At the Association for Accessible Medicines’ GRx+Biosims meeting on Wednesday, we heard hints of a major announcement regarding biosimilar 351(k) application requirements. By the time FDA Commissioner Marty Makary, MD, MPH, left the stage, we knew that a new draft guidance would be announced in an HHS press conference that afternoon.
Indeed, HHS Secretary Robert F. Kennedy Jr; CMS Director Mehmet Oz, MD; and Dr. Makary joined to announce that comparative efficacy studies (CESs) will no longer be required for the vast majority of biosimilar candidates. According to the draft guidance, this decision to nix the mandate for large, phase 3 trials, was based on FDA gaining “significant experience in evaluating data from comparative analytical and clinical studies used to support a demonstration of biosimilarity.” This thinking finally catches up with years of scientific scrutiny and experience.
The Move to Remove the Comparative Efficacy Study Requirement Was not the Administration’s Idea
Biosimilars have been approved for 10 years in the United States and for almost 20 years in the European Union. The idea that these confirmatory studies did not contribute to the totality of evidence of biosimilarity, has been growing since 2019 with advocates like Chris Webster, Hillel Cohen, and Gillian Woollett. Most recently, Sarfaraz Niazi, PhD, has been lobbying Sarah Yim, MD, at the office of biosimilars and biologics to remove the mandate for comparative efficacy studies. We’ve argued in the past that the primary objective of these studies and the study populations used were insufficient to prove any clinically significant difference between a biosimilar candidate and the reference product, based on the work of these scientists.
That the FDA finally was able to pull the trigger on a draft guidance reflecting this reality was both gratifying and frustrating, simply because it has taken so long. At the press conference, the Trump administration took a victory lap for making it happen. In fairness, Health Canada only made this decision on June 10. Dr. Makary claimed that this would reduce the cost of biosimilar development by some $100 million and cut the time to approval by several years. That and future work to streamline biosimilar development could bring the total cost of research and development down below $100 million or considerably less if issues like utilization of a single global reference product were finally resolved.
Critical questions that need to be addressed involve timing. The draft guidance will not become a finalized document for around 6 months. To which biosimilar candidates will it first be applied? For reference drugs expecting biosimilar competition through 2029, CESs have largely begun (at least recruiting), and this includes some of the highly anticipated big-ticket items like Keytruda and Opdivo. When can a prospective biosimilar manufacturer forget about conducting a late-stage CES?
Another Draft Guidance to Come: Interchangeability
Furthermore the press conference promised new draft guidance on the elimination of the interchangeability designation for specific biosimilar products. This also has been many years in the making, though the HHS Secretary, CMS Director, and FDA Commissioner were eager to take credit for finally making it happen. Part of the issue was that interchangeability was written into the BPCIA legislation, and it would seemingly take an act of Congress to remove it. However, acts of Congress seem to be a thing of the past.
Instead, the administration took a different tact, according to Dr. Makary. If the FDA has the authority to designate a biosimilar as interchangeable, it also has the authority to designate all biosimilars as interchangeable with their corresponding reference products. Based on that premise, they decided that legislative action was unnecessary.
Although they have the right idea about removing the designation, they are seemingly confused about its impact. In that press conference, HHS Secretary Kennedy erroneously claimed that removing interchangeability would be a huge step forward in reducing the cost of biosimilars. As any biosimilar manufacturer will tell you, having to litigate endless patents by reference manufacturers is by far the greatest limiting factor in speeding these drugs to marketplace and further lowering the cost of biosimilar development.
Interchangeability has always been a red herring for the FDA; the agency could not seem to create consistent policy on interchangeability for many years, with regard to exclusivity of the designation and how interchangeability is actually assigned. The fact has been that payers have not been able to use interchangeability’s automatic substitution provision for creating rapid biosimilar adoption. Nearly all conversion from reference product use to biosimilars under the pharmacy benefit has been through formulary change and reference product exclusion. Further, automatic substitution plays almost no role in medical benefit covered products, yet FDA designated some buy-and-bill products (e.g., ranibizumab) as interchangeable.
Still interchangeability only referred to substitution between this specific biosimilar and the reference product. It did not allow for automatic substitution between different biosimilars in the same drug category. Nor did it clarify in a timely manner how low-dose and high-dose formulations of the same product would be treated for interchangeability purposes within the adalimumab category. In some cases, it was mystifying how the date of first exclusivity for a product was assigned, further muddying the waters and diluting its potential value.
However, real progress in this area has been a long time in coming. We’ll be happy to see the interchangeability designation placed in the dustbin. It was a confusing and ambiguous attempt at improving the biosimilar environment.