Heart Valve Rings Slip Through FDA Loophole

A riveting, two-part investigative report by The Chicago Tribune, about the $100 billion a year, medical device industry focuses on the annuloplasty ring, which is surgically inserted to repair damaged heart valves.

The Tribune reports: " If you have a faulty heart valve and decide to get it replaced, a surgeon will implant an artificial one that has undergone rigorous examination by the Food and Drug Administration. But if you choose the option recommended for most patients — repairing your valve with an annuloplasty ring — there are no such guarantees, even though both devices are permanently stitched into the heart and considered life-sustaining.

"That’s because, a decade ago, the FDA downgraded the regulatory class of the rings. Instead of being grouped with heart valves and implantable pacemakers, annuloplasty rings were put into a class with most catheters, sutures and hearing aids, which allows the medical device industry to gain approval for new rings without clinical studies."

FDA’s lax approval process for medical devices has shielded  surgeons and manufacturers who have made a killing from a lucrative business venture. FDA has even awarded the seal of approval years after the rings were implanted in patients while still in the experimental stage–without their knowledge or informed consent .

According to the Tribune analysis of FDA data on adverse events, annuloplasty rings have had more deaths associated with them during the past five years than any other device in their class.

Reporters, Jason Grotto and Deborah Shelton, discovered that a single FDA official rubber stamped a petition by the Advanced Medical Technology Association (AdvaMed), which represents medical device companies, allowing the invasive devices to make their way into the hearts of thousands of patients with virtually no scrutiny.

In an interview with the Tribune, FDA officials said the agency thoroughly vetted the 1997 petition in which AdvaMed argued that annuloplasty rings should be switched into Class II.  "Our expert team of engineers, statisticians and cardiac surgeons approved the petition after considerable analysis," said Dr. Bram Zuckerman, director of the agency’s division of cardiovascular devices. "We also did our own independent research and analysis and felt it was appropriate to reclassify the device."

Yet the Tribune found that the internal memo outlining the reasoning behind the agency’s decision lists a single reviewer: a hydrodynamics and acoustics engineer. What’s more, the memo — called a Reclassification Decision Making Document — consists entirely of paragraphs and charts lifted directly from the industry’s petition.

The agency could not produce any material for the Tribune detailing any independent review or analysis of the petition. 

The disturbing findings of this investigative report–in particular, FDA’s dereliction of duty and FDA officials’ outright lies–should prompt Congressional hearings. FDA officials are complicit in undermining public safety–thereby making a mockery of FDA’s mission, as reaffirmed in Congressional testimony by (then) FDA Commissioner, Andrew C. von Eschenbach , M.D, May 1, 2007:

"Ensuring the safety and effectiveness of medical products is a key focus of our commitment to protect and promote public health. FDA only approves new therapies if their benefits (lives saved, extended or enhanced) outweigh the risks they pose. Toward that end, FDA continually assesses its medical product safety programs."  

As the Tribune reporters correctly point out:

"The case of the annuloplasty rings also raises questions about the roles and responsibilities of doctors and hospitals, who stand between patients and the $100 billion medical device industry. For patients with valve disease, the stakes are high. To repair valves, their chests are opened, their hearts are stopped and the life-sustaining device is stitched into the valve while a heart-lung bypass machine keeps them alive."

Vera Hassner Sharav

THE CHICAGO TRIBUNE

Heart-valve rings slip through FDA loophole

Permanently implanted devices OK’d without clinical studies

May 22, 2011  By Jason Grotto and Deborah L. Shelton

If you have a faulty heart valve and decide to get it replaced, a surgeon will implant an artificial one that has undergone rigorous examination by the Food and Drug Administration.

But if you choose the option recommended for most patients — repairing your valve with an annuloplasty ring — there are no such guarantees, even though both devices are permanently stitched into the heart and considered life-sustaining.

That’s because, a decade ago, the FDA downgraded the regulatory class of the rings. Instead of being grouped with heart valves and implantable pacemakers, annuloplasty rings were put into a class with most catheters, sutures and hearing aids, which allows the medical device industry to gain approval for new rings without clinical studies.

"It’s absolutely ridiculous. How could something that is permanently implanted in the heart be regulated this way?" said Diana Zuckerman, president of the National Research Center for Women & Families, a think tank that has fought for stricter oversight of medical devices. "The first question is: Who petitioned this change and what financial interest did they have?"

http://articles.chicagotribune.com/images/pixel.gifThe answer, buried in federal records: the Advanced Medical Technology Association, or AdvaMed, which represents medical device companies.

A Tribune investigation found that the FDA rubber-stamped the group’s petition, allowing the invasive devices to make their way into the hearts of thousands of patients with virtually no scrutiny.

Today, annuloplasty rings have had more deaths associated with them during the past five years than any other device in their class, according to a Tribune analysis of FDA data on adverse events. Although there are many flaws in the way the FDA gathers its data and there is no way to tell if the deaths are directly related to the rings’ performance, the analysis raises questions about whether the agency erred in reclassifying the device.

The newspaper’s findings come amid a heated debate over the FDA’s regulation of the $100 billion-a-year medical device industry.

Despite reports of illnesses, injuries and deaths linked to faulty hip and knee implants, defibrillators, and other products, new devices continue to receive far less FDA scrutiny than new drugs, and patients often are left in the dark about safety issues. The Institute of Medicine is slated to release a study this summer about how devices like the rings are cleared for use, and the FDA is expected to rewrite some of its rules soon after.

http://articles.chicagotribune.com/images/pixel.gif Since annuloplasty rings were reclassified, companies have introduced dozens of new models that fetch higher average prices than older ones, without having to undergo the expense or time of clinical trials. By contrast, pharmaceutical companies must fund extensive research before new drugs are approved.

The regulatory change also paved the way for at least two models of the heart rings to be implanted in more than 700 patients without clearance from the agency. In fact, the FDA didn’t even know the rings existed.

Edwards Lifesciences, the California-based company that manufactured the devices, didn’t submit them to the FDA for clearance, later arguing it didn’t have to because the rings were slight tweaks of products that already had been cleared.

Yet the Tribune found that the company also filed patent applications for one of the rings, listing dozens of ways in which it was different than existing devices.

The agency ultimately decided that Edwards should have applied for clearance before selling them. But it did nothing to punish the company, which has seen its net income rise by 70 percent during the last three years to $218 million, according to filings with the U.S. Securities and Exchange Commission.

Edwards declined to comment on the newspaper’s findings, saying through a representative that the company "followed FDA’s guidance" when it sold the rings and resolved the issue "more than two years ago."

The rings are reclassified

When medical device laws were first put on the books in 1976, panels of medical experts placed every device on the market into one of three classes. Annuloplasty rings were in the highest-risk class, known as Class III, because "the device is implanted and life sustaining."

The FDA was supposed to write regulations outlining what manufacturers must do to gain premarket approval, or PMA, for each Class III device. In the meantime, Class III devices on the market before the laws were enacted could be sold through the less rigorous Class II process, known as 510k.

That had huge implications for manufacturers. Going through a PMA costs hundreds of thousands of dollars and can take years, but the 510k process can be completed in a few months and costs companies as little as a few thousand dollars.

 The FDA began writing PMA rules for that group of devices in 1995. As part of the process, manufacturers could petition the FDA to reclassify devices, which the agency had grouped with devices that were "not likely candidates for reclassification."

In an interview with the Tribune, FDA officials said the agency thoroughly vetted the 1997 petition in which AdvaMed argued that annuloplasty rings should be switched into Class II.

"Our expert team of engineers, statisticians and cardiac surgeons approved the petition after considerable analysis," said Dr. Bram Zuckerman, director of the agency’s division of cardiovascular devices. "We also did our own independent research and analysis and felt it was appropriate to reclassify the device."

Yet the Tribune found that the internal memo outlining the reasoning behind the agency’s decision lists a single reviewer: a hydrodynamics and acoustics engineer. What’s more, the memo — called a Reclassification Decision Making Document — consists entirely of paragraphs and charts lifted directly from the industry’s petition.

The agency could not produce any material for the Tribune detailing any independent review or analysis of the petition. Officials said it is rare for them to issue a reclassification decision document that is taken word-for-word from a petition but that they have done so "when the petition is well-written."

The FDA and AdvaMed say the agency was justified in reclassifying annuloplasty rings, regardless of how it happened. The petition cites numerous studies finding that the rings are safe and effective and argues that medical advances have mitigated the risks associated with implanting the devices.

But not one of the studies is a clinical trial involving patients from multiple institutions randomly assigned into test groups. And many of the authors are heart surgeons who invented medical devices for and receive royalties from manufacturers.

In concluding its argument, the medical device industry wrote: "If certain testing is made prerequisite to obtaining 510k clearance for annuloplasty rings, FDA is able to maintain regulatory control over specific aspects of the device. Thus, FDA is able to reasonably assure that the product that is ultimately marketed is safe and effective."

That conclusion, verbatim, is included in the FDA’s explanation of the reclassification of annuloplasty rings, which the agency announced in 2001.

Yet, less than three years later, at least two rings began to be implanted in the hearts of hundreds of people without the 510k clearance the agency said was necessary to provide safe and effective medical devices to taxpayers.

Years after surgery, patient gets a letter

During annuloplasty ring surgery, patients’ hearts are stopped and bypass machines keep them alive while their chests are cut open and incisions are made in their hearts to expose the tiny valves that the rings are then stitched around.

The rings, made of metal and coated in rubber and cloth, are meant to fix faulty mitral or tricuspid valves, which regulate blood flow to and from the lungs.

If the valves don’t work well, blood backs up into the chambers of the heart, which can lead to shortness of breath and, eventually, heart failure. The consensus among physicians is that repairing valves is preferable to replacing them, in part because it allows patients to avoid taking blood thinners for the rest of their lives.

The surgery was an ordeal Al Edwards, of Lincolnshire, dreaded. He had known about his regurgitating mitral valve since he was a teenager and had no symptoms. But the problem was getting worse as he grew older, and he had developed an irregular heartbeat that required surgery. So Edwards decided to have his valve repaired as well, hoping to avoid further surgery down the road.

Edwards, 61 at the time, chose to have the operation in February 2007 at Northwestern Memorial Hospital in large part because of Dr. Patrick McCarthy, a world-renowned heart surgeon there.

Two years after the surgery, Edwards received a letter from Northwestern’s CEO, Dean Harrison, addressing media reports that the ring inside Edwards, a model called the Myxo ETlogix, "was experimental and not cleared by the FDA for use." The reports, Harrison said, were wrong.

Unlike most patients, Edwards knew a thing or two about FDA regulations. He has a doctorate in pharmacy and spent two decades working on drug approvals, including three years with the FDA. He filed freedom of information requests with the FDA and soon discovered that the agency hadn’t cleared the device.

"I had to pick my jaw off the desk," he said. Although the ring he received apparently fixed his mitral valve, the fact that the FDA hadn’t cleared the device — or even known that it existed — left him feeling betrayed.

It turns out the Myxo wasn’t the only ring for which Edwards Lifesciences failed to get clearance. A second ring, called the IMR ETlogix, had been on the market since 2003 without the FDA’s knowledge.

Under the law, annuloplasty rings and other devices in Class II can gain FDA clearance if the manufacturer submits paperwork that declares the products are "substantially equivalent" to existing, approved devices.

But to spare the agency a flood of paperwork, the FDA also allows new devices to forgo the clearance process if they use the same labels, technology and materials as products that already have been cleared.

Edwards Lifesciences decided that the Myxo and IMR rings fell into this category, so it never sought clearance from the FDA.

Yet, at the same time, the company submitted a patent application to the U.S. Patent and Trademark Office for the Myxo — which McCarthy co-invented — listing 40 characteristics that made the ring distinct from others on the market.

"The present invention provides a novel annuloplasty ring for correcting pathologies associated with mitral valve prolapse," the patent reads.

According to the patent application, McCarthy’s invention was an improvement over other products because it would simplify the surgery needed to implant an annuloplasty ring. Use of the ring would make the surgery available to more patients, the application said.

The FDA says it does not review patent documents as part of its clearance process.

The IMR, meanwhile, was the only ring on the market made specifically to repair the mitral valves of patients who had experienced heart attacks.

In the end, the FDA found that Edwards Lifesciences erred when it failed to seek clearance for the devices because the shapes and materials were different than other rings on the market.

"They made changes to the devices that could impact the safety and effectiveness and, as a result, Edwards should have (sought clearance)," said Dr. Jeffrey Shuren, head of the FDA’s medical device branch, who also said that the agency is working on rules to clarify when manufacturers need to apply for clearance.

The FDA cleared both the IMR and the Myxo, which had been rebranded as the dETlogix, in April 2009 without any fines or even a warning letter. FDA officials said at the time that Edwards Lifesciences, one of the largest heart device companies in the world with a market capitalization of $6.7 billion, had "made an honest attempt" to go through the proper channels but misinterpreted the law.

A month afterward, Al Edwards received a second letter from Northwestern saying his Myxo ring had been cleared by the agency — two years after his surgery.

"It really boils down to your mother, your father, your son or daughter, and whether you would want them to go through this," he said. "My answer is no, I wouldn’t. I would want an approved device."

jgrotto@tribune.com

dshelton@tribune.com

 ~~~~~~~~~~~~~

 

Patients at heart of medical device issue

Recipients of life-saving products may not know of potential conflicts of interest when doctors put their own inventions to use

May 22, 2011|By Deborah L. Shelton and Jason Grotto, Tribune reporters

 Nancy Stone, Chicago Tribune

Antonitsa Vlahoulis knew as she slipped into unconsciousness on the operating room table that her surgeon would choose which medical device she would receive to fix her leaky heart valve.

But when a warranty card arrived in the mail for the device stitched into her heart, Vlahoulis got the first of several shocks.

The card referred to the device by its original name: the McCarthy Annuloplasty Ring. That’s when she realized that Dr. Patrick McCarthy, her surgeon at Northwestern Memorial Hospital, had invented it.

Vlahoulis, of Niles, said McCarthy had told her he would choose a ring from those listed in a booklet he gave her. She flipped through it, but this ring wasn’t there.

She checked the Food and Drug Administration’s website, looking for the ring on the agency’s list of approved devices. But she couldn’t find it. When she contacted the FDA to ask about it, she received a startling email in reply.

"Due to our confidentiality concerns we are unable to provide any information about a product until after it is approved," the public affairs specialist wrote.

"Oh my God," Vlahoulis remembers thinking. "I can’t believe this."

Patients in need of permanently implantable, life-sustaining medical devices may assume that the products have undergone rigorous clinical and regulatory scrutiny and that rules put in place to protect their rights are enforced to the letter of the law.

But that wasn’t the case at Northwestern and other hospitals where two different annuloplasty rings co-invented by McCarthy were sewn into the hearts of more than 700 patients to treat their valve diseases over a number of years though the FDA didn’t clear the rings until 2009.

The situation highlights the tangled web of interests patients face when they require medical devices not just at Northwestern but across the U.S., showing what can happen in a profitable industry with few controls and plenty of gray areas.

It’s especially true when doctors study their own inventions using data from their patients, who don’t always know of the potential conflicts of interest.

That’s what happened at Northwestern, and it’s a cautionary tale that centers on two questions: Were the rings experimental? And was McCarthy conducting clinical research on one of his inventions while receiving royalties or other payments from the manufacturer?

McCarthy is a world-class heart surgeon who has saved thousands of lives, improved the well-being of countless patients and made weighty contributions to the art and science of cardiac surgery. His recruitment to Northwestern from the Cleveland Clinic in 2004 was a coup, instantly making the hospital one of the nation’s premier cardiac centers.

In an interview, he said the rings’ manufacturer had told him they were cleared for use under FDA rules. The hospital received those same assurances, a spokeswoman said.

In fact, the company — California-based Edwards Lifesciences — had not submitted the rings to the agency for review. It would later argue, incorrectly, that doing so was not necessary under FDA regulations.

McCarthy, who does about 150 valve surgeries a year, said that at the time he had no knowledge of the rules governing medical devices and that he relies on industry and the FDA to ensure the ones he uses are safe and effective.

http://articles.chicagotribune.com/images/pixel.gif"There are no guideposts for us," he said. "You don’t learn about this stuff in med school."

He also said he had stopped telling patients some of the heart rings he uses were his inventions because most didn’t seem interested in such details.

The controversy over the device Vlahoulis received triggered an FDA investigation that found Edwards should have sought FDA clearance before allowing surgeons to use two of its annuloplasty rings. But the agency took no action against the company, saying it had "made a good faith effort" to follow the law, and soon allowed the devices back on the market.

"Essentially, what happened here is that they bypassed the federal regulatory system in its entirety," said Vera Hassner Sharav, president of the Alliance for Human Research Protection, an education and advocacy group. "The fact that FDA gives the rings a stamp of approval after all of this only compounds the problems."

$100 billion industry

The case of the annuloplasty rings also raises questions about the roles and responsibilities of doctors and hospitals, who stand between patients and the $100 billion medical device industry.

For patients with valve disease, the stakes are high. To repair valves, their chests are opened, their hearts are stopped and the life-sustaining device is stitched into the valve while a heart-lung bypass machine keeps them alive.

Vlahoulis said she hunted for information about her ring because she had complications following her April 2006 surgery. What she discovered did not set her mind at ease.

She told her cardiologist, Dr. Nalini Rajamannan, that she had not consented to receive an experimental, or "investigational," device or to be part of a study about the ring.

As co-author with McCarthy on a study of the ring — renamed the Myxo ETlogix — Rajamannan thought the device was experimental and that patients had given consent to receive it.

She said she immediately paged McCarthy to tell him that patients didn’t know they had gotten an experimental device — or that they were part of his research on the ring. She also contacted hospital and Northwestern University officials, according to documents she provided to the Tribune. The university oversees research at Northwestern that involves human subjects.

Rajamannan urged the hospital and university to investigate, but they told her Edwards Lifesciences had assured them the ring did not need clearance because it was a minor modification of an existing device.

"Neither Dr. McCarthy nor Northwestern Memorial Hospital has any motivation to do anything other than what is in the best interest of its patients, required to ensure patient safety and is required by the law," spokeswoman Holli Salls said last week.

With patients still getting the ring, an alarmed Rajamannan contacted the FDA in July 2008.

After carrying out its investigation, the FDA told Edwards Lifesciences officials that fall that the company should have sought FDA clearance because the ring’s shape and material made it different from other rings on the market. The company voluntarily recalled the ring and applied for clearance.

Edwards Lifesciences officials declined to be interviewed but said in a statement: "Edwards followed FDA’s guidance relative to our (Myxo) annuloplasty ring and Edwards addressed the requests from FDA and resolved them more than two years ago."

In January 2009, Northwestern hospital’s president and CEO, Dean Harrison, sent a letter to Vlahoulis and other patients who had received the Myxo ring. It stated that "we do not consider this device to be experimental."

The hospital said Harrison’s information was based on an email received from Edwards Lifesciences in August 2007, after the devices had been implanted, saying the Myxo "is not an investigational device."

Yet according to the FDA, between the time the Myxo ring first was being implanted and the time it was cleared, about three years, it was an investigational device.

"If a device is supposed to get cleared by the agency first before you’re marketing it, we consider that investigational," Dr. Jeffrey Shuren, head of the FDA’s medical device branch, told the Tribune.

The Myxo was cleared in April 2009 under yet another name, the dETlogix, along with another Edwards ring used at Northwestern and other hospitals, the IMR ETlogix.

In May, Harrison wrote a second letter to patients, saying the agency had cleared the ring. What patients wouldn’t know from reading his letter is that the FDA considered the device investigational when many of them had it stitched into their hearts.

‘Green-colored glasses’

In 2009, Sen. Richard Lugar, R-Ind., asked the FDA in a letter whether the agency had reviewed any data on the Myxo ring before clearing it.

The agency pointed to a 2008 study submitted by Edwards Lifesciences that compared the Myxo’s performance with that of another ring. The author? McCarthy. It was the same study he had been working on with Rajamannan before she withdrew as co-author.

Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania, said such an arrangement presents a conflict of interest for the physician doing the research.

"You should never, ever be studying what you own, what you have royalties from, what you have patents on," Caplan said. "You need to have independent assessment because of the obvious risk that you’ll see things with green-colored glasses."

McCarthy receives royalties on his inventions through the Cleveland Clinic, where he worked when he co-invented the Myxo and the IMR, though he says he donates that money to the Greater Chicago Food Depository.

McCarthy said he was not researching the rings when he implanted them in patients. He was treating their valve disease using his invention and then reviewing the outcomes.

"We were not conducting research; we were treating patients," McCarthy said. "It was not part of a research study. If from the start we had been told the ring was investigational, we would have followed the clinical trial pathway."

Soon, medical device companies may be required to disclose more information about payments they make to doctors. The Physician Payments Sunshine Act was passed last year, and Congress, the FDA and the industry are wrangling over how to implement it.

Some of McCarthy’s patients also say they did not know data from their surgeries would be used in a study comparing two annuloplasty rings. The need for informed consent is one of the most important rules put in place to protect the rights of patients and shield them from conflicts of interest in medicine that could pose risks.

McCarthy said patients gave permission to use their data when they signed forms agreeing to be included in a cardiac patient database. But Vlahoulis said no one told her the information would be part of a study evaluating the ring.

In the wake of the Myxo controversy, Northwestern hospital said it now informs patients in writing if doctors receive royalties for devices they invent. The hospital also convened a medical device committee to confirm that the FDA has cleared devices before they are used. However, the panel relies solely on information received from manufacturers without checking with the FDA.