RANDOMIZED, CONTROLLED STUDIES FOR REPLACEMENT HEART VALVES

RANDOMIZED, CONTROLLED STUDIES FOR REPLACEMENT HEART VALVES are "highly recommended" by FDA's Center for Devices and Radiological Health in a draft guidance document on data for premarket approval applications for replacement heart valves. "The use of a randomized, concurrent control is highly recommended" when collecting safety and efficacy data on heart valves, the agency says, adding that "while ethical considerations" such as selection of the most appropriate type of valve for each patient "take precedence, it is the feeling of CDRH that the use of randomized controls is appropriate and beneficial." The control for the clinical study "should be a heart valve of similar design which is currently approved for marketing in the United States," FDA states. "As previously required, at least three primary centers should be used in the study." The document applies to prosthetic, stented bioprosthetic and stentless bioprosthetic valves. The heart valve draft, which has not been officially released, would be the first FDA PMA guidance to recommend randomized, controlled clinical trials, the Health Industry Manufacturers Association says. FDA also is drafting a guidance on interventional cardiology devices that will contain a similar recommendation. FDA circulated the draft to trade associations and heart valve manufacturers for comment in late December. The agency plans to discuss the guidance document at an advisory panel meeting in early summer. Alan Andersen, acting director of FDA's office of device evaluation, announced FDA's intent to require more controlled clinical trials as proof of device safety and efficacy at a July Health Industry Manufacturers Association meeting ("The Gray Sheet" Aug. 3, p. 5). In the guidance, FDA acknowledges that heart valve manufacturers may face certain difficulties in conducting randomized trials for the devices. For example, "there are cases where it may not be appropriate to assume that all patients randomized into the control group will be treated in the same manner," FDA says, noting that "this may specifically be true for the stentless tissue valves, as there are none currently approved for marketing in the United States." FDA notes, however, that "it is the responsibility of the manufacturer to deal with statistical complications which may arise from using a mixed control group." The guidance also discusses changes in requirements for the collection of valve hemodynamics data. "The recent introduction of a non-invasive technique (echo-cardiography) for establishing hemodynamic performance of heart valves, has lead to the elimination of the FDA requirement for catheterization data." FDA adds that, "due to the non-invasive nature of echocardiography, hemodynamic performance data should be collected on 100% of the patient population" rather than for seven patients, as was required with catheterization. FDA notes that the change is aimed at "minimizing the risk to which the patient is subjected." In addition to outlining agency recommendations for clinical trials of heart valves, the guidance document makes recommendations for in vitro and preclinical testing. FDA notes that manufacturers may forego the testing methods described in the draft if reasons for doing so are provided. "In some instances, the manufacturer may be able to justify not performing some of the testing outlined in the guidance" if reasonable assurance of safety and effectiveness "can be achieved by other means." However, the manufacturer "should be prepared to demonstrate the equivalence or superiority of the chosen means to the recommended test." The guidance document also makes recommendations regarding labeling and identifies specific heart valve manufacturing information that should be included in a PMA. The manufacturing recommendations say that for mechanical heart valves, "details of the procedure used to insert the occluder and/or leaflets into place should be provided." Manufacturers of pyrolytic carbon mechanical valves are asked to conduct a "detailed validation study to assure that the coating process is well controlled." For tissue valves, "tissue fixation parameters and acceptance criteria for valves as received from the slaughter house should be described." The manufacturing section of all replacement heart valve PMAs also should contain data on sterilization validation, FDA says.