Contributor: To Try or Not to Try? That’s Not the Question—Phase 3 Trials of Biosimilars and Beyond

Are phase 3 trials of biosimilars necessary, valid, ethical? This debate has been simmering for a few years now and every so often it flares up again: heavy on assumptions, positions, opinions, and convictions – which is about as helpful and forward-looking as arguments about politics and religion. So, what about phase 3 trials (Phase 3) for biosimilars?

Phase 3 is not a binary issue, mainly leaning to “no” with little openness to “yes”. Of course, it is easier to find quick reasons to exclude, rather than challenge oneself to find reasons to include. Phase 3 is a qualitative issue: with patients in mind, what do we need to know about a given biosimilar to provide care that is just as effective and safe?

Clinical science. Phase 3 is not a singular issue of equivalence of efficacy. Safety is just as important – and let’s keep the “rule of 3” in mind: “you need 3 times as many subjects to observe an event when you assume that the adverse event of interest does not normally occur in the absence of the medication”. Think cytokine release syndrome, splenic rupture, etc. What is the probability of detecting these in phase 1 trials? Phase 3 trials are underpowered to detect rare adverse drug reactions, but they may be a good start. They may also be the foundation for cross-manufacturer collaboration to establish stronger evidence about safety and efficacy in support of their biosimilars.

Accountability. Phase 3 is not an issue of strong pre-clinical data and selective clinical data. It is an issue of the totality of evidence – all the way down to production. If one biosimilar can be approved with less data while more data are necessary for another biosimilar, let that be the responsibility, judgment, and risk of the regulators. The phase 3 debate is a carve-out debate, when it should be a totality debate.

Evidence. Phase 3 is neither an issue of unnecessity vs necessity, invalidity vs validity, or unethical vs ethical. It is an issue to be seen within a broader framework of due diligence.

Responsibility. Phase 3 is not an issue of marketing. Should a manufacturer be prohibited from running 2 phase 3 trials when the regulator requested only 1 - and be excoriated for doing so merely for marketing purposes? It is doubtful that would pass the manufacturer’s compliance and finance departments.

Cheap shot. There is the argument that the sole function of biosimilars is to stimulate price competition. More generally, the function of biosimilars is to provide more patient access to biologic drugs by exerting market forces that balance cost with quality.

Uninformed. There is the argument that the price of biologics should be regulated. This approach works in single public payer systems. It is doubtful it will work in the United States with its public payers and its (shareholder-owned) commercial payers competing among themselves.

Naïve. To boot, the proposal to regulate the price of biologics comes with a twist: once exclusivity ends. Free-market pricing until then, favoring the manufacturer of the originator, after which biosimilars are squeezed out of the market?

Protectionism resurrected. Even more, this may result in new and possibly better same-in-class biologics competing against a good but now lower priced proven legacy product?

Stifling innovation. How price regulation would be implemented in the absence of independent, objective costing models for human therapeutics is unclear. Remember “Most Favored Nation”?

See you in court. Impose all of this by executive order or law?

See you all the way to the Supreme Court. The regulatory process works just as (imperfectly) well for biosimilars as for other therapeutics. Let regulators regulate what needs to be regulated so that we can provide more patients with just as good and safe, possibly even safer, biological treatments at lower costs.

Thinking and looking forward

Taking another tack might shield us from the squalls of assumptions, positions, opinions, convictions, and even my cynicism. Having worked in biosimilars since the very early days in Europe, I have been surprised by what we can learn from biosimilars, clinically and economically.

Reducing health disparities and inequities. As my colleagues and I have shown, conversion to biosimilars saves money (no rocket science, I admit). We have advocated to use these savings to provide more patients with the same biosimilar. With other biosimilars for instance, applying savings from biosimilar growth factors to biosimilar monoclonals or straight to novel treatments, think immunotherapies. Do this for those who otherwise would get inferior or no treatment. Equity.

Rethink treatment patterns. The MONITOR-GCSF study taught us about prevailing patterns and outcomes of prophylaxis with standard filgrastim: 5 daily injections, often started the day of chemotherapy, and over-treating with prophylactics relative to guidelines produced the same or better results in terms of chemotherapy-induced febrile neutropenia and disturbances to the chemotherapy regimen. It showed that in this case, post-approval prospective studies of biosimilars enable us to answer new questions about older products. Guidance.

Beyond biosimilars. There will be biosimilars that fail—early on or at the regulator’s table. They may fail for poor efficacy or poor safety—the lower boundary of the equivalence margin. Conversely, they may “fail” at the upper boundary of the equivalence margin and prove to be non-inferior but in a trial not designed to demonstrate non-inferiority—so-called “biobetters”. Perhaps one day, we will encounter “biodifferents”. Serendipity.

Regulatory flexibility. The totality-of-evidence is an undeniable strength of the US regulatory approval process for biosimilars. However, the pathway may need to be reconsidered—for instance, as regulators here and abroad grapple with non-inferiority studies that yield, with adequate statistical power, superiority results. Latitude.

Economics of biosimilars. The basic economics of biosimilars are simple. If it costs less, it is cost-efficient and it will impact budgets. Budget impact analyses, often considered the bastard children of the pharmacoeconomic family, are critical. There is little use evaluating cost-effectiveness when the efficacy is equivalent: any differences within the equivalence margin will wash out in sensitivity analyses. Affordability.

Bio

Ivo Abraham is chief scientist of Matrix45 and professor of pharmacy, medicine, and clinical translational sciences at the University of Arizona, where he is associated with the Center for Health Outcomes and PharmacoEconomic Research. He has worked in biologic drugs since the late 1990s and in biosimilars since their introduction in the European marketplace – collaborating closely with Karen MacDonald, who is also his wife. On both the private and academic sides, his group published the first economic evaluations of biosimilars, a line of studies that continues to date. Building on large international observational studies on biological therapies that the Abraham-MacDonald tandem implemented in the late 1990s and early 2000s, they worked with Sandoz on the MONITOR-GCSF and MONITOR-CKD-5 studies that proved to be instrumental in the breakthrough of biosimilars in Europe. As biosimilars entered the US market, Matrix45 added studies in support of biosimilar adoption in the United States. More recently, Matrix45 has ventured into biosimilars in emerging markets, including low- and middle-income countries. He may be reached at cntr4biosimilars@matrix45.com.

Statement of Disclosures of Relevance to this Column

Matrix45 as well as predecessor companies in which I hold or held equity have been contracted for research, analytics, dissemination, and consulting services by Janssen/Johnson & Johnson, Amgen, Novartis, and Roche on the originator side and by Sandoz/Novartis, Coherus Biosciences, Mylan/Viatris, Hospira/Pfizer, and Teva on the biosimilars side; with past and current conversations with Merck KGaA, Celltrion Healthcare, Apobiologix, Apogenix, Fresenius Kabi, and Spectrum. By company policy, associates of Matrix45 cannot hold equity in sponsor organizations, nor provide services or receive compensation independently from sponsor organizations. Matrix45 provides its services on a non-exclusivity basis.