Skylar Jeremias is the Managing Editor for The Center for Biosimilars and The American Journal of Managed Care (AJMC).

Skylar Jeremias

Rising cancer drug costs have pushed payers to search for practical ways to stretch limited budgets, and new modeling data indicate that a broad shift to biosimilar bevacizumab could give Medicare considerably more room to treat older adults with metastatic colorectal cancer (mCRC) and metastatic non-squamous non–small cell lung cancer (mNSCLC) without compromising care.

Biosimilar bevacizumab offers significant cost savings for Medicare, enhancing treatment access for metastatic colorectal and lung cancer patients without increasing spending. | Image credit: japhoto - stock.adobe.com

, assessed whether converting people from the reference bevacizumab product to several FDA-approved biosimilars could improve cost-efficiency in first-line treatment. Investigators conducted the analysis to quantify both direct savings and the number of additional individuals whose therapy could be funded using those savings on a budget-neutral basis—an increasingly relevant question as Medicare continues to spend heavily on biologics for solid tumors.

Researchers developed a simulation model rooted in a Medicare payer perspective, focusing exclusively on drug acquisition costs rather than clinical outcomes. Because biosimilars are expected to match their reference biologic in safety and efficacy, the analysis centered on pricing differences across bevacizumab-bvzr, bevacizumab-awwb, bevacizumab-adcd, and bevacizumab-maly. Costs were derived from 2024 average sales price (ASP) data, using Medicare’s reimbursement markups for originator and biosimilar products.

To estimate the number of beneficiaries likely to receive treatment, the model incorporated Medicare enrollment data, SEER incidence rates among adults aged 65 years and older, and published estimates describing the proportion of individuals who begin systemic therapy. This approach produced an estimated 6,579 people with mCRC and 3,843 people with mNSCLC who would receive bevacizumab-based regimens in an average year.

Modeled treatment reflected guideline-concordant regimens. People with mCRC were assigned bevacizumab-containing FOLFOX for initiation and maintenance. Those with mNSCLC were modeled on bevacizumab with paclitaxel plus carboplatin during induction, followed by bevacizumab alone in the maintenance phase. Dosing and vial counts were calculated using average weight and body surface area from prior research, aligning drug utilization with typical patient characteristics in the Medicare population.

Across both cancers, conversion to bevacizumab-bvzr generated the strongest cost-efficiency profile. In mCRC, switching produced per-patient per-month (PPPM) savings of $4,205, reflecting a 68% reduction relative to originator-based care. When applied to the full modeled population, monthly savings reached $27.7 million. Using these savings, Medicare could fund 13,887 additional patient-months of bevacizumab-bvzr plus FOLFOX on a budget-neutral basis. The “number needed to convert” (NNC) was 47, meaning that converting 47 individuals to the biosimilar would free enough funds to treat 100 more.

Savings were even greater for people with mNSCLC, given the higher baseline cost of originator bevacizumab in lung cancer regimens. Here, PPPM savings totaled $8,410, and full cohort monthly savings reached $32.3 million—a 70% reduction compared with the reference product. These savings could support 8,959 additional patient-months of bevacizumab-bvzr–based therapy. The NNC was 43, the lowest of all biosimilars evaluated.

Alternative biosimilars did produce savings, but to a smaller degree. Bevacizumab-awwb generated meaningful reductions—with PPPM savings of $3,876 in mCRC and $7,752 in mNSCLC—while bevacizumab-adcd offered minimal savings in both conditions.

The authors noted several limitations. The study assumed steady patient counts across the year, although treatment initiation and discontinuation vary in real-world practice. ASP values change quarterly, which may shift relative cost-efficiency over time. The analysis also relied on national averages for weight-based dosing, which may not reflect local population characteristics. Finally, because the model excluded administration or site-of-care costs, total spending differences may differ in real-world scenarios.

Even with these constraints, the findings highlight the potential for biosimilars to extend access to oncology biologics within fixed budgets—an issue of growing importance as Medicare’s oncology expenditures continue to rise. For bevacizumab, the model suggests that bevacizumab-bvzr may offer the most cost-efficient option among available biosimilars, allowing payers to treat more people with cancer without increasing overall spending.

Roth JA, Kratochvil D, Dorman S, Bernauer M. Cost-efficiency and expanded access modeling of conversion to biosimilar bevacizumab in metastatic colorectal and non-squamous non-small cell lung cancer in Medicare. 

. 2025;28(1):378-386. doi:10.1080/13696998.2025.2474884

Articles

Biosimilar bevacizumab offers significant cost savings for Medicare, enhancing treatment access for metastatic colorectal and lung cancer patients without increasing spending.

Medicare Modeling Shows Major Savings With Biosimilar Bevacizumab Use

Efforts to expand access to vision-saving therapies for people with diabetic eye disease increasingly depend on the availability of lower-cost biologic alternatives, and new comparative data add clarity to how one aflibercept biosimilar performs in routine clinical practice. A recently published retrospective analysis evaluated whether the aflibercept biosimilar QL1207 offered similar outcomes to reference aflibercept for individuals with diabetic macular edema (DME), a leading cause of vision impairment among people with diabetes.

eye doctor | Image credit: Coetzee:peopleimages.com - stock.adobe.com

The study was conducted to address a longstanding gap in real-world data. Although QL1207 was approved by China’s National Medical Products Administration in late 2023 based on structural and functional similarity to reference aflibercept, published comparative clinical information in DME populations remained limited. 

Given the high cost of originator anti-VEGF therapy and the chronic, injection-intensive nature of DME management, the investigators sought to determine whether the biosimilar performed comparably in anatomical and functional outcomes, macular perfusion metrics, injection burden, and safety.

The analysis included anonymized clinical data from 80 adults (80 eyes) with nonproliferative diabetic retinopathy and DME who were seen at a single ophthalmology department between June 2023 and April 2024. Participants were treatment-naïve and met diagnostic criteria outlined in the American Academy of Ophthalmology’s 2019 clinical guidelines. Individuals were excluded if they had other retinal diseases, a history of ocular procedures, proliferative disease, significant media opacity, or a hemoglobin A1c greater than 7%.

Demographic characteristics were balanced across treatment groups. The reference aflibercept group included 40 people (20 men and 20 women) with a mean age of 48.6 years. The QL1207 group included 40 people (19 men and 21 women) with a mean age of 46.7 years. Baseline HbA1c levels were similar, and no clinically meaningful differences emerged during the 12-month follow-up period.

All participants received 3 monthly loading doses followed by a pro re nata retreatment approach. Retreatment criteria included central retinal thickness (CRT) greater than 280 µm or a decrease of 5 or more Early Treatment Diabetic Retinopathy Study letters. Best-corrected visual acuity (BCVA), optical coherence tomography measures, and optical coherence tomography angiography parameters—including foveal avascular zone (FAZ) area and superficial and deep vascular density (SVD and DVD)—were collected at baseline and during follow-up. The investigators also recorded injection frequency and adverse events.

The study found no statistically significant differences between groups in BCVA or CRT at baseline or at 1, 3, 6, or 12 months. Both groups demonstrated significant improvement in BCVA relative to their own pretreatment values, as well as substantial reductions in CRT (

 < .05 for all within-group comparisons). At 12 months, mean CRT decreased from 447.1 µm to 280.4 µm in the reference group and from 441.0 µm to 290.3 µm in the QL1207 group. Injection burden was also similar, with mean injection counts of 3.58 in the reference group and 3.40 in the biosimilar group (

Macular microvascular outcomes also aligned closely across groups. FAZ area decreased significantly within each group, while both SVD and DVD increased, indicating improved or stabilized macular perfusion. None of these parameters differed significantly between groups at baseline or month 12.

Safety outcomes were consistent with the known safety profile of intravitreal anti-VEGF therapy. Mild events—including transient intraocular pressure elevations, corneal epithelial damage, and subconjunctival hemorrhage—occurred infrequently and at similar rates in both groups. No individuals experienced endophthalmitis, glaucoma, vitreous hemorrhage, cataract progression, or systemic cardiovascular or cerebrovascular events during the follow-up period.

The authors noted several limitations, including the retrospective design, relatively small sample size, nonrandomized treatment assignment, and 12-month follow-up period. In addition, while statistically significant changes in OCT angiography parameters were documented, their clinical significance remains uncertain. Longer, prospective, randomized studies will be needed to validate long-term comparability between QL1207 and reference aflibercept in DME.

Even with these limitations, the findings contribute to growing real-world evidence showing that aflibercept biosimilars may offer an effective and potentially more affordable option for individuals living with DME. As biosimilar adoption grows globally, studies like this may help inform formulary decisions and support broader access to sight-preserving therapy.

Zhai G, Liu N, Wang S, Zhang X. Comparative efficacy of intravitreal aflibercept biosimilar QL1207 versus reference aflibercept in the treatment of diabetic macular edema. 

. 2025:12:1662735. doi:10.3389/fmed.2025.1662735

Biosimilar QL1207 Demonstrates Equivalent Efficacy and Safety in DME

Widening interest in biosimilar adoption has renewed discussion in Switzerland about how closely priced follow-on agents compare with emerging extended-interval anti-VEGF options. A new cost-minimization analysis offers insight into this question by quantifying how ranibizumab biosimilars stack up financially against their reference product and against both doses of aflibercept for neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME).

Explore the cost-effectiveness of ranibizumab biosimilars versus aflibercept in treating AMD and DME, revealing significant savings and treatment implications. | Image credit: Syda Productions - stock.adobe.com

As Swiss payers continue to evaluate ways to control spending for chronic retinal diseases, biosimilars represent a potential mechanism for reducing direct health care costs without compromising clinical outcomes. Anti–vascular endothelial growth factor (VEGF) therapy remains the standard of care for both nAMD and DME, with treatment costs largely driven by medication pricing and injection frequency. With multiple ranibizumab biosimilars now marketed in Switzerland, the study aimed to clarify how much these agents reduce overall expenditures relative to reference ranibizumab and how their total 2-year costs compare with the more recently introduced higher-dose aflibercept 8 mg.

The model assessed unilateral treatment using real-world Swiss price data and injection frequencies derived from randomized trials. It assumed equivalent clinical outcomes across all evaluated therapies, which included aflibercept 2 mg, aflibercept 8 mg, faricimab, reference ranibizumab, and three ranibizumab biosimilars. The analysis was conducted from the health care payer perspective.

Across both disease areas, ranibizumab biosimilars generated meaningful cost savings relative to their reference product. In nAMD, the biosimilars’ 2-year total costs ranged from CHF 16,243 ($20,200) to CHF 17,618 ($21,900)—representing savings of approximately CHF 800 to CHF 2,200 per individual when compared with reference ranibizumab (CHF 18,424; $22,950). Similar results were seen in DME, where biosimilar costs ranged from CHF 18,187 ($22,600) to CHF 19,596 ($24,400), compared with CHF 20,637 ($25,700) for the reference product. These findings reflect the direct impact of lower acquisition costs, as injection frequencies for reference and biosimilar ranibizumab were assumed to be equivalent.

However, when biosimilars were compared with aflibercept products, the picture shifted. Aflibercept 2 mg carried higher overall 2-year costs than the biosimilars for both nAMD and DME, largely due to higher injection frequency. In nAMD, aflibercept 2 mg costs CHF 15,632 ($19,480)—slightly lower than the biosimilars but still higher than aflibercept 8 mg. In DME, the biosimilars were costlier than aflibercept 2 mg, which totaled CHF 15,243 ($18,990), with the difference driven by dosing intervals derived from clinical trial protocols.

Aflibercept 8 mg, designed to extend treatment intervals to as long as 16 weeks in some individuals, was consistently the lowest-cost therapy across both conditions. Its 2-year total cost was CHF 11,814 ($14,700) in nAMD and CHF 11,242 ($14,010) in DME—substantially lower than all ranibizumab products, including biosimilars. These savings stemmed from reduced injection frequency rather than drug price.

The study authors also performed break-even analyses to estimate how much biosimilar ranibizumab prices or injection frequencies would need to change to match the costs of aflibercept 8 mg. In nAMD, biosimilars would require price reductions of 55% to 59%. In DME, reductions of 76% to 79% would be needed. Similar patterns were observed for injection frequency: biosimilars would require 36% to 46% fewer injections in nAMD and up to 58% fewer in DME.

These findings highlight a central tension in the Swiss retina market. While biosimilars offer immediate, predictable price reductions compared with reference ranibizumab, the introduction of extended-interval therapies—particularly aflibercept 8 mg—shifts the cost landscape by reducing service utilization rather than drug unit cost. For conditions that require long-term maintenance therapy, fewer injections translate directly into reduced administration and visit costs.

The study had several limitations. Injection frequencies were based on clinical trials rather than real-world data, which may change as clinicians gain experience with newer products. The model assumed equivalent clinical outcomes among all agents, did not incorporate safety or adherence considerations, and used a 2-year horizon that may not reflect longer-term treatment patterns.

Even with these limitations, the analysis underscores that ranibizumab biosimilars meaningfully reduce costs relative to their reference product and offer a lower-cost alternative to aflibercept 2 mg, depending on disease area. However, the cost advantages of biosimilars are insufficient to offset the significantly reduced injection burden associated with aflibercept 8 mg, which remains the lowest-cost overall option in this model.

For Swiss health care payers and clinicians balancing immediate price savings against long-term resource use, these findings provide useful context for formulary decisions and treatment planning as biosimilar competition expands and extended-interval options continue to enter the market.

Explore the cost-effectiveness of ranibizumab biosimilars versus aflibercept in treating AMD and DME, revealing significant savings and treatment implications.

Swiss Analysis Shows Biosimilars Cut Costs but Longer-Interval Options Lead Savings

November 2025 marked a period of significant activity in the biosimilar market, characterized by multiple FDA approvals and crucial policy discussions concerning market access and regulatory modernization. Key themes included the expansion of competition in oncology and bone health, global efforts toward regulatory harmonization, and intense scrutiny of US market barriers.

The month saw major advancements in product approvals and interchangeability designations, particularly for denosumab and pertuzumab biosimilars.

The FDA approved multiple denosumab biosimilars throughout the fall, bolstering competition in therapies used for postmenopausal osteoporosis (referencing Prolia) and prevention of skeletal-related events in cancer (referencing Xgeva).

 This momentum included the formal granting of interchangeability (IC) designations to 2 pairs of products in late October: Fresenius Kabi's Conexxence and Bomyntra, and Celltrion’s Stobocclo and Osenvelt (denosumab-bmwo). Interchangeability status allows pharmacists to substitute these products for their reference biologics without prescriber approval, subject to state laws.

Further expanding the oncology pipeline, the FDA approved Poherdy (pertuzumab-dpzb) injection on November 18, making it the first interchangeable biosimilar for Perjeta (pertuzumab).

 Developed by Shanghai Henlius Biotech and commercialized by Organon, Poherdy is approved for all the same indications as Perjeta, including use in combination with trastuzumab and chemotherapy for HER2-positive metastatic, locally advanced, or early-stage breast cancer. The approval was based on evidence demonstrating that Poherdy is highly similar to Perjeta with no clinically meaningful differences. Despite this regulatory success, the product immediately faced patent litigation, as the originator manufacturers filed a complaint alleging infringement on 24 patents.

Global Biosimilars Week Focuses on Access

The sixth annual Global Biosimilars Week (November 3 to 7, 2025) included a webinar, "Aligning Biosimilar Access Policy With Global Health Priorities," which explored how biosimilars can help meet the UN’s Sustainable Development Goals for Health by 2030.

Lisa Hedman of the World Health Organization (WHO) noted that progress toward the WHO target of 80% biosimilar availability is uneven across regions, with public sector availability ranging from 38% to 68%. Julie Maréchal-Jamil of Medicines for Europe highlighted that regulatory convergence initiatives are key drivers for access, stressing the need for a global regulators roadmap toward tailored clinical development. She cautioned that the asynchronous adoption of new regulatory standards might force developers to maintain extended timelines or develop separate programs for different jurisdictions. Separately, in Mexico, where biosimilars are called biocomparables, current local rules still require clinical trials to demonstrate efficacy and safety, determined case-by-case by the New Molecules Committee.

Policy Updates: Regulatory Reform and Economic Impact

Policy discussions in November centered on bridging the gap between regulatory reforms and real-world market uptake.

In the podcast episode "All Things Biosimilars: How Streamlined CES Rules Could Shift the Market," Giuseppe Randazzo and Alex Keeton of the Association of Accessible Medicines (AAM) analyzed the FDA’s draft guidance on comparative efficacy studies (CES) and interchangeability.

 The guidance seeks to streamline development by reducing or eliminating the need for large, costly CES, instead recognizing the scientific value of advanced analytical tools and pharmacokinetic data. This regulatory evolution could save manufacturers years of development time and an estimated $100 million to $300 million per program. 

The hosts noted that while this shift supports competition, Congressional action is still needed to resolve policy gaps, particularly regarding the continuing existence of the interchangeable designation and restrictive state-level substitution laws. They also brought attention to the "biosimilar void," highlighting that over 100 biologics are nearing patent expiration without biosimilars in active development.

The general consensus across policy articles was that changing FDA interchangeability standards, while necessary, is likely insufficient to optimize US biosimilar competition.

 Additional steps needed include amending state pharmacist substitution laws, addressing strategies by payers and pharmacy benefit managers that inhibit competition (such as rebate walls), and enhancing education to build confidence among clinicians and patients.

Rounding out the month's news, an economic analysis underscored the tangible financial benefits of biosimilar uptake.

 A budget impact analysis evaluated the potential financial implications of adopting biosimilar denosumab within a US health plan, projecting substantial cost savings for payers. In a base case scenario, the model projected a 5-year net savings of over $38.6 million. 

Furthermore, the study modeled how reinvesting those savings could expand patient access, predicting that using savings to treat patients previously receiving zoledronic acid could allow for the treatment of nearly 1,000 additional patients over 5 years, thereby preventing 28.2 additional skeletal-related events. These findings suggest that biosimilar denosumab offers a pathway to reduce the total cost of care in oncology while potentially improving patient access to essential supportive therapy.

1. Jeremias S. FDA quietly approves denosumab biosimilars, issues interchangeability for others. The Center for Biosimilars

https://www.centerforbiosimilars.com/view/fda-quietly-approves-denosumab-biosimilars-issues-interchangeability-for-others

2. Jeremias S. FDA approves Poherdy: the first interchangeable biosimilar to Perjeta. The Center for Biosimilars. November 18, 2025. 

https://www.centerforbiosimilars.com/view/fda-approves-poherdy-first-interchangeable-biosimilar-to-perjeta

3. Jeremias S. Webinar: aligning biosimilar access policy with global health priorities. The Center for Biosimilars. November 14, 2025. 

https://www.centerforbiosimilars.com/view/webinar-aligning-biosimilar-access-policy-with-global-health-priorities

4. Jeremias S, Randazzo G, Keeton A. All things biosimilars: how streamlined CES rules could shift the market. The Center for Biosimilars. November 30, 2025. 

https://www.centerforbiosimilars.com/view/all-things-biosimilars-how-streamlined-ces-rules-could-shift-the-market

5. Rome BN, Bhaskar A, Kesselheim AS. Biosimilar interchangeability and substitution in the US: what comes next? The Center for Biosimilars. November 27, 2025. 

https://www.centerforbiosimilars.com/view/biosimilar-interchangeability-and-substitution-in-the-us-what-comes-next-

6. Jeremias S. Economic analysis supports the formulary shift to biosimilar denosumab. The Center for Biosimilars. November 26, 2025. 

https://www.centerforbiosimilars.com/view/economic-analysis-supports-formulary-shift-to-biosimilar-denosumab

November 2025 highlights FDA approvals for denosumab and pertuzumab biosimilars, enhancing competition and access in oncology and bone health markets.

Biosimilars News Roundup: Approvals Surge Amid Policy Changes

All things biosimilars

In the special video podcast episode, produced in partnership with the Association for Accessible Medicines (AAM), co-hosts Giuseppe Randazzo, senior vice president of sciences and regulatory affairs at AAM, and Alex Keeton, the new executive director of AAM's Biosimilars Council, break down one of the most consequential policy shifts in the biosimilar landscape in years: the FDA’s new draft guidance on comparative efficacy studies (CES) and interchangeability. 

Keeton opened the discussion by outlining how the agency’s updated scientific framework aims to streamline biosimilar development by reducing, and in many cases eliminating, the need for large, costly comparative efficacy studies. Instead, the FDA is formally recognizing that advanced analytical tools and pharmacokinetic data are often more sensitive and scientifically meaningful than clinical efficacy trials—an evolution that could save manufacturers years of development time and as much as $100 million to $300 million per program.

Randazzo emphasized the potential impact on access, noting that lower development costs can help expand competition and deliver more affordable biologic alternatives to patients. The hosts highlighted growing political momentum behind biosimilars following a recent press conference in which federal officials framed the guidance as a shift from bureaucracy to science. However, they also pointed to persistent policy gaps, including state-level substitution restrictions and the continued statutory existence of the interchangeable designation—an issue the hosts argued now requires Congressional action to align the law with current FDA science.

The conversation also addressed the “biosimilar void,” a term describing more than 100 biologics that are approaching patent expiration with no biosimilars in active development. Randazzo noted that reducing clinical trial requirements alone will not close this gap; challenges such as manufacturing complexity, market incentives, and payer-side barriers continue to slow progress.

Keeton and Randazzo closed by previewing a future episode dedicated entirely to payer dynamics, reinforcing that regulatory reform is only one piece of the broader effort to make biosimilars more accessible and sustainable across the US health care system.

To learn more about the FDA draft guidance regarding clinical efficacy studies for biosimilars and interchangeability, 

To read more about G's discussion with Sarah Yim, MD, from the FDA from the recent 2025 GRx+Biosims conference, 

To read more on Yim's perspectives on biosimilar policy harmonization, 

Podcasts

In this special video episode of Not So Different, co-hosts Giuseppe Randazzo and Alex Keeton from the Association of Accessible Medicines tackle the FDA's recent draft guidance on comparative efficacy studies (CES) and interchangeability for biosimilars, addressing some of the confusion around the new announcement and remaining action items for the agency.

All Things Biosimilars: How Streamlined CES Rules Could Shift the Market

In 2009, Congress created a regulatory pathway for biosimilars to encourage competition and address rising spending on biologic drugs. One barrier to adopting biosimilars in the US is that the FDA has traditionally required additional testing for biosimilars to be deemed interchangeable with the original biologic. This analysis reviews the history and current status of biosimilar regulation in the US, concluding that changing the FDA’s interchangeability standards—as proposed by some policy makers—is a potentially useful but likely insufficient step to improve biosimilar competition in the US. Other policy options include more state laws allowing pharmacists to automatically substitute biosimilars, addressing strategies by payers and pharmacy benefit managers that inhibit biosimilar competition, and implementing more widespread education of clinicians and patients to build confidence about biosimilars. Other policies to ensure the affordability of biologic drugs include expanding Medicare’s price negotiation to cover biologics with or without biosimilar competition.

Changing the FDA biosimilar interchangeability standards is a necessary but likely insufficient step to improve biosimilar competition in the US. | Image credit: MohamadFaizal - stock.adobe.com

Congress created an expedited approval pathway for biosimilar drugs to compete and lower costs of biologic medications, but biosimilar use has been characterized by slow uptake.

Currently, not all biosimilars are deemed interchangeable with the original biologic, and some policy makers have proposed changing the biosimilar interchangeability laws to improve competition in the biosimilar market.

Such a change is a useful first step, but other changes are needed, including amending state laws to allow greater automatic pharmacist substitution, addressing strategies by payers and pharmacy benefit managers that inhibit biosimilar competition, and ensuring more education of clinicians and patients to build confidence about biosimilars.

Biologic drugs—complex products often synthesized from living cells—make up only 2% of prescriptions in the US but account for approximately half of prescription drug spending.

 To address these high costs, Congress passed the Biologics Price Competition and Innovation Act (BPCIA) in 2009. This law created a framework for the FDA to approve biosimilars, which are biologics made by different manufacturers with no clinically meaningful differences from already-approved biologic drugs.

 The goal was to spur competition between biosimilars and biologics to lower costs, just as generic competition has done for small-molecule drugs. In the decade after the passage of the BPCIA, however, the biosimilar marketplace was characterized by delays in biosimilar approval and availability, slow biosimilar uptake,

Challenges to biosimilar competition include limited interchangeability and lack of automatic pharmacist substitution. The FDA certifies nearly all generic drugs as therapeutically equivalent to the original brand-name drugs, and state laws allow—and often mandate—pharmacists to substitute therapeutically equivalent generics in place of brand-name drugs.

 This automatic pharmacist substitution facilitates rapid adoption of generics.

 By contrast, the BPCIA set additional standards for biosimilars to be deemed interchangeable with the originator biologic, and most state pharmacy substitution laws are more restrictive for biosimilars than generics.

 In recent years, the evidence required by the FDA to meet the interchangeability standards has evolved, and some at the FDA have proposed eliminating the separate interchangeability designation entirely.

 Improving the interchangeability of biosimilars could enhance biosimilar uptake in the US, although additional steps are needed to unlock further savings for patients and the health care system.

The BPCIA required the FDA to affirm that biosimilars have no clinically meaningful differences and are as safe and effective as the original biologic. In practice, this has meant that biosimilars are typically tested in head-to-head randomized clinical trials against the original biologic for at least 1 of the drug’s indications. By contrast, the bioequivalence determinations for generic small-molecule drugs are based on more limited pharmacokinetic and pharmacodynamic data from small studies of healthy volunteers.

For biosimilars to be designated as interchangeable, the FDA requires evidence that a biosimilar could be expected to yield the same results as the original biologic for any individual patient and that switching between the biosimilar and the original poses no additional concerns related to safety or diminished effectiveness. This was initially operationalized via switching studies run by biosimilar manufacturers that evaluated safety and efficacy when patients alternated between a biosimilar and its reference product.

One of the primary motivations for a separate interchangeability standard was concerns that minor differences between biologics and biosimilars could lead to antidrug antibodies when patients switch versions, which could diminish the effectiveness or lead to adverse effects through cross-reactivity with patients’ own proteins. These concerns were based on rare reports of treatment failure related to antidrug antibodies.

 Regulators in other countries, including the European Medicines Agency, did not include similar 2-tier regulatory systems for biosimilars,

 although automatic pharmacist substitution is not standard practice in these countries.

The FDA approved the first biosimilar in 2015, but it was not until 6 years later that the FDA approved the first biosimilar with an interchangeability designation, a version of long-acting insulin glargine-yfgn (Semglee) deemed interchangeable with the original version (Lantus). As of May 2025, the FDA has approved 75 biosimilars, 21 of which were granted interchangeable designations.

Recently, US regulators have signaled a shift in their approach to biosimilar interchangeability. In June 2024, the FDA released an updated draft guidance that eliminated the expectation for switching studies.

 The FDA defended this change based in part on a meta-analysis conducted by FDA scientists that revealed no differences in safety or immunogenicity among patients switching from a reference biologic to a biosimilar.

 These conclusions aligned with those from extensive postmarketing analyses conducted in the European Union and the global experience,

 reinforcing that the FDA’s “highly similar” standards for biosimilars were sufficient for determining interchangeability.

In response to shifting FDA guidance, some policy makers have proposed that Congress alter the BPCIA to eliminate the separate interchangeability standards.

 Such a policy was included in the Biden administration’s 2024-2025 fiscal year budgetand was publicly supported by some leaders at the FDA.

One goal of removing the separate interchangeability designation for biosimilars is to boost competition and further lower costs for biologic drugs in the US. This could be accomplished if the streamlined regulatory standards encourage more drugmakers to introduce biosimilars or if the improved interchangeability standards promote greater uptake of biosimilars by patients.

Key Barriers and Solutions Beyond Interchangeability

Even if Congress were to remove the interchangeability designation, competition in the biosimilar marketplace in the US could be further optimized by addressing state pharmacist substitution laws, reimbursement behavior by pharmacy benefit managers (PBMs), and skepticism from patients and clinicians. Simultaneously, it is sensible to enact alternative policies to ensure the affordability of biologic drugs after patent protection expires, such as expanding Medicare’s price negotiation to cover biologics with or without biosimilar competition.

 The rules about whether pharmacists can (or must) automatically substitute biosimilars in place of the original biologic are set by state legislatures in their oversight of the practice of pharmacists. For generics, substitution laws have been remarkably effective. Generics are used 97% of the time when available, and generic uptake is lower when state substitution laws are more restrictive.

After Congress passed the BCPIA, many state pharmacy substitution laws were modified to allow pharmacist substitution of FDA-designated interchangeable biosimilars. However, these laws were often stricter than the same state’s laws governing generic substitution; for example, many states required physician notification if a pharmacist substituted FDA-approved biosimilars.

 Additionally, unlike the FDA’s generic therapeutic equivalence designations, interchangeable biosimilar designations only apply between each biosimilar and the original drug—the FDA does not certify that 2 biosimilars for the same drug are interchangeable. It remains unclear whether state laws would allow substitution between multiple biosimilars of the same drug.

Thus, current state substitution laws may undermine rapid biosimilar uptake, particularly if these laws do not permit substitution between different biosimilars of the same biologic drug. Even if Congress revises the FDA’s interchangeability standards, it is ultimately up to state lawmakers to determine the role of pharmacists in expanding biosimilar use.

 For pharmacists to freely substitute FDA-approved biosimilars, payers and their PBMs would need to adjust reimbursement policies to be agnostic to which version of a biologic drug patients receive. For generic drugs, public and private payers usually reimburse pharmacies based on a maximum allowable cost schedule, which incentivizes pharmacies to dispense the lowest-cost generic version.

By contrast, PBMs have generally treated biologics and biosimilars separately, negotiating rebates and formulary position with each manufacturer, similar to how they handle competition among multiple brand-name drugs in the same class. Thus, even if biosimilars are interchangeable, pharmacists must fill whichever version is preferred by a patient’s insurance formulary. Additionally, biologic manufacturers can leverage their rebates to block biosimilar competitors.

 For example, several biosimilar versions of the blockbuster drug adalimumab (Humira) entered the market in 2023. However, brand-name Humira continued to account for more than 98% of adalimumab prescriptions, likely because AbbVie offered substantial rebates to PBMs to maintain Humira’s advantage over biosimilars.

In August 2023, CVS Caremark, one of the 3 largest PBMs in the US, announced that it would stop covering Humira and instead cover a biosimilar that it would produce via a comarketing arrangement with the drug’s manufacturer. Three PBMs account for approximately 80% of all prescriptions in the US,

 so if other PBMs pursue a similar comarketing strategy, this could mean that only a limited number of biosimilar makers are able to secure such contracts and market their products successfully in the US. These arrangements may result in short-term savings for patients and the health system, but a market characterized by such agreements might dissuade companies from investing in developing future biosimilars without assurance that their product will generate sufficient sales to cover these costs.

Some members of Congress have asked federal regulators to scrutinize comarketing agreements between PBMs and biosimilar makers for anticompetitive behavior.

 Additionally, state and federal policy makers could consider prohibiting confidential rebates for biologic drugs once biosimilar versions become available in the US to improve price transparency and facilitate more direct price competition. For federal programs such as Medicare, this may require Congress to revise the safe harbor protections that currently exempt rebates from federal antikickback statute. For clinician-administered drugs, CMS could revise its Part B reimbursement rules to create bundled payment rates for biologics and biosimilars, like the current reimbursement rules for generics.

 A prerequisite for relying on pharmacist substitution to facilitate a competitive biosimilar marketplace is that patients and prescribers be comfortable freely switching between versions, even after they have initiated treatment. Switches between generic drug manufacturers are commonplace; although these changes are safe and effective,

 patients who experience a change in the size, shape, or color of their medication (eg, because they receive a version made by a different manufacturer) are more likely to stop taking it.

For biosimilars, regulators in the US and internationally have not found evidence that switching between versions poses risks in terms of safety or effectiveness. Still, surveys of prescribers have shown varying degrees of confidence; some prescribers have expressed concerns about patients switching to a biosimilar after achieving clinical stability with the original biologic.

 Although these concerns are well intentioned, they raise a fundamental question about whether prescribers (and patients) would accept widespread automatic biosimilar substitution. If regulations and laws allowed pharmacist substitution only for new users, for example, this would dramatically limit the ability to rely on substitution to promote competition between biologics and biosimilars.

Although FDA regulators are convinced that switching between different versions of a biologic is safe, more evidence or better communication of existing evidence is needed to educate patients and clinicians. Similar knowledge barriers existed in the early days of generics, when patients and clinicians expressed skepticism about the safety and efficacy of generic medications. Even as late as 2009, 23% of physicians surveyed harbored doubts about the effectiveness of generics, and 50% had concerns about their quality, leading more than 25% to avoid recommending generics as first-line therapy.

 Overcoming these barriers will require robust educational campaigns for patients and prescribers.

 Competition from low-cost generics has been remarkably effective in lowering costs of small-molecule drugs, in large part due to interchangeability and pharmacy substitution. If the same approach proves insufficient for biologic drugs, another option is regulation of prices after a period that allows biologics to earn sufficient sales revenue to recoup research and development costs. The Inflation Reduction Act of 2022 allows Medicare to negotiate prices for certain drugs and includes a statutory minimum price reduction of 60% lower than the nonfederal average manufacturer price after a drug has been on the US market for 16 years.

 Currently, Medicare’s ability to negotiate prices ends once generic or biosimilar competition begins, but Congress could amend this to continue leveraging Medicare’s negotiation authority to lower biologic prices rather than relying solely on biosimilar competition.

Changing the FDA’s interchangeability standards is a necessary step to improve biosimilar dissemination in the US market and thereby increase competition, reduce prices, and improve access to these medications. However, such a policy change would likely be insufficient on its own to optimize the uptake and affordability of biologic medications. So far, the evidence supports the safety and effectiveness of switching between a biologic and its biosimilars, but additional evidence and guidance from regulatory bodies, including the FDA, could help build confidence among providers and patients, which could pave the way for more flexible state pharmacy substitution laws. Policies are also needed to prevent payers and PBMs from inhibiting biosimilar competition and potentially to ensure that biologic prices fall after a period, regardless of biosimilar competition.

 Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (BNR, AB, ASK), Boston, MA.

 This project was funded by a grant from Arnold Ventures.

 Dr Rome and Dr Kesselheim have received consulting fees from Alosa Health and grant funding from the Elevance Health Public Policy Institute and the National Academy for State Health Policy. Dr Kesselheim has served as an expert on behalf of a class of payers in a case against Johnson & Johnson relating to patents on the biologic drug Stelara and on behalf of the Federal Trade Commission in a case against pharmacy benefit managers. Ms Bhaskar reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

 Concept and design (BNR, AB, ASK); drafting of the manuscript (BNR, AB); critical revision of the manuscript for important intellectual content (BNR, AB, ASK); obtaining funding (ASK); administrative, technical, or logistic support (AB); and supervision (BNR, ASK).

 Benjamin N. Rome, MD, MPH, Brigham and Women’s Hospital Division of Pharmacoepidemiology and Pharmacoeconomics, 1620 Tremont St, Ste 3030, Boston, MA 02120. Email: brome@bwh.harvard.edu.

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