Biosimilar Interchangeability: 9 Things to Consider

The topic of interchangeability continues to draw debate when it comes to biosimilars, as perceptions on its value and market impact vary per stakeholder. Below are 9 things to consider when examining biosimilar interchangeability:

1. An interchangeable biosimilar is expected to produce the same clinical result as the reference in any given patient. Under the Biologics Price Competition and Innovation Act (BPCIA), an interchangeable biosimilar is defined as a biosimilar that is expected to produce the same clinical result as the reference product in any given patient. It may be substituted for the reference product without prescriber intervention, and the risk in terms of safety or efficacy of switching or alternating between biological products is no higher than using the reference product alone.

2. The Federal Drug Administration’s (FDA) official guidance on interchangeability is still in draft form.

The FDA released the draft guidance for biosimilar interchangeability in January 2017, and the final guidance is yet to be released. Despite the guidance being in draft form, it is still possible for a manufacturer to achieve an interchangeability designation for a biosimilar, though it would be more difficult to do so. Diligent and frequent interactions between the manufacturer and the FDA would be necessary to ensure that data requirements are met.

Manufacturers have highlighted further challenges with seeking the designation without finalized guidance, and have voiced concerns with the complexity of the FDA’s data requests. For example, some manufacturers describe the draft guidance’s terms of “fingerprint-like” and “residual uncertainty” as vague.¹

3. There are currently no FDA-approved interchangeable biosimilars.

With 9 FDA-approved biosimilars, the United States has yet to experience the potential impact of an interchangeable biosimilar in the market. To date, Boehringer Ingelheim (BI) is the only manufacturer to publicly announce its efforts to seek an interchangeability designation; BI seeks the designation for its adalimumab biosimilar, Cyltezo (adalimumab-adbm), which is approved to treat multiple chronic inflammatory diseases.

Once an interchangeable biosimilar gains FDA approval, the Purple Book—the FDA’s official reference that lists the licensed biosimilars and interchangeable biosimilars regulated under the Public Health Service Act—will be updated to reflect this status.

4. An interchangeability designation is achieved through the submission of additional data.

In order to be designated an interchangeable biosimilar, a product faces rigorous evaluation and must meet additional requirements based on further evaluation and testing. Therefore, a manufacturer would need to provide additional information to demonstrate that the biosimilar is expected to produce the same clinical result as the reference product in any given patient.

Also, if a product will be administered more than once, data must prove that there is no added safety and efficacy risk associated with switching or alternating between the biosimilar and reference product.

It is important to note that there is no additional requirement for an interchangeable biosimilar to be superior in terms of performance to a biosimilar without an interchangeability designation. In fact, if a biosimilar molecule were to be altered in any way, it would essentially require a new assessment from the FDA as a new biosimilar product.

A biosimilar designated interchangeable is still the same molecule, but the difference is that there are more information and data available showing the impact of switching or alternating between the biosimilar and reference biologic.

5. Per the FDA, both biosimilars and interchangeable biosimilars can be used in patients who have previously been treated with the reference product.

The premise of biosimilar FDA approval is that the approved product has been shown to have no clinically meaningful differences in efficacy and safety from the originator product. With that said, the FDA states that both biosimilars and interchangeable products can be used in both treatment-experienced as well as treatment-naïve patients.

Although there are distinctions between biosimilar and interchangeable biosimilars’ approval requirements, both pathways are subject to the FDA’s rigorous approval standards. With these standards in place, the FDA states that patients and physicians can be assured of the safety and effectiveness of the biosimilars, just as they would be for the reference products.

6. Provider and patient confidence in biosimilars could be enhanced through the interchangeability designation.

Many attribute the slow market uptake of biosimilars to stakeholders’ lack of familiarity and comfort with these products. The delay in market uptake can be compared to when generics first became available, although generic products are different in nature. Acceptance of small-molecule generics by physicians and payers took time, despite generics being chemically identical to the original brand-name products. The generics market has been enhanced over the years through strategies such as automatic substitution policies within pharmacies as well as through payer efforts.²

Given the fact that most biologics are covered under the medical benefit and are administered by physicians, the degree of retail-based pharmacy-level substitution may not prove to be as impactful as it has been for generic drugs. However, the interchangeability designation has the potential to significantly enhance provider and patient confidence in biosimilars, as more information about switching these particular therapies would be available as a result of the approval process.

This availability of data could lead to greater use of “therapeutic interchange” policies within Integrated Delivery Networks (IDNs), in which a biosimilar would automatically be dispensed for a reference biologic. The use of therapeutic interchanges within IDNs are key to helping streamline and standardize formularies, and could be enhanced when a biosimilar is deemed “interchangeable.”

7. Some stakeholders, including payers, view interchangeability as a critical factor.

A recent report, based on qualitative research with 10 medical directors at US payer organizations, highlighted findings that the interchangeability designation is playing a role in product management decisions. The report noted that biologics are commonly utilized in patients with chronic conditions, and therefore switching drugs is typically only considered when treatment stops working or results in adverse events. Hence, there is hesitation to switch medically stable patients to biosimilars, even if costs are lower with a biosimilar. The report concluded that interchangeability can help drive formulary decisions and automatic substitution processes, and can also encourage payers to leverage policy to speed up adoption. A medical director from a large national payer stated that they still expect biosimilars to capture half the market, “but only if there is steep discounting, or interchangeability status.”

8. Manufacturers must assess multiple factors when considering whether to pursue interchangeability.

A manufacturer’s decision to pursue interchangeability is multifaceted. The company must evaluate whether the investment of capital and resources required to meet the additional data requirements (after already having incurred significant costs to develop the biosimilar product) is worth the value of the designation.

For example, the development of additional trials and switching studies is not something that can be accomplished overnight. Developing this clinical program can lead to significant delays in market entry, potentially further delaying access to life-saving therapies.

Additionally, there are thoughts that “interchangeability” may not hold as much weight for certain biosimilars, given the therapeutic category and/or site of administration. For example, the pharmacovigilance associated with short-acting or supportive care biosimilar agents utilized in the inpatient setting may enhance provider and patient confidence in the products since patient responses can be monitored and measured much sooner than they can be for disease-modifying agents. Zarxio—a supportive care biosimilar with inpatient utilization—continues to gain market share, with a Sandoz spokesperson stating earlier this year that their biosimilar has 35% of the US filgrastim market for pre-filled syringes, and that this number continues to grow.

9. The interchangeability designation is unique to the United States.

Biosimilar interchangeability, from a regulatory standpoint, does not exist in the European Union. In the United States, interchangeability is provided for under the BPCIA and corresponds with automatic substitution at the pharmacy level.

However, the European understanding of “interchangeability” is that it is a clinical term referring to the practice of substituting 1 product for another that is expected to have the same clinical effect. Unlike the FDA, the European Medicines Agency does not regulate interchangeability, nor does it regulate and switching or substitution practices, which fall under the authority of individual EU member states.

Stakeholders continue to recognize biosimilars as a key tool to increase treatment options for patients, create healthy market competition, and drive down the cost of treatment. Although its eventual impact on market activity is not yet clear, biosimilar interchangeability has the potential to catapult biosimilar acceptance in the United States.

In the meantime, it is important for healthcare providers to leverage current experience with biosimilars in knowledge-sharing opportunities among peers. These real-world experiences (which include switching patients to biosimilars) serve as powerful tools to enhance comfort and confidence with biosimilars, especially in absence of interchangeable biosimilars in the market.

References

1. Barlas S. FDA guidance on biosimilar interchangeability elicits diverse views: current and potential marketers complain about too-high hurdles. P T. 2017;42(8):509-512. PMID: 28781504.

2. Blackstone EA, Fuhr JP. The economics of biosimilars. Am Health Drug Benefits. 2013;6(8):469-478. PMID: 24991376.