Limitations of randomized clinical trials. Proposed alternative designs

Background: The classical two-period crossover and two-parallel-groups desi gns for clinical drug trials are unable to answer many current scientific q uestions, and are sometimes ethically or financially difficult. For example , the classical designs do not allow the study of the effects of combined t reatments and their interactions. Also, the generation of parallel data tha t are no more than a repetition of previous research is ethically debatable and in a sense a waste of money. Objectives are to identify what a classical clinical trial cannot manage, t o summarize and discuss alternative trial designs that are helpful for such purposes. Results: A classical clinical trial cannot: (i) assess combined therapies, (ii) take historical data into account, (iii) safeguard ethics and efficacy during the course of long-term trials, (iv) study drugs, before well-estab lished toxicity information is available, (v) account for the possibility o f therapeutic equivalence between test and reference treatment, (vi) study multiple treatments in one trial, and (vii) adjust change scores for baseli ne levels. Alternative designs helpful for such purposes are respectively: (i) factori al designs, (ii) historical controls designs, (iii) group-sequential interi m analysis designs, (iv) sequential designs for continuous monitoring, (v) therapeutic equivalence designs, (vi) multiple crossover-periods/multiple p arallel-groups design, and (vii) increased precision designs through multiv ariate adjustment. Main problems include the increased risks of type I and type II errors and the loss of validity criteria. Conclusions: Non-classical trial designs are reviewed. They offer relevant scientific, ethical, and financial advantages. The increased risks of type I and type II errors should be accounted for in the design stage of the tri al.