Three biosimilars for rheumatoid arthritis (RA) were approved by the FDA last year, but the regulatory pathway in the U.S. is still considered a new frontier, especially when compared to regulatory guidance in the EU. With our global industry’s growing interest in developing biosimilars, it’s critical that sponsors have a clear understanding of key clinical issues and develop a strategy for navigating today’s regulatory environment.
(Bio)similarities and differences in regulations
In the U.S., biosimilars are defined by the Biologics Price Competition and Innovation Act of 2009, also referred to as BPIC Act. The EU defines biosimilars according to EU Directive 2004/27/EC. While each party has slightly different wording, the spirit of the definitions is largely the same between the US and the EU. The most notable difference between the two is that the FDA will determine interchangeability in their regulatory review, while the EMA will not comment on interchangeability, leaving it up to the individual member states.
Both agencies agree that biosimilars must be systematically engineered to match the reference product. Biosimilarity assessments are conducted against the innovator reference product at all levels of product development. This includes physiochemical attributes, primary, secondary, tertiary, and quaternary structural assessment, biological activity, preclinical in vivo biosimilarity, Phase I PK and safety, and Phase III efficacy and safety. The impact on shelf life on all of the above is also critical.
Given that both biosimilars and their innovator reference products have inherent variability, it’s important to decipher how these differences have a clinical impact. The characterization of the biosimilar will always be much higher than that of a new biological entity and will always include reference product versus biosimilar.
Clinical practice considerations based on regulatory guidance
During development, many key issues need to be considered based on current regulatory guidance. For example, sourcing of the reference product is critical. In recent years, agencies have relaxed their position on the reference products so that sponsors are not running separate studies with each country reference product. Typically, a three-way bridging study in Phase I PK and/or PD study can compare the U.S. reference product, EU reference product and the biosimilar product.
Getting full range of indications in the reference’s label without conducting efficacy studies presents another common challenge. Here, extrapolation of indications beyond those studied is possible. We’ve seen recent approvals supported by regulatory guidance that is based on the overall totality of evidence, an observation that assumes that the efficacy and safety of the biosimilar is justified. For example, with the biosimilar, Inflectra®, the sponsor was able to extrapolate all the indications for the Remicade® reference product.
Exploring the possibility of interchangeability
Switching (or interchangeability) has also become a hot topic in biosimilars. The FDA published a recent guidance document called “Considerations in Demonstrating Interchangeability With a Reference Product.” Switching/interchangeability studies should be designed to determine whether alternating two or more times between a biosimilar and its reference product impacts the safety or efficacy of the treatment course.
Product presentation differences, including the delivery device and container closure system, may also affect the determination of interchangeability. Given the unique delivery devices and presentations associated with biologics, this could potentially be a challenge. The requirements for interchangeability will vary based on the product submitted, stressing the fact that no single data package exists for all proposed interchangeable products.
If a sponsor is hoping that a Phase III pivotal equivalence trial could be designed to include switch data that will be sufficient to support a regulatory designation of interchangeable, it’s more than likely that interchangeability will not be granted with initial approval. However, there may be flexibility in the regulations. As FDA becomes more comfortable with biosimilars, we predict that greater interchangeability may be possible in the near future.
Applying an end-to-end vision
While early and clinical work often takes the spotlight, post-marketing pharmacovigilance should be considered as well, as there’s confusion in naming of the biosimilars for AE drug reports. Possible post-marketing solutions include applying appropriate measures to identify the product and batch number used in patients as well as developing agency-driven risk-management plans to include specifically-focused post-marketing studies.
With many key players in the global market, sponsors are wise to establish early engagement with regulatory strategists to design an efficient proposition. From our experience, we’ve seen that early and frequent engagement with regulatory agencies helps confirm development plans, evaluates the appropriateness of the data being generating and aligns sponsors’ expectations for a more efficient development process.
We provide end-to-end services and have worked on 96 unique biosimilars and 152 biosimilars projects across the full spectrum of drug development: CMC/bioanalytical, exploratory/preclinical, market access/reimbursement and clinical/labs. Contact us to discuss your biosimilars project needs.