Patient Selection

When selecting subjects for inclusion in an IBD clinical trial, many aspects of their disease need be considered. Firstly, the differentiation between CD and UC patients needs to be made. As already described, this is not necessarily completely straightforward, as no one feature is either pathognomonic or appears exclusively in one of these two conditions. However, in the majority of patients, a combination of clinical, laboratory, histopathological, and radiological observations can establish a reliable diagnosis. Still, in approximately 20% of patients, this cannot be made.

Other important factors relating to patient selection are severity and extent of disease. As already discussed, CD can affect any part of the GI tract and consideration must be given to whether patients with disease limited to a specific segment of the bowel (e.g., the colon) or to only a single site will be included. In addition, the presence or absence of complicated disease, including strictures and fistulae, also need to be considered, as penetrating complicated disease tends to be most resistant to medical treatment. In UC, the distal and continuous nature of the inflammation makes disease extent easier to define. The current consensus appears to be that in UC, patients with inflammation extending beyond the rectum (i.e., not limited to a proctitis) are suitable for inclusion. The chronic, yet relapsing, nature of both conditions adds an extra complexity. The therapeutic approach under investigation can also sometimes influence patient selection, as, for example, investigational drugs delivered by enema are likely to have reduced efficacy in all but the most distal instances of the disease.

Disease severity is an important consideration in patient selection. In addition to influencing the magnitude of the response to the investigational agent, disease severity can impact on issues such as likely size of the placebo response and selection of an appropriate comparator agent. Specifically, regression toward the mean may give rise to false positive results in patients with severe disease. Conversely, patients with mild disease may be more likely to spontaneously enter disease remission as part of the natural history of their disease, a factor that becomes more problematic in studies of longer duration. These factors, as well as others, contribute to the 20-50% placebo response observed in clinical trials in IBD. The selection of appropriate comparators is also influenced by disease severity. In severe disease, the use of a placebo is almost certainly unethical, unless no proven therapy exists, necessitating comparison with current standard of care. This can be avoided by studying patients in whom therapy has failed, such as steroid-refractory disease. In mild and moderate disease, the use of placebo is commonplace and can be justified, in particular by the downward pressure such a design has on sample size, thus reducing the number of IBD patients exposed to investigational agents.

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