FDA to Hold Public Meeting on 510(k) Process; Recent Studies Question Level of Evidence Used for Device Approval

January 22, 2010—The US Food and Drug Administration (FDA) announced that it has scheduled a public meeting on February 18, 2010 to discuss key challenges related to the 510(k) premarket notification process used to review and clear certain medical devices marketed in the United States.

At the meeting, FDA staff will present a brief overview of the challenges the agency has faced, organized into four categories: (1) issues related to predicate devices, which are previously cleared devices that may support a manufacturer's claim of substantial equivalence; (2) issues related to new technologies and scientific evidence; (3) issues related to practices the FDA has adopted in response to a high volume of submissions; and (4) issues related to postmarket surveillance and new information about marketed devices. Each of the four overview presentations will be followed by an open comment session. The meeting will close with a public roundtable discussion between FDA staff and selected participants representing a range of constituencies.

The February 18 meeting will run from 8 am to 5:30 pm at the Hilton Washington, DC/North Gaithersburg Hotel in Gaithersburg, Maryland. Those interested in attending or participating in the meeting must register by 5 pm on February 12, 2010. The agency is accepting written or electronic comments by March 5, 2010. More information is available from the FDA Web site. Two recent studies have questioned the level of evidence used by the FDA to evaluate cardiovascular devices for premarket approval (PMA).

In the Journal of the American Medical Association, Sanket S. Dhruva, MD; Lisa A. Bero, PhD; and Rita F. Redberg, MD, published findings from a study of the FDA’s PMA process of cardiovascular devices that sought to characterize the type and strength of evidence on which it is based (2009;302:2679–2685). The investigators concluded that premarket approval of cardiovascular devices by the FDA is often based on studies that lack adequate strength and may be prone to bias.

According to the investigators, the context of the study is that medical devices are common in clinical practice and have important effects on morbidity and mortality, but there has not been a systematic examination of evidence used by the FDA for device approval. The investigators conducted a systematic review of 123 summaries of safety and effectiveness data for 78 PMAs for high-risk cardiovascular devices that received PMA between January 2000 and December 2007. Data extraction included examination of the methodological characteristics considered essential to minimizing confounding and bias, as well as the primary endpoints of the 123 studies supporting the PMAs.

The investigators reported that 33 of 123 studies (27%) used to support recent FDA approval of cardiovascular devices were randomized, and 17 of 123 (14%) were blinded; 51 of 78 PMAs (65%) were based on a single study; 111 of 213 primary endpoints (52%) were compared with controls; 34 of 111 controls (31%) were retrospective; 187 of 213 primary endpoints (88%) were surrogate measures; and 122 of 157 (78%) primary endpoints had a discrepancy between the number of patients enrolled in the study and the number analyzed.

In a study published in the American Journal of Therapeutics, Daniel B. Kramer, MD, et al evaluated all original cardiovascular device PMAs with FDA decisions between January 1, 2000 and December 31, 2007 to assess the quality of clinical investigations submitted by manufacturers (2010;1:2–7). The investigators noted that the quality of clinical data submitted by manufacturers to support FDA cardiovascular device PMA applications varies widely, and formal quality assessment has not been previously performed.

As detailed in the American Journal of Therapeutics, the investigators judged that effectiveness and safety endpoints were high quality if they were clearly defined and associated with a specific time point for analysis. Subject accounting was high quality if 90% or greater of the original cohort was accounted for at study conclusion. In total, 88 cardiovascular device PMAs (77.3% permanent implants), 132 clinical studies, 37,328 study subjects (aged 61 ± 14.5 years; 33.9% women; 86.3% white), and 29,408 device recipients were analyzed. All PMAs contained clinical data.

The investigators reported that primary effectiveness endpoints, primary safety endpoints, and subject accounting were deemed high quality in 81.8%, 60.2%, and 77.3% of pivotal studies, respectively. Key cardiovascular comorbidities (coronary artery disease, 51.1%; diabetes, 36.6%; hypertension, 35.2%; heart failure, 37.5%; and tobacco use, 31.8%) and race (14.8%) were infrequently reported, and studies rarely included patients younger than 18 years (10.2% of studies).

The investigators concluded that poorly defined safety and effectiveness endpoints, poor patient accounting, and incomplete collection of important patient comorbidities make device safety and effectiveness assessments more challenging. Also, women and pediatric and nonwhite populations are underrepresented in premarket cardiovascular clinical trials. Finally, the investigators advised that manufacturers, regulators, and the clinical community should collaborate to address these study shortcomings to ensure that patients are treated with reliable, safe, and clinically useful medical devices.