The Role of Real-World Evidence in the Adoption of Biosimilars

We are more than halfway through the year that Humira^® lost exclusivity. By all counts, as many as 10 adalimumab biosimilars are expected to be available in the US by the end of 2023¹. The biggest-selling drug of all time is now facing a lot of biosimilar competition. But there’s more to it.

Beyond adalimumab, the industry is waiting and watching as we potentially approach a turning point for biosimilar adoption in the U.S. Sponsors see cost savings during research and development phases, in clinical studies, and during production, so biosimilars can be offered at lower cost, ideally allowing for cost savings and broader access. While this has been true in Europe, the U.S. has yet to realize anything close to the 40% cost savings projected by the Congressional Budget Office². Even though biosimilars have been in the U.S. market since 2015 with the launch of Zarxio^® (filgrastim-sndz)², uptake has been slow compared with Europe, which saw its first biosimilar almost a decade earlier. By the numbers, as of May 2023, the US has approved 40 biosimilars³, and the EU has approved 93 biosimilars⁴.

Adoption in the U.S. is dependent on a complicated landscape that includes the current regulatory environment, clinical evidence, patient and provider preferences, and economic incentives. Patient and provider education gaps and formulary preferences for higher-cost originator biologics (thanks to incentives and rebates) are currently the most prominent challenges hindering widespread adoption. Further complicating matters, the landscape is slightly different depending on the therapeutic area. For example, oncologists are comfortable with biosimilars, likely due to the Centers for Medicare and Medicaid Service’s Oncology Care Model⁵, a value-based care initiative where physicians assume greater financial risk in delivering healthcare⁶. But Rheumatologists are more reluctant. This reluctance is the result of questions around efficacy (noted as a “top concern”) and cost savings for patients⁶.

The perception that biosimilars lack efficacy is likely due, at least in part, to the fact that approval is based mainly on analytical studies that demonstrate high molecular similarity and low impurity levels to the originator biologic. This means that biosimilars may not need to be tested in all indicated patient populations. So, providers and patients may have concerns about efficacy, safety, and immunogenicity, including switching from one biologic to another.

Another wrinkle is that, unlike generics, pharmacists cannot determine if a biosimilar can be given in place of an originator biologic that has been prescribed by a physician. However, the U.S. Food and Drug Administration (FDA) can determine if a biosimilar is interchangeable, which allows pharmacist substitution. Interchangeability has been shown to increase biosimilar use when uptake has been slow⁷. However, to receive an interchangeable designation, manufacturers must sponsor clinical trials during which patients switch back and forth from the originator to the biosimilar at least three times without diminished efficacy or any additional safety concerns⁸, increasing the cost to sponsors.

Might the U.S. learn from Europe, where the biosimilars market is very mature?

Europe developed a framework for approving biosimilars in 2005, wherein biosimilars can be marketed through an abridged application⁹. Similarly, in the U.S. in 2010, the Biologics Price Competition and Innovation Act (BPCIA) created the 351(k) Biologics License Applications (BLA) pathway for biosimilars. The BCPIA promotes innovation by providing a period of exclusivity for originator biologics¹⁰ and promotes competition by enabling a quicker, less expensive pathway for approval of biosimilar and interchangeable products once the exclusivity period has lapsed⁹. Specifically, the BCPIA allows follow-on sponsors to partly rely on the FDA’s determination of safety and efficacy for the originator biologic.

In Europe, the real-world setting has been instrumental in addressing the concerns and needs of patients, providers, and payers. In an appraisal of both regulatory and post-marketing activities in second-generation biosimilars (including monoclonal antibodies), post-marketing pharmacovigilance (PV) programs aimed at confirming efficacy and safety have been described as “crucial”¹¹. Study authors concluded that limited information on the safety, efficacy, and immunogenicity of biosimilars at the time of regulatory approval needs to be addressed with long-term patient safety and outcomes research.

The FDA has also stated interest in the use of RWE to analyze biosimilar utilization and outcomes, in both the 2018 Biosimilars Action Plan¹² and the 2021 Biosimilar User Fee Act (BsUFA) Commitment Letter 2023-2027¹³. Furthermore, the FDA is working to maximize scientific and regulatory clarity for biosimilar product development, including efforts to “leverage real-world data to support regulatory decision-making related to biosimilars, when possible”¹⁴. Finally, through the BsUFA Research Pilot Program, FDA announced intent to develop guidance on how RWE can be leveraged to earn an interchangeability designation¹⁵.

How can sponsors leverage real-world evidence?

Sponsors should plan an integrated evidence generation strategy early in product development and regularly revisit and revise the strategy based on internal goals and the external landscape. Identified gaps should be addressed in a way that will satisfy multiple stakeholders, including regulators, payers, providers, and patients. Sponsors must consider what is most important – efficacy, safety, immunogenicity, switch data – when designing evidence generation strategies. Study types may include:

1. Real-world, post-marketing surveillance studies (including registries) that address long-term safety and effectiveness
2. Switch studies that demonstrate safety and efficacy
3. Analysis of diverse patient populations (e.g., patients with comorbidities, patients in different age groups, etc.), either prospectively (if it’s early post-launch) or retrospectively
4. Patient-reported outcomes (PROs), questionnaires
5. Health economics studies
6. Patient preference studies
7. Indirect treatment comparisons (ITCs), matching or external control studies to account for issues like missing data or differences in baseline characteristics

Are you ready to plan your integrated evidence generation strategy?

Identification of evidence gaps through a systematic review of external stakeholder requirements, the current clinical and scientific landscape, and internal strategic initiatives is a good first step. Utilizing existing infrastructure, leveraging efforts already in place, and information already being collected in a real-world setting are other practical solutions. Finally, well-designed studies that leverage modernized technology and data acquisition approaches, including decentralized study design, may reduce burden on providers and patients, and help lower certain barriers to care for patients and/or caregivers or care teams. Having partners well-versed in such study approaches can help reduce the time to plan and operationalize studies by bringing experience and expertise needed to best support study design, operational aspects, recruitment and retention, and the technology and infrastructure needed.

Patient communities, advocacy groups, regulators, coverage bodies, and manufacturers are on the verge of a turning point in biosimilar adoption in the U.S. Having an organization that understands the intersection of these equally important agendas and data requirements to ensure successful outcomes, in concert with the safe and appropriate use of the drug, combined with the need to ensure reasonableness and outcomes of the therapy is a new ground – UBC is ready.

To find out more about how UBC can help plan your RWE strategy, get in touch with our team here.

About the Author

Judy Lytle, PhD, MBEE, PMP, is the Executive Director of Real-World Evidence Study Solutions at UBC. She utilizes her extensive expertise to help biopharma develop evidence generation strategies, powered by rigorous science, that are designed to demonstrate value.

References

1. Jeremias S. (2022). “Part 1: Biosimilars to Bring a Bumper Crop of Adalimumab Options.” AJMC Center for Biosimilars. https://www.centerforbiosimilars.com/view/part-1-biosimilars-to-bring-a-bumper-crop-of-adalimumab-options. Accessed 06/29/2023.
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