Drug and Pharmacodiagnostic Co-development Statistical Considerations

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 entails many new challenges however, including development of an appropriate diagnostic, its analytical validation, clinical validation and utilization in pivotal trials that evaluate the medical utility of the new treatment. The pivotal treatment trials are of increased complexity and require careful prospective planning. Randomized clinical trials continue to be important for evaluating the effectiveness of new treatments but the utilization of the diagnostic in the design and analysis plan should be prospectively detailed. Clear separation of the data used for developing the diagnostic, including it’s threshold of positivity, from the data used for evaluating treatment effectiveness in subsets determined by the diagnostic is usually essential. We review a variety of clinical trial designs for the co-development of new treatments and companion diagnostics. These include enrichment designs in which the diagnostic is used to restrict eligibility, several prospectively defined analysis plans for designs that include both test positive and test negative patients, and adaptive designs in which data from the pivotal trial is used to both refine the diagnostic and evaluate the new treatment in a manner that preserves the overall type I error level of the study.