Eight serious loopholes and cracks in the U.S. Food and Drug Administration's approval process allow potentially unsafe, ineffective yet high-risk machines and materials to be approved for use on patients, according to an article by the advocacy group Public Citizen.
"Discretion has been applied in an expansive manner favorable to industry," the authors wrote.
The researchers say the underlying problem is that the FDA scrutinizes medical devices by using thresholds that are far lower and more lenient than those required for pharmaceutical products, although they have just as much potential to harm. Certain drug-device combinations hospitals use, such as drug-eluting stents, are regulated as devices, as are MRI machines, heart valves and defibrillators, implantable sheaths and scaffolds, as well as grafts and intraaortic pumps.
They say that fixing the problems require actions by Congress, changes in regulation, as well as corrections in the agency's practices.
The group, whose authors include Peter Lurie MD, now a senior advisor in the FDA's Office of Commissioner, and Public Citizen director, Sidney Wolfe MD, published the article in this week's edition of the Public Library of Science Medicine.
"We want to raise awareness about structural defects in the medical device approval process that can allow devices to reach the patients despite knowing very little about their safety or effectiveness," says the report's lead author, Jonas Hines, formerly of Public Citizen now engaged in a medical residency at UCSF.
The authors point to a key failing in the FDA's 510(k) rule, which allows a manufacturer to establish that a device is safe and effective simply by demonstrating that it is substantially equivalent to an existing "predicate" device, based on the intended use, even if the device is quite different. The authors termed this approval process as "predicate creep."
"The 501(k) process allows sponsors to identify a predicate device that was itself substantially equivalent to another device that was substantially equivalent to another, and so on. This iterative process permits a scenario in which, over multiple cycles, a new device can be quite dissimilar to the original predicate device—so-called ?predicate creep,'" they wrote.
The authors used eight examples to illustrate the eight flaws failings in the FDA process. One involved ReGen's collagen scaffold, approved in 2008, which surgeons use as an implant to replace a damaged meniscus in the knee.
Though a clinical trial showed that the scaffold was no better than traditional meniscectomy without the scaffold, it was approved under the 510(k) rule because similar mesh devices had already been approved. However none of the similar meshes were intended to facilitate the regrowth of articular cartilage in a weight-bearing joint.
Looking back, an FDA report last September criticized its own review process in the ReGen scaffold, and described "a contentious review process," with the FDA ultimately acceding to intense pressure from ReGen and its Congressional advocates by altering its typical review procedures.
"Irregularities included unusual involvement of senior FDA leadership—including the then-FDA commissioner—in decisions usually made at lower levels, a shortened review time" and replacement of advisory committee members and a review team that were more likely to favor the device, the authors wrote.
The FDA is now re-evaluating its approval of the scaffold.
In another example, the authors point to the FDA's 2008 approval of a microarray kit used to compare RNA in a tumor of unknown origin with 15 common tumor types as a way of diagnosing cancer. That kit was approved with a "predicate" of a type of support software that was approved in 2005, that helps diagnose autoimmune disorders. The software was determined to be substantially equivalent to a drug profiling system, cleared in 1995, that tests for illicit drugs.
"Thus, a screening test for illicit drugs ultimately allowed for the clearance of a malignancy diagnostic test, simply because both use computer programs to compare samples to an existing database," the authors wrote.
In another example, the authors criticized the FDA's approval of a transcranial magnetic stimulation device intended to treat depression. The FDA allowed TMS to use electroconvulsive therapy as a predicate "even though ECT involves the administration of electrical currents to induce a generalized seizure."
"Despite this claim of equivalence, the manufacturer, Neuronetics, provided no information suggesting it conducted any studies directly comparing the two devices; instead, it conducted a nine-week RCT (randomized clinical trial) comparing TMS to a placebo."
In another example, the authors found problems in the FDA's approval of a vagus nerve stimulator, a surgically implanted device for treating depression that the authors said did not demonstrate a statistically significant benefit after 10 weeks.
But the manufacturer seeking approval relied on follow-up data at one-year "in which treated patients were claimed to have improved more than a non-randomized, unblinded, non-concurrent control group." Also, both of the groups were permitted co-interventions.
The article quoted a psychopharmacology expert in the FDA's drug center who advised that, with similar data for an antidepressant drug, the Center for Devices and Radiological Health (CDRH) would not have permitted the filing of a new drug application. "It is artificial for us to consider one study for a device (that is negative on face) as sufficient to provide evidence for regulatory efficacy when we require positive studies for a drug."
An FDA spokesman Wednesday responded to the article saying the agency will take Public Citizen's recommendations "under consideration as we continue to address many of the issues raised.
"Specifically, we are in the process of conducting an internal review of our 510(k) clearance program to improve our decision making and better support our mission to protect and promote public health. In addition, the Institute of Medicine is in the midst of its review (expected next year) of the same program to determine changes that could help us better achieve our goals."
The spokesman added that the FDA last year began reviewing safety and effectiveness information on the 25 medical device types that are considered Class III, (devices that are considered novel, with the highest risk). The agency is awaiting regulations that will either require manufacturers to submit premarket approval applications or re-classify the devices into lower risk categories, Class I or Class II.
"Both of these efforts are part of a broader set of initiatives published as CDRH's 2010 Strategic Priorities, which outlines the areas we think present significant opportunities to improve our effectiveness. These priorities are accompanied by timeframes so that CDRH can operate with transparency and the public can monitor our progress."
In addition to requiring standards for device approval that match those standards required for drugs, and removing the 510(k) "predicate creep," the authors criticized several other FDA approval routes:
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The FDA has inappropriately allowed use of "De Novo Process" in which a sponsor of a rejected product may request FDA clearance without identifying a predicate device if the device is determined to be low-risk and novel, when many are not. The authors said 52 devices have been cleared through this pathway.
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The FDA has failed to complete regulatory proceedings for 16% of the most high risk medical devices that were in existence prior to the 1976 Medical Device Act, allowing them to continue to be used as predicate devices.
According to a recent U.S. Government Accountability Office report, two-thirds of all class III preamendments devices cleared from FY 2003-2007 were implanted, life-sustaining or posed a significant risk.
Responding to this report, the FDA recently initiated the process of determining whether a PMA would be required for most of the remaining devices.
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The FDA has failed to classify in any risk category more than 200 types of preamendment devices that were overlooked in the original process, such as silicone pectoralis muscle implants, malar implants and certain vertebral body internal fixation devices.
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The FDA's "superfluous appeal mechanism" gives manufacturers a second go for approval after FDA has rejected a device.
In conclusion the authors wrote: "A series of problems with the FDA's premarket regulation of devices at times appears to permit potentially unsafe or ineffective devices to reach the market. Each must be remedied with a mix of legislative, regulatory and discretionary approaches unique to that problem. Most importantly, CDRH should place its decisions on a secure evidence base."
The authors note that medical devices accounted for 6% of U.S. healthcare spending, or $123 billion in 2006.
The Medical Device Management Association did not respond to a request for a comment about the Public Citizen report.