Normally, Charles Rosen embraces scientific advances in back surgery. But the university-based spine surgeon can't imagine using one now being promoted by Johnson & Johnson ( JNJ). The company's Charite artificial discs last year became the first to hit the American market, offering a long-awaited alternative to complex spinal fusion surgery. Rosen, recently filmed by PBS performing another new procedure, likes to provide his patients with cutting-edge services. So he set out to learn about the treatment. Specifically, he wanted to know if the discs could safely reduce chronic back pain while, unlike typical surgery, preserving motion. Charite backers say the new discs do just that and therefore offer the "potential to revolutionize spine surgery." But Rosen says he found that the devices have regularly failed in Europe, leaving patients with life-threatening complications. He says he finds it "unbelievable" that the Food and Drug Administration ever approved the devices. "Any prudent person, who does not have a financial conflict or industry tie, would reasonably conclude that their safety and effectiveness has not been proven by the FDA," says Rosen, an associate clinical professor of spine surgery at the University of California at Irvine. "These artificial disc replacements should be recalled by the FDA to protect the American public." For its part, Johnson & Johnson portrays the implants as "the best solution for the appropriate patients" while stressing that "patient selection is key." In any case, banning the implants could hurt Johnson & Johnson and its competitors, who see the market as a lucrative growth opportunity. Within years, some experts believe, the market for spinal discs could top $1 billion. Goldman Sachs analyst Lawrence Keusch says that Johnson & Johnson itself hopes to rake in $150 million on its brand-new spinal offering in 2005 alone. Meanwhile, companies like Medtronic ( MDT) and Stryker ( SYK) are busy designing artificial discs of their own. In this last of five articles exploring potential conflicts of interest in the drug and medical device business, TheStreet.com examines how a potentially lucrative treatment can reach the market even as questions linger about its safety and effectiveness.
Failed OperationTo win over the FDA, Johnson & Johnson set out to establish that Charite discs work at least as well as Bagby and Kuslich, or BAK, cages used in spinal fusions. But Rosen saw an immediate problem with the study design. "The stand-alone BAK is a failed operation; it hasn't been done in years," Rosen says. "So they picked the worst possible operation to compare these things to." Sarah Colamarino, a spokeswoman for the DePuy Spine unit of Johnson & Johnson, says the BAK was "the standard treatment for single-level degenerative disc disease" at the time the study began. Regardless, Rosen claims the company still failed to prove its case. An FDA transcript shows that the agency's own statistician portrayed the study as "strongly biased" in favor of Charite. The statistician also noted that the company had excluded important data about patients involved in the randomized clinical trials. Rosen, for one, wants to know exactly what happened to the first 71 patients who underwent disc replacements during the "training" part of the study. After formally requesting that information -- and being stonewalled -- he has yet to learn much beyond what surfaced during last year's FDA hearing. "It should be noted that the rate of adverse events was higher in the training subjects group compared to the randomized subjects in the study," Serio del Castillo, one of the FDA's lead reviewers for the disc, said during the hearing process. "However, please note that the training subjects were not included in the assessment of safety." Instead, Rosen says, Johnson & Johnson ignored the first patients who underwent the surgery -- a full 25% of the group -- and simply counted the later cases instead. Ranjan Gupta, an award-winning medical researcher who has landed major grants from the National Institutes of Health, sees reason for concern.
"Any time you do a study, there are certain data that are considered outliers," Gupta acknowledges. "However -- and this is a big 'however' -- in almost all good studies, that is a very small percentage of the total sample size. ... Whenever a significant percentage is excluded, for any reason, it leaves a reviewer skeptical of the data analysis." Colamarino says those patients spent more time in the operating room, lost slightly more blood and suffered a higher rate of adverse events than other participants in the study. However, she says, they actually had better clinical outcomes than the other patients based on two measures. She also stresses that Johnson & Johnson supplied the FDA with safety data on the training patients during the approval process. Still, Brent Blumenstein -- a voting member of the FDA advisory panel -- specifically complained about omitted patients during the Charite hearing. "The sponsor's definition of the ITT (intent-to-treat) population ... is incorrect because it deletes randomized patients," Blumenstein said. "To modify the definition of ITT or analysis by arm by deleting patients is tantamount to saying someone is only partly dead." Like the rest of the panel members, Blumenstein nevertheless went on to vote for approval of the device anyway.
Warning BellsThe panel's decision came despite grave warnings from orthopedic surgeons in the field. Granted, the first -- John Peloza -- was working as a consultant for Johnson & Johnson competitor Medtronic. But his concerns would later be amplified by testimony from a European surgeon who, while flown in for the FDA hearing by Medtronic as well, has studied the Charite discs extensively and implanted many of them himself. Most importantly, Peloza stressed, the discs should last a lifetime in the fairly young patients who would be seeking them.
"Revision surgery to remove the implant ... will be potentially life-threatening in every case," he explained. "And at present, there is no consistently successful strategy to deal with a failed implant." Thus, he said, the implants -- studied for just two years in the U.S. -- should be designed to last four decades. But Paul McAfee, a Johnson & Johnson consultant with a financial interest in the discs, indicated that he would be satisfied with far less. "Well, I hope they will last 40 years," McAfee said during the hearing. But "honestly, to talk to the patients, 10 years is (a) pretty good outcome." McAfee then went on to undermine one of the central arguments favoring implants over traditional -- and highly successful -- spinal fusions. Fans of the device say that it preserves motion and, in turn, reduces wear on nearby parts of the spine. But McAfee confessed that he "cannot find a single study on any motion-preserving device" that proves this theory. Meanwhile, Andre van Ooij -- a Danish surgeon who has tracked hundreds of the operations in Europe -- later offered evidence about the implant's drawbacks. He noted "retrograde ejaculation and erectile dysfunction" in men. He also cited leg complications in others and pointed to joint degeneration as an especially big problem. "All of these patients have really terrible leg and back pain," said van Ooij. And "revision is dangerous and sometimes impossible." Van Ooij went on to cite a 17-year study showing that more than half of Charite recipients wound up with fair or poor results. Moreover, he said, spinal fusion -- which could have been employed in the first place -- rarely offers relief to failed patients down the road. "There was a fusion done, and this is the only one of the re-operations (among those studied) that the patient is satisfied" with, he said. "So I really would stress that it is not a good solution for the problem" in the end.
European ExperienceIronically, fans of Charite kept pointing to the European experience as proof of the disc's success. They also suggested that data from Europe -- where Charites have been on the market for 17 years -- reduced the need for extended clinical trials in the U.S. But many who participated in last year's hearing, including the FDA's own expert engineer, expressed concern about the length of the U.S. study. They indicated that many complications would not even surface until well after the study had ended. "I think that we have already all pretty much agreed that two years is probably not a safe length of time to follow these patients," said Maureen Finnegan, a voting member of the advisory panel with financial ties to the industry. "So I do think that there needs to be a long-term follow-up." In the end, however, the panel unanimously recommended approval of the devices with some conditions attached. Specifically, the group called for continued monitoring of trial participants and specialized training for surgeons who will be performing the procedures. During the FDA hearing process, the so-called Spine Arthroplasty Society had already promised to help with the latter. "Until I read this transcript, I had never heard of this society," Rosen says. "Given that I am a university spine surgeon, one would think I might even be invited to join or participate." Rosen marvels that such a society -- dedicated to a brand-new procedure in the U.S. market -- already exists in the first place. However, industry critics have long claimed that some professional and consumer advocacy groups are, in fact, little more than fronts for the big health care companies themselves. The SAS Web site, which discloses nothing about the society's funding, almost exclusively promotes the new artificial discs.
Of course, Johnson & Johnson itself has been busy marketing its new offering as well. The company is currently targeting orthopedic surgeons, including Rosen, with offers of specialized training courses. As soon as the implants won FDA approval, in fact, the company was already pledging to intensively train orthopedic surgeons -- at sites all over the country -- so that they could begin doing the new operations as soon as possible. But Rosen, for one, will not be among them. "I think there are going to be thousands and thousands of people who suffer failures and wind up in chronic pain with no solution for it," he says. "I don't know how anyone, in good conscience, could put these things in knowing the past history and the potential for so many failures. ... It's just money over everything else, and it's just cruel."