Hybrid clinical trials to generate real-world evidence: design considerations from a sponsor's perspective.

Randomized controlled trials have traditionally been the gold standard for evaluating efficacy and safety of medical products and for regulatory decision-making. With the advancement of information technologies, vast amounts of data pertinent to patient health status and health care delivery are becoming available from a variety of real-world sources, including electronic health records, medical claims, patient registries, and patient-generated data. In 2016, the United States Congress passed the 21st Century Cures Act, mandating the U.S. FDA to establish a program to evaluate the potential use of real-world evidence (RWE) for regulatory purposes. In 2018, the FDA published the framework on its RWE program. One particular study type identified in the framework is the hybrid design - integration of a traditional randomized controlled trial with pragmatic design aspects to collect real-world data on patients. This design preserves the benefit of randomization, provides real-world outcome data while potentially accelerating product development and lowering the cost of data collection and patient follow-up. Here we focus on design considerations for hybrid trials to support regulatory decisions and provide a sponsor's perspective. While applicable to all medical products, we emphasize vaccine development where such hybrid designs are particularly useful given the low incidence rate of some vaccine-preventable clinical outcomes. We propose program strategies on how such hybrid designs may be integrated into a clinical development plan, illustrated by three examples. Major challenges are discussed and recommendations provided. Given the promise of hybrid designs and the challenges in implementation, we encourage proactive discussion with health authorities.