Chasing a ghost: Why is FDA guidance on biosim interchangeability taking so long?
It’s been a little more than five years since the Biologics Price Competition and Innovation Act was enacted in March 2010. Depending on perspective, it may seem that there has been a lot of progress in creating a viable biosimilars market in the U.S., especially given the approval of Zarxio (filgrastim-sndz) in March.
However, many stakeholders feel that everything is moving too slowly and bogged down in procedural delays, especially when it comes to publication of FDA guidance on critical topics, including naming, labeling and the highly confusing issue of interchangeability.
The need to get it right
Last month, Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at the FDA, stood in front of the Senate Subcommittee on Primary Health and Retirement Security and defended the agency’s delay in releasing much-needed guidance documents. In response to the pressure, Woodcock said, “We have to get the science right. We can’t have problems with the first biosimilars out of the block.”
According to Dave Fox, former associate chief counsel for drugs at the FDA and a partner in Hogan Lovell’s Life Sciences practice in Washington, D.C, “We are well into the fifth year of the implementation of the BPCIA, but the process has been intentionally deliberate.”
Now that Zarxio is approved and other biosimilar products are close to approval, the issue of interchangeability is becoming a hot topic and an area where there is a demand for clarification. Fox pointed out that the complexity of the science behind biosmilars informs the process and the pace of creating policy.
He said, “FDA guidance on interchangeability has been discussed for a long time. At this point, the FDA may be trying to publish some options for study design, which is a very technical process that requires large-scale review. They also have to address simulated switching studies, as well as questions related to how to statistically power a safety event. There are many complex details and uncertainties to address.”
Safety, similarity, and sameness
One major incentive associated with interchangeability is the fact that according to BPCIA provisions, interchangeable biosimilars can be switched out at the pharmacy level without any required input from a doctor—a reality that could affect payers’ and physicians’ attitudes and drive adoption. There is also the related issue of safety and the implicit understanding that interchangeable drugs are, by definition, safer than biosimilar drugs.
Fox believes that much of what is happening in terms of the creation of a well-entrenched biosimilars culture in the U.S. is the large-scale conceptualization of what biosimilarity is and what it isn’t. Biosimilar means that a drug is highly similar to the original reference product with no clinically meaningful difference. Biosimilars mimic the activity and safety of the original, but the original and the copycat are not the same.
In contrast, to be considered interchangeable, a biosimilar must produce the same clinical result as the reference drug in any given patient. In addition, these biosimilars must also show that a patient could switch back and forth between the original product and the biosimilar without any increased risk.
Why similarity is not sameness
As straightforward as the definition may seem, no company has yet scientifically developed an interchangeable biosimlar. The bar is set high—so high that some experts think that interchangeability may not be attainable.
For this reason, Fox and other experts caution that biosimlars should not be considered analogous to small-molecule generics. “It is important to emphasize that similarity does not mean sameness,” he said. “Be careful about treating biosimilars like generics. Sameness is a binary concept, while similarity is a relative concept. Everything changes when you go from a “sameness” system to a system based on similarity. The finding of similarity is really only a partial conclusion.”
Chasing a ghost?
The underlying biology of the immune system is a major contributing factor to the difference between a chemically synthesized small molecule drug and a biosimilar. Fox explained, “The body’s immune system instantly detects a protein, because it’s a large molecule, and the immune system immediately reacts to it. A patient whose immune system is attuned to a certain sponsor's version of the protein could react in a sponsor's biosimilar version of that protein.”
The complexity of biologics and how they affect the immune system can make the quest for interchangeability seem like chasing a ghost. But the complexity of biosimilars is part of their therapeutic elegance—and not unrelated to the fact that they can be profoundly effective, yet affordable. In the final analysis, the current challenges are a necessary part of developing a thriving biosimilars industry in the U.S., and most would agree, it’s well worth the effort.