News from EMA: Pharmacokinetic Solidarity [BE/BA News]

posted by EMA.Press.Office – 2019-04-01 00:07  – Posting: # 20110
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To all readers of the BEBA forum:

we have published the press release below on the EMA website today with a copy on the website of PKWP. This may have relevance for readers of this forum.

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Amsterdam April 1st 2019.


The Pharmacokinetic Working Party and the CHMP are pleased to announce a ground-breaking improvement to the approval principles for generics submitted with bioequivalence studies as part of a mutual recognition procedure and/or a decentralised procedure.


The changes are thought to address a multitude of problems associated with the estimation of clearance, elimination constants, and AUC’s.


Dr W. Garlink of the PKWP explains:

“With the introduction of Pharmacokinetic Linearity in 2006, the PKWP demonstrated a clear intention and ability to regulate pharmaceuticals in a manner that is both ethical, economical and solidly founded in science. The clauses describing pharmacokinetic linearity led to rules that allowed biowaivers for several strengths, where applicable, thereby reducing the overall exposure to human volunteers in bioequivalence trial. This concept was overwhelmingly well received by the industry and survives to this day to the ultimate benefit of hundreds of thousands of patients across EU.


Complementary to Pharmacokinetic Linearity, as of June 18, 2019, we will enforce rules relating to Pharmacokinetic Solidarity.


According to the principle of Pharmacokinetic Solidarity, from the date mentioned, only drugs for which the API is quantitatively absorbed before it starts getting eliminated will be accepted for assessment; this has to do with the fact that it is otherwise quite impossible to establish the true end of absorption and the onset of elimination and as a consequence we cannot reliably estimate key pharmacokinetic metrics such as the elimination constants which in turn drives the estimation of the AUC extrapolated to infinity.

The proof of Pharmacokinetic Solidarity can easily be delivered by comparison of pharmacokinetic profiles of Test and Reference with profiles arising from an intravenous bolus of a solution of the API using a modified Wagner-Nelson method, the details of which will be added to the Q&A on the website. We are sure that the slight inconvenience associated with adding a treatment arm of intravenous bolus to bioequivalence trials will easily be offset by the ethical and scientific advantages associated with the vastly improved and more robust determination of essential pharmacokinetic constants. At the end of the day, this serves the interest of patients across the Union.

We expect Pharmacokinetic Solidarity to become as popular with the industry as Pharmacokinetic Linearity has been. Naturally, we also expect it to lead to quicker approval of safer and equally efficaceous medicines.

Conversely, the intention is also to phase out acceptance of dossiers based on APIs not displaying solidarity, i.e. APIs for which a fraction of molecules enters an elimination phase before all molecules have been absorbed. Such APIs will be referred to as Potentially Infracting InGredients, or PIIGs in short. PIIG submission will soon be history. Except in the UK.”



EMA is furthermore pleased to offer scientific advice for companies seeking protocol assistance for the intravenous bolus administration and modified Wagner-Nelson method. Scientific Advice slots are expected to open up from as early as September 2020.


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