in Spanish unfortunately) in which they reset bioequivalence requirements. If the document is approved, bioequivalence will be only required for products registered not longer than 5 years ago and for newly registered products. Older registered products would not require bioequivalence anymore. Are you guys aware of any agency that has ever issued such a regulation?
Thanks a lot for your comments.


Edit: Category changed and document linked. [Helmut]
Helmut
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Vienna, Austria,
2016-04-13 13:12

@ cbertoncini
Posting: # 16198
Views: 3,953
 

 ANMAT – Bioquivalence requirements under consultation

Hi cbertoncini,

» Recently ANMAT issued a new document for consultation (ANMAT-MED-BIO-006-00, only in Spanish unfortunately) in which they reset bioequivalence requirements. If the document is approved, bioequivalence will be only required for products registered not longer than 5 years ago and for newly registered products. Older registered products would not require bioequivalence anymore.

I don’t understand the highlighted parts. The ANMAT’s BE-requirements (2006, amended 2007) are pretty detailed. Is it possible that a generic product was registered without demonstrating BE?

» Are you guys aware of any agency that has ever issued such a regulation?

In the EU the market authorisation is initially valid for five years and becomes valid for an unlimited period upon renewal acc. to Regulation (EC) No 726/2004, Article 14, 1–3. See the Questions & Answers and linked documents. In the renewal procedure BE studies which lead to the MA generally (!) are not assessed again.

Cheers,
Helmut Schütz
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cbertoncini
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Argentina,
2016-04-13 20:18

@ Helmut
Posting: # 16200
Views: 3,917
 

 ANMAT – Bioquivalence requirements under consultation

Thanks a lot Helmut for your reply

» » Recently ANMAT issued a new document for consultation (ANMAT-MED-BIO-006-00, only in Spanish unfortunately) in which they reset bioequivalence requirements. If the document is approved, bioequivalence will be only required for products registered not longer than 5 years ago and for newly registered products. Older registered products would not require bioequivalence anymore.
»
» I don’t understand the highlighted parts. The ANMAT’s BE-requirements (2006, amended 2007) are pretty detailed. Is it possible that a generic product was registered without demonstrating BE?

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.

» » Are you guys aware of any agency that has ever issued such a regulation?
»
» In the EU the market authorisation is initially valid for five years and becomes valid for an unlimited period upon renewal acc. to Regulation (EC) No 726/2004, Article 14, 1–3. See the Questions & Answers and linked documents. In the renewal procedure BE studies which lead to the MA generally (!) are not assessed again.

Thanks for the links. EMA, FDA and other LATAM agencies have set tight deadlines when introducing BE requirements for a given molecule, which affected all marketed authorized products that contain that molecule, irrespective of the date in which they have been authorized. 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.
Helmut
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Vienna, Austria,
2016-04-14 14:41

@ cbertoncini
Posting: # 16201
Views: 3,961
 

 History

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.

Cheers,
Helmut Schütz
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