I took a field trip to the big city last week, to attend the Union of Concerned Scientists’ and George Washington University School of Public Health’s conference, “FDA at a Crossroads.” I have great respect for UCS and their efforts to keep science depoliticized, a topic that I have written and spoken about. They were kind enough to provide a webcast of FDA at a Crossroads, so I’ll share only a bit here.

It’s one thing to read dry facts and reports, another to put a face on things and more vividly understand the magnitude of the problem.

First up was Dr. Margaret Hamburg, who serves as FDA commissioner, an unenviable task, given a balky Congress and critical public. The FDA is charged with oversight of food safety, meds, distribution chain, drugs, and devices—and that account for 25% of consumer spending. They attempt to do this with only ~10,000 employees.

Most chilling to me was that 80% of active ingredients and 40% of finished drugs are manufactured abroad, with little oversight. Hence, there have been growing problems with tainted drugs, like the heparin scandal that killed a number of patients, and counterfeiting. I haven’t understood why this hasn’t appeared to be an obvious top national security priority.

Much of the conference centered on the Prescription Drug User Fee Act (PDUFA), which provides a major source of FDA funding, and is up for renewal. Under PDUFA, the pharmaceutical companies pay annual fees, as well as fees for each prescription drug product they market, in exchange for expected rapid review timelines. There is a similar, though much smaller program for devices, the Medical Device User Fee Act (MDUFA). A recurring theme was that these fees also pose a conflict, as FDA staffers feel pressured to hastily approve drugs or devices to meet these timelines, leaving safety as a lesser concern.

Similarly disturbing is the reminder, via Diana Zuckerman and others, how little oversight there is of medical devices. Class II, or “medium risk” devices, such as hip or knee replacements, or inferior vena cava (IVC) filters to prevent blood clots from traveling to the lungs, are only required to be “Substantially equivalent” to marketed devices—no clinical trials, inspections of manufacturers, or other studies are required. High risk, or Class III devices such as pacemakers can gain approval based on only one tiny trial. It’s no great surprise then that 15% of all devices cleared by the FDA are later recalled. Shockingly, almost ½ billion devices were recalled in 2010 alone as being of high risk.

All of these problems could be caught sooner if there were, at a minimum, a requirement for post-marketing studies, registries, and surveillance. But reviews are costly, and the GAO estimates that the FDA loses $700,000 on each PMA (pre-market approval) device Class III review. One option would be to increase the device review fees to be comparable to those for drugs. Currently, user fee for a new drug application costs $1.8 million vs. $220,000 for a PMA device, and only $4049 for pre-notification and FDA clearance of a 510(k) device, one that is considered by the manufacturer to be “substantially equivalent” to one already on the market—though equivalence appears to be in the eye of the beholder. Unfortunately, historically the FDA staff has been pressured to approve new drugs and devices to support “innovation,” rather than to focus on safety.

Dr. Rita Redberg, of UCSF, further criticized the device approval process, noting that many studies are poorly designed, do a poor job of data analysis, or rely on surrogate endpoints, rather than meaningful patient outcomes. She also emphasized the need for breaking down efficacy and safety results by sex. Although the FDA’s Office of Women’s Health mandates this analysis (since 1994), sex-specific differences are often ignored—in 28% of cardiovascular device studies, for example. Yet in a study of Thoratec Heartmate II Left Ventricular Assist Device (LVAD), women had a 3-fold higher risk of stroke and more infection and bleeding. Published data did not include gender-specific analysis.

Another scary example of the need for post-marketing surveillance (as well as requiring initial clinical trials) is that of inferior vena cava (IVC) filters. These “umbrellas” are placed in patients who are at risk for pulmonary emboli (potentially fatal blood clots to the lungs), yet are at high risk of bleeding from anticoagulant medication. One Pennsylvania study found a 25% fracture rate of IVCs, with embolization to the heart in several cases. And IVCs are considered only class II devices—medium risk—and therefore were approved without clinical safety or effectiveness data under 510(k) clearances. And one might ask why it took 921 adverse event cases before the FDA issued a report warning physicians of these problems.

In other cases, longer follow up needed to detect problems. For example, 3 years after approval, the Medtronic Sprint Fidelis Implantable Cardioverter-Defibrillator (ICD) was found to have a high rate of lead fracture, with resultant deaths. Both of these examples illustrate the problems with expediting approval under this “substantially equivalent” ruse. In fact, this past summer, the Institute of Medicine (IOM) suggested scrapping the 510(k) process altogether, noting that such 510(k) devices are not proven to be either safe or effective.

So why are these questionable device development processes and approval allowed to continue? One need only follow the money. Devices are hugely profitable to involved properties, from the inventor and manufacturer, to the surgeon or radiologist inserting it. (Note that procedures are reimbursed by Medicare and insurers at a far higher rate than “thinking” subspecialties.) Devices cost $76 billion annually in the United States alone, and the profit margin for devices like defibrillators and prosthetic hips is over 20 percent. According to Dr. Peter Groeneveld “between 2003 and 2006, drug-eluting stents implanted in Medicare patients ages 65 to 84 cost Medicare $4.97 billion, representing 89% of the total growth of costs for coronary artery disease patients. The cost increase in the Medicare heart-failure population attributable to ICDs was $893 million, or 29% of total growth in the cost of treating that population.”

Devices have also been profitable for communities and their legislators. In a pointed New York Times piece last month, Barry Meier focused attention on a Minnesota congressman, Erik Paulsen, who pushed for congress to loosen the FDA device approval process even more. The following month, his campaign committee coincidentally received $74,000 in contribution from groups highly interested in the outcome of such legislation—venture capitalists for device developers. Over the past five years, such targeted political donations to ease device regulation have totaled more than $3.3 million. The pace of lobbying has picked up, as the Medical Device User Fee Act is coming up for reconsideration. During the 2nd quarter of this year alone, medical device industry spent nearly $28 million lobbying legislators on various issues.

There have been several congressional hearings on the impact of the FDA on device approval—again with the focus being on speed rather than safety.

Unfortunately, patients have no protection against faulty devices, as the probusiness Supreme Court ruled in Riegel v. Medtronic that a manufacturer couldn’t be sued under state law if its device received marketing approval from the FDA. As a result, thousands of claims have been dismissed. In contrast, in Wyeth v. Levine, the Supreme Court justices did not uphold the argument of preemption, which says that federal regulations trump the states’. So, as it currently stands, device manufacturers have no incentive to be cautiously focused on safety because they are shielded from consequences. Fortunately, the Medical Device Safety Act of 2009, which would level the playing field and hold device manufacturers accountable for product defects, has been introduced in both houses of Congress. Being opposed by industry, it was still languishing in committees as of May 2010. (ref 36)

In most developed countries, medical device registries track the failure or complication rates of products, making comparisons readily accessible. There are no such comprehensive device registries in the U.S.

Device trials may have more financial conflict-of-interest issues than drug trials because clinicians or inventors may have significant equity interests in the device and, because of their technical skills, be vital members of the initial device development team.

So what can be done?

I agree wholeheartedly with the conclusions of the panelists:

Pre-marketing evaluation of devices, especially those of high risk, should require more rigorous, blinded clinical trials and data analysis, and not receive exemptions as being “substantially equivalent.” Subjects should include intended patients—matched for age, sex, race and comorbidities, and not cherry-picked to show unrealistically good outcomes.

There need to be stronger protections for whistleblowers, rather than undermining current limited protection. Conflict of interest regulations should be clarified and strengthened; patient advocacy groups should also reveal their industry backing. And Congressional hearings should be balanced and emphasize scientific input…one can dream, no?

Image credits: Fig.1 GMTA; Fig 2 Future Crimes; Fig. 3 NIH, Fig. 4 Madhero88 on Wikimedia Commons, Fig. 5 Clay Bennett and Christian Science Monitor, with permission.

Previously in this series:

Molecules to Medicine: Clinical Trials for Beginners

Molecules to Medicine: From Test-Tube to Medicine Chest

Lilly’s Shocker, or the Post-Marketing Blues

Molecules to Medicine: Pharma Trumps HIPAA?

Molecules to Medicine: Should pepper spray be put on (clinical) trial?

Addendum: Clarification and update:

The Medtronic Sprint Fidelis was approved under a PMA expedited review process rather than 510(k) process.

However, although it was not a 510(k) review, this FDA review was similar. In fact, according to Dr. William Maisel, Deputy Center Director for Science at the FDA’s Center for Devices and Radiological Health, this Medtronic cardioverter-defibrillator (ICD) lead was approved by the FDA in 2004 “on the basis of bench testing but no human clinical data.” Dr. Maisel further remarked that “Medtronic failed to note that the [small prospective postmarketing] study—which included fewer than 100 pts followed for 2 years—was grossly underpowered to detect even a moderate increase in fracture rate in the Fidelis…”

Today, the Department of Justice announced that Medtronic has agreed to pay the United States $23.5 million to resolve allegations that it violated the False Claim Act by using physician payments related to post-market studies and device registries as kickbacks to induce doctors to implant the company’s pacemakers and defibrillators, the Justice Department announced today. Medtronic did not admit wrongdoing as part of the civil settlement.