Since their commercial introduction in 1982, large-molecule biologic medicines have revolutionized the management of many diseases. However, the development of new biologic agents is costly, the process is considerably more complex than for small-molecule agents, and there are no guarantees that investigational agents will ultimately be approved for use. Due to cost concerns, commercial and government payers have implemented strict criteria for the reimbursement of biologics, which often creates obstacles to patient access.
The introduction of the Biologics Price Competition and Innovation Act (BPCIA) in 2009 paved the way for the development and approval of biosimilar agents. Biosimilars are by definition highly similar agents with no clinically meaningful differences in efficacy and safety parameters when compared with the reference drug.1 The recent wave of patent expirations of widely used biologic agents has been a factor in stimulating manufacturers to accelerate the rate of development and approval of biosimilars.2 Broad adoption of biosimilars offers potential cost-savings and expanded patient access. Their availability and market uptake in the United States has been relatively slow, however.2
As of February 2022, of the 34 biosimilar agents approved by the US Food and Drug Administration (FDA), 21 are available on the market (Table 1).3-5 Although this represents an increase from 2019 when only 11 of 26 FDA-approved biosimilars were available on the market, significant barriers to entry persist.6 This article aims to examine the critical obstacles to biosimilar market entry and propose strategies by which healthcare systems and institutions can take active, organized steps to facilitate systemwide biosimilar implementation and realize their therapeutic and economic potential.
Regulatory Approval Process for Biosimilars
The regulatory approval of a biosimilar agent is based on the totality of the evidence, where the aim is to show that the biosimilar is highly similar to the reference drug and further that there are no clinically meaningful differences between the two with respect to safety, purity, and potency. The process involves rigorous analytical assessments (structural and functional) as well as limited preclinical and clinical studies.1,7-10 The primary goal of biosimilar development and approval is to establish biosimilarity to the reference drug rather than to re-establish the safety and efficacy of the proposed biosimilar.7-10
This process typically begins with detailed analytical characterization, which is usually followed by a limited number of preclinical animal studies to assess for the potential for toxicity.7-9 Subsequent clinical trials include a comparative pharmacokinetic/pharmacodynamic study followed by at least 1 large comparative effectiveness trial to address residual uncertainty regarding potential differences between the proposed biosimilar and its reference drug. Comparative immunogenicity is assessed throughout the clinical development process. From the perspective of the FDA, the approval of a biosimilar agent for additional therapeutic indications is based on extrapolation of the evidence used to show biosimilarity.1,7,9-11
This regulatory pathway does not imply that approval standards for biosimilars are lower than those for the original biologic agent. On the contrary, the totality of the data required to establish biosimilarity is extensive.12
Despite the unique and thoughtful regulatory pathways developed for biosimilars, significant hurdles continue to impede their adoption and slow their implementation by providers and healthcare systems. Although the number of approved biosimilars has increased recently, their potential economic impact remains uncertain.13 While biosimilar uptake has improved in the United States, as evidenced by the successful launch of bevacizumab, rituximab, and trastuzumab biosimilars,13 the combination of payer-imposed formulary preferences14 and provider hesitancy to prescribe biosimilars15 continue to limit their adoption. Subsequent sections of this article will expand on these limitations to biosimilar adoption.
The Biosimilar Expert Panel
In November 2020, an expert panel of 11 US-based stakeholders was convened. This multidisciplinary, multispecialty panel was composed of 5 rheumatologists, 3 gastroenterologists, 2 pharmacists, and 1 nurse practitioner; the panelists are from a variety of community and academic treatment settings. The main objective of the panel was to identify barriers to the adoption of biosimilars by healthcare systems and develop strategies to overcome these barriers. During facilitated panel discussion in which advisors voiced their perspectives, several persistent barriers to biosimilar adoption affecting both prescribers and patients were cited; the panelists also described successful experiences regarding biosimilar implementation in their respective institutions, medical practices, and healthcare systems.
Prescriber-Related Barriers to Biosimilar Adoption
Knowledge gaps among prescribers continue to hinder biosimilar adoption. A recent survey by Herndon and colleagues identified several barriers to adoption, including prescribers’ concerns regarding safety and efficacy of biosimilars; insufficient knowledge about billing, coding, and reimbursement; and lack of a clear understanding of guidance surrounding nonmedical switching.16
These findings are aligned with the results of another recent survey of US gastroenterologists, rheumatologists, and other specialists. In this survey administered to 507 healthcare providers, investigators found gaps in provider knowledge and widespread hesitancy toward biosimilars: nearly half (48.5%) indicated that they would wait until biosimilars were on the market longer before prescribing them, and more than one-third (36.8%) agreed that they were less likely to prescribe biosimilars than originator drugs.15
Another survey of 320 rheumatologists found that the majority (73%) were more likely to initiate treatment with a biosimilar agent in a biologic-naïve patient with rheumatoid arthritis than they were to switch a patient with rheumatoid arthritis who is responding to treatment with its reference drug (35%).17 These findings show that additional education and training is needed regarding the clinical attributes as well as economic benefits of biosimilars relative to reference drugs.
Misleading information that is taken out of context can serve to exacerbate prescribers’ concerns regarding transitioning patients to biosimilars.18 This underscores the need to distinguish between physician-directed switching to a biosimilar, pharmacy substitution from a reference product to a biosimilar, and nonmedical switching of biosimilars, which is dictated by payers in the context of step therapy requirements or preferential formulary status.19
The FDA allows prescribing healthcare providers to substitute an approved biosimilar for its reference drug.12,18 In addition, in the United States, a pharmacist may substitute a biosimilar for its reference drug without the authorization of the prescribing healthcare provider if the FDA has granted the designation of “interchangeable” to that biosimilar, which requires additional data acquired in a switching study.20,21
Unless precluded by state laws, the interchangeability designation is only applicable to biosimilars dispensed through retail or specialty pharmacies where a pharmacist can make a substitution without the prescriber’s approval. It does not apply to biosimilar medications administered in hospitals, outpatient clinics, or physician offices where substitution of such facility-administered medications typically occurs with oversight of the prescribing healthcare provider. That said, however, no biosimilar had been designated as interchangeable at the time of the roundtable, despite the FDA having issued final guidance for industry regarding the design and analysis of switching trials to support a demonstration of interchangeability.19 Subsequently, the first interchangeable biosimilar, insulin glargine-yfgn, was approved for the treatment of diabetes mellitus,22 and adalimumab-adbm has received approval as an interchangeable form of the adalimumab reference drug.23
Despite this noteworthy development, the utility and impact of the interchangeability designation on insulin glargine-yfgn adoption remain to be evaluated in a comprehensive manner. Roundtable participants acknowledged that most physicians oppose nonmedical switching to a biosimilar by payers that takes place without the provider’s knowledge or without appropriate communication to the patient. In fact, a survey of US rheumatologists, dermatologists, and gastroenterologists found that 84% of respondents did not want patients with stable disease activity on treatment to undergo a nonmedical switch to a biosimilar because of concerns related to patient well-being, efficacy, and safety.24 The panel participants agreed that nonmedical switching of patients to biosimilars represents a significant burden, especially when accounting for limited resources and the direct impact on a clinic’s busy workflow, and the logistical implications of forced biosimilar adoption can be prohibitive in independent medical practices due to the need to acquire, store, handle, and manage an inventory of multiple biosimilars.
Economic and Legal Factors
Panel participants also agreed that financial and economic incentives that favor originator biologics continue to slow uptake of biosimilars. There may be significant financial advantages for institutions and healthcare systems, particularly those participating in the 340B Drug Pricing Program, to prioritize using originator biologics because they are more profitable to providers than biosimilars.25 The 340B program, designed to allow covered organizations (primarily eligible hospitals and hospital-based health systems) to reach greater numbers of eligible patients and provide more comprehensive healthcare services, provides favorable pricing for many branded specialty drugs relative to non–340B-eligible institutions and private practices.26
Specifically, manufacturers participating in Medicaid agree to provide outpatient drugs to covered entities at significantly reduced prices.26 Biologic manufacturers may also have established contracts in place with commercial payers that result in preferred formulary status for the originator drug, thereby disadvantaging the biosimilar. Moreover, some payers implement step therapy protocols that require physicians to prescribe biologic therapies before agreeing to provide coverage for biosimilar options.25
A recent survey found that commercial healthcare plans selected biosimilars as the preferred drug only 14% of the time.27 For some Medicare beneficiaries, under the Medicare Part D reimbursement policy, patients may incur higher out-of-pocket costs for using biosimilars, despite their lower acquisition costs.24,25
Patent litigation by manufacturers of originator biologics has also affected the market entry of biosimilars. Originator biologics are often protected by patents on the compound itself and on the complex production processes. Moreover, fewer legal precedents support patent litigation regarding biosimilar agents compared with those for generic agents of small-molecule drugs. As a result, biosimilar manufacturers face inherent risks regarding patent litigation when bringing their agents to market.28
In sum, these external factors have negatively affected biosimilar availability and slowed their adoption by obfuscating the intended financial benefits of using biosimilars.
Studies have demonstrated that positive patient perception of biosimilars is critical for their acceptance and successful adoption. Patients’ acceptance of biosimilars can be improved through structured communication and reassurance from providers, tailored to their level of health literacy, thus allowing them to make informed shared decisions.29-31 Emerging evidence highlights the critical role of nurses and clinical pharmacists in assessing patients’ level of literacy and developing individualized communication strategies.30
The requirement for nonmedical switching of stable patients by payers bypasses and negates these proactive informational discussions with patients and may negatively impact the acceptance of biosimilars. Furthermore, it can increase work for the provider by making it necessary to counsel and educate patients in response to the payer-mandated switch, which may disrupt the clinical workflow and impede the ability of providers to provide optimal care to their other patients.24
Another factor that was found to affect biosimilar adoption is the nocebo effect: a phenomenon that occurs when a patient’s negative expectations regarding a treatment result in the perception of nonresponse and/or adverse effects.31-33 A nocebo effect can be triggered by previous negative experiences with a pharmacologic intervention or by patients’ negative expectations, negative suggestions, or information.32-39
Among patients switched to biosimilar therapy in several pragmatic and open-label clinical studies, the nocebo effect resulted in higher rates of treatment discontinuation than among patients who received the reference drug or those who were treated with a biosimilar in blinded clinical trials.31-33
Misperceptions, misinformation, and knowledge gaps among patients are significant drivers of the nocebo effect.38 These undesired effects can be mitigated by engaging nurses and pharmacists to educate patients proactively about the equivalent efficacy and comparable safety of the biosimilars to their reference drugs. Healthcare providers should also educate patients about the possible occurrence of the nocebo effect that may occur after switching; these efforts can help to alleviate patients’ anxiety that may be associated with the switch.38 Moreover, clinicians should identify and allay symptoms of the nocebo effect promptly by addressing patients’ concerns.38
Misinformation about and disparagement of biosimilars also continue to impede the adoption of biosimilar agents. Exposure to misleading, incomplete, out-of-context, and incorrect information can significantly elevate patients’ concerns.18 A key strategy to mitigate the effects of misinformation is to develop inclusive and balanced educational programming. The FDA has developed and disseminated educational materials on biosimilars to counter such misinformation.18,40
Benefits of Successful Implementation of a Biosimilar
The primary aim of the BPCIA was to create an abbreviated approval pathway for biosimilars and, in so doing, help to lower healthcare costs and create a more competitive marketplace. Recent estimates suggest that with adoption of biosimilars, direct spending on biologics in the United States between 2017 and 2026 could be reduced by $54 billion.40 The introduction of cost-effective alternatives to originator biologics could help to address economic barriers that have historically limited patient access to cutting-edge therapies.41,42
Furthermore, biosimilar adoption could yield indirect economic benefits that may have been overlooked in cost-effectiveness analyses. For example, earlier biologic disease-modifying antirheumatic drug treatment initiation in patients with rheumatoid arthritis could significantly alter the disease trajectory, which could substantially improve workforce productivity and benefit society.42 Competition resulting from the market entry of biosimilars has resulted in reduced average sales prices (ASPs) of both biosimilars and their reference drugs, with improved access to these medications.42,43
Recent price comparisons across 18 European countries revealed that the manufacturer list prices of rituximab biosimilars were 39% lower than that of reference rituximab, and retail prices were 86% lower.44 In addition, price competition after the launch of biosimilar rituximab in Italy resulted in overall savings of €153 million over 5 years.45 Recent care delivery and reimbursement models in the United States that aim to introduce value-based payment, such as the Oncology Care Model and accountable care organizations, seek to improve the efficiency, cost, and quality of healthcare services and are expected to incentivize biosimilar adoption.25,46 In addition, some insured patients may also benefit from reduced copayments.25
The recent experience of Texas Oncology, a community oncology practice, further demonstrated the impact of biosimilar implementation on reducing overall costs. In 2020, this oncology practice partnered with McKesson Specialty Health to create educational materials for patients and clinical staff.46 The plan to switch patients from originator biologics to their biosimilars was communicated to all relevant clinical staff. A central pharmacy team reviewed all new orders and substituted a biosimilar agent for the reference drug, unless a payer insisted on using the reference drug or a biosimilar was not on the practice’s formulary.46
With this initiative, implementation of biosimilars increased between January 2020 and December 2020 from 5% to 80% for rituximab, from 9% to 88% for bevacizumab, and from 8% to 74% for trastuzumab.46 Based on average ASP for a 70-kg patient, the potential monthly savings per administration was $550 for bevacizumab, $850 for trastuzumab, and $1400 for rituximab. This implementation process reduced costs by $4 million (21%) by converting to use of these 3 biosimilars.46
Multidisciplinary Team Approach
The roundtable participants agreed that collaboration by healthcare stakeholders is required to overcome the complex barriers facing the systemwide implementation of biosimilars. Several key influencers, including physicians, pharmacists, nurses, and other healthcare professionals, were cited as potential drivers of implementation. Also, organizational readiness is a critical component for the adoption program’s success.
The support of healthcare system administration and other departments, such as benefit verification personnel, informatics, finance, and contracting, is needed to enable healthcare providers to address the internal and external challenges of biosimilar implementation. The roundtable participants shared case studies of successful implementation of biosimilars at their home institutions founded on the concepts of implementation science (Table 2).18,29,30,35,43,46-50
Overcoming the Nocebo Effect
Raymond Cross, MD, MS, Professor of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, explained several effective strategies employed at the University of Maryland Medical Center to prevent, identify, and address the nocebo effect. Developing effective patient education initiatives that provide concise, accurate, timely, and evidence-based information about the comparative efficacy and safety of biosimilars and their reference drugs is an essential component of these strategies. Nurses and allied health professionals who frequently interact with patients were trained to serve as a trusted resource to provide accurate information about biosimilars and to ensure that the healthcare team delivers unified coordinated messages.
Partnering with patients by ensuring they participate in decision-making regarding switching to a biosimilar is also critical. Before such a change in treatment, patients should have the opportunity to meet with their providers to discuss their concerns. Providers should be sensitive to concerns about switching from a biologic to a biosimilar agent during stressful times in patient lives. Patients should always have the final choice regarding the proposed switch to a biosimilar. Any symptoms that develop after the switch should be investigated to identify recurrent disease activity.
The biosimilar switching program at the University of Maryland has resulted in significant cost-savings. Of 75 patients receiving infusions of originator biologics, 20 patients were switched to receive the biosimilar, and 19 of these patients have remained on the biosimilar after 3 to 5 infusions. This program has resulted in total cost-savings of approximately $7700 per patient per year. Reinvestment of the cost-savings resulting from biosimilar implementation has allowed expansion of patient support programs.
Leveraging Community-Based Rheumatology Providers
Payer-related barriers represent a significant hurdle for biosimilar adoption, especially in independent medical practices. Unlike healthcare systems and large institutions, independent practices often lack the resources and the purchasing power to negotiate effectively with payers. Moreover, due to economic pressures, independent healthcare providers may have limited time to educate patients about their medications. Colin Edgerton, MD, Founding Partner of Articularis Healthcare, a community-based rheumatology network, highlighted a key strategy to overcome payer-related barriers by creating a network of community-based providers to develop collaborative pathways and negotiate value-based care arrangements with payers.
The American Rheumatology Network (ARN) is an example of a multistate physician-led and -owned organization committed to improving healthcare services by supporting independent rheumatology practices. Through this network, rheumatologists and rheumatology practice administrators can access best business practices, innovative practice performance technology, and value-based treatment pathways.47 ARN has been able to successfully expand patient access to disease-modifying therapies by integrating less costly biosimilars into treatment pathways.48 This implementation process was supported by educational initiatives that demonstrated the equivalent efficacy and safety of biosimilars to reference biologics.
Effective negotiation with payers and an emphasis on the potential cost-savings that could be achieved while providing high-quality care were critical to the success of this strategy.48 Peer-to-peer dissemination throughout the network of strategies and experiences using biosimilars has significantly improved provider acceptance of biosimilars.
Adoption of Biosimilar Infliximab-dyyb Through Multidisciplinary Collaboration
Large urban medical centers have complex organizational structures that present unique challenges to biosimilar adoption. For example, the lack of effective communication between administrative and clinical departments and ineffective collaboration between multidisciplinary clinical units may hinder efficient acceptance of biosimilars by key stakeholders. Comprehensive strategies that align key departments and leverage unique resources within large organizations may be required to overcome internal and external barriers to biosimilar implementation.
Bhavesh Shah, RPh, Director of Specialty and Hematology-Oncology Pharmacy Services, Boston Medical Center Health System, described an actionable plan that surmounted obstacles created by fragmented organizational structures. In this model, intradepartmental champions were identified to spearhead the implementation process across multiple departments. In the Boston Medical Center Health System, the Pharmacy Department led the successful transition from originator infliximab to biosimilar infliximab-dyyb.50 The pharmacy team served as a central hub in planning, coordinating, and collaborating with key clinical and administrative departments within the organization and initiated the transition process by reviewing the available clinical evidence and developing a plan based on consultation with European providers who already had experience using biosimilars.50 The team collaborated with relevant clinical departments, including dermatology, rheumatology, and gastroenterology, and identified potential concerns that needed to be addressed before launching the program. The team initiated targeted educational activities and created educational materials for patients to be available at the infusion centers. Patients were contacted individually 2 weeks before switching to help them make informed decisions. In addition, the pharmacy team met with the Pharmacy and Therapeutics Committee to facilitate approval of the formulary change from infliximab to infliximab-dyyb. Of 151 patients who met the inclusion criteria, 146 (97%) patients were successfully switched to infliximab-dyyb. This resulted in an annual forecasted cost-saving for the healthcare system of $500,000.50
The Role of Nurses in Patient Health Literacy in the Community
Effective patient education is essential to address any potential concerns resulting from misinformation and to avoid the nocebo effect. A recent study suggests that improved health-related literacy may contribute to greater patient satisfaction with being switched to a biosimilar.51 Nursing professionals interact frequently with patients and are trusted resources who are uniquely positioned to build rapport with patients and assess their degree of health literacy. Amy Stewart, MSN, FNP-C, Family Nurse Practitioner, Capital Digestive Care, Chevy Chase, MD, described the importance of providing patients with personalized information and materials customized to their health literacy level and understanding of issues related to healthcare coverage and their treatment options. As part of this process, nursing staff share data with patients on the safety and efficacy of switching to a biosimilar.
Generalizability of Successful Strategies
Several commonalities are seen among successful biosimilar switching programs in various healthcare systems, although differences remain. Effective diffusion of knowledge through targeted communication and educational initiatives is a crucial component of any successful strategy.52 Such programs, if designed and delivered in a timely and coordinated fashion, can overcome many of the real-world barriers to biosimilar adoption. Another common aspect is the importance of collaboration between teams of diverse backgrounds to share their knowledge and experiences with the goal of achieving a shared vision.
Despite diverse roles and practice backgrounds, healthcare providers share a desire to provide safe and effective medications expeditiously that minimize patients’ out-of-pocket costs. As a secondary consideration, healthcare providers seek to minimize costs to their practices, institutions, and the overall healthcare system without sacrificing quality.
Once consensus has been reached, institutional “champions,” either individuals or departments, play a vital role to spearhead operationalization efforts in their respective practices and institutions, coordinating with clinical and administrative leaders to gain their support. Coordination of effective collaboration by champions can significantly improve a healthcare system’s readiness to launch an effective switching program and overcome key barriers, including operational hurdles.
Although these institutional efforts are critical, they must be coupled with economic incentives, such as reduced patient out-of-pocket costs and increased institutional savings, which could be reinvested in programs that support patients and healthcare providers.
The successful strategies described here closely align with the concepts of the “quadruple aim” described by Bodenheimer and Sinsky, which supports 4 dimensions of healthcare delivery: improving the health of populations, enhancing the patient experience of care, reducing the cost of care, and significantly improving the lives of healthcare providers.53 Effective implementation of biosimilars through expanded access could help improve population health by allowing treatment of more patients without incremental cost to healthcare systems. In addition, enhancing the patient experience of care through early access to highly effective medications could positively alter the disease course and improve patients’ quality of life. Furthermore, a progressive implementation framework for biosimilar adoption would help to facilitate improvement in the work–life balance of healthcare providers through effective communication, collaboration, and delegation.53
Adoption of biosimilars by health systems could generate direct cost-savings and indirect economic benefits through price reduction because of long-term price competition. These savings could then be reinvested to support long-term clinical and educational initiatives that would benefit both patients and healthcare providers. In sum, widespread adoption of biosimilars could contribute to achieving the goal of providing high-quality, cost-effective, and equitable healthcare to patients without additional encumbrance to healthcare providers.
However, several challenges may limit the generalizability of these strategies to healthcare systems of various sizes and with different operational structures. For example, certain healthcare systems and institutions may not have a pharmacy department that is equipped to coordinate a biosimilar adoption program. Such limitations can be overcome by identifying alternative champions within the system or institution or by outsourcing specific components of the program. In addition, engagement and willingness of the healthcare system administration to address external barriers to biosimilar adoption is required to negotiate operational and financial structures with payers that will incentivize biosimilar adoption.
The results of biosimilar implementation strategies demonstrate that large-scale adoption of biosimilars by healthcare systems is feasible. Moving forward, more institutions and providers will eventually recognize the benefits, which will bring us closer to the full realization of the promise of biosimilar medicines across therapeutic areas.
Technical and medical writing assistance were provided under the direction of the authors by John Welz, MPH, of The Lynx Group.
Funding for this article and the roundtable meeting on which this article is based was provided by Pfizer.
Author Disclosure Statement
Dr Cross is a Consultant to Eli Lilly, Fzata, Magellan Health, and Samsung Bioepis, and has participated in Advisory Boards for AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Takeda; Ms Stewart is on the Advisory Board of Pfizer and is on the Advisory Board and Speaker’s Bureau of Bristol Myers Squibb; Mr Shah is on the Speaker’s Bureau of and has received grant support from Pfizer; Mr Welz has stock holdings of Pfizer; Dr Kay has received research support from Novartis Pharmaceuticals paid to the University of Massachusetts Medical School, and from Pfizer paid to the University of Massachusetts, and is a Consultant to Pfizer, AbbVie, Boehringer Ingelheim, Celltrion Healthcare Co, Merck & Co, Samsung Bioepis, Sandoz, and UCB; Dr Edgerton has no conflicts of interest to report.
- Hung A, Vu Q, Mostovoy L. A systematic review of U.S. biosimilar approvals: what evidence does the FDA require and how are manufacturers responding? J Manag Care Spec Pharm. 2017;23:1234-1244.
- Derbyshire M. Patent expiry dates for biologicals: 2017 update. GaBI J. 2018;7:29-34.
- US Food and Drug Administration. Biosimilar product information. December 2020. www.fda.gov/drugs/biosimilars/biosimilar-product-information. Accessed May 11, 2022.
- Biosimilars Review & Report. Biosimilar approval status. Revised February 8, 2021. https://biosimilarsrr.com/us-biosimilar-filings. Accessed May 11, 2022.
- Amgen. 2020 Biosimilar Trends Report. www.amgenbiosimilars.com/-/media/Themes/Amgen/amgenbiosimilars-com/Amgenbiosimilars-com/pdf/USA-CBU-80723-2020-Amgen-Biosimilar-Trends-Report.pdf. Accessed October 19, 2021.
- Lexchin J. Affordable biologics for all. JAMA Netw Open. 2020;3:e204753. doi: 10.1001/jamanetworkopen.2020.4753.
- Lim S. Biosimilar regulatory policy: understanding the landscape and relevance to medical practice. www.fda.gov/media/112814/download. Accessed February 10, 2021.
- US Food and Drug Administration. Biosimilar development, review, and approval. Updated October 20, 2017. www.fda.gov/drugs/biosimilars/biosimilar-development-review-and-approval. Accessed February 10, 2021.
- Bhatt V. Current market and regulatory landscape of biosimilars. Am J Manag Care. 2018;24(21 suppl):S451-S456.
- Markus R, Liu J, Ramchandani M, et al. Developing the totality of evidence for biosimilars: regulatory considerations and building confidence for the healthcare community. BioDrugs. 2017;31:175-187.
- Kozlowski S, Woodcock J, Midthun K, Behrman Sherman R. Developing the nation’s biosimilars program. N Engl J Med. 2011;365:385-388.
- Alvarez DF, Wolbink G, Cronenberger C, et al. Interchangeability of biosimilars: what level of clinical evidence is needed to support the interchangeability designation in the United States? BioDrugs. 2020;34:723-732.
- IQVIA Institute for Human Data Science. Biosimilars in the United States 2020-2024: Competition, Savings, and Sustainability. October 2020. www.iqvia.com/-/media/iqvia/pdfs/institute-reports/iqvia-institute-biosimilars-in-the-united-states.pdf?_=1647880022165. Accessed January 29, 2021.
- Chen AJ, Bhanot P, Gascue L, et al. Insurer formularies complicate the adoption of biosimilar cancer therapies. Health Affairs Forefront. April 8, 2021. www.healthaffairs.org/do/10.1377/hblog20210405.345071/full. Accessed June 4, 2021.
- Kolbe AR, Kearsley A, Merchant L, et al. Physician understanding and willingness to prescribe biosimilars: findings from a US national survey. BioDrugs. 2021;35:363-372.
- Herndon K, Braithwaite J, Berry B, Bourget K. Biosimilar perceptions among healthcare professionals and commercial medical benefit policy analysis in the United States. BioDrugs. 2021;35:103-112.
- Gibofsky A, McCabe D. US rheumatologists’ beliefs and knowledge about biosimilars: a survey. Rheumatology (Oxford). 2021;60:896-901.
- Cohen HP, McCabe D. The importance of countering biosimilar disparagement and misinformation. BioDrugs. 2020;34:407-414.
- US Food and Drug Administration. Biosimilarity and interchangeability: additional draft Q&As on biosimilar development and the BPCI Act: guidance for industry: draft guidance. November 2020. www.fda.gov/media/143847/download. Accessed March 23, 2021.
- US Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product: guidance for industry. May 2019. www.fda.gov/media/124907/download. Accessed October 29, 2019.
- US Food and Drug Administration. Biosimilar and interchangeable products. October 23, 2017. www.fda.gov/drugs/biosimilars/biosimilar-and-interchangeable-products. Accessed October 29, 2019.
- US Food and Drug Administration. FDA approves first interchangeable biosimilar insulin product for treatment of diabetes. July 28, 2021. www.fda.gov/news-events/press-announcements/fda-approves-first-interchangeable-biosimilar-insulin-product-treatment-diabetes. Accessed October 18, 2021.
- US Food and Drug Administration. FDA approves Cyltezo, the first interchangeable biosimilar to Humira. October 21, 2010. www.fda.gov/news-events/press-announcements/fda-approves-cyltezo-first-interchangeable-biosimilar-humira. Accessed May 15, 2022.
- Teeple A, Ellis LA, Huff L, et al. Physician attitudes about non-medical switching to biosimilars: results from an online physician survey in the United States. Curr Med Res Opin. 2019;35:611-617.
- Boccia R, Jacobs I, Popovian R, de Lima Lopes G Jr. Can biosimilars help achieve the goals of US health care reform? Cancer Manag Res. 2017;9:197-205.
- Health Resources and Services Administration. 340B Drug Pricing Program. www.hrsa.gov/opa/index.html. Accessed May 11, 2022.
- Chambers JD, Lai RC, Margaretos NM, et al. Coverage for biosimilars vs reference products among US commercial health plans. JAMA. 2020;323:1972-1973.
- Rai AK, Price WN II. An administrative fix for manufacturing process patent thickets. Nat Biotechnol. 2021;39:20-22.
- Waller J, Sullivan E, Piercy J, et al. Assessing physician and patient acceptance of infliximab biosimilars in rheumatoid arthritis, ankylosing spondyloarthritis and psoriatic arthritis across Germany. Patient Prefer Adherence. 2017;11:519-530.
- Schapira MM, Swartz S, Ganschow PS, et al. Tailoring educational and behavioral interventions to level of health literacy: a systematic review. MDM Policy Pract. 2017;2:2381468317714474. doi: 10.1177/2381468317714474.
- Tweehuysen L, Huiskes VJB, van den Bemt BJF, et al. Open-label, non-mandatory transitioning from originator etanercept to biosimilar SB4: six-month results from a controlled cohort study. Arthritis Rheumatol. 2018;70:1408-1418.
- van Bodegraven AA, Boone NW. Editorial: nocebo effect and switching to biosimilars. Aliment Pharmacol Ther. 2018;47:850-851.
- Tweehuysen L, van den Bemt BJF, van Ingen IL, et al. Subjective complaints as the main reason for biosimilar discontinuation after open-label transition from reference infliximab to biosimilar infliximab. Arthritis Rheumatol. 2018;70:60-68.
- Boone NW, Liu L, Romberg-Camps MJ, et al. The nocebo effect challenges the non-medical infliximab switch in practice. Eur J Clin Pharmacol. 2018;74:655-661.
- Chavarria V, Vian J, Pereira C, et al. The placebo and nocebo phenomena: their clinical management and impact on treatment outcomes. Clin Ther. 2017;39:477-486.
- Rheker J, Winkler A, Doering BK, Rief W. Learning to experience side effects after antidepressant intake—results from a randomized, controlled, double-blind study. Psychopharmacology (Berl). 2017;234:329-338.
- Häuser W, Hansen E, Enck P. Nocebo phenomena in medicine: their relevance in everyday clinical practice. Dtsch Arztebl Int. 2012;109:459-465.
- Colloca L, Panaccione R, Murphy TK. The clinical implications of nocebo effects for biosimilar therapy. Front Pharmacol. 2019;10:1372. doi: 10.3389/fphar.2019.01372.
- Colloca L, Barsky AJ. Placebo and nocebo effects. N Engl J Med. 2020;382:554-561.
- 40. US Food and Drug Administration. Patient materials: biosimilar basics for patients. October 7, 2020. www.fda.gov/drugs/biosimilars/patient-materials. Accessed June 4, 2021.
- Mulcahy AW, Hlavka JP, Case SR. Biosimilar cost savings in the United States: initial experience and future potential. Rand Health Q. 2018;7:3.
- Kim H, Alten R, Avedano L, et al. The future of biosimilars: maximizing benefits across immune-mediated inflammatory diseases. Drugs. 2020;80:99-113. Erratum in: Drugs. 2020;80:1039-1040.
- Centers for Medicare & Medicaid Services. 2021 ASP drug pricing files. Revised March 4, 2021. www.cms.gov/medicare/medicare-part-b-drug-average-sales-price/2021-asp-drug-pricing-files. Accessed May 11, 2022.
- Manova M, Savova A, Vasileva M, et al. Comparative price analysis of biological products for treatment of rheumatoid arthritis. Front Pharmacol. 2018;9:1070. doi: 10.3389/fphar.2018.01070.
- Simoens S, Vulto AG. A health economic guide to market access of biosimilars. Expert Opin Biol Ther. 2021;21:9-17.
- Wilfong LS, Dave N, Garey JS, et al. A successful model of biosimilar adoption in a community oncology practice. J Clin Oncol. 2021;39(15_suppl):Abstract 6514.
- American Rheumatology Network website. https://americanrheum.com/practice-success. Accessed February 15, 2021.
- American Rheumatology Network. ARN physician featured in: American Rheumatology Network promotes a biosimilar pathway. April 22, 2020. https://americanrheum.com/news/arn-physician-featured-in-american-rheumatology-network-promotes-a-biosimilar-pathway. Accessed February 19, 2021.
- Rossmann L, Cross RK. Just say no…to the nocebo effect. Inflamm Bowel Dis. 2020;26:669.
- Bhat S, Altajar S, Shankar D, et al. Process and clinical outcomes of a biosimilar adoption program with infliximab-dyyb. J Manag Care Spec Pharm. 2020;26:410-416.
- Cvancarova Småstuen M, Brandvold M, Andenæs R. OP0070-HPR. Is patients’ satisfaction with being switched to a biosimilar medication associated with their level of health literacy? Results from a Norwegian user survey. Ann Rheum Dis. 2018;77(suppl 2):86.
- Khan D, Luig T, Mosher D, Campbell-Scherer D. Lessons from international experience with biosimilar implementation: an application of the Diffusion of Innovations model. Healthc Policy. 2020;15:16-27.
- Bodenheimer T, Sinsky C. From Triple to Quadruple Aim: care of the patient requires care of the provider. Ann Fam Med. 2014;12:573-576.