Minimizing placebo effect in inflammatory bowel disease clinical studies

With 93 Crohn’s Disease (CD) and 168 Ulcerative Colitis (UC) Phase I-III industry-sponsored studies planned and open to enrollment, there is a significant focus on research into new therapies for inflammatory bowel disease (IBD)¹.

Remission is the main aim of IBD therapy, but IBD studies often face challenges with minimizing the placebo effect^2,3,4. Placebo effect can be categorized into placebo response/benefit (patients demonstrating an improvement) or placebo remission (patients achieving remission). Factors believed to impact the level of placebo effect can be contradictory depending upon whether a study’s focus is upon placebo response/benefit or placebo remission⁵.

Examining placebo remission rates in CD and UC studies, with a brief literature review of meta-analyses, reveals some interesting patterns.

Table A: Reported Impact of Key Factors Upon Placebo Remission Rates in IBD Studies

The above findings align well with several key themes:

1. Designing Patient-Centric Studies – “Patient centricity” within studies has become a key priority in recent years. With so much competition, your study has to be more “attractive” than the others. Reducing the number of clinic visits and study duration is a simple means of doing this and is more likely to result in a lower placebo remission rate^6,7,8 (although study duration must obviously take into account the study drug’s pharmacodynamics and regulatory guidance, e.g., European Medicines Agency (EMA) guidance^2,3).
   
    
2. Impact of Competitive Trial Environment on Number of Sites – When running clinical studies, the natural tendency is to try and deliver the study utilizing the minimal number of sites for both logistical and financial reasons. However, it turns out that the highly competitive IBD trial environment is possibly doing us a favor in forcing us to utilize more sites than we might otherwise have planned and this may contribute to a lower placebo remission rate⁵.
   
    
3. Patient Selection for Studies Targeting Moderate-Severe Disease – It is reasonable to expect the finding that a lower placebo remission rate is typically observed in studies targeting patients that have a longer disease duration^5,10 and/or have a greater disease severity^5,6,7,9 (and those with a greater disease severity have typically had the disease for a longer duration). These patients are the ones less likely to spontaneously enter disease remission. However, this is not good news for those studies targeting newly diagnosed patients who typically have lesser disease severity. In these studies it is, therefore, even more important to introduce other initiatives to minimize placebo rates (see further below).   
   
    
4. Good Science – Given that objective study endpoints have long been known to provide more robust data, the EMA’s guidelines for CD² and UC³ studies now propose endoscopic remission as a co-primary endpoint in efficacy studies (and centralized reading of endoscopies is highly encouraged). The requirement for endoscopy to confirm remission is also supported within the U.S. FDA draft guideline for clinical trial endpoints in UC studies⁴. The referred to meta-analyses would further tend to support this approach as there is evidence, certainly with UC, that centrally read endoscopies lead to lower placebo remission rates¹⁰.  

There are other initiatives that sponsors can and should employ with the aim of minimizing placebo rates, such as:

• Developing protocols with no ambiguity within the eligibility criteria
• Speaking openly to site personnel about the potential for placebo response
• Declaring a state of enhanced surveillance by examining quantitative patterns of the study, such as screen failure rates
• Encouraging site personnel to create a research alliance rather than the usual therapeutic alliance between site and patient

Finally, sponsors need to ensure patients fully understand that the purpose of the study is to determine if the drug is effective while personnel involved in the study should be trained to avoid raising patients’ expectations that the medication will be effective. These joint efforts, along with patient-centric practices, can help avoid inducing a high placebo response when studying new therapies for IBD.

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