Regulatory Considerations for Coronary Drug Coated Balloons (DCBs) Tara A. Ryan, MD, MS, MBA Center for Devices & Radiologic Health Office of Device Evaluation Division Of Cardiovascular Devices CRT 2017 Washington, DC February 20, 2017

I have no relevant financial information to report. Disclosure Statement of Financial Interest I have no relevant financial information to report.

Components of a DCB System PTCA Balloon Delivery System Therapeutic Agent Coronary drug-coated balloons are one component of a device system. In addition to the actual balloon platform and the components of the system used to deliver the balloon, there will be a drug carrier – also referred to an excipient. This is often a coating applied to the balloon and intended to hold the drug on the balloon and control its release and then of course the therapeutic agent; in most cases this will be a drug or a biologic. Each of these components influence the performance of a DEB in terms of durability, deliverability and uptake of the drug into the vessel wall. Carrier

Combination Product (21 CFR Part 3) Includes product consisting of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product [21 CFR 3.2(e)] Covered by more than one FDA product center A combination product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity;  

Who Has Jurisdiction? Governed by Primary Mode of Action Primary mode of action is the therapeutic action that is expected to make the greatest contribution to the overall intended effect of the combination product. Whichever product has the greatest therapeutic effect, the center that the product is regulated in will have jurisdiction.

For Coronary DCBs → CDRH has jurisdiction Because: The primary mode of action (PMOA) is the balloon opening the artery (or re-stenotic stent). Therefore: Premarket review and regulatory responsibility for DCBs has been assigned to CDRH with consultation from CDER. The Agency has determined that for current DCBs where the device component maintains coronary artery patency and the drug component augments the safety and/or effectiveness of the uncoated (bare) balloon by preventing restenosis, the device mode of action is the primary mode of action.

Regulatory Submission Pathway Approval of an Investigational Device Exemption (IDE) application will be required to conduct a clinical study in the United States. Approval to market in the United States will require a premarket approval application (PMA)

Review Team for Coronary Drug-Coated Balloons Biopharmacology (CDER) Clinical Trial Design (CDRH) Engineering (CDRH) Animal (CDRH) Chemistry Manufacturing and Controls (CDER)

Inter-center Consult Pilot Tiered consult approach that streamlines interactions across centers Identifies a clear process for identifying appropriate experts for a consult Defines clear roles and responsibilities for the head center, the consulted Center(s), and the Office of Combination Products Over the last few months, FDA has implemented a pilot program (and DCD is one of the participant divisions in his pilot ) intended to improve the review of combination products. This pilot involves a tiered approach…… it is hoped his iterative approach will ensure implementation of a robust ICCR process that enables efficient, effective collaboration on the review of combination products. 

Issues in IDE applications for coronary drug-coated balloons Has the device been completely characterized? Is the pre-clinical testing provided adequate? Will the proposed clinical protocol support device approval? To provide for you some useful information regarding what are important items that should be considered the follow questions are listed….and this is reflective of the major deficiencies we see in IDE applications….

Device Characterization Complete information on how the drug is loaded to the balloon. Data showing how the release of the drug into the vessel wall is controlled during inflation (drug dosing/transfer efficiency/toxicity). Dose of drug released systemically

Pre-Clinical Testing of Coronary Drug-Coated Balloons See FDA Guidance documents For PTCA Component Class II Special Controls Guidance for PTCA Catheters (http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm225145.htm) For Drug Component: Draft Coronary DES Guidance (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072193.pdf) There are two FDA Guidance Documents that I would like to reference for you. The first one is the PTCA Component Class II Special Controls Guidance for PTCA. In this document you will find a list of many of the tests that will need to be conducted to qualify the balloon and the delivery system – test such as balloon fatigue testing, inflation testing, etc. The 2nd document if the Draft Coronary DES Guidance document where useful information relevant to testing of the drug component can be found. While the testing listed in these guidances is not all inclusive, they are very helpful to get started early in the planning process.

Pre-Clinical Testing of Coronary Drug-Coated Balloons (cont.) Particulate testing and coating integrity. Testing should be developed to mimic the process of tracking, deployment and drug delivery. Testing should encompass the extremes of the product matrix.

Animal Testing Deliverability of the device (including quantification of amount of drug lost). Drug pharmacokinetics. Histopathologic assessment of inflammation, thrombus, re-endothelialization, embolic potential (down-stream effects).

Clinical testing: What Indication is Being Evaluated? De novo coronary arteries In-stent restenosis Bare metal Drug-eluting stent

Clinical Considerations Trial design will be determined by the clinical indication being sought. A randomized clinical study should be considered in order to show benefit of treatment. The current “Standard of care” as well as comparator device approval status should be considered in trial proposals.

FDA Recommendations Talk to FDA early in the development process. Use of pre-submissions is encouraged to ensure appropriate testing will be gathered to support approval of regulatory submissions.

FDA Recommendations (cont.) Post-approval studies (PAS) will likely be required for PMA approved devices. Incorporation of a patient cohort that undergoes mandatory imaging may be useful. Consideration of DAPT duration based upon the proposed intended use of the coronary DCB.

Thank you Tara A. Ryan, MD, MS, MBA Medical Officer/Biomedical Engineer Food & Drug Administration CDRH/ODE/DCD/ICDB Tara.Ryan@fda.hhs.gov