In an article published recently in TheNew England Journal of Medicine, Gary H. Lyman, MD, MPH, FACP, FRCP (Edin), FASCO, of Fred Hutchinson Cancer Research Center in Seattle, and colleagues reviewed opportunities, issues, and challenges posed by the advent of biosimilar medications, focusing on biosimilars in cancer treatment.1 Although these agents could help to meet the health-care goals of high-quality care with cost containment, there are challenges facing their adoption and use in clinical practice.
Biosimilars arebiologic agents that are highly similar but not identical to approved reference biologic agents. Regulatory approval of these agents requires the absence of meaningful differences in efficacy, safety, and purity compared with reference agents. Pricing of biosimilars can be lower than reference agents, because their development is not associated with some of the costs incurred by pharmaceutical companies in the development of reference agents, including the costs of extensive clinical trial programs.
As individual states work to regulate the use of biosimilars, oncologists and patients must be aware of regulations, authorities, and responsibilities that may affect their treatment choices.— Gary H. Lyman, MD, MPH, FACP, FRCP (Edin), FASCO, and colleagues
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Thus far, four biosimilars have been approved by the U.S. Food and Drug Administration (FDA) in oncology settings: the myeloid growth factor filgrastim-sndz (Zarxio) as a biosimilar to filgrastim (Neupogen), bevacizumab-awwb (Mvasil) as a biosimilar to bevacizumab (Avastin), trastuzumab-dkst (Ogivri) as a biosimilar to trastuzumab (Herceptin), and pegfilgrastim-jmdb as a biosimilar to pegfilgrastim (Neulasta). As related by the authors, once filgrastim-sndz became available, it gained 24% of the market within 4 months, at a price that was 15% lower at launch than that of filgrastim; currently, a 300-µg vial of filgrastim costs $377.80 and a 300-µg vial of filgrastim-sndz costs $330.79, with the cost of 480-µg vials being $601.60 and $526.78, respectively.
Overall, biologic oncology products expected to lose patent protection by 2020 account for more than $20 billion in annual spending worldwide. Biosimilars may capture much of the market share for many of these drugs, and the associated cost savings could be substantial. As noted by the authors, a recent RAND Corporation analysis estimates that the availability of biosimilars could reduce direct spending by $54 billion between 2017 and 2026.
The availability of biosimilars may help reduce health-care costs and improve access to treatments. However, as stated by the authors, “Challenges remain concerning the acceptance of biosimilars by physicians and patients in the United States. Their overall effect on health-care costs will be heavily influenced by provider, payer, and patient understanding of their safety and efficacy.”
In contrast to the regulatory process for biologic agents, with approval depending most heavily on the demonstration of safety and efficacy in clinical trials, regulatory review of biosimilars focuses on molecular characterization and preclinical studies along with pharmacokinetic and pharmacodynamic studies to establish biosimilarity, with additional studies assessing immunogenicity and other potential toxicities. Clinical trials are performed if uncertainty remains regarding safety and efficacy of the biosimilar.
[T]he potential for biosimilars to mitigate rising health care costs while improving access to highly effective therapies provides a true opportunity to reduce disparities in access to care and limit the financial burden of new treatments….— Gary H. Lyman, MD, MPH, FACP, FRCP (Edin), FASCO, and colleagues
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As noted by the authors, often 50% or more of the data in applications for approval of biosimilar agents concern manufacturing processes. Further, the regulatory approval process for biosimilars does not require the performance of clinical trials across all approved indications of the reference drug; with approval, a biosimilar drug may have labeling that is identical to that of the reference product across multiple indications.
Thus, as noted by the authors, clinician appraisal of and confidence in biosimilars will initially depend less on large clinical trials than on preclinical and pharmacologic data establishing bioequivalence and on their own clinical experience. In the absence of data from large clinical trial programs, there is also uncertainty regarding how biosimilars can be integrated into evidence-based clinical practice guidelines. Dr Lyman notes that the recent approval of pegfilgrastim-jmbd (Fulphilia) by the FDA without review of the supporting evidence by the Oncology Drug Advisory Committee has already raised concerns about integration into clinical practice.
Interchangeability and Substitution
The advent of biosimilars also comes with new concepts in use and labeling, including substitution and interchangeability. An “interchangeable” biosimilar is one that is expected to produce the same clinical outcomes and no greater safety concerns as the reference drug upon substitution at any point in treatment.
No biosimilar has been approved as interchangeable thus far in the United States, such a designation could affect substitution, which is regulated at the state level; state-specific laws could allow pharmacists to substitute an interchangeable biosimilar for a reference product without consulting prescribers, as is often done with generic drugs.
The authors noted, “As individual states work to regulate the use of biosimilars, oncologists and patients must be aware of regulations, authorities, and responsibilities that may affect their treatment choices.”
Reliance on Postmarketing Reporting
As stated by the authors, “minor modifications in manufacturing, processing, and packaging may result in lot-to-lot differences in both biosimilars and originator products, potentially leading to a small but real risk of differences in immunogenicity and overall adverse-event profiles appearing over time.”
In the absence of data from clinical trials, both the FDA and clinicians will have to rely on postmarketing surveillance to confirm both the safety and efficacy, of biosimilars. However, as noted by the authors, many clinicians feel that the process of postmarketing reporting is cumbersome and do not participate in the current reporting system due to time and resource constraints.
Cost and Reimbursement
According to the authors, the Centers for Medicare and Medicaid Services has determined that all newly approved biosimilars that have a common reference product will be coded separately and reimbursed at the current rate of the average sales price plus 6% of the average sales price of the originator reference product minus any mandated sequester adjustment. Medicaid categorizes biosimilars as “single source,” resulting in different reimbursement rates for each biosimilar. However, under Medicare Part D, biosimilars are exempt from the Medicare Coverage Gap Discount Program—which requires manufacturers to provide a 50% discount on brand-name drugs and brand-name biologic drugs.
The authors state: “As a result of this coverage gap, seniors and persons with disabilities will pay higher out-of-pocket costs for biosimilars than for competing reference biologic drugs. To close this gap, a legislative solution will be necessary to modify the definition of ‘applicable drugs’ to include biosimilars.” In the absence of such a solution, the potential cost savings arising from the use of biosimilars could be lost.
Need for Ongoing Education
ASCO recently published a statement on biosimilars in oncology that addresses issues regarding the assessment of safety and efficacy of biosimilars and their integration into clinical practice.2 As stated by the authors of The New England Journal of Medicine article, “The [ASCO] statement highlights the need for ongoing professional and patient education to establish confidence in the safety and efficacy of biosimilars as their availability increases. Continued generation of evidence will require innovative and coordinated efforts across agencies, organizations, and institutions and will undoubtedly invoke emerging big-data capabilities.”
In concluding their article, Dr. Lyman and colleagues stated:
As patent exclusivity expires on [biologic agents], the opportunity to favorably bend the cost curve through the development of competing biosimilars has now emerged. At the same time, practitioners must rely on more limited clinical safety and efficacy data and must be educated regarding novel naming and labeling and new concepts such as interchangeability and switching; in addition, there is uncertainty about coverage and reimbursement and an even greater need for postmarketing surveillance. Nevertheless, the potential for biosimilars to mitigate rising health care costs while improving access to highly effective therapies provides a true opportunity to reduce disparities in access to care and limit the financial burden of new treatments for cancer and other major illnesses. It is essential that professional organizations provide educational programs about biosimilars to inform the medical community of the opportunities and the challenges that these new agents provide for our patients now and in the years to come. ■
DISCLOSURE: Dr. Lyman has been a paid consultant or advisor for G1 Therapeutics, Halozyme, and Coherus and has received an institutional research grant from Amgen. For full disclosures of the other authors, visit www.nejm.org.
1. Lyman GH, Zon R, Harvey RD, et al: Rationale, opportunities, and reality of biosimilar medications. N Engl J Med 378:2036-2044, 2018.
2. Lyman GH, Balaban E, Diaz M, et al: American Society of Clinical Oncology statement: Biosimilars in oncology. J Clin Oncol 36:1260-1265, 2018.