Comparability of Biologics: Global Principles, Evidentiary Consistency and Unrealized Reliance

Abstract

The principles of comparability assessments have been accepted globally as offering sensitive and reliable tools with which to evaluate potential changes to biologics that may arise either through processing changes or through the creation of a copy (biosimilar) by a different sponsor. The comparability approach has evolved through systematic advances in four areas: clear and convergent guidelines for evaluation of potential changes to biologics; risk-based systems of weighting analytical data; progressive improvements in analytical methods; and advanced understanding of post-translational modifications. Routine regulatory expectations for clinical equivalence data are being reevaluated, as they seldom contribute to the assessment of similarity. Similarly, we show that requirements to compare biosimilars and locally sourced versions of their reference products are of questionable scientific value and represent a double standard by comparison with the invariable acceptance of the clinical profiles of novel biologics without reference to their sources. The consistent application of evidentiary standards for comparability to all biologics offers an opportunity for regulators to curtail their own assessments of new biosimilars and instead to recognize comparability assessments made in another jurisdiction (reliance), thereby gaining important efficiencies in the regulatory review of biosimilars and improving the competitiveness of the biosimilars market. Such consistency can also enhance the confidence of all stakeholders, especially patients and their providers, in all biologics.

The Role of PD Biomarkers in Biosimilar Development – To Get the Right Answer One Must First Ask the Right Question

“…Indeed, other regulators and institutions would appear to be initiating these approaches based on the current state of regulatory science in the highly regulated markets. 12,13,23 FUNDING This work was funded by Samsung Bioepis Co., Ltd.…”

“…The latter itself already being open to questions of scientific and therefore ethical validity. 23 Hence, the title of this commentary.…”

“…Likewise, the sensitivity of a PK study for showing a match in physiological response to a biologic is accepted, even if the clinical meaning of that response derives solely from the experience of the originator product (or the pre-manufacturing change product). 23 Where available, a PD biomarker can further augment the PK match, but it does not add greater sensitivity. 36,37 The clinical PHASE III type study by definition gives a clinical outcome but is the least sensitive response and remains important to wholly new molecular entities where no head-to-head comparator is available, and where safety and efficacy are being established for the first time.…”

Interchangeability for Biologics is a Legal Distinction in the USA, Not a Clinical One

“…However, just as quality and good manufacturing control is important for every biologic, the same concept of comparability between manufacturing changes can be applied between the reference and the biosimilar [36]. Different versions of the originator products have been interchangeably used by both definitions-both clinically and at the pharmacy level-usually unconsciously; and based on less substantiated data than are required for a biosimilar.…”

“…Analytical differences will be understood and known not to alter the clinical outcome, just as is the case for manufacturing changes today [48]. This is the strength of comparability based on fit-for-purpose analytics and the importance of its application consistently by regulators to all biologics independent of the sponsors business model [36].…”