Objective Performance Goals, Clinical Trial Design Suggested for Endovascular Treatments of CLI

December 3, 2009—In the Journal of Vascular Surgery (JVS), Michael S. Conte, MD, et al discuss the role of Objective Performance Criteria and Goals (OPC and OPGs) in the US Food and Drug Administration’s (FDA) premarket assessment of devices for the treatment of critical limb ischemia (CLI) (2009;50:1459–1461). The article notes that unique statutory requirements, such as the "least burdensome mandate," have allowed the FDA to employ nonconcurrent controls in its evaluation of prospective therapies. The use of OPC and OPGs for the premarket evaluation of cardiovascular devices has become established as an alternative to randomized, controlled trials. According to the authors, these single-armed comparisons may facilitate rapid entry of novel devices to the market. Unlike randomized, controlled trials, they do not establish superiority or noninferiority of the examined therapy, and study populations must be carefully inspected to ensure validity of comparisons to historical controls.

Dr. Conte and colleagues then published an analysis in JVS that sought to develop a set of suggested OPG for evaluating new catheter-based treatments in CLI, based on evidence from historical controls (2009;50:1462–1473). The investigators reviewed randomized, controlled trials of surgical, endovascular, and pharmacologic/biologic treatments for CLI according to specified criteria regarding study population and data quality. Line-item data were obtained for selected studies from the sponsor/funding agency. Specific outcome measures were defined in accordance with the treatment goals for the CLI population. Risk factors were examined for their influence on key endpoints, and models of stratification based on specific clinical and anatomic variables developed. Sample size estimates were made for single-arm trial designs based on comparison to the suggested OPG.

According to the investigators, bypass with autogenous vein was considered the established standard, and data compiled from three individual randomized, controlled trials (N = 838) were analyzed. The primary efficacy endpoint was defined as perioperative (30-day) death or any major adverse limb event (amputation or major reintervention) occurring within 1 year. Results of open surgery controls demonstrated freedom from the primary endpoint in 76.9% (95% confidence interval, 74.0%–79.9%) of patients at 1 year, with amputation-free survival of 76.5% (95% confidence interval, 73.7%–79.5). An additional 3% noninferiority margin was suggested in generating OPG for catheter-based therapies. Defined clinical (age > 80 years and tissue loss) and anatomic (infrapopliteal anatomy or lack of good quality saphenous vein) risk subgroups provided significantly different point estimates and OPG threshold values.

The investigators concluded that for new catheter-based therapies in CLI, OPGs offer a feasible approach for premarket evaluation using nonrandomized trial designs. Such studies should incorporate risk stratification in design and reporting as the CLI population is heterogeneous with respect to baseline variables and expected outcomes. Guidelines for CLI trial design to address consistency in study cohorts, methods of assessment, and endpoint definitions are provided.

In an accompanying editorial in JVS, Allison Kumar et al of the FDA reviewed aspects of this proposal from the perspective of the authors in terms of their understanding of the statutory obligations of the FDA to regulate the marketing of cardiovascular devices based on valid scientific evidence (2009;50:1474–1476).