The Danger Within Us

by Jeanne Lenzer

  Which brings us to the slippery issue of off-label use. Off-label use occurs when a drug or device that has been approved for one condition (as written on the product’s label) is instead prescribed or implanted for a different use or condition. For example, an aspirin-like drug might be approved by the FDA to treat pain—but not to treat cancer. Doctors could legally prescribe an aspirinlike drug for cancer—an off-label use—but it’s likely they would be held liable for harm to a patient if he or she died of an untreated cancer. On the other hand, many drugs, such as penicillin, have never been tested or approved for use in children, yet the use of penicillin to treat pneumonia in children is effective and widely used. Off-label prescribing carries certain risks and requires the physician to use judgment.

  Complications of rhBMP-2 are generally related to two distinct problems. The first is an early, intense inflammatory reaction to the biologic product that occurs within several days of surgery. This is the type of reaction that first caught Yaremchuk’s attention during the mysterious outbreak of respiratory distress at her institution. The second type of problem is a late-occurring complication caused by exuberant bony overgrowth, the complication that affected Lew. Bony overgrowth takes longer to develop and often occurs months after surgery. It can compress spinal nerves and the spinal cord itself, and impinge on structures in the neck, causing anything from difficulty breathing and swallowing to strokes, paralysis, and death.

  While complications caused by rhBMP-2 in the lower spine (a use approved by the FDA) could include urinary incontinence and impotence, its complications when used off-label in the neck could be deadly because of its proximity to the airway and upper spine. Despite this, off-label use of rhBMP-2 was proving to be the rule, not the exception. One study found that between 85 and 96 percent of rhBMP-2 use is off-label.287

  The dangers of implanting rhBMP-2 in the neck were known before Wang ever performed surgery on Lew. On July 1, 2008, more than nine months before Lew’s operation, the FDA issued a warning about off-label use of rhBMP-2 in the neck, stating that it had received reports of “life-threatening complications” and that its “safety and effectiveness…in the cervical spine have not been demonstrated.”288 Unfortunately for many patients, implanting rhBMP-2 in the neck—an off-label use—would prove to be life-altering and life-threatening. Studies began to emerge showing that between a quarter and half of patients treated with Infuse and rhBMP-2 for on- and off-label uses would experience complications—including death.289, 290 Some researchers reported a possible connection between rhBMP-2, which stimulates cell growth, and an increased risk of cancer activation or progression.289, 291, 292

  Lew initiated legal proceedings against Wang, the surgeon who implanted BMP-2 in his neck. The tangled web of financial relationships, false claims by the manufacturers of spinal devices, and failed oversight by the FDA that he unearthed in the process explains a great deal about the dangers to patients inherent in the rise of the medical-industrial complex.

  Lew charged in his suit that when Wang told him he needed surgery, he didn’t disclose that he was a consultant for Medtronic and that he had research and financial ties to the company.293 Together with two other spine-device manufacturers, Medtronic paid Wang $459,500 in speaker’s fees and consultancies from 2004 to 2007. Wang also developed a technique for surgically implanting a plate manufactured by Biomet for which the company paid him $303,102 in royalties in 2011. It was the same plate Wang recommended for use at UCLA and that he implanted in Lew along with the Infuse component, rhBMP-2. And while Medtronic was funding Wang’s research, Wang “consistently checked ‘no’” on conflict-of-interest forms at UCLA when asked whether he received $500 or more from any company sponsoring his research.295

  Wang wasn’t the only UCLA faculty member who failed to declare his industry ties. According to Robert Pedowitz, the former chair of orthopedics at UCLA, the university benefited from turning a blind eye to financial conflicts.296 Pedowitz charged in a whistle-blower suit that industry payments to doctors and the university may have compromised patient care and that the university retaliated against him when he raised concerns, forcing him out of his position. In April of 2014, UCLA regents agreed to pay Pedowitz $10 million as part of a settlement agreement. In July of 2016, UCLA confirmed that it had also settled the case brought by Lew, for $4.2 million.297 Medtronic separately entered into a confidential settlement with Lew.

  The details of the story Lew brought to light in his lawsuit and in a presentation to the FDA can be difficult to follow. But the bottom line is this: Medtronic and other device companies promoted off-label use of rhBMP-2 by creating a spinal cage that was sized and shaped for the neck, allowing surgeons to implant rhBMP-2 in the neck and helping off-label use become the norm.

  The FDA approved Infuse in 2002 as a high-risk class III device comprising a cage containing its component rhBMP-2, after going through the FDA’s “most stringent” testing, or premarket approval (PMA) process. The device was used in the lower spine in clinical tests and was approved for that use only.

  Soon after Infuse hit the market, the company manufactured a much smaller cage that fit into the small bones of the neck. Here’s where things get tricky: by declaring that the new, smaller cage was intended for use in the lower spine and that it was “substantially equivalent” to the already approved cage used in that part of the body, the company was able to have the smaller cage, known as VERTE-STACK, cleared through the quickie, down-and-dirty 510(k) process, which doesn’t require any clinical testing.

  Because the VERTE-STACK cage is hollow, it can be used to implant rhBMP-2-impregnated sponges, which is exactly how surgeons began using it, because they knew its shape and size were right for the much smaller bones of the neck. It was a slick ruse: if Medtronic had openly stated that it wanted to sell the device for the neck, that would have constituted an entirely new use or indication and should have triggered a demand for clinical testing. But Medtronic sidestepped that hurdle (and expense) by saying that the tiny dime-sized cage was meant for the lower back.

  So why didn’t the FDA recognize the size difference and its implications when Medtronic submitted its 510(k) clearance application? The dimensions were clearly stated for anyone to see. Zafar Khan, a codeveloper of the cage, said he helped develop it specifically for use in the neck—a point that appears to have been either missed or glossed over by the FDA.298

  Whether the FDA was rushed (the very problem the Institute of Medicine said was causing serious problems at the agency), whether it was asleep at the wheel, or whether someone was in line for the revolving door between the FDA and industry is not clear, but the agency would fail again and again to protect the public despite multiple warnings from experts.

  John W. Brantigan, an orthopedic surgeon who patented the first modern spinal cages, warned the FDA in 2003 that the agency was clearing spinal devices that were “impossible to use for the labeled purposes.” In other words, a device labeled for use in the lower back but sized and shaped for the neck couldn’t possibly be used in the lower back. Brantigan told the FDA that failing to require clinical trials of spinal cages would mean that “many patients will be subjected to unnecessary failures, chronic pain, and ruined lives.”

  His concerns were echoed by others.

  Dr. Nancy E. Epstein, professor of clinical neurosurgery at the College of Medicine, State University of New York at Stony Brook and the chief of neurosurgical spine and education at NYU Winthrop-University Hospital, says she has seen serious problems with the use of rhBMP-2, especially when used off-label in the neck.299 She and a colleague conducted a one-year study (2010) at one institution and found that complications were common. They found that 96 percent (170 of 177) of patients were treated off-label at a cost of $4,547,822; and of those treated off-label, nearly one in five patients (18.8 percent) underwent reoperation within just one year.287

  Epstein conducted a separate review of 183 patients who had been offered operations by spine surgeons, and she det
ermined that many didn’t need surgery at all.300

  But even before Yaremchuk and Epstein reported their findings, there had been warning signs that something was wrong with Medtronic research.

  Eugene J. Carragee, professor of orthopedic surgery at Stanford University and editor in chief of The Spine Journal, began to hear about “frequent and occasionally catastrophic complications” associated with rhBMP-2 and Infuse. Yet industry-sponsored research reported virtually no serious complications. Carragee was suspicious. He said, “Their results were simply too good. Medtronic said thirteen published RCTs [randomized controlled trials] involving eight-hundred-plus patients showed there were no ‘BMP-2 related’ complications despite using the potent growth factor at approximately one million times the normal concentration” in humans.301

  As an editor, Carragee knew plenty about scientific literature becoming distorted when industry-supported authors downplay harms of medical devices and drugs by submitting only positive results for publication. And he knew something about conflicts of interest. The sums the authors were raking in from Medtronic were simply stupendous. “It was more money than anything we’d seen before,” he said, citing payments of more than $23 million paid to one author and $6 million paid to a handful of doctors who coauthored articles about the device while failing to mention the known dangers.302 A 2013 Senate investigation would find that Medtronic paid a total of approximately $210 million to physician authors who failed to report adverse events.303 And doctors were paid kickbacks to implant the device: one consulting agreement showed that spine doctors would be paid $4,000 a day for “services performed.”304

  Determined to understand the divergent claims about the safety of the device, Carragee and his colleagues at Stanford launched their own study. They analyzed safety and efficacy data reported in the thirteen original industry-sponsored studies, then compared those results with data they obtained from the FDA. The Spine Journal published the results in 2011: at a minimum, with greater than 99 percent statistical confidence, the risk of harms associated with Infuse were ten to fifty times higher than what was stated in the Medtronic-sponsored peer-reviewed publications.290

  For his efforts, Carragee was rewarded in 2013 with a two-year barrage of attacks led by the device entrepreneur and industry consultant Robin R. Young, who sought to have Carragee removed as editor of The Spine Journal. Young, who is not a physician, charged that Carragee was failing readers of the journal because “he has abandoned even the pretense of impartiality,” and he alleged that Carragee “accuses researchers of financial bias where none, in fact exists.” Young had a pulpit from which to preach: he is also the publisher of Orthopedics This Week, an industry publication, and in it, he published his editorial under the headline CARRAGEE MUST RESIGN, written in all-capital letters and set in a massive font.305

  But Carragee, a former lieutenant colonel in the Army Reserve Medical Corps who was seriously wounded in Iraq, is not someone to blink under fire. His research on the device had been vetted by peer reviewers, including the dean of Stanford’s medical school. Carragee says, “I was a tenured professor at Stanford, and I wasn’t worried about my job.” Instead he was worried that patients were being harmed and that his profession was being sullied by what he called “Elmer Gantry–style revival meetings” where rhBMP-2 and Infuse were promoted by individuals on Medtronic’s payroll, writing, “Ten years after BMP-2’s introduction, we cannot identify a single well-proven area of benefit, but we know it can kill you in the cervical spine and probably can promote cancer, which can then kill you.”305

  Despite reports of adverse events long known to the company, Medtronic was not to be deterred. Even though off-label use of Infuse was increasingly common, Medtronic anticipated even more sales if it could legally and openly promote the device for use in the neck. The company was upbeat about the possibilities and told its shareholders that Infuse would become the “standard of care in spinal fusion therapy.”306

  To win the right to legally promote additional uses, the company would have to first submit a study to the FDA showing that the device was safe and effective for each additional use. The company did undertake a study—however, the results were disastrous. But rather than report the bad outcomes, it kept mum.

  The whole matter only came to light more than a decade later, when three investigative reporters with the Minneapolis Star Tribune published a report in April of 2016 entitled “Question of Risk: Medtronic’s Lost Study.”306 As in the case of the VNS and other devices, the MAUDE database reflected only a small part of the problem. More than a thousand injuries and deaths associated with rhBMP-2 from 2002 to 2007 had been dubbed commercial trade secrets and were not made public.229, 306

  The study had little (if any) scientific merit, though Medtronic said it employed the study design after consulting with someone at the FDA, but it declined to tell the Star Tribune who that someone was. The company had obtained the data by asking doctors for reports on roughly one out of every ten patients implanted with Infuse. After collecting reports on 3,600 patients, it had uncovered more than one thousand injuries and a handful of deaths. This was not good news for Medtronic. And it wasn’t likely to win a new approval from the FDA. Rather than present the entire data set, Medtronic presented a small subset of selected cases to the FDA, requesting broader approval for use. The FDA turned Medtronic down.306

  By 2011, several state attorneys general and the Senate finance committee had gotten wind of problems with the device and subpoenaed documents from Medtronic, requesting information on all associated adverse events. According to the Star Tribune reporters, “Medtronic handed over thousands of pages—but not the retrospective study, which the company says was misfiled in its archives.”

  The company shut down the study in the spring of 2008. At that time, there were only 261 adverse events reported in the FDA’s database. More than five years after the study was ended and long after the thirty-day reporting requirement was over, Medtronic approached the FDA about how to report the 1,024 adverse events it had collected years earlier. The FDA took no action against Medtronic for late reporting, even though the agency had previously sent warning letters in 2009 and 2011 to the company for failure to report adverse events. When the FDA released a three-sentence summary of the study in 2013, it blacked out the number of adverse events, redacted on behalf of Medtronic as a “corporate trade secret,”306 only releasing the total number after the Star Tribune criticized the agency’s suppression of important information.

  * * *

  Even industry insiders, who should be the most knowledgeable consumers of healthcare, can be victimized by the careless use of devices for off-label purposes.

  Medtronic executive Kimberly Pickett started out as a sales representative at the company in 2005. She had been pre-med, has an outgoing personality, and is attractive—a combination prized by companies that use representatives to sell devices to doctors. Representatives are given expense accounts and encouraged to schmooze doctors. They take them out for meals, tell them about their companies’ products, set up educational meetings, and cultivate doctors they designate as key opinion leaders (KOLs).

  Pickett started out in the gastrointestinal division of Medtronic, but by 2007 she had moved over to the prestigious cardiovascular group, where she would specialize in artificial heart valves and other implanted cardiovascular devices. When she began her training, she says, “I got about twelve binders dropped at my front door.” The huge binders from Medtronic contained vast amounts of data and information. She was expected to learn every aspect of cardiac anatomy and function as well as the pressure gradients within the heart and the great vessels. She also had to learn every detail about the devices she would sell: what conditions they treated, how they were constructed, which FDA regulations governed each device, and which surgical approaches were right for each device.

  Pickett loved her job. She had a strong anatomy background from her years in pre-med, and those twelve fat binders were just
one part of a bigger challenge she thrived on. The company sent her to a lab to perform valve surgery on dead pig hearts—and, once, on a live pig. She recalls, “That one was hard for me because I’m an animal lover, but they treated the pigs very humanely.…As far as I know, he [the pig] is still alive today.”

  Because surgeons often deal with devices from several companies, and because each device can require a different approach, surgeons often want a manufacturer’s representative in the OR with them. Eventually Pickett was flying across the country and spending up to four or five hours per case in operating rooms at the “head of the table” with cardiothoracic surgeons as she guided them through the details of implanting Medtronic’s artificial heart valves.

  Pickett was a hard worker and was good at what she did. So good that she rose through the ranks with surprising speed. By the time she was thirty-seven, she had been promoted to an executive position as Medtronic’s director of strategic sales for the cardiac and vascular group. She was responsible for multimillion-dollar accounts with hospitals in California and Arizona. Her salary and compensation package put her income on par with that of a typical cardiologist.

  Not only was she thriving in her profession, she also truly believed in what she was doing. Medtronic’s heart valves were FDA-approved and had extensive long-term data to support their safety and efficacy. No question that those heart valves saved lives.

  Pickett was also a company loyalist. Once, she participated in a go-kart race at a company team-building event during which a colleague tried to pass her and snagged her rear wheel, causing her vehicle to slam into the racetrack wall. It was a hard impact, and her head snapped back, causing immediate pain in her neck. Despite her pain, she returned to work right away. She was not one to take sick time. Nor did she want to make waves, so she didn’t ask her manager to file an incident report, which was required but which he neglected to do.