RESUMEN
BACKGROUND: Single-arm clinical trials (SAT) are common in drug and biologic submissions for rare or life-threatening conditions, especially when no therapeutic options exist. External control arms (ECAs) improve interpretation of SATs but pose methodological and regulatory challenges. OBJECTIVE: Through narrative reviews and expert input, we developed a framework for considerations that might influence regulatory use and likelihood of regulatory acceptance of an SAT, identifying non-oncology first indication approvals as an area of interest. We systematically analyzed FDA and EMA approvals using SATs as pivotal evidence. The framework guided outcome abstraction on regulatory responses. METHODS: We examined all non-oncology FDA and EMA drug and biologic approvals for first indications from 2019 to 2022 to identify those with SAT as pivotal safety or efficacy evidence. We abstracted outcomes, key study design features, regulator responses to SAT and (where applicable) ECA design, and product label content. RESULTS: Among 20 SAT-based FDA approvals and 17 SAT-based EMA approvals, most common indications were progressive rare diseases with high unmet need/limited therapeutic options and a natural history without spontaneous improvement. Of the types of comparators, most were natural history cohorts (45% FDA; 47% EMA) and baseline controls (40% FDA; 47% EMA). Common critiques were of non-contemporaneous ECAs, subjective endpoints, and baseline covariate imbalance between arms. CONCLUSION: Based on recent FDA and EMA approvals, the likelihood of regulatory success for SATs with ECAs depends on many design, analytic, and data quality considerations. Our framework is useful in early drug development when considering SAT strategies for evidence generation.
RESUMEN
Technological advancements are dramatically changing the landscape of therapeutic development. The convergence of advances in computing power, analytical methods, artificial intelligence, novel digital health tools, and cloud-based platforms has the potential to power an exponential acceleration of evidence generation. For regulatory agencies responsible for evidence evaluation and oversight of medical products, these advances present both promises and challenges. Ultimately, realizing the translation and impact of these innovations that could potentially enhance therapeutic development and improve the health of individuals and the public will require a nimble and responsive regulatory approach. Supporting an adaptive policy-making infrastructure that is poised to address novel regulatory considerations, creating a workforce to ensure relevant expertise, and fostering more diverse collaborations with a broader group of stakeholders are steps toward the goal of modernizing the regulatory ecosystem. This article outlines approaches that can help provide the flexibility and tools needed to foster innovation, while ensuring the safety and effectiveness of medical products.