The question of replacing reference drug therapy with a biosimilar goes to the heart of provider confidence in attaining equivalent patient outcomes using the latter. There is relatively little resistance today in starting new patients with a biosimilar if there is a convincing economic case for it. Switching treatment in patients whose conditions are stable has been more concerning for patient advocates and specialty physician groups.
That is not because of the existence of little information on biosimilar switching. Investigational trials and postmarketing studies from Europe especially have been remarkably consistent in their findings (but with a couple of notable exceptions): Switches between biosimilar and reference biologics have not yet raised any serious warning flags.
A new literature review supports this conclusion. Published in Clinical Pharmacology & Therapeutics, researchers from Belgium and The Netherlands included 178 biosimilar switch studies in their analysis. Liese Barbier and her colleagues evaluated investigations on a wide array of switches involving biologics (some of which, like teriparatide, somatropin, follitropin alpha, and insulin glargine, were/are not regulated under the 351[k] biosimilar pathway in the US). They did not have information on any pegfilgrastim or bevacizumab biosimilar switching studies. The number of switching studies on some other drug categories include: 100 for infliximab, 25 for etanercept, 20 for epoetin medications, 7 for adalimumab, 7 for rituximab, 5 for filgrastim, 4 for insulin glargine, and 1 for trastuzumab.
Seventy-nine percent of the studies included were based on real-world evidence (including registry studies), and 21% were randomized clinical trials. The vast majority of these investigations concluded that biosimilar switches did not result in any significant differences in clinical effectiveness, safety, key disease markers, or immunogenicity. Importantly, the literature review did not yield concerning findings on the formation of anti-drug antibodies.
Differences had been seen in discontinuation rates of some trials of infliximab and in one study of etanercept. However, clinical outcomes or disease activity scores were no different among the biosimilar and reference groups following the switch to biosimilars in these trials. In one study of 29 patients with rheumatoid arthritis who were treated with rituximab, the authors noted six patients (20%) reported loss of effectiveness of the biosimilar.
The authors pointed out, “Some open‐label and observational studies reported increased discontinuation rates after switching, which were mainly attributed to nocebo effects.”
The nocebo effect occurs when a study participant knows he or she is receiving a particular drug and expects to have negative results. This is found in open-label studies in particular. The lower rates of persistence in real-world studies generally reflect what happens outside of a clinical trial protocol: increasing percentages of patients stop their treatment over time.
They advise that the nocebo effect should be addressed by prescribing physicians in the office. “The nocebo effects highlight the importance of shared, evidence-based decision making between the physician and the patient. Strategies mitigating the nocebo effect may improve patient outcomes and discontinuation rates.”
In other biosimilar news…In January, we reported on the main players in the upcoming ranibizumab market. Recently, Big Molecule Watch provided an update on the team of Xbrane and STADA. The partners have apparently agreed to work with a commercialization partner if approval is granted in the US and Canada. Bausch & Lomb will be responsible for marketing the biosimilar in this country, marking the US eye care manufacturer’s first foray into the biosimilar industry.
Dear Stan,
Thank you for this nice review of our recent CPT-published study. You rightly point out that in this review only 1 trastuzamab switch trial was included. We investigated the tastuzumab clinical trials in a seperate paper, that was published earlier in the Brit J of Cancer (The arrival of biosimilar monoclonal antibodies in oncology:
clinical studies for trastuzumab biosimilars; https://www.nature.com/articles/s41416-019-0480-z ; open access ). The conclusion of these studies is actually the same: no safety signals, and similar efficacy in a variety of settings. As you have noticed in an earlier blog, 2 trials suffered from a decreased potency of the reference product. The bevacizumab and adalimumab studies unfortunately became available after closing our database.
In general, the biosimilar case looks very reassuring under strict guidance of regulators like EMA and FDA, and we in Europe are just astonished to see that American patients are denied access to most these best value biologicals als we call them. In Europe we are saving billions of euro’s to give patients better access to biologicals, while in the US healthcare systems increasingly are soaring. There seems to be something terribly, terribly wrong (as you well described in your recent report).