The talk at the GRx+Biosims 2018 meeting this month in Baltimore was about challenges, but extrapolation was not one of them. Biosimilar interchangeability was. That was not entirely surprising. In market research projects I’ve been involved with over the past year, payers and physicians in medical groups have broadly indicated that they’ve gotten past the extrapolation question. They are willing to accept the Food and Drug Administration’s (FDA’s) decisions on approval for indications for which clinical studies were not performed. In fact, some payers have noted a willingness to not discourage a biosimilar’s use for an indication for which the reference product was approved but the biosimilar was not. This, of course, assumes that it makes economic sense to do so. Many physicians still harbor concerns about switching therapy but not in treatment-naïve patients. In other words, if the payer prefers one product over another in a new patient, they would change their prescribing practices. In other words, they would not “rather fight than switch.”
Instead, the meeting, which was sponsored by the Association for Affordable Medicines and its Biosimilars Council, raised other questions, including the rationale behind the four-letter suffix and the complexities around biosimilar interchangeability.
Are Four-Letter Suffixes Needed?
Two greater questions were raised, one very practical and one theoretical one. The first involves the issue of the random (or sometimes not, as in -sndz) four-letter suffix, which is required for biosimilars in the US, but nowhere else in the world. Japan requires biosimilars to be designated with a standard “–bs” suffix. However, the European Medicines Agency does not utilize any suffixes and relies upon the international nonproprietary name (INN) for tracking purposes.
To make matters more complicated, the FDA intends to retroactively provide a suffix to all reference products as well, which no doubt will challenge billing and coding systems. The question is currently unanswered in the US as to whether interchangeable products will carry a unique suffix or share the same suffix as the reference product.
Hillel Cohen, PhD, Executive Director of Scientific Affairs for Sandoz, believes that these suffixes will not enhance the ability to track the use of biosimilars. Despite not using any special designations, “if you look at the European experience,” he said, “96% of safety reports have been made with proper attribution.” He pointed to the small database of biosimilar use accruing in the US. “Out of 65 safety reports registered so far, 62 came in with the brand name,” Dr. Cohen said. “None of the 65 reports were entered with the four-letter suffix.”
More on Biosimilar Interchangeability
Questions around biosimilar interchangeability still abound, partly because the FDA has not yet issued final guidelines around the approval process. Apart from the misconception that a product earning the FDA’s interchangeable stamp of approval is a “better” product than an ordinary biosimilar, two specific questions were explored, one of which is mind-boggling, the other merely frustrating.
The challenge extends from the expectation of lot-to-lot variation that occurs with biologic manufacturing. Assume that biosimilar A obtains FDA approval as an interchangeable medication, based on the switching studies against a reference product. As time passes, this manufacturing “drift” occurs. In a conversation with Dr. Cohen, he asked, “Is the biosimilar still interchangeable with the reference agent?” In other words, will the drug maker have to conduct more clinical switching studies to maintain this level of confidence, proving once again that the drug will provide equivalent outcomes in all patients compared with a reference product that is now also subtly different?
The second theoretical question arises from one I had discussed in an earlier post, the law of transitivity. If drug B is a biosimilar to infliximab, and drug C is approved as a biosimilar to infliximab, too, are drugs B and C biosimilars to each other? The answer, according to the FDA, would be no, because they have not be evaluated for physiochemical similarity to each other, only separately to the reference product. However, for payers, the answer is not so clear.
Dr. Cohen took that question one step further. If at some point in time, there are biosimilars A and D, both of which have been granted interchangeable status to adalimumab, are they interchangeable with each other? Again, the official answer would be no, because that is not how the testing was performed.
This brings up another intriguing question: if I’m living in a state that passed legislation allowing for automatic substitution of an interchangeable product, can a payer substitute interchangeable biosimilar A for interchangeable biosimilar D, if the former is the preferred product based on contracting? Technically, if the physician prescribed biosimilar D specifically, the pharmacy would not be able to substitute, without the doctor’s consent. The FDA has not designated biosimilars A and D as interchangeable for each other, only the reference product Humira®. The concept of biosimilar interchangeability is still, many years after passage of the BPCIA, an enigma.
Of course, based our situation in September 2018, this scenario is purely speculation, and will require multiple drug makers spending their R&D dollars to attain interchangeable status (to the same originator drug). That’s one reason why I like attending these conferences—they offer exposure to new, often confounding ideas!