Benjamin N. Rome, MD, MPH

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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