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.

Effect of a weight loss program in obese adolescents: a long-term follow-up

Objectives: Obesity during adolescence is an increasing health problem in industrial countries. The comorbidities associated with obesity include important metabolic diseases. Methods: To analyze the effect of a weight-loss program, we recruited 12 obese, male adolescents before entering this program. We determined body weight measures at baseline, 6-week and 36-month follow-up. Also, the long-term changes of blood pressure, HbAlc, and CRP were evaluated. Twenty healthy age-matched adolescents served as controls. Results: Within the intervention group ((body mass index [BMI, kg/m²] > 95th percentile for age and sex, age 13-17 years) the BMI and BMI-standard deviation score [SDS] were significantly reduced in the 6-week follow-up after completing the weight loss program. However, the significant weight-reduction effect was not persistent until the 36-month follow-up. Conclusion: The 6-week weight-loss program had beneficial short-term effects on body weight, BMI, and BMI-SDS in obese adolescents, but these effects could not be maintained until the 36-month follow-up.