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In March 2015, the US Food and Drug Administration (FDA) granted Abiomed premarket approval (PMA) for the Impella 2.5 percutaneous ventricular assist device (PVAD) after reevaluating the product under its 515 Program Initiative, a recent FDA program examining certain high-risk devices already in widespread use. The Impella draws blood from the left ventricle and expels it into the ascending aorta to provide support during high-risk percutaneous coronary intervention procedures and cardiogenic shock. More than 25鈥�000 US patients have received treatment with the Impella since 2008, with use growing nearly 30-fold in recent years.¹ The experience leading up to Impella鈥檚 first-of-a-kind approval offers important insights into how the FDA can promote rigorous assessment of commonly used cardiovascular and other high-risk devices previously exempt from regulatory requirements for safety and effectiveness.

The Medical Device Amendments of 1976 established risk classification for medical devices and stipulated that all high-risk devices undergo FDA review prior to marketing via the PMA pathway, which requires reasonable assurance of device safety and effectiveness and usually involves at least 1 pivotal clinical trial. Under that legislation, the FDA classified more than 170 device types that were already in use (ie, preamendment) as high-risk, such as replacement heart valves and implantable pacemakers. Because the FDA did not have the resources to conduct PMA reviews for all high-risk devices already in use, as a transitional measure, Congress mandated that preamendment high-risk device types be temporarily regulated via the 510(k) pathway intended for moderate-risk devices. In contrast to PMA, 510(k) clearance requires manufacturers to demonstrate only that a new device is substantially equivalent to another predicate device already on the market, which usually does not require clinical study. This flexibility gave the FDA time to determine whether each device type truly warranted PMA review or could be down-classified in risk, while preserving patients鈥� access to these products in the interim.

The FDA鈥檚 plan to move preamendment high-risk devices away from the 510(k) pathway has been slowed by manufacturer petitions opposing reclassification, as well as competing regulatory priorities and insufficient internal resources. In 1990, Congress passed the Safe Medical Devices Act, mandating that the FDA finalize classification for the remaining 128 high-risk preamendment device types before 1996; however, 84 high-risk preamendment device types remained eligible for 510(k) clearance following this deadline.² During the delayed transition, prominent cases of high-risk devices cleared on the basis of substantial equivalence were found to pose health risks to patients (eg, metal-on-metal hip implants).³

In 2009, the FDA launched the 515 Program Initiative to finalize classification for the remaining 26 high-risk preamendment device types, among which are widely used cardiovascular devices such as intra-aortic balloon pumps (IABPs), ventricular pacing leads, and automated external defibrillators. In 2012, the FDA adopted a 5-step reclassification process for these preamendment device types: (1) review existing scientific information to assess risks and benefits, (2) convene an expert advisory panel, (3) issue a proposed risk classification, (4) consider public comments, and (5) issue a final risk classification. Manufacturers of device types maintaining their high-risk classification must subsequently obtain PMA for both existing and future products, with the former remaining available for use throughout the regulatory review process.

Abiomed originally obtained 510(k) clearance for the Impella in May 2008 by claiming substantial equivalence to a lineage of devices tracing back to preamendment nonroller cardiopulmonary bypass pumps, which were subsequently targeted for reclassification under the 515 Program Initiative. As the first step in the reclassification process, the FDA reviewed existing scientific information to assess the risks and benefits of nonroller pumps, but found that the Impella and other PVADs were different enough that use of these preamendment devices as predicates was not appopriate.⁴ Next, the FDA performed a systematic review to assess the risks and benefits of PVADs, identifying 40 relevant clinical studies. Twelve of these directly studied the Impella, including PROTECT II, a superiority trial sponsored by Abiomed comparing the Impella with IABP therapy in patients undergoing high-risk percutaneous coronary intervention that was terminated early due to futility. FDA review of subgroup data in this trial failed 鈥渢o provide full clarity regarding the safety and effectiveness of this new treatment paradigm.鈥�⁵ The FDA concluded that nonroller bypass pumps should be down-classified as moderate-risk while the Impella and other PVADs should be classified as a new high-risk device type. The FDA then convened an advisory committee in December 2012, which voted 10 to 3 in favor of this revised classification. The FDA officially proposed this classification in January 2014, completing the third step of the reclassification process and prompting Abiomed to seek PMA for Impella 2 months later.

Abiomed鈥檚 PMA submission primarily consisted of evidence from 3 clinical studies: PROTECT I feasibility study (20 patients; completed 2007), PROTECT II pivotal study (452 patients; completed 2010), and Abiomed鈥檚 ongoing retrospective USpella registry (637 patients).⁶ Based on subgroup and post hoc analyses of the PROTECT II 90-day composite secondary end point of 10 major adverse events, the FDA determined that the Impella likely offered clinical benefit compared with IABP therapy. Impella safety was established by showing in-hospital mortality was no greater for Impella registry patients compared with historical controls from the IABP therapy group of PROTECT II. As a condition of approval, Abiomed was required to conduct a prospective, multicenter, single-group study of Impella use among 369 patients.

The Impella鈥檚 recent PMA raises important questions about whether robust clinical evidence will be generated for preamendment high-risk devices through the 515 Program Initiative. Large-scale, real-world outcomes assessments of the Impella could not be conducted with electronic health records and administrative claims data, as there is no way of identifying which type of PVAD patients receive. The FDA has begun implementing a unique device identification system to facilitate postmarket surveillance using routinely collected health information, which may enhance evaluations of 515 Program Initiative devices already in widespread use. However, until this system is in place, manufacturers may propose that the FDA consider potentially problematic historical evidence in support of approval, including clinical data from the literature, existing patient registries, or prior trials.

These sources of evidence are each flawed in important ways as mechanisms of evaluating device safety and effectiveness. There is publication bias in the biomedical literature; for instance, a recent study demonstrated that many high-risk cardiovascular device trials were unpublished and those that are published focusing on favorable outcomes.⁷ Although registries can be important sources of safety and effectiveness data, they generally collect information on short-term procedural care, whereas long-term outcomes assessments require linkage to administrative claims data that may not exist. In addition, adverse events may be underreported within registries due to lack of documentation or nonsystematic ascertainment.⁶

Finally, clinical trials must be consistent with current clinical practice standards, using patient-important outcomes as end points and proven therapies as comparators. For example, the probable benefit of the Impella compared with IABP therapy found in PROTECT II is of uncertain clinical significance, as a recent systematic review of IABP therapy found no associated 30-day mortality benefit when compared with medical therapy.⁸ In fact, IABP therapy is no longer recommended under 2014 joint guidelines set forth by the European Society of Cardiology, European Association for Cardio-Thoracic Surgery, and European Association of Percutaneous Cardiovascular Interventions. To generate meaningful clinical evidence in support of approval, manufacturers may consider partnering with investigators supported by the Patient-Centered Outcomes Research Institute to conduct large, pragmatic comparative effectiveness studies.

The FDA deserves applause for the important steps it has taken in modernizing device regulation to ensure all high-risk devices undergo clinical testing. Though the FDA faces the difficult task of requiring meaningful evidence for approval without placing undue burden on manufacturers, these last preamendment devices being considered through the 515 Program Initiative are already in widespread use, suggesting that there should be ample opportunity for manufacturers to conduct large, robust clinical studies examining patient-important outcomes to ensure that patients and physicians may continue using these high-risk devices with assurance of their safety and effectiveness.

Corresponding Author: Joseph S. Ross, MD, MHS, Section of General Internal Medicine, Yale University School of Medicine, PO Box 208093, New Haven, CT 06520 (joseph.ross@yale.edu).

Published Online: March 9, 2016. doi:10.1001/jamacardio.2016.0002.

Author Contributions: Mr Rathi and Dr Ross had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kesselheim reports receiving grants from the FDA Office of Generic Drugs and Division of Health Communications. Dr Ross reports receiving research support from Medtronic, Johnson and Johnson, the US Food and Drug Administration, the Blue Cross Blue Shield Association, and Centers of Medicare & Medicaid Services. No other disclosures were reported.

Funding/Support: This work was supported by the Yale University School of Medicine Office of Student Research (Mr Rathi), the Harvard Program in Therapeutic Science (Dr Kesselheim), grant K08 AG032886 from the National Institute on Aging (Dr Ross), and the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program (Dr Ross).

Role of the Funder/Sponsor: The sponsors had no role in the preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.