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. There is a need to streamline the process of developing biosimilars without compromising their quality, safety, or efficacy. This opinion piece considers the efficiencies that could be achieved within the biosimilar approval process. In clinical trials for biosimilars, clinical efficacy endpoints have been shown to be less sensitive measures of biosimilarity than biochemical, biophysical, and biological functional assays. Additional clinical efficacy studies comparing potential biosimilars and reference products do not add information that is useful for regulatory purposes. Large clinical studies of biosimilars with immunogenicity endpoints are of limited value, given the quality control processes in place for all biologics, including biosimilars. The expectation for multiple-switch studies for US interchangeability designation should be reconsidered immediately, and the category should be eliminated in the future. As biosimilars are typically approved globally based on a single set of clinical trials, and all subsequent manufacturing changes are already carefully monitored by regulatory authorities, comparative pharmacokinetic testing of EU and US reference products is unnecessary. Manufacturers and regulators could take greater advantage of existing real-world evidence. Streamlining biosimilar development would enable biosimilar development of more and a wider variety of biological drugs, accelerating biosimilar development without impacting patient safety or effectiveness.

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. Consequently, the comparative analytical assessment and the head-to-head PKs will have already answered the core questions as to the biosimilarity of the candidate product to its reference. No further actionable information is obtained with either a PD study or a comparative clinical phase III study even as they may provide some reassurance of what is already known. When a suitable PD biomarker is available for the originator reference product they have already been used for biosimilar development. We must carefully consider the core requirements and timelines inherent in biosimilar development and how they occur in parallel rather than in the series we see for originator products. In order to improve the efficiency of biosimilar development, we need to ask the right questions based on a full understanding of how biosimilars have been developed to date and can be in the future.

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

Biologics are increasingly vital medicines that significantly reduce morbidity as well as mortality, yet access continues to be an issue even in apparently wealthy countries, such as the USA. While patient access is expected to improve with the introduction of biosimilars, misperceptions in a significant part based on terminology continue to make a sustained contribution by biosimilars difficult. Patients are and will continue to suffer needlessly if biosimilars continue to be impugned. Consequently, it is increasingly urgent that semantics are clarified, and in particular, the implication that interchangeable biologics are better biosimilars dismissed. This paper distinguishes between the real differences between biologics that matter clinically to patients and discusses the actual meaning of a US Food and Drug Administration designation of interchangeability for a biosimilar product. This will help highlight where there is need for further Food and Drug Administration education and which stakeholders likely need that education the most.

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. 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.

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. We propose a new paradigm ('confirmation of sufficient likeness', CSL) that emphasizes the demonstration of analytical resemblance between the biosimilar candidate and its reference, and permits the conclusion of biosimilarity upon this basis. CSL does not entail bridging studies between reference products, in vivo nonclinical studies, or powered efficacy studies and is, therefore, substantially more efficient than ToE while maintaining equivalent scientific rigor. Such efficiency will contribute to the attractiveness as well as the sustainability of biosimilars as a therapeutic modality.

Pharmacovigilance of Biologics in a Multisource Environment.

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. In this article, periodic safety update reports were used to assess current postapproval safety monitoring for 3 biosimilars (epoetin alfa, somatropin, and filgrastim) that collectively represented nearly 350 million patient days of treatment worldwide. The reference products have each been marketed for over 10 years, forming a strong baseline of postmarketing safety data against which the safety of biosimilars can be compared. Published data from Denmark were also reviewed as additional evidence of how current pharmacovigilance systems are able to attribute adverse events to particular medicines. Collectively, the data show that spontaneous adverse drug reactions are reported by brand name in the majority of cases and are attributable to a specific medicine. Also discussed are the informational elements critical to monitoring biologics, or indeed any medicine, to ensure the availability of complete information so medicines that a patient has received can be quickly identified should a safety event occur. We support the addition of a single data element, the batch/lot number, to enhance the value of current pharmacovigilance systems. Adoption of 2-D barcodes in the European Union (EU) and standardized numerical identifiers in the United States addresses this need, since they include batch/lot numbers. These identifiers are already being implemented in the United States and the EU to improve patient safety, reduce medication errors, facilitate anticounterfeiting, and enable effective product recalls and adverse event reporting. Importantly, electronic identifiers will ameliorate safety reporting concerns with respect to biosimilars, while concurrently achieving these much broader public health objectives through more complete pharmacovigilance data. DISCLOSURES: This work was funded by Sandoz, a Novartis division. The authors were fully responsible for the content, editorial decisions, and opinions expressed in this article. No author received an honorarium related to the development of this manuscript. Sagi and Cohen are employees of Sandoz, and Woollett is an employee of Avalere Health. Study concept and design were contributed by Sagi and Woollett, along with Cohen. Data were primarily collected by Sagi, along with Woollett, and data interpretation was provided by all the authors. The manuscript was written by Woollett, along with Sagi and Cohen, and revised by Sagi and Cohen, along with Woollett.

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. The fact that a biosimilar is usually expected to be licensed in multiple jurisdictions, in each case as similar to the local reference product, confirms that minor analytical differences between versions of reference biologics are typically inconsequential for clinical outcomes and licensing. A greatly simplified basis for selecting a reference comparator, that does not require conducting new bridging studies, is proposed and justified based on the shared data of the reference product versions as well as the proof offered where biosimilars have already been approved. The relevance of this proposal to the interchangeability designation available in the US is discussed.