Review article: Externally derived control arms—An opportunity for clinical trials in inflammatory bowel disease?

Abstract

SummaryBackgroundOne of the greatest challenges in the current IBD clinical trial landscape is, perhaps, the recruitment and retention of eligible participants. Seamless testing of promising investigational compounds is paramount to address unmet needs, but this is hindered by a number of barriers, particularly patient concerns of placebo assignment.AimsTo review the use of novel trial designs leveraging externally derived data to synthetically create control groups or augment existing ones, and to summarise the regulatory position on the use of external controls for market authorisation.MethodsWe conducted a PubMed literature search without restriction using search terms such as ‘external controls’ and ‘historical controls’ to identify relevant articles.ResultsExternal controls are increasingly being used outside the context of cancer and rare diseases, including IBD, and increasingly recognised by regulatory bodies. Such designs, particularly in earlier phase trials, can inform key nodes in drug development and permit evaluating efficacy of interventions without combating the ethical and numerical enrolment challenges described. However, the lack of randomisation and blinding subjects them to significant bias. Groups require robust statistical and computational approaches to ensure patient‐level data across groups are adequately balanced.ConclusionsWhile this approach has several pitfalls, and is not robust enough to replace traditional randomised, placebo‐controlled trials, it may offer a compromise to address key research questions at a more rapid pace, with fewer patients, and lower cost.

Toward Patient Centricity: Why Do Patients With Inflammatory Bowel Disease Participate in Pharmaceutical Clinical Trials? A Mixed-Methods Exploration of Study Participants

“… 14 However, ethical concerns and potential harm associated with prolonged placebo exposure are valid. 15 Several strategies have been employed to reduce the chance and length of exposure to placebo including asymmetrical randomization, inclusion of an active comparator arm, and early transition to open-label therapy after induction in placebo nonresponders. Omitting exposure to placebo would increase patients’ readiness to participate, and may enhance recruitment rates, even though differences in screening failure rates to conventional placebo-controlled trials need to be explored.…”