Paper Argues That Bridging Studies Are Redundant, Unnecessary

A recent paper, published in BioDrugs, argues that, in biosimilar development, bridging studies between locally licensed and internationally licensed reference biologics may be unnecessary. The paper, authored Christopher J. Webster and Gillian R. Woollett, DPhil, suggests that bridging studies between approved versions of an originator biologic add cost to biosimilar development, but do not provide either a patient benefit or scientific value for the approval of a biosimilar.

Most regulatory systems mandate bridging studies to justify the use of a foreign product as a reference for a biosimilar. The EU’s European Medicines Agency (EMA) was the first to develop guidelines for biosimilar development that permit the use of foreign reference products, preferably from nations that follow the guidelines of the International Conference on Harmonization (ICH). The authors note that the EMA’s guidelines, which set a precedent for the rest of the world’s regulatory bodies, do not allow a biosimilar applicant to leverage shared development history and data to demonstrate similarity between local and foreign reference products. Instead, the guidelines require costly bridging studies. Today, in Australia, Switzerland, and the United States, bridging studies are explicitly required in regulatory guidance.

While representing only a fraction of the entire development budget for a biosimilar product, bridging studies can still be costly. Costs associated with sourcing products, evaluating 20 to 40 variables for multiple batches, and the performance of in vivo nonclinical studies and pharmacokinetic studies can range from hundreds of thousands to millions of US dollars. Multiple biosimilar developers incurring such costs, the authors say, leads to inefficiency and the replication of data.

The authors argue that, because data from the drug produced in the first manufacturing facility authorized to produce a new biologic is used repeatedly in marketing authorizations, both in its local domain and internationally, core data for the drug remains the same as it did when it was first submitted to the market. This “commonality of data can effectively vitiate the need for new bridging studies between product versions,” they say, pointing to the fact that the same clinical data were used to support the approvals of originator infliximab, etanercept, adalimumab, pegfilgrastim, bevacizumab, and ranibizumab in the United States, EU, Canada, and Australia.

The authors suggest the use of a simplified system for selecting a reference product to compare with proposed biosimilars in clinical studies. They suggest that a single, approved version of a biologic could serve as a “global reference” for all biosimilar development in order to save on development costs. They propose that no bridging studies be required for the chosen reference if it meets the following criteria:

• The reference has been approved by a jurisdiction that adheres to ICH guidelines
• The formulation of a foreign reference has the same form, route of administration, content, and composition as the locally approved reference (or no data demonstrating that differences in composition affect clinical efficacy or safety)
• Substantial evidence in the public domain exists to show that the local reference and the foreign reference relied on the same original data, including clinical safety and efficacy data, for approval

The authors note that their proposal may not be adequate to address the developing US criteria for interchangeability. The FDA’s current draft guidance on interchangeability highlights the need to demonstrate that multiple switches between the biosimilar and its reference will not degrade clinical efficacy or safety; however, current data typically demonstrate the safety and efficacy of using a biosimilar in patients who have received a reference product, though not the opposite.

The paper concludes that eliminating a need for bridging studies between local and international versions of reference products could prevent the incursion of unjustified and redundant costs, thereby streamlining the development of biosimilars for the benefit of patients worldwide. “Biosimilars provide a potent means of reducing the cost of care, and add surety of supply,” the authors state. “This opportunity is shared by all healthcare systems and, as such, all regulators share a mission to make pragmatic but scientifically justified and consistent choices about approval requirements in order to maximize biosimilars’ rapid development and availability to patients, even those outside their own jurisdictions.”