Clinical trials in biologic therapy for Crohn's disease: Comparing designs and data

Crohn's disease is a chronic inflammatory bowel disease with no known cure, estimated to occur in more than 500,000 Americans. Induction and long-term maintenance of remission are the major goals of Crohn's disease therapy. Over the past several decades, standard therapy for Crohn's disease patients has included immunomodulatory drugs such as azathioprine and 6-mercaptopurine, anti-inflammatory drugs such as 5-aminosalicylate, steroids, and antibiotics. Unfortunately, many patients become refractory to therapy over time or dependent on therapies such as corticosteroids, which are not feasible for long-term use. Over the past decade, several biologic agents have emerged with potential to induce response of active disease and maintain remission in Crohn's disease patients. Most of these agents, including infliximab, adalimumab, and certolizumab pegol, target the pro-inflammatory cytokine tumor necrosis factor. Several pivotal clinical trials have been conducted to investigate the safety and efficacy potential of these agents. Infliximab was evaluated in the key ACCENT I and II studies, while certolizumab pegol has been studied in the PRECiSE 1-4 trials. Adalimumab has been extensively studied in CLASSIC I and II, as well as the GAIN and CHARM trials. Several thousands of CD patients treated with infliximab have also been followed through the TREAT registry, in order to determine long-term effects of the therapy. Although each of these trials have provided considerable data regarding individual agents, these agents have not been directly evaluated in a head-to-head comparison. Varying clinical designs and endpoints make comparison of data across clinical trials a complex task. This monograph will focus on methods and criteria to consider when judging similarities and differences among these biologic agents.