Alternative Designs for Clinical Trials

Abstract

Background: The classical two-period crossover and two-parallel-groups designs for clinical drug trials are unable to answer many current scientific questions, and are sometimes ethically or financially impossible.

Objectives: To identify what a classical clinical trial cannot manage, to summarize and discuss alternative trial designs that are helpful for such purposes.

Results: What a classical clinical txkI cannot manage

1. assess multimodal therapies

2. account historical data

3. safeguard ethics and efficacy during the course of long-term trials

4. study drugs, before well-established toxicity information is available

5. account the possibility of therapeutic equivalence between test and reference treatment

6. study multiple treatments in one trial

7. adjust change scores for baseline levels.

Alternative designs helpful for such purposes are respectively

1. factorial designs

2. historical controls designs

3. group-sequential interim analysis designs

4. sequential designs for continuous monitoring

5. therapeutic equivalence designs

6. multiple crossover-periods / multiple parallel-groups design

7. increased precision designs through multivariate adjustment.

Main problems include the increased risks of type I/II errors, 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 MI errors should be accounted for in the design stage of the trial.