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The Food and Drug Administration’s decision on Wednesday to approve a long-acting insulin called Semglee (insulin glargine-yfgn) as the first interchangeable biologic licensed for the U.S. market represents a major step forward to greater competition and access for patients. What it means in practice, however, depends on where you sit.

The term “interchangeable” sounds simple but is defined by law as a set of requirements to be evaluated by the FDA. The interchangeable designation allows pharmacists (subject to state law) to substitute a biosimilar biologic for its brand-name (reference) product without the permission of the original prescriber, much as occurs today for generic drugs.


When the Biologics Price Competition and Innovation Act became law in 2010, it granted the FDA authority to approve biologics made by different sponsors as biosimilar to a previously FDA-approved biologic. For those biologics not administered by the physician who prescribed them, but by the patients themselves, there is the additional option of an FDA interchangeability designation. The way the law was written requires a demonstration that switching between a biosimilar and its reference products does not change clinical outcomes for patients. The FDA issued guidance both for interchangeability in general in May 2019, and specifically for insulins in November 2019.

Since 2015, the FDA has approved 30 biosimilars for 10 reference products and, once Semglee is on the market, 20 of these biosimilars will be launched and commercially available in the U.S. Until now, none of them had been designated as interchangeable with their reference product.

The FDA has previously stated that all of the biosimilars it has approved are interchangeable for the purposes of physician prescribing. This means the agency is already confident that biosimilar medications will behave the same way for patients as their reference products. Indeed, the science behind their development makes this inevitable.


Three decades of experience with interchangeability decisions

The FDA has been making interchangeability decisions for biologics for decades, but only when applied to products from the same sponsor that have been subject to manufacturing changes. In these cases, sponsors are proving “sameness” for different versions of their own products and they have access to their own history of making the products, often for decades. Nonetheless, this shows that demonstrating “sameness” is possible and the FDA, by evaluating the data to approve each change — sometimes 50 or more in series have occurred for a single biologic product — is concurring that patients will get the same clinical benefit.

Given its experience, the FDA clearly knows the science and clinical aspects of biologics extremely well. This is highly pertinent because these are the biologics that comprise the reference products for biosimilars. And as Janet Woodcock, then deputy commissioner and chief medical officer of the FDA, testified in 2007, rarely does the agency require any clinical studies at all for manufacturing changes. So the data expectations for such changes remain considerably less than for biosimilars even without their receiving an interchangeability determination.

It’s important to note that the FDA’s decisions about approving “sameness” after manufacturing changes to specific biologics have not been subject to public comment. Patients and their health care providers are not aware of the changes occurring to the biologics they are using and the label of the product stays the same. And there have been no concerns about safety or effectiveness following manufacturing changes, indicating that everyone is doing a good job, both originator sponsors and the FDA. Such manufacturing changes will also be made to biosimilars as facilities scale up and more capacity is needed. This is OK too.

Is the first interchangeable biologic a big deal?

At one level, no. Science supports interchangeability and there is every reason to believe that switching between these essentially indistinguishable products will be fine and no different for patients than changing between batches of their current medicine. The FDA knows what it is doing with biologics, biosimilars, and interchangeability, and Viatris/Biocon, the sponsors of Semglee, have huge experience with making insulin as Biocon already manufactures a vast proportion of the insulin consumed worldwide. The quality standards are the same for all biologics approved by the FDA.

At another level, the decision is a big deal. The FDA’s first interchangeability determination for Semglee (insulin glargine-yfgn), referring to Lantus (insulin glargine) from Sanofi Aventis, represents the first public regulatory decision anywhere in the world that two biologics from different sponsors can be substituted by someone other than the original prescriber.

That is a lightning rod for slippery slope advocates who don’t follow the science or understand from biochemistry 101 that function must follow form.

The potential economic ramifications of the generic model being presumed for specialty biologic medicines are considerable and the professional sensitivities of physicians not far behind.

Economics will now drive the debate

While such substitutions occur every day for small-molecule drugs like statins and antibiotics, it is new for biologics. Though biologics are clearly more complex than small-molecule drugs, and are made by living cells rather than chemical processes, these differences are irrelevant given that the FDA has approved the products involved and allowed those making them to tweak their manufacturing processes for decades. This is a good thing, as manufacturers need efficient ways to update their facilities and expand capacity to serve more patients.

It’s peculiar that there is a suffix on the nonproprietary name (especially because the same product, Semglee, had already been approved without one), and so this first interchangeable biologic may appear to have a different active ingredient to its reference even though this is not the case. Pharmacy workflows will need to consider this, since this is not the case for generic drugs.

What now matters is the public perception of a product change by patients and their health care providers, especially since other stakeholders have fostered such concerns using intuitively pejorative phrases like non-medical switching. The savings that patients, health systems, and insurers could accrue from easier access to biosimilars mean that someone else loses revenue they previously received. Money is zero sum whereas science, fortunately, is cumulative.

In looking toward the sustainability of competition from biosimilars and interchangeable biologics, another important consideration is the cost to develop these products. Developing a biosimilar is expensive — by some estimates up to 100 times that of developing a generic to a small molecule drug — and interchangeability will usually require additional studies that add further cost. Given these expenses, biosimilar sponsors, with or without interchangeability designations, must balance market share and price. They need to achieve a return and that means market share at sustainable prices.

But it’s wrong to assume that the cheaper product gets the greatest market share, especially for insulins which are traditionally high list price/high rebate products. In the past, some companies had to increase their price to gain market share.

And right or wrong, what we see for this first interchangeable biologic will have implications for the big one — adalimumab (Humira), a blockbuster monoclonal antibody used to treat rheumatoid arthritis, Crohn’s disease, and other autoimmune diseases.

Gillian Woollett is a principal research scientist at Avalere, a health care business consulting firm headquartered in Washington, D.C.

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