Biosimilar Clinical Development: Scientific Considerations and New Methodologies

Kerry B. Barker, Sandeep M. Menon, Ralph B. D'Agostino, Sr., Siyan Xu, Bo Jin, PhD, Kerry B. Barker, Sandeep M. Menon, Ralph B. D'Agostino, Sr., Siyan Xu, Bo Jin, PhD

• Publisher: Chapman and Hall/CRC
• Year: 2016
• ISBN:
  9781315355900
• Edition: 1
• Topic: Mathematics
• Subtopic: Probability & Statistics
• Index: Mathematics

Biosimilars have the potential to change the way we think about, identify, and manage health problems. They are already impacting both clinical research and patient care, and this impact will only grow as our understanding and technologies improve. Written by a team of experienced specialists in clinical development, this book discusses various potential drug development strategies, the design and analysis of pharmacokinetics (PK) studies, and the design and analysis of efficacy studies.

1

Biosimilars for Drug Development: The Time Is Now!

Bo Jin, Sandeep M. Menon, Kerry B. Barker, and Ralph B. D’Agostino

CONTENTS

1.1 Background

1.2 Definitions of Biosimilar

1.3 Different Development Requirements for Generic, Biosimilar, and Innovator Products

1.4 Stepwise Approach to Demonstrate Biosimilarity and Assessment of Biosimilarity Based on Totality of the Evidence

1.5 Nonclinical Program for a Biosimilar Development

1.6 Clinical Program for a Biosimilar Development

1.6.1 Pharmacokinetic and Pharmacodynamic Studies

1.6.1.1 Selection of Population and Dose

1.6.1.2 Pharmacokinetic Parameter as Primary Endpoint, Bioequivalence Design, and Analysis

1.6.1.3 Pharmacodynamic Data Collection

1.6.1.4 Pharmacokinetic and Pharmacodynamic Clinical Studies May Not Conclude Biosimilarity

1.6.2 Comparative Efficacy and Safety Studies

1.6.2.1 Selection of Population and Dose

1.6.2.2 Study Endpoint and Similarity Assessment Metrics

1.6.2.3 Study Design: Equivalence versus Noninferiority

1.6.2.4 Equivalence Hypothesis Test and Equivalence Margins

1.6.2.5 Statistical Analysis for Primary Endpoint

1.6.2.6 Sample Size and Duration of Study

1.6.2.7 Safety and Immunogenicity Data

1.6.2.8 Meeting the Requirements by Different Regulatory Agencies

1.7 Extrapolation from One Indication to Other Indications

1.8 Postapproval Safety Monitoring

1.9 Topics in the Book

1.9.1 Systems Biology Approach for the Discovery of Therapeutic Targets and Biomarkers

1.9.2 Understanding Immunogenicity to Biologics and Biosimilars

1.9.3 Interchangeability

1.9.4 Metrics to Measure Similarity

1.9.5 Average Inferiority Measure and Standardized Margins

1.9.6 Design and Analysis of Noninferiority Trials

1.9.7 Novel Method in Inference of Equivalence

1.9.8 Multiplicity Adjustments in Testing for Bioequivalence

1.9.9 Case Studies on the Applications of Bayesian Methods

References

ABSTRACT Biological drugs have taken a fast-growing segment in the pharmaceutical industry. At the same time, a number of top-selling biologic brands are attributable to lose product patent protection over the next few years, opening a wealth of opportunities for the development of biosimilar products. In fact, legal and regulatory pathways have been established in the past decade in many countries throughout the world, which allow the development of biosimilar products for the global market. This chapter presents an overview of the development of biosimilar products. Among others, the evolution of legal and regulatory requirements on the development of biosimilar products is presented in this chapter. The differences among the development requirements for generic, biosimilar, and innovator products are illustrated. The stepwise approach to demonstrate biosimilarity and assessment of biosimilarity based on totality of the evidence are described. General scientific considerations in the clinical program for a biosimilar development are discussed in detail. At the end of this chapter, an overview of the topics to be covered by this book is provided.

1.1 Background

With the rapid development of modern biological technology, biologic drug products have played more and more import roles in treating many life-threatening and chronic diseases. Consequently, biologic drugs are a fast-growing segment in the pharmaceutical industry. A report by Visiongain predicts that the world market for biologic drugs will reach US$270 billion in 2019 [1]. At the same time, a number of top-selling biologic brands in various therapeutic areas such as oncology, rheumatoid arthritis, and diabetes is attributable to lose product patent protection over the next few years, opening a wealth of opportunities for biosimilar players. IMS Health estimates that US$67 billion in global sales will be off-patent by 2019.

In the past decade, legal and regulatory pathways have been established in many countries throughout the world, which allow development of biosimilar products for the global market. The European Union (EU) is the first region in the world to have set a legal framework and a regulatory pathway for biosimilars. The “concept of similar biological medicinal product” was adopted in the EU legislation in 2004 and came into effect in 2005 (Directive 2001/83/EC, as amended by Directive 2003/63/EC and Directive 2004/27/EC) (European Commission, 2001). Thereafter, European Medicines Agency (EMA) has developed overarching and product-specific scientific guidelines providing a robust regulatory process in which to be able to grant marketing authorization for biosimilar medicinal products. These guidelines, both overarching and product specific, are revised on a regular basis to reflect the experience gained with biosimilar applications and approvals and to take into account evolving science and technology. The most recent revisions in 2014 on three overall guidelines: the overarching guideline [2], quality issues guideline [3], and nonclinical and clinical issues guidelines [4] outlined the general principles on biosimilar development, introduced the possibility of using a non-EU reference product throughout the comparability program, and addressed some issues for biosimilars on the extrapolation of efficacy and safety from one therapeutic indication to other.

Many other regions and/or countries have followed and adopted the EU standard. The Japanese Ministry of Health, Labor, and Welfare (MHLW) published a guideline for quality, safety, and efficacy of biosimilars in 2009 [5], which followed the similarity concept outlined by the EMA. Other regulators, including some Asian countries or regions such as South Korea, Malaysia, Singapore, Taiwan, and Sir Lanka, have also followed and developed local guidelines to reflect the EMA guidelines. The World Health Organization (WHO) published guidelines on biosimilar [6] in 2009, which share much common ground with the EU guidelines in terms of the requirements for proven similarity, clinical immunogenicity, indication extrapolation, risk management, and pharmacovigilance plan. The Canadian guidelines issued by the federal regulatory authority Health Canada (Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs); Health Canada, 2010) [7] shares comparable concepts and principles of both the EMA and WHO guidelines. The emerging markets such as Brazil, Russia, China, and India largely recognize the WHO biosimilars guidelines although they have some country-specific requirements.

The legislative route for biosimilars in the United States started with the enacted health care reform law, the Patient Protection and Affordable Care Act (PPAC Act) (2010), which was signed into law in March 2010. Among others, the PPAC Act amends the Public Health Service (PHS) Act to create an abbreviated approval pathway for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with a Food and Drug Administration (FDA)-approved biological product. These statutory provisions are also referred to as the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) (Title VII, 2010) [8]. After a few years following the BPCI Act, FDA have developed several guidance for the pharmaceutical industry on the submissions of biosimilar product applications. Most recently, the FDA guidance in 2015 on scientific considerations in demonstrating biosimilarity to a reference product [9] recommends that sponsors use a stepwise approach in their development of biosimilar products and indicates that FDA considers the totality of the evidence provided by a sponsor to support a demonstration of biosimilarity. General scientific principles are discussed in the guidance on conducting comparative structural and functional analysis, animal testing, human pharmacokinetic (PK) and pharmacodynamic (PD) studies, clinical immunogenicity assessment, and clinical safety and effectiveness studies. The other FDA guidance in 2015 on quality considerations [10] provides some recommendations on the scientific and technical information of the chemistry, manufacturing, and controls (CMC) section of a marketing applicant for a proposed biosimilar product. The FDA 2014 draft guidance on clinical pharmacology data to support a demonstration of biosimilarity to a reference product [11] discusses some concepts related to clinical pharmacology testing for biosimilar products, the approaches for developing the appropriate clinical pharmacology database, and the utility of modeling and simulation for designing clinical trials.

1.2 Definitions of Biosimilar

According to the EMA guidelines [2], biosimilar is a biological medicinal product that contains a version of the active substance of an already authorized original biological medicinal product (reference medicinal product) in European Economic Area (EEA). Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and efficacy based on a comprehensive comparability exercise needs to be established. The U.S. FDA guidance [9] defines a biosimilar as the biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency.

Biosimilar products are also referred to as follow-on biologics (FOBs) by the U.S. FDA, similar biotherapeutic products (SBPs) by WHO, and SEBs by Health Canada. WHO defines SBP as a biotherapeutic product, which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product [6]. Health Canada defines SEB as a biological drug that enters the market subsequent to a version previously authorized in Canada and with demonstrated similarity to a reference biologic drug [7]. Table 1.1 presents various definitions of biosimilar products. Although the definitions vary by different regulatory agencies, there are three necessary conditions...