As knowledge of the pathogenesis of inflammatory bowel disease (IBD) has grown, many new medical therapies have become available. Evaluation of the efficacy and safety of new drugs has conventionally been established with placebo-controlled randomized trials. However, given that highly effective and safe biologic agents such as tumor necrosis factor (TNF) antagonists, vedolizumab, and ustekinumab are currently available, the continued use of placebo-controlled studies to evaluate new molecules should be questioned. Although alternate study designs are available, their implementation presents multiple challenges that need to be overcome. Other challenges in the current investigative landscape include poor recruitment rates, enrollment of highly refractory patients, and substantial changes in the regulatory standards required for drug approval. In this article, we present an overview of these challenges and discuss potential solutions with an emphasis on implications for the practicing clinician.