By Anna Rose Welch, Chief Editor, Biosimilar Development
A few months ago, the biosimilar industry celebrated a big milestone: the publication of a literature review of 90 biosimilar switching studies which established that lingering hypothetical safety and efficacy concerns about biosimilars are not supported by data. As I wrote in a previous article, this review, entitled “Switching Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes” by Cohen, et. al., established a much-needed baseline of biosimilar switching knowledge and laid the groundwork for follow-up lines of inquiry. This publication was an accomplishment I deemed worthy of the industry creating many large and glittery banners with which to proclaim the news. (Apparently, the glitter was a big hit.)
In recent weeks, this literature review faced some pushback in the form of a Letter to the Editor of Drugs written by several experts at Janssen (Pires, et.al.). When it came to my attention that there had been some pushback, I’ll admit I was skeptical about what the authors had found questionable in what was a sound, honest, and comprehensive literature review. I also felt indignant. Given the fact we’ve spent years in the U.S. confronting and disproving a lot of misinformation, the last thing we needed was another attempt at undermining biosimilars’ extensively demonstrated safety and efficacy. Upon my review of this letter, as well as a response published in Drugs by Cohen et. al., I felt there were a few brief, but positive takeaways I’d like to offer the industry from what, on the surface, may have seemed like another pesky pothole in the road.
For those of you who may not have read the letter to the editor, the basis of Pires, et. al, argument was that the literature review “did not comprehensively address the question as to whether switching from innovator to biosimilar could lead to altered outcomes.” There were several reasons they cited to support their argument, including the diversity of clinical trials surveyed, Cohen et. al.’s methods, and the “dismissal” of certain topics — especially the drop-out rates in several studies.
Though I intend to share some positives from this discussion, the method at which this letter to the editor highlighted the drop-out rates in particular is worth noting. Pires et. al. referenced higher discontinuation rates and unfavorable switching outcomes in studies they felt Cohen et. al. “overlooked” or “dismissed as chance” in their lit review. But what the letter failed to acknowledge is that the drop-out rate data came from studies that ultimately concluded there were no meaningful differences in safety and efficacy following switching. In fact, as Cohen et. al. explained in their response, the drop-outs in patients that switched to the biosimilar were primarily attributed to subjective reasons, as opposed to objective, pharmacological differences. So, though the letter was mostly accurate in its claim that drop-out rates weren’t discussed in depth within the literature review, the decision to overlook the totality of evidence in those studies makes their argument less impactful and honest. Cohen et. al. put it best (and gracefully) in their response stating, “It is inappropriate to select specific data points while ignoring the totality of evidence from the same study.”
Though it’s easy to get frustrated by this letter casting doubt on Cohen et. al.’s review (and biosimilars in general), it’s important to note that this letter, despite its flaws, was published in a leading publication. As such, we should view its questions about discontinuation rates as legitimate opportunities for biosimilar makers to contribute more to the medical literature supporting biosimilars.
For one, though Cohen et. al. prove through their response that many of the letter’s arguments don’t hold water, there still is room for more attention to be paid to the reasons behind discontinuation rates. It will also be interesting to see, if, as suggested by a few studies, discontinuation rates with biosimilars can be lowered by providing biosimilar education to physicians who in turn could alleviate concerns of their patients.
It was also interesting to see that the letter and response both homed in on manufacturing changes to the reference biologic — a topic that was broached in three brief sentences in the original literature review. As Cohen et. al. discussed previously, manufacturing changes to a biologic can lead to differences in Critical Quality Attributes (CQAs). This ultimately means that patients receiving different batches of the reference product will be encountering a product with varying structural and functional CQAs. In their review, Cohen et. al. argued this should be considered a de facto switch for patients taking a reference product after a manufacturing change. However, in current switching literature, this is not the case, and, as such, was not treated as a switch in Cohen et. al.’s review. Pires et. al. argued that manufacturing changes do not count as de facto switching because any CQA changes are kept in line with ICH comparability guidelines and, therefore, are clinically non-meaningful.
The topic of manufacturing changes is an interesting one that has been explored in scientific literature — for instance, in a recent article in Expert Opinion on Biological Therapy, as well as in a 2016 issue of Current Medical Research and Opinion. While it’s now well known by scientists and regulatory authorities, this reality has yet to be broached meaningfully in literature directed towards physicians. For patients and physicians today, there are concerns about jumping from a reference product to a biosimilar product because of concerns that the slight differences in structure will cause long-term efficacy changes. But there is certainly more room in the medical literature today to highlight a concept that cannot be stated enough within the healthcare community: biologics also differ from batch to batch. As such, from a patient perspective, receiving a new batch of a biologic with different CQAs would be considered a de facto switch and there have been exceptionally few cases where this has led to safety or effectiveness concerns.
Overall, the letter to the editor presented a questionable attempt to throw shade on a monumental study supporting the safety and efficacy of Remicade’s prime competitors — an act which is well within their rights as an originator to do. Though there are a number of troublesome aspects to their letter, I thought the response of Cohen et. al. to these efforts was notable. It’s integral for the biosimilar industry and its stakeholders to continue speaking up in situations such as these, meeting each claim with scientific data, integrity, and the willingness to present additional data until there can be no more arguments.