Rumors of the Death of Biosimilars Have Been Greatly Exaggerated

Over the past two decades, biologic therapies derived from living systems have revolutionized many areas of clinical medicine and dramatically improved outcomes in patients with serious life-threatening conditions including cancer. While the beneficial effects of these new therapies are clear from clinical trials, the economic impact of these costly medicines with rapidly rising drug prices has placed an enormous financial burden on patients and their families. Such “financial toxicity” often limits drug access and may result in curable patients stopping effective treatment altogether with potentially devastating consequences. One strategy proposed by a range of stakeholders including the US Food and Drug Administration is to encourage the development and regulatory approval of highly similar forms of these agents (biosimilars) to provide competition in the hopes of curtailing the unacceptably high prices of the original biologics (1). As patents expire on the original biologics, other companies are developing such biosimilars and seeking approval through an expedited process requiring extensive preclinical analytic and pharmacologic testing in animals and humans in exchange for limiting the need for multiple large and very costly comparative clinical trials (2).

While such biosimilars have only recently appeared in clinics in the United States, some have already started to question whether they are worth the effort, or even harmful, to the development of new even better drugs. (Bach and Trusheim; Wall Street Journal Op Ed; Aug 21 2019). While this and other opinion pieces represent interesting and provocative reading, we would argue that not only is their suggestion that it is “time to throw in the towel on biosimilars” is unjustified and many of their arguments are fundamentally flawed. For example, the conclusion that biosimilars will not have a significant impact on the rapidly rising costs of biologic therapies in the US is, at best, premature. While a few biosimilar supportive care agents have been on the US market for 3-4 years, the majority of the current 23 FDA approved biosimilars are recent approvals many of which have not yet made it into the market place, either due to very recent introduction or ongoing patent disputes or slow ramp up in production (https://www.fda.gov/drugs/biosimilars/biosimilar-product-information).

There are, indeed, now 5 FDA approved trastuzumab biosimilars of the originator (Herceptin). However, 4 of these have only been approved within the past 6 months and several are not yet available clinically. For competition to have an impact on drug prices, it will be necessary for multiple competitors in a class to be clinically available for a significant period of time. While acknowledging that they represent very different healthcare environments, a glance at the European experience with biosimilars, which is at least 8–10 years ahead of the US, may be reason for some optimism. In most European markets, net discounting with biosimilars compared to originators has started to stabilize at approximately 40–50%. By comparison to Europe, the US biosimilar market place is in its infancy and the eventual impact on drug prices, access, and overall healthcare costs unknown.

At the same time, the argument that biosimilars curtail innovation has no basis in fact or fiction. In fact, just the opposite could be argued. Many of the more recent technological advances in the measurement of the quality and performance of biologic therapies have come out of the effort to develop biosimilars and demonstrate that they are highly similar to the original biologics. The US FDA now requires compliance with some 60 preclinical quality metrics for further consideration of a proposed biosimilar. Many of these advances have occurred because of, not in spite of, the development of biosimilars. Recent studies, in fact, have demonstrated that by close monitoring of biologics using a large number of quality metrics may demonstrate deviation for acceptable performance for either the originator biologic over time or the new biosimilar (3). These studies have confirmed that critical quality measures of both new biosimilars as well as the originator biologic may drift over time due to changes in materials, conditions, and facilities involved in their production. Drift in the performance of any biologic agent has the potential to adversely affect both efficacy and safety and requires careful monitoring and comparative analysis. Recent experience has demonstrated that the development and regulatory monitoring of biosimilars has, in fact, increased, not decreased innovation related to the increasingly important realm of biologics for cancer and other devastating diseases (4). Any suggestion that less testing should be performed in a setting where there are fewer clinical study requirements for FDA approval, is puzzling at the very least and potentially dangerous. The US FDA is, rightfully, putting the focus of biosimilar regulatory approval on rigorous and thorough analytical testing and both preclinical and early clinical pharmacologic evaluation in order to provide assurance that the biosimilar is, indeed, highly similar to the originator in every conceivable way. If it fails on any of these analytic assessments, the reason for the deviation must be fully investigated, and any problems addressed before regulatory approval. Likewise, to enhance utilization of biosimilars to foster competition requires acceptance and utilization by clinicians and patients. Doing less testing as a part of regulatory approval would likely to lessen and not strengthen confidence in the efficacy and safety of these agents resulting in even greater resistance to use and further slow the uptake of biosimilars in practice.

The suggestion that biosimilar studies are steeling patients from other clinical trials and inhibiting the development of other innovations is ludicrous. The entire regulatory strategy for biosimilar approval in the US is to limit the number and size of clinical trials required following the extensive analytic and preclinical analysis that is required (inverted pyramid). It should also be noted that, to date, the majority of patients accrued to early phase and comparative biosimilar studies have come from outside of the US. Within the US, it has been estimated the only about 5% of treated cancer patients are on formal clinical trials. Therefore, the problem is not that small biosimilar trials are steeling patients away from trials of promising new treatments but that cancer patients are not entering clinicals of any type in sufficient numbers. The reasons for this are multiple, systemic, and need to be addressed, but diversion of patients away from novel therapy trials to biosimilar trials is not at the heart of the problem.

One aspect of the issue upon which we can all agree is that the biosimilars in and of themselves, will not solve the US national healthcare crisis without fundamental structural change in the way drugs and other high cost heath care interventions are approved, priced, and marketed. Limiting what drugs cost by price capping, linking drug prices to net efficacy or value, and Congressional authorization for CMS to negotiate drug prices with the pharmaceutical industry have all been offered as possible solutions. Each of these efforts will require political will, aggressive implementation, and professional and public education. Nevertheless, such fundamental changes are essential for meaningful and sustainable reductions in the continuing rise in prices of biologics and a reduction in the financial burden of devastating diseases like cancer while improve access to these exciting, often lifesaving, therapies.

Disclosure statement

Dr Lyman has consulted for G1 Therapeutics, Partners Healthcare, Agendia, Genomic Health, Mylan, Samsung Bioepis, Spectrum Pharmaceuticals, and Amgen outside of the submitted work.

Dr Kuderer has consulted for Janssen, Pfizer, Bayer and Halozyme outside of the submitted work.