title: A case study comparing a randomized withdrawal trial and a double-blind long-term trial for assessing the long-term efficacy of an antidepressant.
abstract: Assessing long-term efficacy in psychiatric drugs involves a number of complex questions, and the priaority of these questions is different for different disorders and for different stakeholders. Therefore, it is essential that we not adopt a one-method-fits-all approach, but rather adapt the specific details of the designs and analysis of data from long-term trials to individual disease states. Randomized withdrawal (RW) designs, even though addressing a specific question of particular interest, face some difficult methodological and ethical challenges. A less common alternative design, termed the double-blind long-term efficacy (DBLE) design, is logistically similar to traditional responder extension designs. However, use of an analytic approach that includes all randomized patients rather than only the selected subset that continued beyond acute treatment avoids the major criticism of the extender design. The present paper illustrates the attributes of the RW and DBLE designs by analyzing data from trials adopting these designs. The RW and DBLE designs address different questions, and are thus not directly comparable. Potential benefits of the DBLE design include: (1) the parsimonious use of patients and the resultant reduced exposure to placebo as each patient can contribute to multiple developmental objectives; (2) the results are generalizable to actual clinical practice as the design matches treatment guidelines; and, (3) results of safety assessments are meaningful as they involve all randomized patients. Our case study suggests that the DBLE design can provide definitive answers to important questions and may be a useful design for assessing long-term treatment effects.
authors.affiliation: Eli Lilly and Company, Indianapolis, IN 46285, USA. cmallinc@lilly.com
authors.forename: Craig
authors.initials: C
authors.lastname: Mallinckrodt
authors.forename: Christy
authors.initials: C
authors.lastname: Chuang-Stein
authors.forename: Paul
authors.initials: P
authors.lastname: McSorley
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schwartz
authors.forename: Donald G
authors.initials: DG
authors.lastname: Archibald
authors.forename: David G
authors.initials: DG
authors.lastname: Perahia
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Detke
authors.forename: Larry
authors.initials: L
authors.lastname: Alphs
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D003627:Data Interpretation, Statistical; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D005060:Europe; D006801:Humans; D009656:North America; D012008:Recurrence; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents