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Endpoints, reliability, and meaningful changes in clinical trials for children with irritable bowel syndrome. The Rome foundation pediatric subcommittee on clinical trials

Dear editors, We are grateful for the thoughtful and constructive comments conveyed by Dr Collignon and Pétavy in their letter to the editor.1 Their comments provide important statistical input that could be of great value for future endeavors. Collignon and Pétavy raised a convincing argument on the circumstances and benefits of interim analysis. The committee agrees with the comments, as long as the interim analysis is part of the original design and not an afterthought. Collignon and Pétavy successfully argue that the use of binary measures may be associated with a loss of information and power compared to analytical approaches using continuous outcome measures. This is well supported in the statistics literature. There is no doubt that the proposed endpoints (binary endpoints and the Reliable Change Index (RCI))2 are more restrictive than the alternative endpoints proposed by Collignon and Pétavy and as such will require a larger sample size. The requirement of a larger sample size is a legitimate concern in studies in children that frequently struggle to recruit study subjects. Moreover, a larger sample size would make the study costlier and tasking. The committee deliberated continuous vs dichotomous outcome measures and recommended the binary endpoint even if considered somewhat restrictive. In recommending a standard in which change needs to exceed the RCI, the committee deliberately raised the bar on what should be considered an improvement. The use of the RCI helps to avoid that a participant may be considered “improved” even if the change shown by that patient was not reliable. The goal of the committee was not only to focus on the statistically most prudent approach but weigh this with the clinical meaningfulness of endpoints. As clinicians invested in the wellbeing of our patients, we wanted to reassure parents that consented for their children to participate in a research study, that in case of a positive study outcome, their child will be able to perceive meaningful benefits. The enrollment of children with more than mild intensity of baseline pain would assure that the beneficial effect could be more easily perceived (avoiding a floor effect). The choice of binary outcomes was guided by the current FDA3 and EMA4 guidelines that recommend a binary approach. The committee found it prudent to stay close to current guidelines given the dearth of data in pediatric trials. In line with the regulatory agencies, most clinicians prefer to recommend treatments aiming for a “recovery” or at least marked improvement. Treatments are better understood if presented as effective vs noneffective (a binary outcome measure). Although a good argument can be made that a statistical significance of a trial can be used as the binary measure (effective vs noneffective), if only based on statistical significance, treatments that are not clinically significant, may become adopted. In fact, the size of the effect is becoming a more important measure in clinical trials and has even been adopted in the GRADE criteria for the evaluation of clinical trials.5 Thus, it was thought that findings of statistically significant differences alone could be considered as secondary outcomes but should not be recommended as primary outcomes of a clinical trial. Concerning the suggestion of integrating both abdominal pain and stool consistency as a single primary endpoint, currently there is no validated scale for combining changes in bowel movements and abdominal pain as a single endpoint in children. The committee considered this possibility at the time of issuing the recommendations but it was thought that more discussion and data were required before a composite score could be adopted. In summary, the committee feels the current report is reflective of the current circumstances in which trials are being performed. We thank the input from Dr Colignon and Pétavy. Although we may not agree with all the points raised by the authors, constructive criticism is always welcome and appreciated. The scientific process thrives and benefits from the respectful dialogue between experts with different viewpoints. We wholeheartedly support more data and education of proper trial analysis and hope research will soon outdate the current criteria. The committee hopes that the response to Dr Collignon and Petavy’s letter will help create a greater collaboration across disciplines and more actual data on which to base future recommendations. This fruitful exchange of ideas makes us hope that we will be able to count with the active collaboration of experts from the regulatory agencies in next endeavors.