Biosimilar Approval and Uptake Impacted by Global Regulatory Frameworks

Policies promoting product-specific guidance, extrapolation, shorter exclusivity periods, and substitution are linked to greater biosimilar approval and uptake, potentially increasing access to affordable biologics globally, according to an evaluation of international biosimilar policies published in the Journal of Law and the Biosciences.¹

Biologic drugs have potential to treat serious illnesses but are often very expensive. In 2021, pembrolizumab (Keytruda) cost nearly $175,000 annually in the US.² To address this, many countries have implemented strategies to approve similar, less expensive biologics called biosimilars.¹

This study compared biosimilar regulations in the European Medicines Agency (EMA), FDA, Health Canada, the Medicines and Healthcare products Regulatory Agency (MHRA), and the Therapeutic Goods Association (TGA) based on their governing laws and regulatory practices. Factors like testing requirements, indication expansion, market exclusivity, and automatic substitution, which can influence the adoption of biosimilars, were further examined.

Testing Requirements

The biosimilar must have the same amino acid sequence, comparable structure, and folding as the originator. Higher-level structure confirmation can be challenging for complex molecules as well.

Comparative nonclinical studies, often in vitro pharmacodynamic and toxicology studies, assess the biosimilar's safety. In vivo animal studies may be required by regulators, but Health Canada and MHRA often consider in vitro studies sufficient.

Comparative clinical studies, including pharmacokinetic, pharmacodynamic, and potentially efficacy trials, are conducted. Regulatory requirements for these trials vary. Some regulators may waive efficacy trials if comparability is demonstrated through pharmacodynamic studies.

Manufacturers periodically meet with regulators to review study data. This process can influence the types of studies conducted. The EMA's detailed guidance has encouraged biosimilar development and approvals. In contrast, less specific guidance from the FDA and Health Canada may contribute to fewer approvals.

Indication Extrapolation

Once originator biologics near exclusivity expiration, they often have multiple approved indications. As biosimilars enter the market, regulators may not require studies for each indication. Instead, biosimilars can be approved for additional indications based on their similarity to the originator biologic through extrapolation. This decision relies on similarities in disease states and pharmacologic properties.

All 5 major jurisdictions have guidance on the necessary evidence for indication extrapolation, which typically includes mechanism of action, pharmacokinetics, pharmacodynamics, safety, efficacy, and immunogenicity. Despite similar standards, regulators have made differing decisions on the same medications.

These discrepancies may arise from varying data requirements, approaches to extrapolation, intellectual property considerations, or manufacturer decisions regarding approval timelines.

Exclusivities

Regulatory agencies grant originator biologics data and market exclusivities to delay biosimilar competition. Data exclusivity prevents biosimilars from relying on the originator's clinical data, while market exclusivity blocks their market entry for a specified period. These periods can overlap, and market exclusivity may extend beyond data exclusivity.

Certain market exclusivities protect specific indications, allowing biosimilar approval for other indications through a "skinny label" approach. Varied exclusivity periods and manufacturer strategies can impact biosimilar access and approval across different jurisdictions, contributing to disparities in biosimilar utilization.

Biosimilar Substitution

A patient's receipt of an originator biologic or a biosimilar can depend on the way the prescription was written. Pharmacists may be allowed to substitute biosimilars for originators, based on local laws.

Substitution laws have boosted generic drug use, especially in the US. However, differences between generics and biosimilars create distinct regulatory roles. The 5 jurisdictions examined don't directly influence substitution decisions.

All jurisdictions require regulatory approval of biosimilar products for substitution to be allowed. While no other regulators studied have a similar influence on substitution decisions, some regulators have made statements reflecting their views on switching between reference products and biosimilars.

Medicines regulator approaches for biosimilar approvals, especially those concerning biosimilar testing requirements, indication extrapolation, exclusivities, and substitution, contribute to the overall outcome of biosimilars across various global markets.

“Reforms to these policies can create a regulatory environment more supportive of biosimilar approvals, promoting access to more affordable biologics for the benefit of patients globally,” concluded the authors.

References

1. Knox RP, Desai V, Sarpatwari A. Biosimilar approval pathways: comparing the roles of five medicines regulators. J Law Biosci. 2024;11(2):1-27.  doi:10.1093/jlb/lsae020
2. Herman B. The Keytruda boom. Axios. October 29, 2021. Accessed November 25, 2024. https://www.axios.com/2021/10/29/keytruda-sales-merck-drug-prices