Future Evolution of Biosimilar Development by Application of Current Science and Available Evidence: The Developer's Perspective.

Biosimilars have been available in the USA for over a decade, and in Europe for almost two decades. In that time, biosimilars have become established in the treatment landscape for a wide range of diseases, facilitating patient access and affordability of healthcare. However, patients can still struggle to access biological therapies in some markets.

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

The potential for pharmacodynamic (PD) biomarkers to improve the efficiency of biosimilar product development and regulatory approval formed the premise for the virtual workshop Pharmacodynamic Biomarkers for Biosimilar Development and Approval hosted by the US Food and Drug Administration (FDA) and Duke Margolis, September 2021. Although the possibility of PD biomarkers replacing the to-date routine comparative phase III confirmatory study currently expected by the FDA was discussed, the motivation and feasibility for biosimilar sponsors developing such markers and the regulatory risks entailed largely were not. Even more fundamental is the already established greater comparative value of the pharmacokinetic (PK) study as the most sensitive clinical assay for detecting subtle differences between two products.

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

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.

An Efficient Development Paradigm for Biosimilars.

The current development paradigm for biosimilars required by regulators in highly regulated jurisdictions is derived from the development of novel drugs and is unnecessarily burdensome and inefficient. It requires the accumulation of data from analytical, nonclinical (including in vivo studies in some jurisdictions), and clinical studies (including powered efficacy studies in most cases); this paradigm is known as 'totality of evidence' (ToE) and does not admit a conclusion of biosimilarity from analytical data alone. The record of biosimilar approvals in these jurisdictions shows that no biosimilar candidate that has been found highly similar to its reference in analytical and pharmacokinetic studies has failed to be approved.

Pharmacovigilance of Biologics in a Multisource Environment.

Unlabelled: It is important that systems are in place to ensure that appropriate and comprehensive records are kept for use of all medications. It is fundamental to an effective pharmacovigilance system that patient medical records contain sufficient information to identify which medication has been prescribed, when it was administered, and at what dose. The availability of biologics from multiple sponsors has raised questions by some health care providers about the ability of current pharmacovigilance systems to trace specific biologics.

A 'Global Reference' Comparator for Biosimilar Development.

Major drug regulators have indicated in guidance their flexibility to accept some development data for biosimilars generated with reference product versions licensed outside their own jurisdictions, but most authorities require new bridging studies between these versions and the versions of them licensed locally. The costs of these studies are not trivial in absolute terms and, due to the multiplier effect of required repetition by each biosimilar sponsor, their collective costs are substantial. Yet versions of biologics licensed in different jurisdictions usually share the same development data, and any manufacturing changes between versions have been justified by a rigorous comparability process.