The Future of Biosimilar Gene Therapies: Key Issues and Potential

While biosimilar competition for gene therapies may help lower prices and improve patient access, significant challenges in regulatory requirements, manufacturing, intellectual property, and market size could hinder the development and market entry of these biosimilars, according to a study published in the Journal of Law and the Biosciences.¹

By addressing these challenges, the researchers emphasized the potential of biosimilars to reduce costs and improve patient access to these innovative therapies, especially as cell and gene therapies (CGTs) begin to target more common diseases with larger patient populations. The findings underscore the need for strategic approaches to foster competition and ensure the sustainability of health care systems in the face of these high-cost treatments.

As of August 2, 2024, the FDA has approved 38 CGTs for various conditions.² The Center for Biologics Evaluation and Research (CBER) regulates CGT products, using the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act for oversight.³

These therapies include cellular immunotherapies, cancer vaccines, and gene therapies that modify gene expression or alter cell properties for therapeutic use. CBER not only approves these products but also provides scientific and regulatory guidance to support the rapid growth of research and development in this field.

The study was conducted to investigate the potential for creating biosimilar competition in the rapidly evolving field of CGTs which have revolutionized treatment options for genetic disorders, cancers, and chronic conditions but have also introduced significant economic challenges due to their high costs.¹ The study is particularly concerned with the impact of CGTs on health care budgets, especially for payers like states and small businesses that face difficulties in managing the high upfront costs and the uncertainty surrounding long-term efficacy.

This study was conducted by integrating multidisciplinary literature and conducting interviews with 21 subject matter experts across 4 key areas: regulatory, manufacturing, intellectual property, and pricing/payment. The experts included regulators from the FDA, commercial payers, drug manufacturers, intellectual property attorneys, manufacturing organizations, and academic experts, as well as former government personnel from pivotal agencies like the FDA and CMS. These experts were selected through purposive and snowball sampling, drawing from publicly available information, past research, and expert recommendations.

The interviews with experts highlighted key regulatory challenges in the emerging CGT space, noting the need for greater clarity from the FDA, which regulates both CGTs and biosimilars. Experts emphasized the complexities of CGT development, including manufacturing, testing, and demonstrating safety and efficacy, and called for more detailed FDA guidance, particularly for cell therapies. They noted the high incidence of clinical trial holds for CGTs and welcomed FDA efforts to streamline the process, such as ‘umbrella’ trials and the reorganization of review offices.

As the regulatory landscape evolves, the intersection between biosimilar products and CGTs raises questions about defining biosimilarity for these therapies. Experts suggested that gene therapies, which can be defined by genetic sequencing, may be more feasible for biosimilar development than cell therapies, which involve more complex elements like cellular starting material. Some believe that certain cell therapies, like CAR-T, could be subject to biosimilarization if no clinically meaningful differences are shown compared to the reference product, though others argue that their autologous nature poses challenges to this approach.

Overall, the applicability of the current biosimilar paradigm to CGTs remains uncertain, with manufacturing standardization and evidence collection posing significant hurdles. Experts stressed the importance of defining critical quality attributes and parameters for comparability to establish biosimilarity. As scientific understanding advances, it is expected that the FDA will eventually provide more detailed guidance on comparability assessments for CGT biosimilars.

The future for CGT biosimilars requires adapting existing pathways to their unique needs. As scientific understanding evolves, new standards may emerge, with the FDA expected to offer clearer guidance and streamline approvals despite current resource constraints. The 2023 Consolidated Appropriations Act could boost gene therapy development by enhancing efficiency in production and review.

Challenges in manufacturing CGT biosimilars include high costs and complex processes, with limited standardization hindering development. Investment in CGT infrastructure is essential to foster competition, innovation, and the entry of CGT biosimilars.

Therapeutic protein biologics are protected by a broad range of patents due to their complex nature, including formulation and manufacturing processes. From 2010 to 2023, 271 patents related to 12 originator biologics were litigated, with nearly half involving manufacturing process patents that extend exclusivity periods. This complexity is even greater for CGTs, where manufacturing is critical to product function and leads to a more intricate patent landscape.

In addition to patents, manufacturers use trade secrets to protect proprietary processes, offering indefinite protection as long as the information remains confidential. This is particularly common in CGTs due to the complexity of their production.

Pricing and payment dynamics affect CGT biosimilars. Markets for CGT biosimilars targeting rare diseases may be limited, reducing competition incentives. Medicare and Medicaid present challenges, with Medicare’s complex pricing and Medicaid’s difficulties managing high-cost CGTs. The Inflation Reduction Act could indirectly impact CGT biosimilars through increased add-on payments and future price negotiations, while outcomes-based contracts might offer solutions for managing CGT costs and improving access.

References

1. Canter B, Sussman S, Colvill S, Arad N, Staton E, Rai A. Introducing biosimilar competition for cell and gene therapy products. J Law Biosci. 2024;11(2):lsae015. doi:10.1093/jlb/lsae015

2. Approved cellular and gene therapy products. FDA. Updated August 2, 2023. Accessed August 21, 2024. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products

3. Cellular & gene therapy products. FDA. Updated March 20, 2023. Accessed August 21, 2024. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products