Clinical trial designs of new medicinal products for treating schizophrenia: discussion of EMA's Guideline and a Better Long Term Trial Design

Background and Objectives: Schizophrenia is a severe chronic disease. Endpoint variables lack objectivity and the diagnostic criteria have evolved with time. In order to guide the development of new drugs, European Medicines Agency (EMA) issued a guideline on the clinical investigation of medicinal products for the treatment of schizophrenia. Methods: Authors reviewed and discussed the efficacy trial part of the Guideline. Results: The Guideline divides clinical efficacy trials into short-term trials and long-term trials. The short-term three-arm trial is recommended to replace the short-term two-arm active-controlled non-inferiority trial because the latter has sensitivity issues. The Guideline ultimately makes that three-arm trial a superiority trial. The Guideline discusses four types of long-term trial designs. The randomized withdrawal trial design has some disadvantages. Long-term two-arm active-controlled non-inferiority trial is not recommended due to the sensitivity issue. Extension of the short-term trial is only suitable for extension of the short-term two-arm active-controlled superiority trial. The Guideline suggests that a hybrid design of a randomized withdrawal trial incorporated into a long-term parallel trial might be optimal. However, such a design has some disadvantages and might be too complex to be carried out. Authors suggest instead a three-group long-term trial design, which could provide comparison between test drug and active comparator along with comparison between the test drug and placebo. This alternative could arguably be much easier to carry out compared with the hybrid design. Conclusions: The three-group long-term design merits further discussion and evaluation.

Endoscopic incision for the treatment of refractory esophageal anastomotic strictures: outcomes of 13 cases with a minimum follow-up of 12 months

Background and aim: Endoscopic incision is an alternative method for refractory esophageal strictures; however, little is known about its long-term efficacy. The aim of the study is to assess the long-term outcomes of endoscopic incision for treating refractory esophageal anastomotic strictures. Methods: Between September 2011 and September 2014, 13 patients with refractory esophageal anastomotic strictures were treated with endoscopic incision. Their clinical data were retrospectively collected to evaluate the efficacy and safety of the technique. Results: All the 13 patients underwent the procedure successfully with median operation duration of 15 minutes. A total of 27 sessions were necessary to maintain lumen patency until September 2015, and 7 patients needed retreatment. The symptoms relieved in all the cases, and the median dysphagia score decreased from 4 to 1 during a median follow-up of 24 months. The median diameter of stricture was enlarged from 4 mm to 12 mm. As a short-term effect, dysphagia symptoms improved in 100% (13/13), 84.6% (11/13) and 76.9% (10/13) of the patients one, three and six months after a single treatment. As long-term effect, the dysphagia improved in 61.5% (8/13), 63.6% (7/11) and 60% (6/10) of the patients 12, 18 and 24 months after a single treatment. Conclusions: The efficacy of endoscopic incision is favorable in the short term. However, retreatment is needed to maintain the long-term lumen patency for parts of the patients.