Dermatologists need to be aware of margin of error and related issues that can affect the results of biosimilar clinical trials. Sample size, study population variability, study site geography, and clinical expertise can impact trial results.
The statistical margin used to define the maximum allowable difference between biosimilar and a reference agent for psoriasis may be “unacceptably wide” to some prescribing clinicians, authors of a recent meta-analysis have concluded.
The margin of error, sometimes referred to as the similarity margin, is decided upon by regulatory bodies and may be too imprecise depending on the clinician’s perspective, the authors wrote in a research letter published in the Journal of the American Academy of Dermatology.
For example, if a study’s margin of error is ±15% and the originator biological product has a PASI 75 response rate of 65%, a biosimilar with a PASI 75 of just 50% could be deemed equivalent, wrote authors who were led by Marilyn T. Wan, M.B.Ch.B., M.P.H., of the University of Pennsylvania Perelman School of Medicine in, Pennsylvania.
“One physician might consider these parameters sufficient and comfortably prescribe the biosimilar as a replacement for the originator; however, another clinician might require more conservative margins,” Dr. Wan and colleagues wrote.
This study was a a systematic review of statistical margins in comparative clinical trials of biosimilars. They considered trials published through Feb. 17, 2017, and sought data from unpublished or unidentified studies. The studies included adult patients with plaque psoriasis who were randomly assigned to receive a biosimilar or originator drug.
They narrowed the search to four clinical trials including 1,746 patients, which had margins of error ranging from ±14% to ±18%, the meta-analysis shows.
Another five clinical trials were excluded, according to the report, due to data that was insufficient and not obtainable through subsequent requests sent to corresponding authors.
“As biosimilar approvals accrue and their use increases, possibly delivering decreased healthcare costs and better patient access, practitioners require a deeper understanding of the design and conduct of clinical trials to better interpret the true likelihood of achieving the same clinical outcome regardless of drug choice,” the authors wrote.
Biosimilar study goals
Biosimilars are typically investigated in equivalence trials designed to show the drug is not too dif erent (ie, not superior or inferior) in comparison to the reference product.
Because biosimilars are intended to have no clinically meaningful differences in safety, purity, or potency versus the approved reference drug, understanding the margin of error is “critical” to determine if “potentially clinically important differences in efficacy were ruled out statistically by study design,” the authors wrote.
The quandary of the margin of error question is compounded by the issue of sample size. In a trial powered at 0.80 with a ±15% margin of error, 382 patients would be needed. However, with a narrower ±10% margin of error, an additional 476 patients would be needed.
These and other critical factors not well understood by the average dermatologist include study population variability, study site geography, and clinical expertise.