Biosimilar Regulatory Best Practices: Don't Fear Exploration

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

Over the past two years, the U.S. has celebrated seven FDA biosimilar approvals. However, despite these approvals and the agency’s release of draft/final guidances, there has been what I’d consider to be a “shocking lack” of insights and regulatory best practices shared from companies’ perspectives.  When I carry out interviews, one of my favorite topics to discuss is working with regulators, especially in emerging markets since there are often variations from country to country. But what I’ve found has been missing from conferences and editorial on the topic of biosimilar development are the basic best practices companies have noted when working with the FDA prior to approving a biosimilar. Given the fact this industry is full of different types of players with varying capabilities — Big Pharma and Big Generics hybrids, small biotech, pure-plays — this topic is ripe from an editorial standpoint.

So I was pleasantly surprised (thrilled, actually) that, at last month’s AAM Biosimilars Council conference, there were actually two presentations dedicated to unpacking best practices when working with the FDA. Some of these key takeaways are as you would expect: Of course, it’s not going to be a simple journey. It involves planning early and staying in regular contact with the FDA. Biosimilar development will be a cognitive and even a “cultural” transition (as I’ll discuss later). And we’re all familiar by now with the phrase “totality of the evidence.” The takeaways shared during the conference panel clearly demonstrate the FDA’s ability to approach all the evidence and make science-based decisions.

But the two presentations during this panel — one by Cindy Cao, U.S. biopharmaceutical regulatory affairs for Sandoz, and the other by Tracy Dianis, director of global regulatory affairs, biosimilars, for Pfizer —  revealed what I’d argue is the central tenet to creating a biosimilar: Being open to learning throughout development. I’ve heard the phrase “telling the biosimilar story” in a number of keynote addresses by FDA members, and this concept was clearly demonstrated and reiterated throughout both Cao’s and Dianis’ presentations.

The U.S. biosimilar space is a strictly regulated arena, and the FDA has set high bars for biosimilar makers to ensure this market gets off on the right footing (and rightfully so). But in this age where there is emphasis on strict and early planning and risk-management, both of these presentations revealed that there is still a lot of room for exploration and innovation in biosimilar development. This two-part article exploring the lessons learned, first from Sandoz’s Cao, then Pfizer’s Dianis, will show that exploration and innovation are central parts of each of their biosimilar stories, and that each company had to embrace these in different ways.

Learning Through Development: Leave Room For Exploration

Makers of novel biologics (or any medicines, for that matter), are certainly going to be faced with a number of scientific and regulatory adventures. As Cao said, working with the scientific unknowns (e.g., safety, efficacy, immunogenicity, and the structure/function relationship of the molecule) was one of the greatest challenges during her time in novel drug development. But it’s often been said that making a biosimilar is more challenging than making a novel drug for a number of reasons. One of the most commonly cited reasons is because a biosimilar must follow the reference product, which is not a fixed target. It’s constantly moving and changing. After all, as biologics go through manufacturing changes, there can and will be slight changes from batch-to-batch. In fact, as Cao shared, Sandoz noticed some striking (but ultimately non-clinically meaningful) differences in later batches of Enbrel during Sandoz’s development of Erelzi, the now-approved biosimilar to Enbrel. The variations noted in later batches of Enbrel could be attributed to a manufacturing change — though this can’t be entirely proven because a company’s manufacturing changes are confidential.

Similarly, Cao was a great person to present on the challenges of biosimilar development and regulatory affairs because Sandoz’s development of Erelzi revealed information about the originator molecule that had previously been unknown. In the past, the FDA has acknowledged that some of the biologics molecules approved years ago were not quite what they thought they were. And, thanks to new technology and the development process of Erelzi, scientists and the FDA came to scientifically understand an incorrect disulfide bond variant within Enbrel.

Now, being of the right-brained variety where poetry, art, and music rule and science abides in lands I dare not tread, I’ll admit what Sandoz did to understand this variant seems (to me) like something from a sci-fi film. (But this is exactly why I enjoy my time in this space as much as I do.) In keeping with the theme of innovation and exploration in biosimilar development, Sandoz scientists developed an in-vitro system, called the redox system, which mimics the in-vivo physiological condition. By exposing batches of Erelzi and Enbrel to this redox system, scientists found the incorrectly folded variant was converted into the correctly folded variant.

As Cao explained, these variants are common to the etanercept molecule. “It doesn’t matter if you’re looking at Enbrel or our biosimilar Erelzi,” Cao explained. “You will see these variants in both. However, these variants can be reshuffled under the redox system, which, in turn, normalizes the potency.” (In fact, as the FDA briefing documents for Erelzi note, the biosimilar actually has lower levels of the incorrect disulfide bond in comparison to both the U.S.- and EU-approved Enbrel.)

FDA Dedicated To Scientific Decisions

As Cao went on to explain, this was new scientific information to both Sandoz and the FDA. This information was shared in April of 2016, just four months prior to the advisory committee meeting in July 2016. Though it’s been said companies must always plan ahead, there will inevitably be instances, like Sandoz’s, in which the company will need to learn while in the midst of their development program.

While much of this story took place in Sandoz’s labs, these developments were taken into account and explored by the FDA as well. In fact, though the central goal of biosimilar development is “matching” the reference product, there may even be instances in which companies realize their biosimilar product is actually a “purer” version of the reference product. For instance, in side-by-side comparisons of Erelzi and Enbrel, Sandoz was able to determine that Erelzi had a much lower level of impurity. And the FDA was open to this data.

We’ve all heard the phrase “totality of the evidence,” and early on, the FDA proved it was abiding by the totality-of-the-evidence-approach when it approved the earliest approved biosimilars with extrapolation to all indications. As the Sandoz experience continues to reinforce, the FDA is committed to looking beyond a single piece of data.   

“The FDA acknowledged Erelzi’s lower level of impurity, and they accepted it,” Cao said. “This confirms that the FDA applies a science-driven approach in their review. The tests and analysis you carry out will not be viewed through a pass-fail lens. As long as you provide them with the totality of evidence and convince them that you’ve gleaned a thorough understanding of how the molecule performs in vitro and in vivo, they will make a scientific decision.”