title: Designs and adaptive analysis plans for pivotal clinical trials of therapeutics and companion diagnostics.
abstract: BACKGROUND
  Developments in genomics and biotechnology provide unprecedented opportunities for the development of effective therapeutics and companion diagnostics for matching the right drug to the right patient. Effective co-development involves many new challenges with increased opportunity for success as well as delay and failure.
  
  
  OBJECTIVE
  Clinical trial designs and adaptive analysis plans for the prospective design of pivotal trials of new therapeutics and companion diagnostics are reviewed.
  
  
  CONCLUSIONS
  Effective co-development requires careful prospective planning of the design and analysis strategy for pivotal clinical trials. Randomized clinical trials continue to be important for evaluating the effectiveness of new treatments, but the target populations for analysis should be prospectively specified based on the companion diagnostic. Post hoc analyses of traditionally designed randomized clinical trials are often deeply problematic. Clear separation is generally required of the data used for developing the diagnostic test, including their threshold of positivity, from the data used for evaluating treatment effectiveness in subsets determined by the test. Adaptive analysis can be used to provide flexibility to the analysis but the use of such methods requires careful planning and prospective definition in order to assure that the pivotal trial adequately limits the chance of erroneous conclusions.
authors.affiliation: Chief National Cancer Institute, Biometric Research Branch, 9000 Rockville Pike, Bethesda, MD 20892-7434, USA +1 301 496 0975 ; +1 301 402 0560 ; rsimon@nih.gov.
authors.forename: Richard
authors.initials: R
authors.lastname: Simon