The regulatory pathway for a combination product consisting of an IVR delivering one or more antiretroviral agents modified with the adherence module is more complex than that of a drug or device alone. For incorporation of the adherence monitor into an IVR for HIV prevention, there are two primary regulatory concerns: (1) safety of the adherence module itself, and (2) demonstrating that addition of the adherence module does not negatively affect the safety, stability, or dreg release characteristics of the IVR. Because the primary mode of action (the mode expected to have the greatest overall therapeutic effect) of the combination device is antiviral drug delivery, the FDA Center for Drug Evaluation and Research (CDER) has regulatory jurisdiction, and clinical evaluation will take place under an Investigator New Drug (IND) application using a series of clinical trials (Phase 1, Phase 2, Phase 3).The adherence module is being developed primarily, but not exclusively, for incorporation into the pod-IVR platform that is currently in early clinical evaluation [26, 29]. Initial clinical evaluation of an adherence IVR to demonstrate feasibility would be conducted on the device without drug product under an Investigational Device Exemption (IDE) if the device is determined to be Significant Risk (SR). A SR designation for the adherence monitoring IVR is likely because it is an implantable device maintaining mucosal contact for more than 28 days. For initial clinical studies lasting fewer than 28 days, however, it is likely that the device would be designated Non-significant Risk (NSR), and evaluation could proceed without an IDE and only approval by the clinical investigator’s Institutional Review Board (IRB). This initial evaluation without drug product would provide a foundation of safety data to use in preparing the combination product IND as well as serve as Phase 1 clinical evaluation of an IVR that could be used in placebo groups in future clinical trials.