FDA further blurs the line between biosimilars and interchangeables

Life Sciences | By RACHEL COE, MSC

Jun. 21, 2024

First, FDA removed the “reward” for product developers who successfully demonstrated product interchangeability. Now, in a new guidance document, it’s gone further and reduced the “risk” for developers considering biosimilar product development who may previously have been deterred by the ambiguous, resource-draining process of obtaining biosimilar interchangeability.

Biosimilar product development and approval

  • The Biologics Price Competition and Innovation (BPCI) Act of 2009 intended to increase the number of biologic products on the market by creating two types of approvals for biosimilar products. Both types of approvals (biosimilars and interchangeables) utilize the same 351(k) pathway but have slightly different requirements. Biosimilars are biological products that are highly similar (but not identical) to a previously approved biologic, referred to as the reference product. Because of the complexities involved in the production of biological products from living organisms, minor differences between a reference product and its biosimilars are anticipated. Instead, approval hinges on the ability of sponsors to demonstrate there are no “clinically meaningful differences” between the proposed biosimilar and the reference product.
  • To demonstrate bioequivalence, the FDA recommends a stepwise approach. This process starts with extensive structural and functional characterization (i.e., benchtop studies), followed by nonclinical (animal) studies, and finally, ends with the conduct of comparative human pharmacokinetic (PK) and pharmacodynamic (PD) studies along with an assessment of the product’s clinical immunogenicity. While these studies may be conducted separately, the PK and PD study can usually be combined (though the immunogenicity evaluation might be conducted in a subset of the intended population, or in a slightly different population). Oftentimes, PK studies are explained as studies that describe “what the body does to the drug” (i.e., how it absorbs it, breaks it down, and excretes it), while PD studies describe “what the drug does to the body” (i.e., what biological responses are triggered by the drug). Thus, PD measures should be relevant to clinical outcomes; however, suitable PD endpoints are not always available. In cases where there is not a suitable PD measure or if, following the clinical PK/PD/immunogenicity assessments, there is still “residual uncertainty” regarding biosimilarity, the sponsor is then expected to conduct additional, comparative clinical studies. These “additional” clinical studies are generally understood to mean comparative efficacy studies (CES).
  • However, the biosimilars pathway has not enjoyed the same level of success as the generic drugs approval pathway (created via the 1984 Hatch-Waxman Amendments). In general, the generics approval process offers significant cost savings for sponsors, which has spurred their development and driven down costs for patients. A January 2022 Seminars in Arthritis and Rheumatism publication noted that a “generic [drug] may only cost $1 million to $4 million and take two years to develop vs $100 million to $250 million and seven to eight years for a biosimilar.” Why the discrepancy? A few reasons: the analytical characterization of biosimilars is challenging, and biosimilar developers have limited insight on the manufacturing process for the reference products against which biologic products are compared. However, reference products’ manufacturing processes are typically proprietary, so biosimilar products cannot replicate them precisely, making it hard to demonstrate that their manufacturing process will result in a biosimilar that is “highly similar” to the reference.
  • Most of all, costly clinical studies have stifled biosimilar product development. Though originally conceived as a last resort, comparative clinical studies have become a common and costly aspect of biosimilar drug development, which even the FDA admits are “substantially more resource-intensive in terms of time and money” than lab assessments. One study found that most comparative efficacy trials for FDA-approved biosimilar products were at least as rigorous – and often “larger, longer, and more costly” – as the pivotal trials to approve new molecular entities. Most of the studies involved “both an initial comparative efficacy period and additional follow-up, during which a subset of patients was switched between the biosimilar and reference products.”

In the past year, regulators from around the world have signaled they are ready to face this issue head-on, by doing away with requirements for clinical studies

  • Are comparative clinical studies really necessary? Back in the fall, the FDA and the International Pharmaceutical Regulators Program (IPRP) Biosimilars Working Group (BWG) cohosted a three-day meeting to discuss options to reduce the barriers stifling biosimilar product development. Representing FDA was STACEY RICCI, Director of the Scientific Review Staff in the Office of Therapeutic Biologics and Biosimilars (OTBB). Ricci stated that while, conceptually, the stepwise process for demonstrating bioequivalence seems reasonable, FDA has learned this is simply not the case. She highlighted that FDA first developed its guidance on biosimilarity and recommended this approach just a few years after the passage of the BPCI Act of 2009: before it had ever actually reviewed a biosimilar product. At the time the guidance was written, regulators, manufacturers, and clinicians in the U.S. were generally unfamiliar and inexperienced with evaluating this product type, so the guidance called for clinical data to assure stakeholders that biosimilars were truly just as safe and effective as their originator, reference products. [Read AgencyIQ’s full coverage of the meeting here]
  • Lessons learned: Since then, the FDA has learned that many of these steps must actually be conducted in parallel by sponsors, and that there are significant financial implications for requiring such large investments from sponsors before the analytical assessments are completed (the step which FDA thought would be completed well in advance of any other studies). Other regulators agreed the biosimilars regulatory framework developed 15 years ago resulted in recommendations that, today, do not necessarily reflect current science nor the experience that has been gained since. To quell very small uncertainties, “Is it reasonable to expect that a clinical study could detect a difference where no significant differences are seen in physiochemical or biological activity assays?” asked Health Canada’s BRADLEY SCOTT. The resounding answer was “no.” Presenters said these studies are often statistically underpowered, challenging and costly to conduct, and—most of all—provide little useful evidence regarding biosimilarity where only minor residual uncertainties exist.
  • Things have changed: Today, we are on the verge of a paradigm change, Ricci contended. “Clinical endpoints simply are not as sensitive as analytical data to detect differences between products,” she explained, arguing instead for a streamlined approach and the development of risk-based criteria for justifying when a more limited clinical assessment will provide value. Rather than using comparative clinical studies as “comfort blankets” (a term used by multiple speakers during the meeting), efforts must be made to bolster stakeholder confidence in comparative analytical assessments. There’s a need for stakeholder education and reassurance that robust structural and functional analytical comparisons can demonstrate that products are highly similar, and that the biosimilar will have the same clinical performance as the reference product.

At the same time the agency is working to stimulate biosimilar product development, the FDA has been rolling back incentives for interchangeable biosimilar development.

  • Interchangeable products were established by the BPCI as a subset of biosimilars that are demonstrated to produce the same clinical result as the reference product in any given patient. In practice, the biggest difference between interchangeable products and biosimilars are that pharmacists can substitute interchangeable biosimilars without consulting the prescriber (though different state laws may apply). For sponsors, interchangeable products require further evidence collected via additional studies. For example, switching studies must confirm that the biosimilar product is expected to produce the same clinical result as the reference product in any given patient, and that alternating or switching between the biosimilar and reference products will not cause any ill effects.
  • Unlike comparative clinical studies, which are used to resolve any residual uncertainty about a biosimilar compared to its reference product, switching studies are a slightly different type of clinical study. For products used more than once by patients, switching studies are intended to ensure that “the risk in terms of safety or diminished efficacy of alternating or switching between use of the [proposed interchangeable products] and the reference product is not greater than the risk of using the reference product without such alternation or switch.” In these studies, a two-arm trial design is commonly employed. During the lead-in period, all patients are assigned to the reference product followed by randomization to either the “switching arm” or “non-switching arm” of the study.
  • In theory, interchangeable products were intended to represent a sort of higher standard for sponsors to achieve, with rewards given to developers capable of achieving that standard. New interchangeable products would be eligible for periods of marketing exclusivity upon their approval by the FDA, with up to 42 months of protection from competition. And because many state legislative bodies passed laws preventing the pharmacy-level substitution of reference biologics for biosimilars unless it had been determined to be interchangeable by the FDA, sponsors similarly had an incentive to seek interchangeable status. But in practice, the FDA hasn’t seen many interchangeable products approved. At present, there are just 13 interchangeable products that have been approved by the agency (although some are approved for multiple doses).
  • The labeling for biosimilars and interchangeable products is expected to be similar—though not identical—to that of their reference products. In 2018, the FDA published a detailed guidance on labeling requirements for biosimilar products. It explained that products should be declared as biosimilar near the top of the Highlights of Prescribing Information section, with an asterisk to a specific, agency-provided statement explaining the meaning of “biosimilar.” Two years later, the agency FDA published separate recommendations for interchangeable products in a completely new guidance. The November 2020 document, entitled Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act, clarified that, for the most part, labeling for interchangeable products should follow the same guidance proposed for other biosimilars. It also stated that no biosimilar or interchangeable products should include a description of or data from clinical studies conducted to support a demonstration of biosimilarity or interchangeability. Additionally, it provided specific “Interchangeable Product (IP)” language to be used in place of the “biosimilar” explainer language provided in the 2018 guidance.
  • Less than a year ago, the FDA released an updated draft guidance on labeling for biosimilar and interchangeable products, suggesting a dramatic change in approach. Among other changes, this guidance proposed eliminating the distinction between “biosimilar” and “interchangeable” in the product labeling. The September 2023 draft guidance said that all products, whether biosimilar or interchangeable, should be referred to as “biosimilar” on the product label, with a general definition explaining the term biosimilar. According to the document, the agency no longer recommends the use of the term “interchangeable” in any portion of the labeling, nor does it provide a definition for this term. [ Read AgencyIQ’s analysis of this guidance here.]
  • By way of explanation for this shift in policy, the guidance stated that “It has become clear that an applicant may choose to submit a single 351(k) biologics license application (BLA) seeking to license both biosimilar and interchangeable biosimilar products. Draft labeling for such applications would need to address both biosimilar and interchangeable biosimilar products, and the status of a particular product within such a BLA can change over time, for example, as relevant exclusivities expire. Determining how to appropriately label such products and keep labeling up to date without causing undue confusion has proven challenging.”
  • The reactions to this shift in policy were varied. Overall, most stakeholders acknowledged a general state of confusion and misinformation regarding biosimilars, most of which relates to a lack of clarity regarding the meaningful distinction between biosimilarity and interchangeability. In response, an array of arguments were made both for and against maintaining “interchangeability” as a unique regulatory distinction. [Read Agency IQ’s breakdown of the comments submitted here]
  • As AgencyIQ first reported in December 2023, the FDA moved to implement the aforementioned guidance – which was still in draft form and in its comment period – almost immediately. An AgencyIQ review found that the labeling statements of all interchangeable biosimilar products approved by the FDA (including labeling changes) after the release of the September 2023 guidance no longer contained any mention of the word “interchangeable.” The search addressed Abrilada (adalimumab; interchangeable with Humira), Byooviz (ranibizumab; interchangeable with Lucentis) and Wezlana (ustekinumab; interchangeable with Stelara). [ Read AgencyIQ’s analysis here.]
  • Furthermore, in April 2024, FDA also released a revised draft guidance document on promotional labeling, indicating that even if sponsors have obtained interchangeable status, they are not to imply that their product is safer or more effective than a biosimilar competitor in promotional materials. “When multiple products are licensed as biosimilar to and interchangeable with or biosimilar to but not interchangeable with the same reference product, promotional communications should avoid representing or suggesting that any of these products (i.e., the reference product, any interchangeable biosimilar product(s), or any non-interchangeable biosimilar product(s)) are less safe or effective than each other for their approved uses based on their licensure pathways,” the guidance states. That is likely to make it difficult to promote a product’s interchangeable status using anything other than a legal definition of the term ”interchangeable.” [ Read AgencyIQ’s analysis of this guidance here.]
  • The extent to which the FDA seeks to pursue this approach is most apparent, however, in its Fiscal Year 2025 budget proposal, which for the first time contains a request for Congress to “eliminate the statutory distinction between the approval standard for biosimilar and interchangeable biosimilar products.” As the agency explained in the request, “The statutory distinction between biosimilars and interchangeable biosimilars has led to confusion and misunderstanding, including among patients and healthcare providers, about the safety and effectiveness of biosimilars and about whether interchangeable biosimilars are safer or more effective than other biosimilars.” It asks Congress to eliminate the separate statutory standard for a determination of interchangeability “and to deem all approved biosimilars to be interchangeable with their respective reference products.” [Read AgencyIQ’s analysis of this issue here]

FDA has just closed the gap between these product types just a little more

  • A new draft guidance, published in the Federal Register today, takes the FDA’s stance on the lack of differences between biosimilar and interchangeable products a step further. The seven-page draft is a little unusual in that it puts stakeholders on notice that the FDA is planning to update a different, existing guidance. The previous guidance, Considerations in Demonstrating Interchangeability with a Reference Product, was finalized in May 2019 and provides recommendations to biosimilar developers on when and how to conduct switching studies to demonstrate product interchangeability.
  • Currently, the guidance says that A switching study or studies will generally be expected” for sponsors to meet the criteria for interchangeability “set forth in section 351(k)(4)(B) of the PHS Act.” Furthermore, while it may seem like an attractive option for sponsors to first seek authorization of their product as a biosimilar and then collect postmarketing data to demonstrate that the biosimilar produces the same clinical result as the reference product, the guidance cautions against this idea. Instead, it states: “Our current thinking is that postmarketing data collected from products first licensed and marketed as a biosimilar, without corresponding data derived from an appropriately designed, prospective, controlled switching study or studies, generally would not be sufficient to support a demonstration of interchangeability.” Furthermore, for some products both a switching study plus the collection of postmarketing data may be necessary.
  • Per the new guidance, the FDA intends to rescind most of these requirements. It says that “Since publication of the Interchangeability Guidance, experience has shown that for the products approved as biosimilars to date, the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product. Accordingly, FDA’s scientific approach to when a switching study or studies may be needed to support a demonstration of interchangeability has evolved.” In line with this context, the FDA plans to “replace certain sections in [the interchangeability guidance] such as Sections VI.A and VII, to reflect FDA’s current thinking regarding the subject addressed in this guidance.”
  • Analytical technologies now outperform clinical studies, says the FDA. Near the end of the draft, the guidance reaffirms the FDA’s authority to determine what is and isn’t required for a product to be considered “interchangeable.” The draft also offers further context for the move away from switching studies: “Moreover, currently available analytical technologies can structurally characterize highly purified therapeutic proteins and model in vivo functional effects with a high degree of specificity and sensitivity using in vitro biological and biochemical assays.”
  • Instead of performing dedicated, switching studies, applicants need only to provide FDA with an assessment of “why the comparative analytical and clinical data provided in the application or supplement support a showing that the switching standard set forth in section 351(k)(4)(B) of the PHS Act has been met. Any such assessment should include any other information the applicant considers relevant to support a showing that the risk, in terms of safety and diminished efficacy, from alternating or switching between the reference product and the proposed interchangeable product is not greater than the risk of using the reference product without such alternation or switch.”
  • Sponsors can now simply send in an amendment requesting interchangeability, instructs the guidance. Applicants with a pending 351(k) BLA for a proposed biosimilar product may choose to submit an amendment to their pending BLA with the above-described assessment along with any additional data and/or information that they consider relevant to address the requirements in section 351(k)(4) of the PHS Act and request that their BLA be reviewed as a proposed interchangeable biosimilar,” concludes the guidance.

What does it mean?

  • Regulators are really trying to stimulate biosimilar products development. To do so, they’re actively looking to do away with the need for large, comparative clinical studies because they cost sponsors a lot and generate very little, new evidence. While the FDA’s reasons for wanting to accelerate biosimilar product development have not changed (to improve access, stimulate competition, and lower prices for patients, for example), it’s the improvements to analytical technologies that have made FDA’s justification for these policy changes possible. Finally, analytical tools offer a better way to assess product comparability over clinical studies.
  • At the same time, the FDA has been seemingly rolling back many of the benefits offered to sponsors whose products achieved biosimilar interchangeability. So far, the FDA has primarily implemented these changes by stripping back the “reward” offered to sponsors, through things like removing the interchangeability statement from product labeling. In sum, the agency has been working hard to close the gap between these two product types.
  • However, this guidance marks the first time the FDA has changed what is required for interchangeability. Whereas the labeling and promotional guidances downplayed the rewards that sponsors who successfully demonstrated product interchangeability were afforded, the agency is now removing the “risk” these companies endured by shelling out significant resources to perform switching studies. Essentially, the guidance signals that the FDA is eliminating the costly and time-consuming switch study requirement for interchangeability, making it significantly easier for sponsors with biosimilar products to gain interchangeability status and reap the reimbursement benefits. However, this change does not represent a change in the evidentiary standard required by FDA for biosimilar product approval. Instead, FDA leadership would almost certainly argue that this shift in policy is a result of the agency responding to the latest scientific information and permitting different data to be used to meet the threshold for approval.
  • When lawmakers created both the biosimilar and interchangeable biosimilar approval pathways, much was still unknown. To meet this uncertainty, the FDA created a more rigorous process for sponsors to go through in order to prove product interchangeability. Since then, studies have found that the risk of adverse reactions caused by switching between biological products is less than was originally estimated.
  • The new draft points to the same argument that FDA has made for why comparative clinical trials for biosimilar approval are not necessary: For one, analytical tools have significantly improved, making them superior to clinical trial data. Secondly, the FDA (and other regulators) have now conducted studies where they assessed the value of information provided by switching studies. As was the case with comparative clinical studies, regulators found that switching studies offered information of little additional value. Both factors contribute to the FDA’s shift in policy, showcased in this latest guidance.
  • FDA’s recent guidances on labeling for biosimilars and interchangeable products held that removing the statements of interchangeability from product labeling would ease the burden on sponsors and regulators, making it easier for products that were already authorized as biosimilars to make the switch to interchangeables. Only 13 interchangeables have been approved to date (even fewer at the time that guidance was issued). However, now that the labeling process has already been streamlined, the agency could be receiving a flood of amendments requesting that products be denoted as interchangeable rather than just biosimilar to their reference products.

Featuring previous research by Alec Gaffney and Chelsey McIntyre.
To contact the author of this item, please email Rachel Coe ( rcoe@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com)

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