By Gary H. Lyman, MD, MPH, FASCO
- Unlike generic medications, a biosimilar is a biologic that is highly similar but not identical to an approved reference biologic with no differences in efficacy, safety, or purity between the biosimilar and the reference product—except for minor differences in clinically inactive components.
- The process by which biosimilars are approved makes it less likely that large phase III comparative clinical trials will be conducted. Therefore, preclinical and limited clinical data will be used to extrapolate the indications for which the original biologic was approved, and clinicians must decide on the appropriate incorporation of biosimilars.
- With appropriate oversight by regulatory authorities, professional organizations such as ASCO, and patient and clinician education programs, we will see the potential for considerable cost savings and increased access and equity of cancer care through the use of biosimilars.
The rapid increase in health care costs—most notably in cancer care and the price of cancer drugs in the United States—has prompted increasing consideration of strategies for containing the cost of cancer care. Spending on cancer medicines remains at the top in terms of spending by therapeutic areas in the United States.1 Despite considerable enthusiasm about the rapid advances in our understanding of cancer biology and the identification of critical molecular targets for potentially less toxic and more precise biologic therapies, nowhere has the increase in the cost of cancer care been more apparent than in the costs associated with such products. Clearly, the continuing rise in the cost of cancer care has substantially affected providers and practices, payers, and the larger health system. However, nowhere has this had a more dramatic effect than on the costs passed on to patients, resulting in concerns about patient access and equity of care because of the financial burden imposed on patients and families, sometimes prompting mortgaging of homes and even filing for bankruptcy.
Regulation of Biosimilars in the U.S.
Biologics represent medical products produced in living systems, as well as a large proportion of the novel first-in-class therapies for cancer over the past 2 decades. Unlike traditional drugs regulated under the Food, Drug, and Cosmetic Act, biologics are regulated by the U.S. Food and Drug Administration (FDA) Center for Biologics Evaluation and Research under the Biologics Control Act to ensure purity, safety, and efficacy. The Patient Protection and Affordable Care Act amended the Public Health Service Act to allow for an abbreviated license pathway for the approval of biosimilars. Unlike generic medications, a biosimilar is a biologic that is highly similar but not identical to an approved reference biologic with no differences in efficacy, safety, or purity between the biosimilar and the reference product—except for minor differences in clinically inactive components. Although biosimilars have the same amino acid sequence, they may differ in three-dimensional structure, glycosylation sites, isoform profiles, and protein aggregation, necessitating pharmacokinetic and pharmacodynamics studies to further evaluate their biologic activity.2-4 Product information related to the originator remains proprietary, contributing to the different physical, chemical, or immunogenicity profiles of biosimilars compared with the original product. Likewise, product drift because of minor differences in manufacturing, processing, and packaging may result in meaningful differences in both biosimilars and the originator biologic over time. If overall safety and efficacy remains unaffected, biosimilars may be approved for the same indications. Nevertheless, the universal adoption of a biosimilar to all indications of the originator drug remains controversial.
Available data from Europe have not suggested that switching a reference product to a corresponding biosimilar leads to any safety or efficacy concerns. The Biologics Price Competition and Innovation Act of 2009 provides a framework by which biosimilars may be evaluated, including the distinction of interchangeability whereby the product may be substituted for the reference drug and alternating between the two products would be considered safe and effective. Currently, there are no biosimilars in the United States approved by the FDA as interchangeable biologics. In early 2017, the FDA issued guidance on demonstrating interchangeability of a biosimilar with a reference product. This draft guidance encourages further studies to gather evidence to substantiate interchangeability when the biologic product has been developed in the United States. However, the final regulatory criteria for successfully demonstrating interchangeability, including multi-switch clinical data, await final FDA guidance. In the end, the appropriate biologic product prescribed should be determined by the patient and treating oncologist.
Potential Impact of Biosimilars on Health Care Costs
Although biosimilars have already been approved in Europe and now in the United States, a number of biosimilars with potential use in oncology are ready for FDA review and approval as patents of originator biologics expire. In fact, nearly 10 biologics losing patent protection over the next 5 years are anticipated to yield more than $20 billion with a total global spend well over $200 billion.5
However, there remain challenges concerning the uptake and utilization of biosimilars in the United States and the overall impact on health care costs.6,7 The FDA approval process for biosimilars makes it less likely that large phase III trials will be undertaken for all approved indications for originator use. In fact, if the same level of evidence were required for biosimilars as for original biologics, the driving potential for cost reduction would not likely be realized. Therefore, approval of the biosimilar for other indications must largely be based on extrapolation, and the appropriate incorporation of biosimilars into practice is left largely to clinical experience and judgment. The complexity of manufacturing and the extensive preclinical analytic structural and functional studies required, however, result in biosimilars requiring a considerably longer period of time to develop and test at costs that will likely be 100-fold greater than the development of traditional generics. The impact of biosimilars on health care costs, therefore, is likely to be proportionately less dramatic than that experienced with the introduction of generics. Nevertheless, the high overall costs for development and approval of biologics suggest that the impact of biosimilars on health care costs should still be quite substantial in the decades to come. A number of additional challenges to the forthcoming oncology biosimilar marketplace include challenges with nomenclature and tracking, pricing, coverage determinations, and the impact of new payment models.
Current Status of Biosimilars in Oncology
As of early 2017, the FDA has approved four biosimilar products in the United States including filgrastim-sndz, utilized as supportive care in patients receiving cancer chemotherapy to reduce the risk of febrile neutropenia. Filgrastim-sndz demonstrated identical protein structure, mass, size, charge, and hydrophobicity to the originator product, while pharmacokinetic and pharmacodynamic modeling confirmed that the mechanism of action occurs through the binding of the G-CSF receptor as with the originator.8 Clinical data leading to the approval of filgrastim-sndz were predominately based on information gathered from healthy volunteers and data in patients with cancer in the context of the prevention of chemotherapy-induced neutropenia. Once granted approval for this indication as a biosimilar, the FDA approved the agent for all indications of the originator filgrastim. Clinical practice guidelines now consider this biosimilar and other approved forms of G-CSF as therapeutic options for patients receiving cancer chemotherapy.
ASCO’s Policy Brief on Biosimilars
In 2015, ASCO issued a policy brief on biosimilars to provide guidance to its members and to policymakers on the evolving regulatory landscape of biosimilars. The policy brief articulated the following principles, among others9:
- Biosimilar clinical trials should demonstrate efficacy and safety, including lack of immunogenicity.
- The FDA should establish a transparent regulatory pathway for approval of biosimilars.
- Physician choice between biologic products in the best interest of patients should not be restricted.
- Approved biosimilars should be subject to careful post-market safety surveillance.
- Interchangeability should be established by clinical trials that are adequately designed and performed to support substitution.
- Congress should ensure adequate FDA funding to meet new demands.
The Need for a Formal ASCO Policy Statement on Biosimilars in Oncology
Despite a slow start compared with Europe—where 21 biosimilars have been approved, including 10 for treating or supporting patients with cancer—a wave of biosimilars is expected in the United States, with cancer treatments likely to make up a significant proportion of biosimilars approved. Nevertheless, confusion persists related to extrapolation, switching or automatic substitution, interchangeability, the naming and labeling of biosimilars, the value of biosimilars, issues related to coverage and reimbursement, and when and how biosimilars should be incorporated into standard clinical practice and guidelines. In response to growing concern about the adequacy and appropriateness of regulation, 23 states and Puerto Rico have enacted varying state legislation related to biosimilars in an effort to prevent automatic substitution as with generic drugs and ensure proper patient and physician notification. In January, the FDA issued final guidance on the naming of biologic products indicating that they bear a nonproprietary name that includes an FDA-designated suffix that is devoid of meaning and composed of four lowercase letters. The FDA is continuing to consider the appropriate suffix format for interchangeable products.
Continuing confusion around the appropriate regulation and role of biosimilars in oncology practice have led state affiliates to reach out for guidance that goes beyond ASCO’s prior policy brief. Therefore, an ASCO Policy Initiative has been initiated to specifically address both the opportunities and the challenges confronting oncologists regarding the use of biosimilars in the cancer setting. A Working Group has been established to review all available evidence and regulatory information and to develop a formal ASCO Policy Statement on Biosimilars in Oncology. This statement is intended to provide education and guidance to ASCO members and other practicing clinicians on the emergence of biosimilars in the cancer setting and how their safety and efficacy are assessed, as well as to offer guidance to states on various biosimilars bills to ensure that ASCO continues influencing the regulatory and overall biosimilars policy landscape. This policy will affirm ASCO’s commitment to a comprehensive education campaign for its members, provide recommendations for biosimilar use at the state level, and highlight the importance of post-market evidence generation to further evaluate the effectiveness and safety of biosimilars and to identify issues and make recommendations related to coverage and reimbursement for biosimilars in cancer care.
The Future of Biosimilars in the U.S.
Biosimilars will have an important role in future cancer care and scientific innovation. Although many biosimilars in oncology will be available in the next several years, their use and impact on patient care and health care costs will depend largely on patient and provider acceptance based on an adequate understanding of the safety and efficacy of these agents in cancer care. The process by which biosimilars are approved makes it less likely that large phase III comparative clinical trials will be conducted. Therefore, preclinical and limited clinical data will be used to extrapolate the indications for which the original biologic was approved, and clinicians must decide on the appropriate incorporation of biosimilars, relying on fewer comprehensive studies and more on clinical experience and judgment. Furthermore, the nature of biosimilars reflects variation in manufacturing that could result in differences in efficacy and safety that may require longer study evaluation. Therefore, continuous post-approval effectiveness and safety surveillance will be essential to monitoring these drugs moving forward.
Clinicians should be alert to any complications presented in the literature or in their patients. Accurate and timely disclosure of any variation in expected outcome with the biosimilar compared with the originator filgrastim will be of paramount importance. Accurate tracking and tracing of adverse events and efficacy with biosimilars will be essential. However, with appropriate oversight by regulatory authorities, professional organizations such as ASCO, and patient and clinician education programs, we will see the potential for considerable cost savings and increased access to and equity of cancer care.
About the Author: Dr. Lyman is co-director of the Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, and professor of medicine at the University of Washington.