Interchangeability: Another Challenging Perspective

Although the FDA has offered a pathway for the interchangeable designation, a recent presentation at the AMCP Nexus meeting shone a new light on some fairly important challenges posed by the interchangeable designation.

Edward Li, PharmD, MPH, Professor of Pharmacy, University of New England, Portland, Maine, raised the Web image 3well-trod issue of manufacturing drift—that over time, the reference product in particular is often subject to slight changes in structure that may be due to manufacturing changes, or other factors. This is an extremely important concept in biosimilars, as it highlights that these biologics can never be exact copies of the biologic drug. In fact, the originator biologic produced today cannot be expected to be exactly the same as the medication that was first approved 15 years ago. Although the structure may have changed subtly in these complex molecules, the clinical effects and outcomes have not materially changed. With interchangeability, Dr. Li said, “There should be no clinically meaningful differences,” in terms of safety, purity, and potency.

Once the FDA assigns the interchangeability designation to a prospective biosimilar or one that has already been marketed (and subsequent studies have provided FDA with the data to conclude that it is interchangeable with the originator), payers expect to be able to freely substitute this biosimilar for the originator at the point of dispensing—an expected boon to health plans and insurers, as well as the biosimilar maker.

However, what of the interchangeable biosimilar in the future? If manufacturing drift continues to occur over the course of time, the variation in the biosimilar and originator product will have introduced new subtle changes compared with that previously used in the approval process. “Differences may accumulate over time,” said Dr. Li, and hypothetically, these can lead to differences in safety and efficacy.” Does the biosimilar manufacturer need to prove interchangeability all over again, five years later? Is there a possibility that the biosimilar can be reduced back to the ranks of ordinary biosimilars?

These are important questions. Only after we have a biosimilar  designated as interchangeable will we be able to broach this question. However, it does perhaps give the reference drug maker a line of defense in sparing loss of marketshare.

Will Approval of an Interchangeable Biosimilar Mean that Others Are Inferior?

In terms of the biosimilar market and utilization, the US has been at least one full decade behind Europe in every respect but one. Yes, we have the EU beat in a game they avoided playing: The interchangeability gambit. The Europeans never defined interchangeability as a separate concept for biosimilars, thus leaving the individual countries to decide whether to allow unencumbered switching of biosimilars for their originator drugs.

As in other areas of biosimilar policy and regulation, the US started very slowly. Leah Christl, PhD, Associate Director for Therapeutic Biologics, OND Therapeutic Biologics and Biosimilars Team, Food and Drug Administration (FDA) stated last week at the Drug Industry Association’s annual meeting in Chicago that she expects the first interchangeable biosimilar to be approved within about 2 years. This is probably realistic, based on the timeline of the adoption of the agency’s interchangeability guidelines. Comments on the draft guidance are being read by the FDA at this time. Seven years after the passage of the legislation calling for the biosimilar approval pathway. If there were competitors in this game, we’d be desperately trying to catch up!

It seems unlikely that the FDA has any active 351(k) applications seeking the interchangeability designation, although Dr. Christl did not reveal whether this was the case. The application process is confidential; a submitted application is publicized only if the drug maker issues a press release on its ownDeck 1.png. It would seem premature to seek the interchangeability designation before the FDA’s own guidance on what the review entails is released. This may not prevent a biosimilar manufacturer that has already received approval from taking the quick step towards interchangeability, especially if they have conducted a series of switching studies that meet the FDA’s criteria (e.g., NOR-SWITCH).

Payers are chomping at the bit for an interchangeable product in the 36 states (and 3 pending) that have signed legislation allowing pharmacies to automatically substitute a biosimilar for an originator biologic.

Others have pointed out that the interchangeable biosimilar may be a boon to its manufacturer, but it may have negative effect on competitive markets. For example, a noninterchangeable infliximab may be considered by prescribers or patients somehow inferior to the interchangeable version, devaluing this biosimilar. On the other hand, the maker of “infliximab-int” could experience increased demand and boost prices (or avoid decreasing prices in the face of other noninterchangeable biosimilars coming to the market). And this may be justified. No one really knows the manufacturer’s incremental cost of achieving this designation, based on:

  • The cost of conducting additional switching studies
  • The potential cost of responding to FDA requirements for more data
  • The opportunity cost in marketing time, resulting from a delay in the application or approval

The race for a product with this extremely valuable designation drags on at a snail’s pace. I hope I’m still writing about it by the time someone reaches the finish line.


What Happens When Switching Among Biosimilars?

Late last year, I wrote about a biosimilar challenge that could be on the horizon. With the approval of the second infliximab biosimilar (infliximab-abda by Samsung Bioepis), that horizon is a lot closer. However, we are no closer to understanding how to address the issue.

When Renflexis™ is launched in October (it is unknown whether the US Supreme Court ruling that wiped away the 180-day postapproval waiting period will affect this), 3 noninterchangeable versions of infliximab will be available. Based on patient turnover in health plans, the following scenario will soon occur.


Lee 2
Image Copyright 2017 by Lee Fogel

Mr. Jones, a 39-year-old man with Crohn’s disease, works for a large self-funded employer. He has been taking Remicade®, the reference product, for some time. In January 2018, his employer decides to change its plan offerings. His new health plan does not cover Remicade, favoring Inflectra® (infliximab-dyyb) instead. He could seek a medical exception to continue on Remicade, but his new plan actually offers considerable incentives to switch, including significantly lower cost sharing. After discussing the situation with his doctor, he makes the change, and experiences much the same clinical results. In 2019, his employer makes another change in plan. And this plan covers Renflexis on the specialty tier but has Remicade available on the higher-cost nonpreferred specialty tier. He and his physician are unsure of the best move.

Keep in mind that it would be rare and probably makes little sense for a health plan to cover both biosimilars and the reference product. At some point, the plan will seek a contract that leverages marketshare. In the scenario above, at what point does the patient unduly risk the development of neutralizing or antidrug antibodies?

No data have been published on switches among 3 biosimilar products. These agents are not designated as interchangeable—though Pfizer’s Inflectra may be closest to it based on its NOR-SWITCH investigations; therefore, no one is truly confident of what might or might not occur with regard to efficacy or safety. I suspect it may be some time before switches among reference product, biosimilar A, biosimilar B, or even biosimilar C may be considered routine.

Patients receiving biologic products for serious chronic diseases may also be subject to case/care management. This is not a clean transition when changing health plans. The situation described above will likely happen in the near future with infliximab and possibly adalimumab (once the patent litigation is cleared). It would be a good idea for health plans and insurers to start reviewing their options now to ensure both patient safety and cost-effective decision making.

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 for instructions.

Some of the Conflicting Concepts Around Interchangeability

At the Biosimilar Multistakeholder Summit, a closed meeting of 17 executives that was held November 30–December 2 in San Diego, organized by StrategiX, a number of important issues were raised regarding the daunting question of interchangeability. In this post, we’ll address how interchangeability was framed at the conference.

Although the Biologics Price Competition and Innovation Act (BPCIA) tried to apply the concept of interchangeability, used in the generic marketplace approval process, to the more complicated biologics arena, few expected a smooth translation. In fact, the US Food and Drug Administration (FDA) has tacitly acknowledged the difficulty, when they postponed the release of their all-important guidance on the topic until late 2017.

The concept of interchangeability, as it applies to biosimilars, is unique to the US; the regulatory concept does not exist in Europe, where switching of products is not expressly prohibited. We assume that the FDA will eventually approve interchangeability in 2 ways: (1) tighter prespecified equivalence margins than now seen with conventional biosimilar testing and (2) additional clinical studies. Although manufacturers may decide someday to spend the additional money to to prove the extreme similarity of their agent to the originator, it may not have the impact on marketplace uptake that one might expect. For example, if a biosimilar product without the interchangImage result for raising the bareability designation is already approved upon the launch of the new biosimilar, and it is already being switched at the point of prescription, by the clinicians themselves, based on payer coverage policies, then what does the new product bring to the table?

If safety is is important to gauging the interchangeability of the product, this ignores the levels of confidence gained with the 10-year global experience with biosimilars—a virtually spotless record that seems to contradict the notion that interchangeability is important.

Another very interesting and valid consideration involves a bit of reverse logic regarding the standard biosimilar approval process. The biosimilar manufacturer does everything required to prove that their product is equivalent in safety and efficacy compared with the originator product. No manufacturer seeks to demonstrate that their biosimilar is not interchangeable with the originator product. If it was deemed not interchangeable, the participants agreed, the molecule would not be able to pass the basic test for biosimilarity.

Actions taken by US payers (e.g., CVS Health, UnitedHealthcare, the Department of Veterans Affairs) to exclude coverage from originator products should compel the move towards switching by the physician’s pen, in the absence of FDA action on interchangeability. By the time an interchangeable product is approved by the FDA, we may likely have a couple of biosimilars being used in this way already.

Largest French Hospital System Decides on Infliximab Substitution

Although Celltrion and Pfizer’s Inflectra® was not approved as an interchangeable product to Remicade®, this will generally not matter to US payers when deciding the coverage of the product in patients who have not had anti-TNF treatment in the past. This is of even less importance to French prescribers, where the European Medicines Agency does not have a mandate to rule on the interchangeability of biosimilars. That means it’s entirely up to the health systems and physicians to decide this matter, including whether to allow substitution or switching.

The basic question is whether the evidence exists this biosimilar monoclonal antibody is close enough therapeutically to the innovator product to justify substitution. In a commentary, French physicians stated that substitution is a foregone conclusion in their country. There is a French law forbidding the practice of automatic therapeutic interchange, preventing systematic institution of the practice.

The biosimilar version of infliximab was approved in 2014, and as governments in the EU have generally not taken a stance on substitution, hospitals and other healthcare systems have addressed this issue, building a consensus based on the experience of the Assistance-Publique Hôpitaux de Paris (AP-HP) (this is the largest public hospital group in Europe, accounting for 22,000 beds and caring for 12 million patients). Unlike in the US, infliximab is administered in the hospital setting in France.assistance-publique-hôpitaux-de-paris-office

However, AP-HP does have its version of the typical US Pharmacy & Therapeutics Committee, called the Committee on Medicinal Products (COMED). This hospital system decided that COMED should decide for itself whether infliximab biosimilars yielded essentially equivalent outcomes and on substitution issues within its hospitals. Last year, it came to the conclusion that the two available biosimilars were substitutable for each other and the originator product.

Furthermore, COMED recommended that (1) “a vigorous post-approval surveillance (full traceability) of these products should be implemented in AP-HP” and (2) “physicians should be encouraged to take part in the registries that will be implemented by the medical disciplines concerned in the AP-HP.”

Back in the US, will payers make their own public statements on switching? This is unlikely, owing to the potential for negative press, but it could ease any concerns prescribers have in using biosimilars. Again, the choice of prescription, without an interchangeability designation, is still in the doctor’s hands. It will be largely up to them to speed adoption.