Regulating Unapproved Drugs in the US: the Role of DESI and FDA Approval Pathways

Purpose: To examine the U.S. Food and Drug Administration (FDA) historical role in regulating unapproved drugs with a focus on the Drug Efficacy Study Implementation (DESI) program and to assess how its outcomes influenced the development of approval pathways for pharmaceutical products. Methods: This review analyzes DESI’s origin under the 1962 Kefauver–Harris Amendments and traces its impact on subsequent FDA approval mechanisms, including the Abbreviated New Drug Application (ANDA) and the 505(b)(2) pathway. A structured literature and regulatory document search was performed. Results: DESI categorized pre-1962 drugs into efficacy-based classes, guiding market continuation or withdrawal. These determinations laid the groundwork for modern pathways (ANDA and 505(b)(2)), enabling older drugs to transition into compliance. However, DESI was often slow, leading to delayed withdrawals, shortages, litigation, and price increases. Conclusion: DESI served as a historical model for structured drug evaluation but is unlikely to be revived. Instead, modern regulatory tools (NDA, ANDA, 505(b)(2)) are intended to confirm that a drug product meets standards for safety, efficacy and quality (CMC-Chemistry, Manufacturing and controls). A simplified re-approval pathway—transparent, time-bound, and globally adaptable—could strengthen efforts to address unapproved drugs while minimizing shortages and protecting public health.