Understanding the biosimilar approval and extrapolation process—A case study of an epoetin biosimilar
Introduction
While the vast majority of therapeutics are small-molecule drugs (SMDs), the last two decades have seen the rise of biologics in the treatments of various disease states. SMDs are generally simple molecules that are highly reproducible. Biologics, in contrast, are intricate and complex molecules that are produced in living cells through processes such as recombinant DNA technologies. Their production process is exclusive; hence, it is impossible for manufacture to replicate exactly. Consequently, the end product cannot be considered a “biogeneric,” but is termed a “biosimilar.”
The World Health Organization defines a biosimilar as “a biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product” (World Health Organization, 2009). Biosimilars, and their manufacture/approval processes, are very different from their chemical counterparts, generics, as Table 1 summarizes (Roger, 2006, Calvo and Gόmez, 2013, Schellekens, 2005, Sekhon and Saluja, 2011, Ventola, 2013, Davit et al., 2009).
Biosimilars are intrinsically more complex, less reproducible, and susceptible to even small changes in manufacturing and product characterization. The production platform and chosen cell line/expression system defines the product’s attributes. Variability in bioreactor conditions can lead to ranges in product attribute (Roger, 2006, Schellekens, 2005, Mellstedt et al., 2008), which can lead to alterations to the three-dimensional structure, pattern of posttranslational modifications and/or impact levels of other product quality attribute levels (Schellekens and Ryff, 2002, Schellekens, 2002, Hesse and Wagner, 2000), potentially impacting safety and efficacy. Consequently, unlike generics, biosimilars must undergo a highly regulated, stringent approval process that is based on a multistep comparability exercise.
Section snippets
Regulation of biosimilar development
The European Union (EU) was the first to establish legislative procedures for the approval of follow-on biologics, with the original overarching biosimilar guidelines published in 2005 by the European Medicines Agency (EMA) (European Medicines Agency, 2005). A series of complementary guidelines has since been published to reflect the evolving knowledge base (European Medicines Agency, 2012a, European Medicines Agency, 2013a), and the overarching biosimilar guidelines (European Medicines Agency,
Extrapolation
The EMA defines extrapolation as “Extending information and conclusions available from studies in one or more subgroups of the patient population (source population), or in related conditions or with related medicinal products, to make inferences for another subgroup of the population (target population), or condition or product, thus reducing the need to generate additional information (types of studies, design modifications, number of patients required) to reach conclusions for the target
Epoetin biosimilars
As described above, biosimilar approval and extrapolation is a tightly regulated process. To highlight the level of information required during the process we will consider a case study using epoetin biosimilars to demonstrate how the data package for a biosimilar is scientifically tailored.
Erythropoiesis is the complex physiological process of producing mature erythrocytes. It is primarily regulated by erythropoietin (EPO), a glycosylated 165-amino acid hematopoietic growth factor produced by
A comparability exercise in the EU – the biosimilar Retacrit™ versus the originator Eprex®
Based on comparability exercises and data obtained in oncology patients, several epoetin biosimilars have now been approved for use in patients with CIA, in addition to the original indication of anemia in patients with chronic renal failure. Retacrit will be considered as a specific example. This biosimilar was approved by EMA in 2007 for patients with chronic renal failure on hemo- or peritoneal dialysis, or in patients with advanced renal disease not yet on renal replacement therapy. This
Conclusion
This review details the data requirements that should be fulfilled when seeking approval of a biosimilar in one indication and extrapolation to another. The comprehensive comparability exercise that was conducted in support of an application to the EMA to use Retacrit to treat anemia in patients with chronic kidney disease or CIA was also described. Retacrit was compared against its originator, Eprex, across multiple levels, including the manufacturing process steps, assessment of the active
Conflict of interest
Amit Agarwal has no conflicts of interest for this publication.
Ali McBride has served on advisory boards for Amgen and for Hospira, a Pfizer company.
Role of the funding source
Hospira, a Pfizer company, provided financial support for manuscript preparation, including medical writing and editorial assistance. Hospira reviewed the manuscript for medical and legal accuracy.
Author contributions
Dr Agarwal was involved in the conception and design of the manuscript. He has critically reviewed and provided contributions to each draft of the manuscript. Dr McBride was involved in the conception and design of the manuscript. He critically reviewed and provided contributions to each draft of the manuscript. Both authors have approved the final article.
Acknowledgments
Editorial and medical writing support was provided by Joanne Franklin, PhD at TRM Oncology, The Hague, The Netherlands and was funded by Hospira which was acquired by Pfizer Inc in September 2015. Hospira, a Pfizer company provided editorial comments for consideration, although the authors are fully responsible for content and editorial decisions for this manuscript.
Amit Agarwal, MD, PhD, is an assistant professor of medicine at the University of Arizona. After completing his medical education in India, he joined the human genetics PhD program at Virginia Commonwealth University. Dr Agarwal’s thesis involved development and characterization of mouse models of cancer, and he used these models to study functional differences between oncogenes. He subsequently completed a residency in internal medicine and a hematology/oncology fellowship at the University of
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Amit Agarwal, MD, PhD, is an assistant professor of medicine at the University of Arizona. After completing his medical education in India, he joined the human genetics PhD program at Virginia Commonwealth University. Dr Agarwal’s thesis involved development and characterization of mouse models of cancer, and he used these models to study functional differences between oncogenes. He subsequently completed a residency in internal medicine and a hematology/oncology fellowship at the University of Arizona. Dr Agarwal’s clinical focus involves the treatment of hematologic malignancies. His research efforts are focused on clinical and translational research on multiple myeloma and related hematologic disorders. The work focuses on testing novel drugs and combinations that are effective in the treatment of hematologic malignancies, initially in the laboratory and eventually in patients through clinical trials.
Ali McBride, PharmD, MS, is a pharmacist and the clinical coordinator of hematology/oncology at the University of Arizona Cancer Center, and coordinator of supportive oncology research trials. Dr McBride has been working on oncology drug shortages since the cytarabine drug shortage in 2009, and has testified on behalf of the Hematology/Oncology Pharmacy Association at a US Food and Drug Administration Drug Shortage Workshop and the American Society of Health-System Pharmacists drug shortage stakeholders meeting. Dr McBride has published numerous articles focusing on drug shortages, oral chemotherapy adherence, stem cell transplant, biosimilar development and implementation pathways, and oncology supportive care management.