While the growing number of new drugs in development is a promising sign, the number of patients enrolled in the studies has not increased at the same rate; in fact, enrollment rates for IBD trials in recent years have shown a significant decline. For example, during a 20-year period from 1998 to 2018, the average recruitment rate in moderate-to-severe UC decreased from 0.32 to 0.13 patients per site per month, while the average recruitment rate in moderate-to-severe CD decreased from 0.65 to 0 to 0.10 patients per site per month.1
Enrollment was influenced by success in drug development, particularly by the FDA approvals of vedolizumab in 2014, ustekinumab in 2016, and tofacitinib in 2018. With new therapies available, the interest to placebo-controlled trials (a frequent clinical trial design in the IBD setting) has decreased. In our opinion, this is the leading factor contributing to slow enrollment; however, there are challenges that may influence enrollment potential. For instance, traditionally, CROs try to approach big academic centers and it seems reasonable, as they have experienced staff and equipment, and most importantly, patients followed at academic centers were almost twice as likely to have participated in randomized clinical trials.8
On the other hand, over half of enrolled patients were followed in private practice settings.8 Focusing on large institutions leads to a situation of a high competition rate between different clinical trials. For instance, as of October 2022, in the University of California San Francisco (UCSA) alone, there were 29 active IBD clinical trials and 9 of them were enrolling.9 We also can’t ignore increasing complexity of clinical trials design, and namely, complex study endpoints and a growing list of excluded concomitant medications.1 In addition to these existing challenges, during the COVID-19 pandemic, IBD trial activity has reduced majorly, even across sites with historically high levels of research involvement.10
This metric – the number of patients enrolled at the site in a certain period of time, typically one month) – is primarily dependent on the selection of an ideal geomix for the study, taking into account the incidence of the disease, treatment standards, and availability of the medications in accordance with these standards. Other factors that must be considered include the health insurance environment (the likelihood that insurance companies will approve less efficient generic medications over specialty ones) and the presence of preferred study sites (sites with whom the CRO has a long history of cooperation and appropriately trained study teams). More accurate selection of participating countries is one of the key reasons the incidence of IBD is increasing in Asia, Africa, and Latin America, driving interest in shifting clinical trials to these regions.1 PSI benefits from having not only well-established site relationships and operations in these areas, but also pre-selected sites and trained personnel.
Over the past decade, screen failure rates in IBD trials have grown, approaching 50% in UC and 70% in CD primarily due to failure to meet minimal endoscopic or biomarker criteria for active disease and a growing list of exclusionary concomitant medications.1 In PSI studies, we’ve seen a screen out rate of 26-48% in UC and up to 64% in CD.
While there is no universal solution to this problem, general recommendations may include higher drug-to-placebo rates – not 1:1 but rather 2:1 or even better 3:1 ratio, more broad use of patient reported outcomes (PRO) as the primary study endpoint, optimization of study visits’ duration and
complexity (less procedures and less endoscopies), an option of a long-term open-label extension for patients responding to therapy, and increased involvement of smaller hospitalsand increased involvement of smaller hospitals and private practices or in other words, patients’ primary GI physicians. We believe that this last point is of critical importance as primary care doctors see patients at the earlier stages of the disease course and there is a better chance that such patients
are more likely to meet eligibility criteria than those admitted to larger hospitals or academic institutions when the disease is frequently more severe and potential complications are more frequent.