In the hallways and boardrooms we occupy, there is a lot of talk of interchangeability of biosimilars right now. Despite all the conversation, there doesn’t seem to be a consensus opinion about its relative value or worthiness. To help you to be more knowledgeable around the watercooler and to help inform your own opinions, let’s start from the beginning, define some key terms, explain what the interchangeability hub-bub is all about, and detail why it is a hot topic that you are hearing more and more about now.
In Europe, the European Medicines Agency (EMA) was first out of the gate, pioneering a dedicated route for biosimilar legal and regulatory approval (known as the centralized procedure) in 2004. The U.S. followed suit in 2009, with the Biologics Price Competition and Innovation Act (BPCIA), which established an abbreviated licensure pathway—351(K)—for the development and approval of biologic products shown to be “biosimilar” to an already FDA-licensed biologic product.
Despite the existence of these pathways for a combined 20-plus years, which have seen the approval of over 50 biosimilars, there’s still a lot of confusion. At the center of the misunderstanding are a lot of terms and concepts that get thrown around and are often conflated or misinterpreted. To provide clarity, let’s start by deciphering the relevant biosimilar terminology.
Novel biologic: Also called the originator or reference product, this is the original FDA/EMA-licensed biologic entity that has been approved based on comprehensive clinical trial investigations of de novo safety and efficacy.
Biosimilar: A biologic product that is approved (via the FDA’s 351(K) pathway or the EMA’s centralized procedure) based on a totality of evidence demonstrating it to be highly similar to an already-approved reference biologic product. According to a presentation by Sue Lim, director of the scientific staff, therapeutic biologics and biosimilars staff at the FDA, the biosimilar should:
- Utilize the same mechanism of action (MoA), to the extent it is known, as that of the reference product;
- Have the same route of administration, dosage form, and strength as the reference product; and
- Adhere to the same stringent manufacturing, processing and packaging standards as all other approved products
Ultimately, the application data package must demonstrate that there are “no clinically meaningful differences between the proposed product and the reference product in terms of safety, purity, and potency.”
Interchangeability: A condition in which the biologic product “may be substituted for the reference product without the intervention of the healthcare providers who prescribed the reference product,” according to Lim. To achieve that designation, according to draft guidance issued by the FDA, the product must be a biosimilar of an FDA-approved reference product, and it must also satisfy additional criteria set forth in the BPCIA. Specifically, Lim indicates the biosimilar must show that:
- “It can be expected to produce the same clinical result as the reference product in any given patient; and
- “For a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alteration or switch.”
To demonstrate the points above, the FDA requires that applications for interchangeability include what’s called a switching study, which is an additional clinical trial to evaluate product performance with changes in treatment that result in two or more alternating exposures (i.e., switch intervals). A product that the FDA has approved as interchangeable means that the FDA has concluded that the product can be substituted without consulting the prescriber. More on this below.
Switching (physician-mediated): A prescribing decision made by a physician to change a patient’s treatment to another course of therapy—either between a reference product and a biosimilar or between two biosimilars—in the same way they prescribe other medications. There is no statutory standard for physician-mediated switching, either in the U.S. or the EU. Such decisions take place in normal medical practice and are independent of both substitution and interchangeability.
Substitution: As opposed to physician-mediated switching, this is the act of switching a product at the pharmacy (for example, from the originally prescribed reference product to a biosimilar) without needing to consult the prescribing physician. In the U.S., a biosimilar product may be substituted at the pharmacy without consulting the prescribing physician if the product has been granted interchangeable status by the FDA and where state law permits the substitution of biological products. It is important to note that while the FDA does make determinations on interchangeability (and therefore substitutability), the EMA does not. In Europe, the decision of whether to allow interchangeable use and substitution is made at the national level, and there is wide variability across the EU in terms of country-level adoption of such substitution practices.
The U.S. has not yet approved a biosimilar that has also been granted interchangeability status. There are several considerations at play that can help to explain why that is the case. I’ll summarize them, but, put simply, it is because the ROI of interchangeability is very uncertain.
- The investment: As explained above, in order to be granted interchangeability status by the FDA, a biosimilar application must include additional data in the form of a switching study to satisfy the criteria set forth in the BPCIA. The switching study is an additional clinical trial that would cost the applicant company additional years, resources and millions of dollars, just as any other clinical trial for a novel drug or biologic would. Given the accelerated pathway that biosimilars currently enjoy, the switching study is a very significant (and, strictly speaking, unnecessary) incremental investment for a company to make.
- The return: As opposed to the investment, whose cost can be estimated relatively accurately, the ROI of an interchangeable designation is far more uncertain. There are two schools of thought:
- Go for it: Proponents of interchangeability (and the pharmacy-level substitution it enables) argue that the designation will increase patient, provider and payer confidence in it, and that the halo effect would not only boost uptake through added comfort in usage, but potentially also allow the manufacturer to command a price premium relative to other biosimilars. There is also the idea of empowering the pharmacist to make the substitution, just as manufacturers and payers have been able to do with generics.
- Don’t do it: Detractors argue that the halo effect is overstated because the designation is in no way a determination that the product is any more efficacious or safe than another biosimilar. Also, they argue that the benefit of pharmacy-level substitution is negligible, because most biologics are currently a medical benefit (as opposed to a pharmacy benefit) and are administered in physician offices, hospitals or infusion centers. The desired biosimilar switch, they argue, can be more efficiently achieved through contracting, rather than through the interchangeability designation. There is also the very real consequence of stripping physicians of their prescribing and decision-making power, and the political storm that may erupt with the American Medical Association and other powerful stakeholder groups should this power be eroded.
- Will an interchangeable designation increase biosimilar uptake with payers, systems and HCPs, even though it is not a determination of product superiority?
- Will an interchangeable biosimilar be able to command a premium price in the market?
- Does pharmacy-level substitution mean anything for medical benefit products?
- How will developments in the U.S. affect the EU and the rest of the world?
Since there are no interchangeable biologics currently on the market for us to study, these questions remain unanswered. However, a few recent developments lead us to believe that the situation may rapidly evolve in 2019, which is why the buzz about this timely topic is not likely to abate anytime soon. First, the FDA has set the end of May 2019 as its timeline for releasing revised or final guidance on a number of topics, including “statistical approaches to evaluate analytical similarity” and “considerations in demonstrating interchangeability with a reference product.” Second, Boehringer Ingelheim, the first company to invest in a switching study (back in 2017), expects to have results in the second half of 2019 for its adalimumab (Humira) biosimilar. Third, these two developments together have already spawned the competition to come out with its own “interchangeability does not mean superiority” campaign.
In the grand scheme of things, the global biosimilar experiment—if we can call it that—is relatively nascent. On topics such as interchangeability, the FDA is still operating with draft guidance, and the landscape continues to evolve rapidly. Stay tuned as we will continue to follow and report on these developments as more puzzle pieces fall into place.