How Confusing Is Biologic and Biosimilar Substitution?

Evidence is mounting, especially from Europe that biosimilars to a single reference product result in the same clinical outcomes, with no appreciable safety issues. Evidence of this type from America will take time to accumulate, because competition in categories with multiple biosimilar options has been much more limited.

British Columbia biosimilar uptake

The recent announcement in British Columbia of the province’s decision to switch patients with inflammatory bowel disease from Remicade® to biosimilars has once again inflamed some passions. This is part of a broader effort by the Canadian province to increase utilization of biosimilars to gain economic savings. The Canadian GI Society, an advocacy group, published a letter firmly against the plan. They believe only the physician and patient should decide whether a biosimilar switch should occur. The British Columbia government, on the other hand, will pay for either Renflexis® or Inflectra® but not Remicade® after March 5, 2020. Even if patients have been taking the reference product, they will have to switch to one biosimilar or the other.

The Biosimilar Switching Argument

With medical experience supporting the case for switching, the argument by this Canadian advocacy group is less than solid. There may be the need for a medical exception for the infrequent patient taking infliximab, but these drugs can be effectively switched: there is no meaningful difference in effectiveness and safety outcomes on a population-wide basis among infliximab choices.

That said, here is where the supporting arguments get somewhat messy. The Food and Drug Administration (FDA) approves a biosimilar based on its equivalence to a reference product (not to other biosimilars). At the implementation of the Biologics Price Competition and Innovation Act, a biosimilar manufacturer has been required to show that its biosimilar was comparable in physiochemical, pharmacokinetic, and clinical studies to a designated reference product (i.e., US-licensed version of the originator). That required some manufacturers to first prove the equivalence of the US-licensed version to the EU-approved originator in a “bridging study.” This requirement was borne from the understanding that the US- and EU-licensed originator biologics make not be exactly the same either—biosimilars of each other. With more experience, the FDA has backed away from this requirement, understanding that the clinical outcomes differences between two licensed originator products are negligible.

The Laws of Transitivity and Biosimilar Switching

However, the FDA has not revised its opinion on whether two drugs proved to be biosimilar to one reference product are biosimilar to each other. Nor whether an interchangeable biosimilar might be considered interchangeable with other biosimilars. The answer remains: The evaluation process does not require such testing to gain basic biosimilar approval. In other words, the evidence did not yet exist.

This all relates to the basic premise of so-called “nonmedical substitution.” The issue is whether a payer-initiated change with a noninterchangeable biosimilar is considered to be more like therapeutic or generic substitution. Therapeutic interchange or substitution takes place when a drug is switched for another in the same category (e.g., switching Lipitor for a different statin rather than the generic atorvastatin).

Therapeutic Interchange vs. Biologic Substitution

A payer would be hard pressed to justify an unauthorized switch of adalimumab for infliximab. They are very different TNF-inhibitors. Patient outcomes would likely be affected in some way. Are Inflectra and Renflexis—different infliximab biosimilars—to be considered wholly different biologics? Because the FDA does not endorse that Inflectra and Renflexis are biosimilar to each other, it does imply (whether wrongly or rightly) that they are different biologic brands. If this was considered in the traditional sense, switching might be construed as an example of therapeutic interchange.

Framing the argument in this manner can drive patient and provider resistance to biosimilar uptake. Misinformation? Rather, I believe that this is an embodiment of the ambiguity of our regulatory policies. Certainly, payers don’t subscribe to it; they cover one versus another based more on net costs—certainly not on clinical outcome differences. For payers, it is more black and white; for certain other groups, much remains gray, especially when people believe more decision-making authority is being challenged. Only greater biosimilar clinical utilization, proof of savings, and better dissemination of education about this experience will change advocacy’s perspective .

Leave a Reply