Biosimilar Drug Product Development

Laszlo Endrenyi, Dr. Paul Declerck, Shein-Chung Chow, Laszlo Endrenyi, Dr. Paul Declerck, Shein-Chung Chow

• Publisher: CRC Press
• Year: 2017
• Print ISBN: 9781498718790
• eBook ISBN: 9781351646185
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

When a biological drug patent expires, alternative biosimilar products are developed. The development of biosimilar products is complicated and involves numerous considerations and steps. The assessment of biosimilarity and interchangeability is also complicated and difficult. Biosimilar Drug Product Development presents current issues for the development of biosimilars and gives detailed reviews of its various stages and contributing factors as well as relevant regulatory pathways and pre- and post-approval issues.

1 Introduction

Scientific Factors in Biosimilar Product Development

Laszlo Endrenyi

University of Toronto

Paul Declerck

University of Leuven

Shein-Chung Chow

Duke University School of Medicine

CONTENTS

1.1 Background

1.2 Fundamental Differences from Generics and Assumptions for Biosimilars

1.2.1 Fundamental Differences from Generics

1.2.2 Fundamental Assumptions

1.3 Scientific Factors and Practical Issues

1.3.1 Criteria for Biosimilarity

1.3.1.1 Absolute Change versus Relative Change

1.3.1.2 Aggregated versus Disaggregated Criteria

1.3.1.3 Moment-Based versus Probability-Based Criteria

1.3.1.4 Remarks

1.3.2 Statistical Methods

1.3.3 The Manufacturing Process

1.3.4 Similarity in Size and Structure

1.3.5 Biosimilarity in Biological Activity

1.3.6 The Problem of Immunogenicity

1.3.7 Drug Interchangeability

1.3.8 Development of the Biosimilarity Index

1.3.9 Remarks

1.4 Aim and Scope of the Book

References

1.1 BACKGROUND

When an innovative drug product is going off patent, generic companies may file an abbreviated new drug application (ANDA) for the approval of the generic copies (with an identical active ingredient) of the innovative drug product under the Hatch–Waxman Act. For approval of generic drug products, the United States Food and Drug Administration (FDA) as well as other regulatory agencies require that evidence in average bioavailability be provided through the conduct of pharmacokinetic (PK) bioequivalence (in terms of rate and extent of drug absorption) studies. The assessment of bioequivalence as a surrogate endpoint for the evaluation of drug safety and efficacy is based on the Fundamental Bioequivalence Assumption. It states that if two drug products are shown to be bioequivalent in average bioavailability, it is assumed that they are therapeutically equivalent and can be used interchangeably.

Unlike drug products with identical active ingredients, the concept for the development of copies of biological products is different because they are made of living cells. The copies of biological products are referred to as biosimilars by the European Medicines Agency (EMA), similar biotherapeutic products (SBPs) by the World Health Organization (WHO), and subsequent-entry biologics (SEB) by Health Canada.

Biosimilars are fundamentally different from generic (chemical) drugs. Important differences include the size and complexity of the active substance and the nature of the manufacturing process. Because biosimilars are not exact copies of their originator products, different criteria for regulatory approval are required. This is partly a reflection of the complexities of manufacturing and the safety and efficacy controls of biosimilars when compared to their small-molecule generic counterparts (see, e.g., Chirino and Mire-Sluis, 2004; Crommelin et al., 2005; Roger and Mikhail, 2007; Schellekens, 2005). Since biological products are (recombinant) proteins produced by living cells, manufacturing processes for biological products are highly complex and require hundreds of specific isolation and purification steps. In practice, it is impossible to produce an identical copy of a biological product, as changes to the structure of the molecule can occur with changes in the production process. Since a protein can be modified during the process (e.g., different sugar chains may be added, the structure may have changed due to protein misfolding and so on), different manufacturing processes may lead to structural differences in the final product, which may result in differences in efficacy and safety, and may have an impact on the immune responses of patients. In some cases, these issues also occur during the postapproval changes of the innovator’s biological products.

Since 2006, the EMA has provided several guidelines for the development of biosimilars. These have been followed by guidelines established by other regulatory agencies (Australia, Japan, South Korea, Canada) and the WHO. In 2015, the FDA published several guidances on the development of biosimilar products (FDA, 2015a–c). The guidance entitled Scientific Considerations in Demonstrating Biosimilarity to a Reference Product recommends a stepwise approach for obtaining the totality of the evidence for assessing biosimilarity between a proposed biosimilar product and its corresponding innovative biological drug product. The stepwise approach starts with analytical similarity assessment for functional and structural characterization of critical quality attributes (CQAs) that are relevant to clinical outcomes at various stages of the manufacturing process; animal studies for toxicity; pharmacokinetics and pharmacodynamics for pharmacological activities; clinical studies for efficacy confirmation; immunogenicity for safety and tolerability; and pharmacovigilance for long-term safety. Accordingly, the purpose of this chapter is to outline scientific factors and practical issues that are commonly encountered in the development of biosimilar products.

Section 1.2 describes fundamental differences and assumptions between conventional drug products and follow-on biologics. Section 1.3 presents scientific factors and practical issues that are commonly encountered in the development of biosimilar products. The aim and scope of the book are provided in Section 1.4.

1.2 FUNDAMENTAL DIFFERENCES FROM GENERICS AND ASSUMPTIONS FOR BIOSIMILARS

1.2.1 FUNDAMENTAL DIFFERENCES FROM GENERICS

In comparison with conventional drug products, the concept for the development of follow-on biologics is very different. Webber (2007) defines follow-on (protein) biologics as products that are intended to be sufficiently similar to an approved product to permit the applicant to rely on existing scientific knowledge about the safety and efficacy of the approved reference product. Under this definition, follow-on products are intended not only to be similar to the reference product, but also to be therapeutically equivalent with the reference product. As a number of biological products patents have expired and many more are due to expire in the next few years, the subsequent follow-on products have generated considerable interest within the pharmaceutical/biotechnological industry as biosimilar manufacturers strive to obtain part of an already large and rapidly growing market. The potential opportunity for price reductions versus the innovator biologic products remains to be determined, as the advantage of a cheaper price may be outweighed by the potential increased risk of side-effects from biosimilar molecules that are not exact copies of their innovators. In this chapter, we focus on issues surrounding biosimilars, including manufacturing, quality control, clinical efficacy, side-effects (safety), and immunogenicity. In addition, we attempt to address the challenges in imposing regulations that deal with these issues.

1.2.2 FUNDAMENTAL ASSUMPTIONS

As indicated by Chow and Liu (2008), bioequivalence studies are performed under the so-called Fundamental Bioequivalence Assumption, which constitutes the legal basis for the regulatory approval of generic drug products. As noted earlier, the Fundamental Bioequivalence Assumption states:

If two drug products are shown to be bioequivalent, it is assumed that they will reach the same therapeutic effect or they are therapeutically equivalent and hence can be used interchangeably.

Note that this statement can be interpreted to mean that the confidence interval for the ratio of geometric means is between 80% and 125%. An alternative would be to show that the tolerance intervals (or a distribution-free model) overlap sufficiently.

To protect the exclusivity of a brand-name drug product, the sponsors of the innovator drug products will make every attempt to prevent generic drug products from being approved by regulatory agencies such as the FDA. One strategy used in the United States is to challenge the Fundamental Bioequivalence Assumption by filing a citizen petition with scientific/clinical justification. Upon receipt of a citizen petition, the FDA has the legal obligation to respond within 180 days. It should be noted, however, that the FDA will not suspend the review/approval process of a generic submission of a given brand-name drug even if a citizen petition is under review within the FDA.

In spite of the Fundamental Bioequivalence Assumption, one of the controversial issues that has arisen is that bioequivalence may not necessarily imply therapeutic equivalence and therapeutic equivalence does not guarantee bioequivalence either. One criticism lodged in the assessment of average bioequivalence for generic approval is that it is based on legal/political considerations rather than scientific arguments. In the past severa...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Preface
• Contributors
• Chapter 1 Introduction: Scientific Factors in Biosimilar Product Development
• Chapter 2 Analytical Characterization: Structural Assessment of Biosimilarity
• Chapter 3 Analytical Similarity Assessment
• Chapter 4 Characterization of Biosimilar Biologics: The Link between Structure and Functions
• Chapter 5 Manufacturing and Process Control Issues: Quality Development of Biosimilar Medicinal Products
• Chapter 6 Nonclinical Studies for Biosimilars
• Chapter 7 The Clinical Development of Biosimilar Drugs
• Chapter 8 Statistical Methods for Assessing Biosimilarity
• Chapter 9 Extrapolation of Indications for Biosimilars: Opportunity for Developers and Challenges for Regulators
• Chapter 10 Interchangeability, Switchability, and Substitution of Biosimilar Products
• Chapter 11 Design and Analysis of Studies for Assessing Interchangeability
• Chapter 12 The Role of the Immunogenicity Evaluation for Biosimilars
• Chapter 13 Pharmacovigilance of Biosimilars
• Chapter 14 Patent Exclusivities Affecting Biosimilars in the United States, Canada, and Europe
• Chapter 15 Biosimilars in the EU: Regulatory Guidelines
• Chapter 16 Biosimilars and Biologics: The Prospects for Competition
• Chapter 17 Plant-Based Production of Biosimilar Drug Products
• Index