Authors of Systematic Literature Review on Biosimilar Switching Stand by Findings Despite Criticism

This week, Drugs published a letter to the editor concerning a systematic literature review that showed a low risk of safety concerns or loss of efficacy after switching from a reference biologic product to a biosimilar.

The letter’s authors, all of whom report affiliations with Janssen Pharmaceuticals, say that switching is a beneficial topic for exploration but criticized the review for “over-interpretation of the available data.”

According to the letter, a clear objective, outcome specification, and grading of the quality of evidence were lacking; the data, they say, should have been weighted to reflect their relative strength. Furthermore, the number of innovator biologics, diseases states, populations, study types, and study outcomes considered are “too diverse to apply a single approach to the review and draw any specific conclusions,” they write, and called for greater study on the topic.

Notably, the commenters indicated that randomized clinical trials and real-world evidence that showed unfavorable outcomes associated with switching from reference to biosimilar infliximab were available before the cut-off date but were not included in the review, and results from studies that show higher rates of discontinuation or adverse clinical outcomes in patients who switched to a biosimilar were not described.

They also argue that the switching studies involving multiple switches of 3 drugs with biosimilars are not generalizable to all biologics, and say that “conclusion that there are no differences in efficacy or safety based on a limited number of switch studies in these unrelated molecules should be questioned.” These studies, they note, are also insufficient to demonstrate interchangeability according to the FDA’s draft guideline.

In a reply to the letter, the authors of the systematic review in question stood by their findings. In their own letter to the editor of Drugs, they write that the intent of their paper was “to neutrally assess whether there is any credible and consistent evidence that switching from originator biologics to biosimilar biologics is problematic,” and that the “overall pattern remains clear and unambiguous and is what would be expected when the authors of 88 out of 90 publications reach similar conclusions about their own individual study results.”

In fact, say the authors, the diversity of products studied, and the diversity of indications, study designs, endpoints, and analyses of individual studies is a strength of the systematic review.

They indicate that they attempted to be as inclusive as possible with the literature, and did not censor for positive or negative results. They highlight the fact that, in cases of elevated discontinuation rates in individual studies, there are addition results—sometimes from the same studies—that indicate no change in clinical outcomes. “It is inappropriate to select specific data points while ignoring the totality of evidence from the same study,” they remark.

The authors also took issue with the commenters’ point that the switching studies are not suitable for an interchangeability demonstration, saying, “These comments are not relevant to our review because these studies were designed to assess the clinical impact of multiple switches and not to address a specific regulatory requirement.” They note that interchangeability is “a legal issue and regulatory interpretation beyond the clinical evidence that we review.”

In response to a call for more study on the matter, the review’s authors say that “It is incorrect to presume that there may be a problem with switching and that further study is necessary, or to impose a data burden on biosimilars not applied to other biologics, especially when there is no credible basis for such a request.” The survey, with more than 14,000 patients in a total of 90 studies, they say, “provides stronger evidence than any individual study could be expected to provide.”

References

1. Pires A, Goyal K, Greenspan A. Comment on: “Switching reference medicines to biosimilars: a systematic literature review of clinical outcomes. [Published online May 21, 2018.] Drugs. doi: 10.1007/s40265-018-0918-2.

2. Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Wollett G. Author’s reply to Piers et al: Switching reference medicines to biosimilars: a systematic literature review of clinical outcomes. [Published online May 21, 2018.] Drugs. doi: 10.1007/s40265-018-0919-1.