The Changing Application of Vulnerability Across the Different Phases of Clinical Research

The United States Food and Drug Omnibus Reform Act (FDORA) of 2022 established a legislative mandate requiring sponsors of pharmaceutical research to actively enhance the inclusion of historically underrepresented populations in clinical trials. This policy reflects the growing recognition that diversity in research is not only a scientific and medical necessity, but an ethical imperative rooted in the principle of justice. However, as efforts to increase diversity expand, the inclusion of individuals traditionally viewed as "vulnerable" introduces complex ethical considerations that necessitate a reassessment of current research practices. Historically, clinical research has often adopted an overly protective stance toward individuals classified as vulnerable, such as children, pregnant women, older adults, or those with cognitive or socioeconomic disadvantages, leading to their exclusion. This exclusion, while intended to prevent harm, paradoxically perpetuates inequalities restricting access to the potential benefits of research participation and evidence generation to support the broader use of the product. Moreover, this cautious approach is applied inconsistently across the phases of clinical development, suggesting a lack of ethical coherence in how vulnerability is defined, interpreted, and operationalized. A reexamination of the concept and treatment of vulnerability across all phases of clinical research is therefore essential. The consistent and ethically justified inclusion of vulnerable populations would advance the generalizability of scientific findings, promote health equity, and uphold the bioethical principles of autonomy, beneficence, nonmaleficence, and most critically, justice. Ensuring equitable inclusion is not merely a regulatory expectation but a moral obligation that underpins the legitimacy and integrity of clinical research.