By Anna Rose Welch, Director, Cell & Gene Collaborative
Most of you have probably seen images depicting how biosimilar development differs from a “stand-alone” biologic. My favorite graphic is this one featuring two inverted triangles. While clinical studies make up the base of the biologics development triangle, these studies are only the small tip of the biosimilar development triangle. Rather, analytical studies make up the large base of the biosimilar triangle. As Sandoz stated in its recent advisory committee (AdCom) presentation, biosimilars turn the familiar world of biologics development upside down. For those of you who paid close attention to the FDA AdCom meetings for Amgen’s adalimumab biosimilar and Sandoz’s etanercept biosimilar, you’ll know that experts familiar with the world of biologic development are not yet used to the “upside down” world of biosimilars.
Though both committees unanimously recommended approval and extrapolation of each biosimilar, this process was not as cut-and-dried as expected following the overwhelmingly positive FDA briefing documents. Committee members expressed numerous concerns about extrapolation, “non-medical switching,” and adverse event reporting, while also demonstrating a general sense of confusion over the biosimilar pathway. As such, these two AdComs highlighted five points manufacturers will need to keep in mind as their own biosimilars approach FDA submission.
- Slow Down—There’s A Big Disconnect Between FDA & Advisory Committees: The FDA’s briefing documents found both the biosimilar candidates to be highly similar. But as Amgen’s data was reviewed in its AdCom, it became clear — even after eight hours of discussion — that the committee was still struggling to understand the basic tenets of biosimilarity. As one clinician on the committee emphasized, ruling on extrapolation of the adalimumab biosimilar into the gastroenterology indications, for instance, was asking “us to make a judgement that is out of our comfort zone.” As such, manufacturers will need to emphasize the differences in the data needed to prove biosimilarity. (Take, for instance, Sandoz, which presented its case starting with the analytical work — in essence starting with the most important data for biosimilars.) Arguably, one of the reasons the Sandoz biosimilar AdCom went much more quickly was because Sandoz’s Mark McCamish, head of global biopharmaceutical development, stepped back and opened his presentation with the biologic vs. biosimilar development triangles image. As he expressed, he has had 10 years to learn about and understand the biosimilar development paradigm shift. U.S. experts have only had four biosimilar AdComs worth of experience. Compared to10 years, that is definitely not enough time to expect the basics of biosimilarity will be completely understood by those considering your product.
- Extrapolation Needs To Be Approached Differently: Extrapolating a biosimilar to untested indications is a frightening concept to a clinician. As the development triangles show, clinical studies are the life-blood of biologic development. Clinical trials are the way novel biologics demonstrate their efficacy and safety in each individual indication. But as the FDA’s Leah Cristl emphasized, biosimilar development is not about demonstrating safety and efficacy — it’s about demonstrating biosimilarity. As such, a manufacturer must emphasize in an AdCom that extrapolation is from molecule to molecule (biosimilar to reference product) — not indication to indication. The clinical experiences of a patient will obviously vary from condition to condition. (For reference, here is McCamish’s presentation slide on extrapolation.) McCamish also referred to a slide documenting Enbrel’s manufacturing changes over the years. Despite these slight changes, however, the product was still found to be highly similar from molecule to molecule and, therefore, was still suitable to treat all approved indications. Once Sandoz emphasized that extrapolation is justified by comparing molecule to molecule, many clinicians in the committee seemed more comfortable with the notion of extrapolation.
- “Sameness” Should Replace “Similarity”: When referencing Sandoz’s candidate, McCamish relied on the word “sameness” rather than similarity. In fact, the key to biosimilarity and extrapolation relies on the regulatory concept of sameness, which was established when small molecule generics hit the market. As McCamish said, it is the biosimilar manufacturer’s job to provide “copious information our molecule is the same.” The manufacturer must continue to emphasize that the active substance is “essentially the same,” regardless of small structural differences because of the complexity of the molecule and the processes creating it.
- “Non-Medical Switching” Is A Big Concern: The Amgen AdCom was the first time I’d ever heard this term. It was being used to describe insurance companies and payers mandating a switch from a brand biologic to a biosimilar — in essence taking the choice to switch out of patients’ and physicians’ hands. But this term then begs the question: What is “medical switching?” After all, patients don’t switch from the brand to the generic or biosimilar for medical reasons — this change is made solely to save money. The prolific use of “non-medical switching” in these AdComs emphasizes the confusion that continues to persist about switching and interchangeability. The fact that many seemed to express concerns about interchangeability — regardless of the fact that Amgen was not applying for interchangeability — also leads to the question: Did the FDA shoot itself in the foot by creating another “tier” for biosimilars to attain?
- Prepare For Biosimilar Adverse Event Reporting To Become A Key Industry Topic: A number of committee members questioned how adverse events for biosimilars would be reported. As RAPS reports, one voting expert said, “I find it shocking that we’re still relying on passive systems to track adverse events.” Another expert questioned if we would ever test the “biosimilar premise” — that analytical similarity can truly be indicative of a drug’s clinical performance. But the hope is that, with more experience, there will be publications demonstrating successes and failures, because the information about the failures is just as important. This suggests one way biosimilar makers can help enhance comfort about the “biosimilar premise” is through heightened transparency.