By Josh Rising, MD, MPH, Ian S. Reynolds, MPH, and Art Sedrakyan, MD, PhD
More than 500,000 U.S. patients have received metal-on-metal hip prostheses, most of which were implanted between 2003 and 2010. These prostheses entered the market through the 510(k) pathway at the Food and Drug Administration (FDA), whereby manufacturers need only demonstrate substantial equivalence to a device already on the market to gain approval. Unfortunately, there is now compelling evidence that these implants fail at a higher rate than hip prostheses made of other materials; indeed, one type of metal-on-metal hip has a failure rate of nearly 50% at 6 years. Moreover, a number of unresolved questions related to these devices remain, including what the relationship is between serum metal ion levels and the occurrence of local and systemic adverse events, what relationship exists between serum metal levels and the need for revision surgery, how much product-level variation there is in revision rates and adverse events, and which patient- and clinician-level variables are associated with those rates and events.
On May 6, 2011, in response to these public health concerns, the FDA ordered manufacturers of metal-on-metal hip implants to conduct postmarket surveillance studies on their products. (The FDA can require such studies under the Food, Drug, and Cosmetic Act [FDCA] if failure would be reasonably likely to have serious adverse health consequences, if the device is expected to have considerable use in pediatric populations, if it's intended to be implanted for more than 1 year, or if it's intended to be a life-sustaining or life-supporting device used outside a device user facility.) The FDA directed the implant manufacturers to examine both adverse events and patients' pre- and postimplantation levels of chromium and cobalt. The agency recommended a cross-sectional study design to capture data on patients from the time of initial implantation to 8 years later. It also recommended that manufacturers conduct a failure analysis to evaluate the devices that had been explanted from patients who had participated in clinical studies and all other reasonably available explants.
According to the FDA's website, which is updated monthly, just 24 of the 104 metal-on-metal hip products (23%) for which manufacturers face an active order to complete a study were categorized as having a “Study Pending,” which indicates that the FDA has approved the study plan. The studies for the remaining 80 products were listed as having either a “Plan Pending” or a “Plan Overdue.” (We exclude products with a study status of “Other” or “Terminated,” which indicate that there is not an active study for these products — because they were never marketed, for example.)
Several factors may contribute to delays in study initiation: the development of a scientifically sound study protocol is time-consuming and resource-intensive; manufacturers lack incentives to conduct studies that may reveal adverse information about their products; and delays at the FDA may slow down the process of finalizing study protocols. Strategies for reducing delays must address at least one of these factors.
Unfortunately, even when the studies proceed, limitations may constrain the amount of useful information that emerges. One significant shortcoming is that each manufacturer is permitted to conduct its own independent study on its product or products. The resulting lack of harmonization among studies will lead to challenges in pooling the data and making cross-product comparisons. For example, variations in definitions of outcomes, collection of patient- and provider-level data, and patient follow-up could undermine attempts to understand product-level differences. Similarly, companies may measure chromium and cobalt levels differently, using varied assays, laboratories, and protocols and introducing uncertainty into attempts to pool results. Although identical protocols would not necessarily be appropriate for all products, this lack of harmonization limits the public health benefit of the studies.