Demonstration Of Biosimilarity Research Articles

The Coming of Age of Biosimilars: A Personal Perspective

Biosimilars have come of age over the past 17 years, with 84 approvals in the EU and 35 in the US, representing almost 90% of the world market. While the acceptance of biosimilars in the US is catching up with that in the EU, the cost benefits remain elusive due to the high development barrier and complex distribution system involved, mainly in the US. In the EU, the cost of biosimilars has already dropped 70% or more, and interchangeability is a routine in some European jurisdictions, unlike in the US, where a separate regulatory approval is required. This paper projects significant changes coming in the US and EU’s biosimilars approval requirements that will impact the approval procedures in the rest of the world, leading to dramatic changes in the cost of biosimilars to patients. This perspective is based on the author’s first-hand experience to secure FDA approvals of biosimilars and an extensive analysis of the rationality of testing to demonstrate biosimilarity. Multiple citizen petitions by the author and meetings with the FDA may have prompted the recent announcement by the FDA to award a $5 million research grant to scientists to develop novel testing models to establish biosimilarity, including modifying the interchangeability protocols. Soon, demonstration of biosimilarity will not require animal testing and, in most cases, clinical efficacy testing; over time, the clinical pharmacology testing will be reduced as the regulatory agencies develop more confidence in the safety and efficacy of biosimilars. Biosimilars have come of age; now it is the turn of the developers to grow up, and one way to show this is to challenge the current regulatory guidelines but only on scientific grounds to seek more concessions, for which both FDA and EMA are ready.

Biosimilars: evolution of approaches to the development, regulation, life cycle control and interchangeability management

The legal framework for biosimilar medicinal product was first established in 2004 in the European Union and later in the USA. Since then, based on the scientific and regulatory experience with biosimilarity assessment, regulatory approaches have evolved considerably. A clear understanding of the capabilities of each development stage in assessing comparability in terms of power to identify differences and assess their relevance to the final clinical outcome gradually accumulated. In addition to the commitment to the biosimilarity approach, it is important to comply with the general requirements applicable to any drugs produced at an industrial scale. Experience showed that the demonstration of biosimilarity based on a range of analytical and functional tests and mainly clinical pharmacological studies is universal and allows extrapolating therapeutic indications. The establishment of biosimilar interchangeability, since the active substance by definition is a version of the active substance of the corresponding reference biological product, can introduce additional difficulties. A single approach to the establishment of biosimilar interchangeability has not yet been developed.

Current Issues in Analytical Similarity Assessment

In 2017, Food and Drug Administration (FDA) circulated a draft guidance on analytical similarity assessment to assist the sponsors for providing totality-of-the-evidence in support of the demonstration of biosimilarity between a proposed biosimilar product and an innovative biological product. The guidance was subsequently withdrawn by the FDA due to some major criticisms received from general public. These major criticisms include, but are not limited to, (i) the use of 90% confidence interval (CI) versus 95% CI, (ii) tiered approach for analytical similarity evaluation, and (iii) current practical issues related to analytical similarity assessment. In this article, these major criticisms and issues are discussed. In addition, some recommendations regarding alternative thinking or methods for analytical similarity evaluation are provided.

Recommendations for the Development and Validation of Immunogenicity Assays in Support of Biosimilar Programs.

For biosimilar drug development programs, it is essential to demonstrate that there are no clinically significant differences between the proposed biosimilar therapeutic (biosimilar) and its reference product (originator). Based on a stepwise comprehensive comparability exercise, the biosimilar must demonstrate similarity to the originator in physicochemical characteristics, biological activity, pharmacokinetics, efficacy, and safety, including immunogenicity. The goal of the immunogenicity assessment is to evaluate potential differences between the proposed biosimilar product and the originator product in the incidence and severity of human immune responses. Establishing that there are no clinically meaningful differences in the immune response between the products is a key element in the demonstration of biosimilarity. An issue of practical, regulatory, and financial importance is to establish whether a two-assay (based on the biosimilar and originator respectively) or a one-assay approach (based on the biosimilar) is optimal for the comparative immunogenicity assessment. This paper recommends the use of a single, biosimilar-based assay for assessing immunogenic similarity in support of biosimilar drug development. The development and validation of an ADA assay used for a biosimilar program should include all the assessments recommended for an innovator program (10-16, 29). In addition, specific parameters also need to be evaluated, to gain confidence that the assay can detect antibodies against both the biosimilar and the originator. Specifically, the biosimilar and the originator should be compared in antigenic equivalence, to assess the ability of the biosimilar and the originator to bind in a similar manner to the positive control(s), as well as in the confirmatory assay and drug tolerance experiments. Practical guidance for the development and validation of anti-drug antibody (ADA) assays to assess immunogenicity of a biosimilar in comparison to the originator, using the one-assay approach, are described herein.

Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment

The American Association of Pharmaceutical Scientists (AAPS) biosimilar focus group on nonclinical and clinical assays has developed this manuscript to guide the industry on best practices and testing strategies when developing neutralizing antibody (NAb) assays for biosimilar programs. The immunogenicity assessment to biosimilar and originator drug products is one of the key aspects of clinical programs for biosimilars to demonstrate biosimilarity. Establishing that there are no clinically meaningful differences in immune response between a proposed product and the originator product is a key element in the demonstration of biosimilarity. It is critical to collect, evaluate, and compare the safety and immunogenicity data from the clinical pharmacology, safety, and/or efficacy studies especially when the originator drug product is known to have potential for immune-mediated toxicity. This manuscript aims to provide a comprehensive review and recommendations on assay formats, critical reagents, approaches to method development, and validation of the neutralizing antibody assays in extrapolation within the scope of biosimilar drug development programs. Even if there are multiple options on the development and validation of NAb assays for biosimilar programs, the type of drug and its MoA will help determine the assay format and technical platform for NAb assessment (e.g., cell-based or non-cell-based assay). We recommend to always perform a one-assay approach as it is better to confirm the biosimilarity using one-assay for NAb. If a one-assay approach is not feasible, then a two-assay format may be used. This manuscript will provide all the details necessary to develop NAb assays for biosimilars.

Equivalence Test for Two Emax Response Curves

ABSTRACTThe evaluation of equivalence of response profiles including both dose–response and time–response curves plays an important role in the development of biosimilars. The 2014 FDA draft guidance of clinical pharmacology data to support a demonstration of biosimilarity to a reference product indicates that “if clinical pharmacology similarity between products is demonstrated, in some instances this may complete the clinical evaluation, and in others it may support a more targeted clinical development program.” The methodology how to demonstrate the equivalence on two response profiles, however, seems to be unclear in the regulatory guidance. In this article, we study the problem of equivalence test for two Emax response curves. First, we find the location where the largest absolution difference between the two Emax curves occurs, and show that the location only depends on the ratios of the parameters between the two Emax models. Then we propose a new method to test the equivalence between the two Emax curves. We compare this new method with several other methods using simulation, and show that the new method has good statistical properties. At the end, we discuss the implications of our findings in the application to the development of biosimilars.

Demonstration of biosimilarity, extrapolation of indications and other challenges related to biosimilars in Europe.

The regulatory framework for biosimilars was established across Europe in 2005 based on the concept of biosimilarity. This legislation secures the manufacturing, evaluation, and market authorization (MA) of high-quality safe and efficacious biopharmaceuticals that are highly similar to their reference medicinal product (biosimilars). Demonstration of biosimilarity is documented by full-scale comparability exercises between the biosimilar and the reference product at quality, preclinical, and clinical level. However, the complexity, diversity, and heterogeneity of biosimilars, both in structure and manufacturing, combined with the scientific knowledge accumulated in biotechnological analysis of recombinant therapeutic proteins requires continuous improvement of the regulatory framework based on the evolution and experience gained in this field. This current opinion article presents the concept of biosimilarity, discusses the extrapolation of indications that is acceptable based on a case-by-case basis by CHMP/EMA and uncovers other challenges lying ahead in the development of biosimilars. Biosimilars are still quite 'young' products that require worldwide attention.

Comments on the FDA draft guidance on biosimilar products

The Food and Drug Administration issued on February 9, 2012, drafts of three new guidance documents about the demonstration of biosimilarity. One of these deals with scientific considerations. It suggests, among others, that demonstration of biosimilarity be developed by a stepwise (step-by-step) approach and that it be assessed by considering the totality of the evidence. This communication provides comments on some scientific factors and issues that still remain unanswered or unsolved. They include the question 'how similar is considered to be highly similar?' considerations of criteria for and the degree of biosimilarity; alternatives of study design and sample size requirements; statistical methods for achieving the totality of the evidence needed for biosimilarity; and methods needed for the assessment of drug interchangeability. It is anticipated that the comments will assist the revision of the guidance documents.