Interchangeability Guidance Released, FDA to Require Switching Studies

On January 10, the Food and Drug Administration (FDA) released its long-awaited draft guidance on the interchangeability standard for biosimilar manufacturing.

It’s been quite a while since we have been able to discuss progress on interchangeability, so as a reminder, the practical differentiator between a product designated as biosimilar versus interchangeable is that the latter “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

Not surprisingly, the critical mandated addition in clinical studies of an interchangeable biosimilar is the conduct of a sufficient number of switching studies; that is, studies where patients are alternatively given the originator product, switched to the biosimilar, and possibly back to the originator, without any measurable risk to patient safety or efficacy. Or as the FDA puts it “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

Interestingly, the FDA does restrict switching studies to between the biosimilar and the US-licensed reference product only (i.e., no EU versions with bridging studies). The reason is related to slight, nonclinically meaningful differences that may be introduced in the EU version that is not present in the US originator product.

The draft guidance is subject to a 60-day public comment period. For those interested in commenting on the guidance, they can visit https://s3.amazonaws.com/public-inspection.federalregister.gov/2017-01042.pdf for instructions.

Supreme Court to Hear Sandoz v. Amgen Arguments on the 180-Day Notification Period

It seems that the Supreme Court will in fact hear Novartis’ case in an attempt to overturn the 180-day notification period, as part of the “patent dance.” Its biosimilar-making subsidiary (Sandoz) will finally get its day in the nation’s top court in April, with a decision expected sometime in July.

The announcement has taken many by surprise because of an announcement by the court in December that it would not hear a similar case involving Apotex v. Amgen.

Although any new decision by the Supreme Court will have no bearing on the circumstances of the original case—Sandoz launched in September 2015 after sitting out the 180-day notification period—it will have important ramifications for biosimilars coming to market in the future. It is widely viewed that this notification is wholly unnecessary. This mandate of the BPCIA was intended to allow the completion of patent litigation, but instead is seen as an extension of the originator product’s exclusivity period.

However, even if the Supreme Court rules to strike down this unintended additional period of exclusivity, it may have relatively little effect in getting biosimilar products to the market sooner. Instead, the remaining patent litigation will prevent most drug makers from a quick launch after receiving Food and Drug Administration approval.

Are 2 Biosimilars to the Same Originator Product Biosimilar to Each Other?

In Europe, several manufacturers are marketing approved biosimilars to the same originator product. In fact, 7 manufacturers compete for the biosimilar filgrastim market, 5 biosimilar versions of epoetin are sold, and 3 biosimilars of infliximab seek marketshare from Remicade®. In the US, this situation is not a reality yet. It will be one day, however, and it raises a couple of important questions.

We know that the biosimilars are not exactly the same structurally as the originator products, but how similar may they be to each other? In other words, at some point, payers will prefer one biosimilar version of filgrastim over another one, as some do currently with Zarxio® versus Neupogen®. We can assume that with 3 filgrastim biosimilars sold in the US, payers will seek to leverage 1 against the others and make it their preferred or only available form of filgrastim available. However, is another manufacturer’s version of filgrastim biosimilar to Zarxio? We can also assume that the new manufacturer’s product has received US Food and Drug Administration approval through testing for comparability only with the originator product—not against Zarxio. How about compared with Teva’s product tbo-filgrastim (a follow-on biologic, not a biosimilar according to the regulatory and statutory rules)?

What does this mean for switching products, much less interchangeability? Is one biosimilar interchangeable with another? Based on what we know about the FDA, the answer is likely no, as the agency seems to be having difficulty devising interchangeability guidelines for a biosimilar and its originator product.

Why is this important? Consider the patient with Crohn’s disease in 2019 who changes health plans. The patient was receiving biosimilar A, and the new plan covers only biosimilar B. Maybe he or she needs to enroll in a new plan in 2020, and the reverse is true. Regardless of whether we like it, that patient may be unintentionally providing real-world evidence of interchangeability.