Rheumatologists Dr. Thomas Dörner from Charité – Universitätsmedizin Berlin, Department of Medicine, Rheumatology and Clinical Immunology, and Dr. Jonathan Kay of the University of Massachusetts Medical School in Worcester have collaborated on a research effort to analyze clinical data on biosimilar drugs that have received approval for use. The term “biosimilars” refers to drugs based on biopharmaceuticals approved by regulatory agencies that are no longer under patent protection, and while they are not required to be identical to their originator products, they must be comparable to their reference products in efficacy, safety, and tolerability — the promise being that, once patent protection has elapsed on established biologics, access to effective and well-tolerated drugs will become more affordable for more patients.
In 2001, as part of a project led by the European Medicines Agency, step-by-step guidelines were introduced to regulate the approval of biosimilars, and to acknowledge specific differences distinguishing biosimilars from the originally patented products. The regulatory pathway and approval process for biosimilars are different from those addressing generics, since biosimilars are not required to be molecularly identical to their reference products. Thorough information must be provided on analytical and non-clinical procedures to show similarity. Moreover, clinical trials demonstrating equivalent efficacy and safety to the reference product are absolutely required for all biosimilars.
A particular focus of a paper published in the current issue of Nature Reviews Rheumatology, entitled “Biosimilars in rheumatology: current perspectives and lessons learnt”(Published online 18 August 2015, Corrected online 25 August 2015 doi:10.1038/nrrheum.2015.110), is the efficacy of biosimilars that have received approval for treatment of rheumatic diseases within the past three years as a new therapeutic option to treat inflammatory diseases.
Drs. Dörner and Kay stress that biosimilars must be distinguished from “biomimic” or “biocopy” drugs that are marketed in some countries but have not been evaluated according to the stringent regulatory pathway used for biosimilars. They cite as an example the biosimilar CT-P13, based on infliximab, which was the first biosimilar approved for the treatment of inflammatory diseases, noting that some countries did not allow extrapolation of indications to all eight diseases for which the reference drug infliximab is approved. The researchers found that while antidrug antibodies can reduce drug levels and affect clinical efficacy, available data suggest that biosimilars and their reference products have comparable immunogenicity in general, although this important property may vary among individual biopharmaceuticals. This review discusses biosimilars already approved within the past 3 years to treat rheumatic diseases, as well as others that are currently under development. The co-authors note that the main challenges posed by biosimilars are also addressed in the paper, such as the extrapolation of indications to diseases only studied for the reference drug, and the definition of strategies for adequate pharmacovigilance to monitor biosimilars after marketing approval.
IN the U.S., the Patient Protection and Affordable Care Act (Affordable Care Act), signed into law by President Barack Obama on March 23, 2010, amended the Public Health Service Act (PHS Act) to create an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act) under which a biological product may be demonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved biological product. Ergo: a biosimilar product is a biological product approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.
The investigators note that drugs produced using biotechnology are among the most expensive medicines available, and biosimilars that offer a real alternative are becoming increasingly available on the market, this being particularly the case pertaining to pharmaceuticals used in treating of patients with cancer and autoimmune diseases, and also drugs used for treatment of rheumatic diseases. They observe that one of the main distinctions is, of course, that biosimilars are, or are proposed to be, available to patients at significantly lower prices than those of the originator products.
Dr. Dörner stresses in a release that introduction of these medicines needs to be handled in a responsible manner, and requires the input of experienced practitioners. Prof. Dörner adds that decisions regarding which medicine a patient is to be prescribed should remain the responsibility of the treating physician. What he maintains must not be allowed to happen is what is currently happening with traditional generics — namely, that pharmacies are permitted to automatically substitute one product for another.
Under current FDA guidance, an interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional standards for interchangeability. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the healthcare provider who prescribed the reference product.
The FDA requires both licensed biosimilar and interchangeable biological products to meet the Agency’s rigorous standards of safety and efficacy, maintaining that ensures that patients and healthcare professionals will be able to rely upon the safety and effectiveness of the biosimilar or interchangeable product just as they would the reference product.
Drs. Dörner and Kay report that, in researching the Nature Reviews Rheumatology article, they analyzed a large body of information on development of biosimilars. Their review, which covers almost every biological drug available, also addresses enormous variations currently observed in approval processes globally. For example, several copy biologics have been used widely for several years in India and South America but have not undergone a formal regulatory approval process for biosimilars. Their findings suggest that the introduction of biosimilars into clinical practice must go hand-in-hand with the creation of national registers to allow data on potential side effects to be collated. They conclude that approval and introduction of biosimilars offer access to both established and new treatment options, noting that biosimilars are also likely to reduce costs associated with the treatment of inflammatory diseases in the fields of rheumatology, dermatology, and gastroenterology.
In September, Janet Woodcock, MD, Director of the FDA Center for Drug Evaluation and Research, stated before the U.S. Senate Committee on Health, Education, Labor and Pensions, that the agency is supportive of and fully engaged with development and approval of biosimilar and interchangeable biological products. Dr. Woodcock noted that many of our most important drugs are biological products used to treat patients who have serious and life-threatening medical conditions, including rheumatoid arthritis, diabetes, and cancer, and said it is important for the public health of the U.S. population to have access to safe, effective, and affordable biological products.
“Biosimilars can provide more treatment options for patients, and possibly lower treatment costs, enabling greater access for more patients,” Dr. Woodcock declared, noting that “To earn and sustain both physicians’ and patients’ confidence in biosimilar and interchangeable products, FDA must apply a scientifically rigorous review process and approval standard. Healthcare providers have consistently indicated the importance of assurance that biosimilars will have the same clinical performance as the originator, or reference product. FDA is committed to providing this assurance, and recognizes its importance to the uptake and acceptance of these products, and the future success of the biosimilars program.”
However, Helio Rheumatology reports that Sen. William Cassidy, MD, (R-Louisiana), chair of the Sept. 17 hearing, voiced concerns to Dr. Woodcock because a detailed, specific definition about what would qualify as interchangeable had not been released.
Dr. Kay is also co-author of a recent study entitled “Biosimilars in rheumatology: what the clinician should know” (RMD Open 2015;1:e000010 doi:10.1136/rmdopen-2014-000010) published in the journal RMD Open. Dr. Kay and co-authors — Rodrigo González-Ramírez of Centro Latino Americano de Pesquisa em Biológicos, Rio de Janeiro, Brazil; Gilberto Castaeda-Hernandez of the Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México, Distrito Federal, Mexico; and Morton A. Scheinberg of Hospital Israelita Albert Einstein, São Paulo, Brazil — note that there is now considerable interest in biosimilars among rheumatologists, although the distinction between a true biosimilar and a biomimic (or intended copy) may not be clear to most. They observe that many countries have changed their regulatory requirements to accommodate this new class of medicinal products and to distinguish them from generics and that, for instance, following the lead of the European Medicines Agency (EMA), regulatory agencies in other countries, including South Korea, Canada, Japan, Turkey and Colombia, have approved the infliximab biosimilar. However, the approved indications differ among these countries. For example, the EMA allowed results of clinical trials conducted in rheumatological diseases to be extrapolated to inflammatory bowel diseases, while Health Canada did not. Recently, BOW015, an infliximab biosimilar with the commercial name Infimab, and ZRC-3197, an adalimumab biosimilar with the commercial name Exemptia, were approved in India, while HD203, an etanercept biosimilar, was approved in South Korea. Whether other countries will approve these products with the data currently available remains to be seen.
The investigators observe that currently, numerous biosimilars are in development and it is likely that some of them will be commercialized in the near future, and that understanding the principles by which these trials are designed and analysed will help the clinician to evaluate and use these drugs in practice.
The co-authors maintain that perception of biosimilars in rheumatology has evolved over the past several years, and distrust about the use of biosimilars in clinical practice has waned as regulatory pathways have been implemented and applied to the approval of a biosimilar infliximab, suggesting that familiarity of clinicians with issues regarding study design and the methods of analyzing data obtained in comparative effectiveness clinical trials undoubtedly will improve decision-making surrounding the prescription of biosimilars to patients with rheumatological diseases.
Charité – Universitätsmedizin Berlin
University of Massachusetts Medical School
Nature Reviews Rheumatology
U.S. Food and Drug Administration (FDA)