Physician Survey Reveals "Disconnect" Between Expectations, Feasibility in Bioequivalence Studies

January 22, 2018
Kelly Davio

Some data that physicians would like to see demonstrated in bioequivalence studies may not be feasible in clinical trials due to the number of patients who would have to be enrolled in the studies.

As novel therapies and biosimilars of existing biologics are being developed for the treatment of inflammatory bowel disease (IBD), an increasing number of bioequivalence, head-to-head, superiority, and non-inferiority trials are expected in the near future. In order to better understand physicians’ perspectives on the clinical meaningfulness of trial results in IBD, a research team, led by Pablo Olivera, MD, of the Centro de Educación Médica e Investigaciones Clínicas in Buenos Aires, Argentina, conducted an online survey of International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) members (adult or pediatric gastroenterologists, surgeons, or pathologists specializing in IBD) to better understand their view of the clinical relevance of such trial results. The full results of the survey were published in Alimentary Pharmacology and Therapeutics.

A total of 88 IOIBD members were invited to take the survey, and 46 (52.3%) completed the questionnaire. Most of the participants, who resided in more than 20 countries, had over 20 years of clinical experience and worked in high-volume centers.

With respect to bioequivalence studies comparing an originator biologic to a biosimilar, most participants answered that a clinically important difference between groups would be as follows for:

  • Pharmacokinetics (PK): plus or minus 5% (45.7% of respondents) or plus or minus 10% (28.3% of respondents)
  • Clinical efficacy: plus or minus 5% (41.3% of respondents) or plus or minus 10% (26.1% of respondents)
  • Safety profile: plus or minus 2.5% (39.1% of respondents) or plus or minus 5% (45.7% of respondents)
  • Immunogenicity: plus or minus 2.5% (39.1% of respondents) or plus or minus 5% (43.5% of respondents)

The survey’s authors note that, although such data do not yet exist for studies of biosimilars specific to patients with IBD, results of equivalence studies of infliximab biosimilars (CT-P13 and SB2) for other immune-mediated diseases, which have led to approval for IBD indications by extrapolation, have used an equivalence margin of plus or minus 15%.

“An interesting observation from the results is that there is a disconnect between what physicians consider adequate, [and] what is feasible to demonstrate from the statistical point of view,” write the authors. For example, considering a statistical power of 80%, in order to demonstrate a 5% bioequivalence limit for all variables, the number of subjects required per group in the trial would be 822, write the authors, which would be “clearly very difficult to fulfill, and if implemented would limit access to biosimilars.”

The authors state that some of the data that physicians would like to see demonstrated may not be feasible in clinical trials due to the number of patients who would have to be enrolled in these studies. Given the fact that IBD is still relatively rare (compared with diseases such as hypertension or cardiovascular disease), a large population would be “difficult to impossible” to recruit.

“Finding a middle ground between what is desired in an ideal world and what it is feasible from a sample size/statistical perspective is necessary. In this regard, the results shown in this survey might influence the design of future IBD clinical trials,” the authors write.

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