4 Revelations From The FDA's Biosimilar Part 15 Hearing

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

The highly anticipated FDA Part 15 hearing has come and gone, and since then, I’ve been juggling a variety of thoughts and feelings. Overall, hearings such as these are a valuable touchpoint for me to stay abreast of what the industry is focusing on and concerned about. And this did not disappoint. I enjoyed the presentations, which touched on pretty much every big talking point to date — education, real-world evidence, abbreviated development strategies, naming (still), the Purple Book, risk evaluation and mitigation strategies abuse (REMS), and interchangeability. (I can officially say extrapolation is no longer a concern because it did not get a single mention. Thank goodness.) To some extent, I’d even say switching from a reference product to a biosimilar got less discussion than it has in the past, though references to non-medical switching still eked in on occasion.

My responses to this hearing could easily be summed up with some GIFs of vigorous head nodding or of people throwing popcorn at a screen. But I found this particular event even more valuable than normal because of the FDA panel itself. While the presentations provided a good overview of where we stand as an industry today — as frustrating as it may be — the FDA’s comments and questions throughout the hearing were quite telling, and, at times, left me downright giddy.

In addition to laying out some of the concerning themes that came up throughout the hearing, I will unpack some of the FDA’s lines of inquiry which I feel illuminated the agency’s efforts to challenge certain claims for the first time. 

Hypothetical Safety Concerns Keep Evolving

If this Part 15 hearing was an indication of anything, it was that we are stuck playing an endless game of whack-a-mole. In our brief time with biosimilars in the U.S., we’ve made progress, thanks to evolutions in scientific understanding and real-world experiences. But our progress is often underscored by what feels like never-ending safety and efficacy concerns. As soon as one concern is ticked off the list, we hear a new list of what-ifs about the possible monsters lurking in the shady biosimilar closet. It’s this constant grasping for new concerns that left me most frustrated coming out of the Part 15 hearing.

In the early days with Zarxio, ensuring the development pathway of biosimilars promoted safety and efficacy of all biosimilars was the most talked-about concern. But given all the positive safety and efficacy data from Europe (because there was lots of it) and the fact that Zarxio isn’t a chronic or an immunogenic treatment, most of the concerns quickly turned toward Inflectra. After all, it was a more complex monoclonal antibody — what wouldn’t go wrong with extrapolation or non-medical switching? Well, here we are two years later with scores of real-world evidence (again from overseas) proving the abbreviated regulatory pathway is sound, and safety and efficacy in naïve starts and in switched patients are no longer questions.

As such, it was not a coincidence that certain innovators and a few patient organizations turned up the volume on the need for the FDA to communicate that biosimilars from different manufacturers are not interchangeable with each other. I’m certainly not surprised to hear this new safety and efficacy concern; there have been some quiet mumblings over the past few years about this. But I didn’t expect it to be so loud at this Part 15 hearing. If anything, I’m surprised the conversation jumped straight to biosimilar-to-biosimilar switching and skipped calls for data from multi-switch trials. I would’ve bet a large greasy tub of popcorn that the need for multi-switch trial data was waiting next in the big sorting hat of biosimilar questions and concerns.

Interchangeability Remains A Clear Thorn In The FDA’s Side

Biosimilar-to-biosimilar switching is quite timely, given the biosimilar industry’s call for reform to payer rebate and contracting practices. (Coincidence? I think not.) Similarly, as education was a core topic on which the FDA requested additional information, it’s not surprising interchangeability was a central theme. And if I’m being frank, this event was a good reminder that we’ve really shot ourselves in the foot with the interchangeability designation.

Not only is interchangeability being inaccurately portrayed as a “higher-quality” biosimilar, but it also demands a much more complicated and science-heavy educational campaign. And if there’s one thing the industry has emphasized, but not quite succeeded with yet, it is to put education about these products into layman’s terms. That’s not to say there aren’t excellent and working examples being released around the world. If you review examples of educational materials from other nations, you’ll find information about the development and review of biologics and biosimilars, the similarities and differences in the development programs, and the benefits of biosimilars on the society as a whole. In fact, many of these educational efforts ensure biosimilars are seen as biologics and that the concerns often associated with biosimilars are also concerns with all biologics.

The FDA does this as well, but the presence of two regulatory designations for biosimilars overshadows any attempts at making biosimilars appear to be a normal member of the biologics regulatory and treatment paradigm. If you look into the FDA’s educational strategy for physicians, it’s weighed down by discussions of interchangeability. A quick glimpse at the website, and you’ll see one page discussing what an interchangeable product is, how it differs from a “non-interchangeable” biosimilar, and then a completely different set of questions discussing how interchangeability will affect prescribing decisions. (I use italics to signify how even the wording used suggests if it’s interchangeable, it’s not a biosimilar — you know, one of those products that’s only similar, not the same.) Now, after the hearing, it’s clear the FDA needs to dig even deeper into this designation and share “the scope” of interchangeability and explain why interchangeable biosimilars from different manufacturers are not interchangeable with each other.

The very presence of the interchangeability designation is not only confusing across the world because it differs by country, but it also seriously underrates the work the FDA does to approve biosimilars in the first place. It establishes just enough room to doubt the FDA’s own reviewing capabilities and dismisses the 12 years of experience other nations’ regulators and patients have had with biosimilars. If this evidence overseas did not exist and the FDA were carving its own path alongside the rest of the world, then perhaps there would be a need for an interchangeability designation. But with the information we have now, this designation simply stands to keep the U.S. market separate and behind the rest of the world.

Nationalism Does Not Belong In Regulatory Policy

In fact, it’s these nationalist undertones that truly concern me. Politically, we are a fragmented nation, to say the least, and there has been much chatter about keeping jobs in and bringing them back into America. There is nothing wrong with wanting to have a strong and sustainable economy. But it concerns me to see this U.S.-centric mindset being applied to the development of the biosimilar regulatory pathway and market. Interchangeability is only one way we can see ourselves suggesting the rest of the world’s experiences and data do not and will not match up to our own here in the U.S. I’ve heard stakeholders discuss requests for U.S. safety and efficacy data with these products. Similarly, during this Part 15 hearing, there was one claim that the percentage of safety reporting overseas was not a standard the FDA would be OK with. I have absolutely no patience for claims such as these suggesting the FDA is better than say, the EMA, given the success and amount of biosimilar knowledge EMA has accumulated by comparison.

I truly respect the FDA and its biosimilar team, especially because their scientific brains operate so differently from my own. But as the agency continues to emphasize its efforts to better align with other nations and conduct parallel reviews of certain products, this mindset from certain stakeholders and, indeed, some of the regulations in place will always stand in the way of true alignment.

FDA Panelist’s Questions Challenge Innovator Claims

Not everything is lost, however. Though I’ve just spent 1,400-plus words on the most angsty biosimilar topics, I felt the agency panel at this Part 15 hearing was on top of its game in ways I had not previously observed. During the Q&A period following speeches by AbbVie and J&J representatives — two of the loudest proponents of the “biosimilars-are-not-interchangeable-with-each-other” campaign — the FDA’s Steven Kozlowski posed several critical lines of questioning that made me do a double-take. (And I daresay I was not the only one silently cheering.)

For one, he continued to push for the answer to whether switching between biosimilars was perceived as a higher risk than switching patients amongst brands in the same therapeutic class. Now obviously, a switch from Remicade to Humira would be a bigger leap than moving from Remicade to Inflectra. For one, the slight and biologically natural differences between a reference and biosimilar are tightly controlled and have not posed problems. A move between two innovators is a much larger switch, given that they’re two very different molecules with different immunogenicity profiles. This helped ground switching as a biologics concern, not just a biosimilar concern.

Kozlowski also raised a question about whether the level of residual risk would change should a biosimilar already have undergone two switching studies and not demonstrated any issues. I interpreted this as a challenge to the current whack-a-mole approach to safety and efficacy data. Of course, it will always be critical to keep tabs on the performance of these products and find ways to use real-world evidence to dispel concerns. This evidence will encompass the diverse and complex ways these products are used on the market. But at some point, we need to trust the data we have, and our understanding of these products and their risks must evolve with it. I felt this line of questioning was particularly refreshing, especially as we wait to hear the FDA’s response to Pfizer’s recent Citizen Petition on misrepresentation of biosimilars’ safety and efficacy in innovator educational strategies.   

In an upcoming article, I will share my thoughts on the FDA’s Biosimilars Action Plan (BAP), and how the industry can best help the agency as it addresses the many topics broached in this Part 15 hearing. Stay tuned!