Competition in Inflammatory Bowel Disease Clinical Trials

Inflammatory bowel disease (IBD) has been a field with increasing drug development interest in the last decade by academic and biopharmaceutical researchers. As a result agents with new mechanisms of action have been brought to market, including tumor necrosis factor-alpha inhibitors, anti-interleukin 12/23 antibodies, and oral Janus kinase inhibitors. In addition to an increase in the number of new agents being tested, there has also been a movement to create stricter definitions for remission (including clinical, endoscopic, and deep remission).¹ These are just 2 factors that have increased competition for participants in clinical trials in IBD. A recent report by Harris et al summarized these and additional barriers.²

The authors surveyed a pharmaceutic database in April 2019 and found that 47 companies were conducting studies of 70 investigational or approved IBD medications. These studies included 48,834 patients among 13,762 sites. The authors further analyzed this database from 1998 to 2018 and found that the average recruitment rates for both moderate to severe ulcerative colitis (UC) and Crohn disease (CD) fell from 0.32 to 0.13 and 0.65 to 0.10 patients per site per month, respectively. This was in the background of a dramatic increase in the total number of clinical trials from 7 in 1998 to 147 in 2018. This increase in number of studies has also had a substantial impact on global competition for clinical trials. In 2008, there was a global average of 5 and 6 trials per country in UC and CD, respectively. In 2018, this global average increased to 16 trials per country for both UC and CD. North America and Europe continue to lead in the number clinical trials, with the greatest increases in Asia and South America.

The pure increase in number of investigational IBD medications and subsequent clinical sites has led to a dramatic increase in competition for patient enrollment. Although the number of patients with IBD in the United States increased from approximately 2 million in 1999 to 3 million in 2015, this has not proportionally met the increase in IBD medications. Not only are there IBD medications with new mechanisms of action, there are also different formulations (eg, intravenous, subcutaneous, oral), varying pharmacokinetic profiles requiring longer wash-outs, and biosimilars that have crowded the market.

IBD clinical trials have become increasingly complex as more specific clinical endpoints have gathered support within the academic arena. Some IBD trials may require multiple colonoscopies, blood draws, and follow-up visits, which can become arduous for many patients. The screen failure rates can vary between 50% and 70%, which typically can be the result of not meeting certain strict endoscopic or biomarker criteria and/or which previous agents were prescribed but failed to control the disease. Within each trial, the use of more innovative biomarkers such as fecal calprotectin and therapeutic drug monitoring can potentially prolong study enrollment or may be a deterrent to certain patients. There has also been an emphasis on long-term extension safety and efficacy data, which can further complicate recruitment.

Based on these issues, the authors offered several potential solutions to help alleviate some of the competition for clinical trials. The authors believe there should be a focus on increasing the number of qualified clinical sites within countries with already active programs rather than trying to find new countries without many sites. This may be accomplished by having workshops and more formal training of smaller sites by clinical study experts. Another solution is the possibility of forming research boards led by gastroenterologists with knowledge of the patient landscape within certain regions or countries to help improve and identify clinical sites.

The authors propose a shift toward increasing early phase 1 and 2 studies with an emphasis on pharmacodynamics and pharmacokinetic data to attempt to determine a new medication’s promise earlier in the drug development process. There should also be a push toward optimizing central reader algorithms to limit inter-reader variability. A movement toward more standardized study protocols may also help reduce duplicate work among companies and lead to more streamlined recruiting. This would require increased collaboration among potentially competing companies as well as buy-in from certain regulatory agencies and certain IBD and gastroenterology societies. There could be a “central screening” site that would screen patients with IBD for multiple studies and potentially direct them toward the most appropriate studies.

References

1. Zallot C, Peyrin-Biroulet L. Deep remission in inflammatory bowel disease: looking beyond symptoms. Curr Gastroenterol Rep. 2013; 15(3):315.

2. Harris MS, Wichary J, Zadnik M, Reinisch W. Competition for clinical trials in inflammatory bowel diseases. Gastroenterology. 2019; 157(6):1457-1461.