Integrated Prospective Regulatory Governance: A Quality-by-Design Operating Model for High-Risk Class III Medical Device Clinical Investigations

Abstract High-risk (Class III) medical device clinical investigations under the U.S. Investigational Device Exemption (IDE) framework are recurrently delayed by preventable regulatory failures: documentation deficiencies triggering clinical holds, authorization gaps during investigator transitions, fragmentation between regulatory and clinical functions, and reactive compliance postures. This paper describes Integrated Prospective Regulatory Governance (IPRG), a four-component operating model that embeds regulatory requirements as prospective design constraints across the clinical investigation lifecycle. The model was derived from U.S. and international regulatory requirements governing IDE investigations and quality systems, and refined through prospective application within an FDA-authorized IDE investigation of a transcatheter structural-heart closure device. The implementation setting was a ClinicalTrials.gov-registered IDE investigation (NCT05537753); no patient-level data are reported. Each component—Prospective Compliance Architecture, Cross-Functional Regulatory Integration, Investigator Lifecycle Management, and Risk-Stratified Submission Strategy—is mapped to its governing regulatory basis and positioned against the contemporary regulatory inflection represented by the Quality Management System Regulation (QMSR) and ICH E6(R3) Good Clinical Practice. Applied prospectively, the model maintained regulatory authorization continuity across investigator and site transitions, with deviations confined to minor procedural events having no effect on subject safety or data integrity. These observations illustrate feasibility rather than comparative effectiveness. IPRG operationalizes the quality-by-design and risk-proportionality principles formalized in ICH E6(R3) and the QMSR. Built on requirements common to every Class III sponsor, it is structurally transferable and offers a candidate template for prospective compliance governance. Controlled, multi-program evaluation is warranted.