REGISTRY ASSESSMENT OF PERIPHERAL INTERVENTIONAL DEVICES (RAPID): Superficial femoral and Popliteal EvidencE Development (SPEED) A NEST Coordinating Center Demonstration Project Overview of the Process and Statistical Analysis Plan Yu-Ching Cheng, PhD FDA/CDRH/OSB/DEPI On behalf of the RAPID/SPEED Project September 10, 2018 VISION Think Tank Meeting

Agenda RAPID/SPEED Overview Statistical Analysis Plan for Developing the Dynamic Objective Performance Criteria (OPC) in SPEED

RAPID- Registry Assessment of Peripheral Interventional Devices Launched on June 5, 2015 & managed by the Duke Clinical Research Institute (DCRI). Collaborators from: Professional societies and their registries Academia Medical device manufacturers United States federal agencies International partners Health information technology vendor and clinical research organizations Reference: Morales JP, Cronenwett J and Thatcher R. Endovascular Today 2016;15:85-94; Jones WS et al. J Vasc Surg 2018;67:637-45

RAPID Leadership Principal Investigators Pablo Morales, MD FDA Robert Thatcher 4C Medical Technologies Jack Cronenwett, MD Society for Vascular Surgery (SVS), Vascular Quality Initiative (VQI) MDEpiNet Key Advisors Mitchell Krucoff, MD Duke Clinical Research Institute (DCRI) Danica Marinac-Dabic, MD, PhD, MMSc Project Management and Informatics Support Mina Baqai, Katy Knowlin, Sarah Palmer, Rebecca Wilgus DCRI

RAPID Objective Designed to advance the foundational elements of a total product life cycle (TPLC) assessment of medical devices used to treat and manage peripheral artery disease.

RAPID Phases Phase I (completed) Phase II/III PROJECT (ongoing) To identify the minimal set of core data elements for registry assessment of peripheral arterial interventional devices. Phase II/III PROJECT (ongoing) Use the RAPID core data elements to facilitate peripheral device development while addressing regulatory needs. SPEED- Superficial Femoral and Popliteal Evidence Development: To use the VQI database to develop contemporary, dynamic objective performance criteria (OPC) for superficial femoral (SFA) and popliteal artery (POP) endovascular interventions. Working Groups: Protocol & Statistics Governance Informatics Outreach/Visibility GUDID

RAPID/SPEED Overview PPP w/ reps from Industry, Regulatory, Payers, Prof. Societies, and Patients Develop clinical, statistical and informatics teams to address detailed issues Identify a minimum core data set Identify potential sources of information with acceptable quality Prospectively develop a protocol and statistical analysis plan Identify incl/excl, key covariates, analysis populations, and outcomes execute the analysis and report results sub-teams provide feedback Partnership agrees to OPC and website with calculator created Review OPC and update every x years SNIS 24JUL2018

Agenda RAPID/SPEED Overview Statistical Analysis Plan for Developing the Dynamic Objective Performance Criteria (OPC) in SPEED

VQI participating center and physicians Data Source Vascular Quality Initiative (VQI) Peripheral Vascular Intervention Registry (PVI) VQI participating center and physicians Collecting: Patient demographics Comorbidities procedure detail including device class in-hospital and one-year outcomes Data validation through CMS claims data

Patient Selection Including patients with lesions in the superficial femoral arteries (SFA) or popliteal arteries (POP) that were treated with angioplasty, stent, and/or atherectomy between 2010 and 2015. Excluding: Aneurysmal disease of the SFA or POP and non-atherosclerotic etiology Treatment for acute limb ischemia Treatment of common femoral artery or profunda femoral artery occlusive disease Emergency procedures Patients treated with PVI and concomitant femoral endarterectomy at any time prior to the index procedure Surgery SPEED: Overview of SAP 5/2/2018

Data Completeness Assess the completeness for each outcome, covariate and their combinations. The data completeness are reported at the patient, limb, artery, and lesion level depending on the variable. The above information, in consultation with the protocol & statistics team, will be used to determine if any of the covariates needs to be imputed. SPEED: Overview of SAP 5/2/2018

Analytical Populations Subgroups based on treated vessel: Patients where the index procedure has treated lesions that are located in the SFA alone Patients where the index procedure has treated lesions that are located in the POP alone Patients where the index procedure has treated lesions in either the SFA, POP or both For each vessel-based subgroup, an OPC will be developed for the following sets of treatment procedures: All patients with any of the following: PTA, Stent, or Atherectomy Percutaneous Transluminal Angioplasty (PTA) only Stent with or without PTA Atherectomy with or without PTA Stent + Atherectomy 5/2/2018

Outcomes of Interests Mortality: any cause Major amputation: below or above knee amputation of index limb Amputation free survival (AFS): composite of freedom from mortality and major amputation Target lesion revascularization (TLR): repeat intervention (open surgical or percutaneous) on the index artery(ies): Open surgery: any endarterectomy or infrainguinal bypass of target lesion previously treated with PVI Interventional: any angioplasty, atherectomy, stent or stent graft or thrombolysis performed on target lesion previously treated with PVI Target lesion occlusion: binary loss of patency or occluded at follow-up Target vessel revascularization: Any new qualifying procedure within the target vessel Technical failure: inability to cross lesion or occlusion, SFA-POP artery dissection or perforation requiring treatment, distal embolization requiring treatment, or residual stenosis >=30%. 

Covariates of interest History (Left and Right): Indication Pathology Prior inflow bypass Prior inflow PTA/Stent Prior leg bypass Prior leg PTA/Stent Prior major amputation Prior minor amputation Pre-rx TBI Pre-rx ABI Baseline Age Gender Date of death Race/Ethnicity Weight, Height, BMI Smoking Hypertension Diabetes Coronary Artery Disease (CAD) Symptoms Prior CHF COPD Dialysis Creatinine Living Status Discharge Status Ambulatory Status ASA Class Pre-operation medications Prior bypass Prior PVI Prior major amputation Procedures: Urgency Largest sheath size Side (lesion level) TASC-Trans-Atlantic Society Consensus (lesion level) Total occlusion length (lesion level) Total treated length (lesion level) Adjunct (lesion level) Balloon/stent max diameter (lesion level) Arterial dissection Arterial perforation Distal embolization Proximal run off score (SFA, POP, Profunda) (L and R) Distal run off score (AT, PT, Peroneal) (L and R) Post-op: Access site stenosis/occlusion Discharge medication: ASA, anticoagulation, betablocker, platelet inhibitor, statin 5/2/2018

Data Analyses Descriptive statistics for baseline characteristics Univariable analyses of covariate and outcomes of interests, by vessel*treatment type. Multivariable analyses for outcomes of interests, by vessel*treatment type. OPCs for outcomes of interests, by vessel*treatment type: Estimates adjusted for various covariates 5/2/2018

SPEED Analytical Team FDA Team: VISION Programming Team Analysts: Yu-Ching Cheng, PhD & Li Wang, PhD (Division of Epidemiology; Director: Danica Marinac-Dabic, MD, Ph.D.) Advisors: Office of Surveillance and Biostatistics (Director: Thomas Gross, MD, MPH) Nelson Lu, Ph.D. (Division of Biostatistics; Director: Ram Twari, Ph.D.) Office of Device Evaluation, Division of Cardiovascular Devices Misti Malone, PhD VISION Programming Team SPEED Analytical Team works interactively with the RAPID Statistical Work Group (Lead: Roseann White, PhD) throughout the analyses

Dataset for SPEED Analysis 30,899 patients transferred from VQI: 25,077 patients with 1 procedure 5,822 patients with more than 1 procedure 38,344 procedures: 26,389 procedures with follow-up information # of lesions treated: SFA: 32,385 (22,362 with follow-up information) POP: 15,886 (11,001 with follow-up information)

Summary SPEED project: use the VQI database to develop contemporary, dynamic OPCs for superficial femoral (SFA) and popliteal artery endovascular interventions These OPCs could potentially be used in designing a device approval clinical trial. Demonstrate the feasibility of data extraction from a registry and lay the groundwork for a coordinated registry network (CRN). Extensive analyses are conducted: Analyses for completeness: ~60 covariates x 9 outcomes OPC Analyses: 3 sub groups (SFA, POP, SFA and/or POP)  5 sets of treatments  9 outcomes x ~60covariates (univariable + 1 multivariable) Status Evaluating OPC for TLR

Questions? RAPID website: http://www.mdepinet.org/rapid