Lena Groeger, ProPublica: May 3, 2012

Each prescription drug you take has a unique code that the government can use to track problems. But artificial hips and pacemakers? They are implanted without identification, along with many other medical devices. In fact, the FDA doesn’t know how many devices are implanted into patients each year – it simply doesn’t track that data.

The past decade has seen numerous high profile cases of malfunctioning medical devices, which have led to injury or even death. Critics say the FDA’s minimal monitoring of devices contributes to these problems.

“If you’re lucky, you might find a sticker on the operating room note that was left over from the product,” said Richard Platt, who runs the Harvard Pilgrim Health Care Institute. Otherwise, there is little way of knowing what device was used.

Right now, the FDA depends mostly on voluntary reports from doctors, patients, manufacturers and hospitals to notify them of problems with devices already on the market. The agency does have some power to require manufacturers to conduct further studies or track a particular device once it is sold. But many devices don’t get that level of surveillance.

“It’s much like a patchwork of streams of information getting to the FDA,” said cardiologist Frederic Resnic of Brigham and Women’s Hospital, who has worked with the FDA on medical device safety monitoring. “The FDA is relying on anecdotal and very variable information about the safety of medical devices.”

If manufacturers get word from a doctor or hospital about a death or injury that occurred as a result of their product, they are legally obligated to investigate the event and report it to the FDA. But the process isn’t straightforward, as has become clear in the recent controversy over the malfunctioning St. Jude’s Riata defibrillator leads (wires that connect a defibrillator to the heart). The FDA said an individual doctor’s report helped alert them to the problem, but it was months before the device was recalled.

According to attorney William Vodra, a regulatory law expert and member of the Institute of Medicine panel that published a report on medical device safety last year, the number of doctors who actually contact manufacturers is small.

And after being notified of patient harm, manufacturers can minimize their own responsibility if they point the blame elsewhere, said health policy expert Diana Zuckerman, president of the National Research Center for Women & Families.

For example, if someone dies from complications in a surgery to remove an implant, the manufacturer may argue that it was the surgery – not the implant – that killed the patient.

“You have a system that is not rigorous, the standards are not always understood, and they are interpreted differently by different people,” Zuckerman said.

The FDA responds to the criticism by pointing out that while every medical device carries a potential risk, the vast majority of devices perform well and improve patient health. An FDA spokeswoman emphasized that the agency must evaluate thousands of medical devices each year, and is constantly looking for ways to better and more quickly identify problems.

While the FDA makes the adverse event reports publically available in a searchable database, it doesn’t have a standardized system for reviewing reports once they are sent in, said Vodra, the attorney. A disclaimer on the site specifically states that the data is “not intended to be used either to evaluate rates of adverse events or to compare adverse event occurrence rates across devices.”

“What you would normally consider the simplest kind of data analysis is not done,” said Zuckerman. Often, doctors catch a malfunctioning device before the FDA ever notices.

In one case, a group of Pennsylvania doctors noticed that several patients were showing severe complications a few years after getting an IVC filter – a device designed to capture blood clots. Bits of the filter were breaking off, causing chest pain and a dangerous build-up of fluid and pressure around the heart. In 2010 the doctors conducted their own study and found that the filter broke in a quarter of all patients who used it.

On the day that study was published, the FDA issued a warning saying it had received over 900 reports of problems with IVC filters since 2006, and that the device was meant to be removed after a few months, not left in permanently.

There have been numerous attempts at reform. Five years ago Congress ordered the FDA to set up a post-market surveillance system to track the safety of all medical projects, but a system hasn’t yet been set up for medical devices.

A year later the FDA announced the Sentinel Initiative, which would combine existing data from electronic health records and medicalclaims to track drugs, vaccines, and devices. Some groups of hospitals or other organizations have voluntarily set up registries to collect information about the make and model of devices.

While the FDA has made significant progress on tracking drugs, it’s not yet in a position to do the same thing for devices, according to Harvard’s Platt, who is the principal investigator of Mini-Sentinel, the FDA’s pilot program for the national system. The data isn’t there.

The FDA has long acknowledged the need for a unique device identifier system, and got permission from Congress to set one up five years ago. No such system of ID-tags exists yet, but after several recent high profile medical device failures, the issue getting some attention from Congress. A proposed Senate bill, which cleared the Health, Education, Labor and Pensions Committee last week, sets a timeframe for implementing a unique identification system, among other reforms.

“If UDI’s were used in a consistent way, we could use the same kinds of techniques we’ve developed for drugs for devices,” said Platt. “It would be a huge breakthrough.”

Rob Stein, Washington Post: November 19, 2011

The Obama administration revoked approval on Friday of the top-selling cancer drug Avastin for treating advanced breast cancer, despite appeals from distraught women, some patient advocates and the company that makes the drug.

Food and Drug Administration Commissioner Margaret A. Hamburg issued a 69-page decision that said a review had clearly shown the drug was harming women more than it was helping them. Studies have found that Avastin can increase the risk of dangerous bleeding, heart attacks and other problems.

“Sometimes, despite the hopes of investigators, patients, industry and even the FDA itself, the results of rigorous testing can be disappointing,” Hamburg said. “This is the case with Avastin when used for the treatment of metastatic breast cancer.”

While medical advances have reduced the death toll from breast cancer, the malignancy remains the most common cancer among women, and the decision leaves few last-ditch options for many of those fighting the most advanced form of the disease. As a result, the fate of the drug had sparked one of the more emotional and acrimonious debates in years over a medical treatment among patients, oncologists, women’s health advocates, health-care policymakers, politicians and the pharmaceutical industry.

Some patients likened the FDA decision to a death sentence. Advocates of quicker access to new treatments and critics fearing health-care rationing called it a prime example of government overstepping. But many leading researchers, public health analysts and even prominent breast cancer doctors and advocates praised the decision. They saw it as a crucial demonstration that careful examination of the scientific evidence trumped emotion and intense public pressure.

Despite the revocation, Avastin will remain available to treat other cancers, enabling doctors to prescribe it “off-label” for breast cancer patients. But several insurance companies have already stopped paying for the drug for breast cancer, and the decision will probably prompt more to follow. Avastin costs about $99,000 a year per patient. Breast cancer patients also will lose eligibility for a program sponsored by drugmaker Genentech that caps the annual cost at about $58,000 for women making less than $100,000 a year and helps cover insurance co-payments.

Medicare, however, will continue to pay for Avastin, at least for now, officials said. Genentech’s foundation also will help women who do not have insurance or whose insurance refuses to pay for it, and will refer women to other charitable groups that could help them, said company spokeswoman Charlotte Arnold.

“We are disappointed with this outcome. We remain committed to the many women with this incurable disease and will continue to provide help through our patient support programs to those who may be facing obstacles to receiving their treatment,” she said.

The decision was condemned by some patient advocacy groups.

“By not recognizing the fact that a subgroup of women with metastatic breast cancer respond well to Avastin, we have yet another tragic mistake by the FDA,” said Frank Burroughs, founder of the Abigail Alliance, which advocates for greater access to new treatments. “Because of FDA drug rejections like Avastin for breast cancer, the terribly slow FDA approval of lifesaving therapies and the FDA’s blocking of compassionate access, we are losing thousands of lives of cancer patients and others with serious life-threatening illnesses each year.”

‘I am stunned’

Individual patients also expressed outrage and despair.

“I am devastated,” said Patricia Howard, 66, of Summerfield, Fla., who pleaded with the FDA’s advisory committee to retain the approval. “I am stunned by the lack of compassion of the FDA for those of us who are successful on this drug. . . . Every time I sit in the infusion chair I worry if this will be my last infusion.”

In a statement, J. Leonard Lichtenfeld, deputy chief medical officer of the American Cancer Society, said he hoped that, at the very least, insurance companies would continue to pay for the drug for women “with metastatic breast cancer who are currently on the drug and who are showing a benefit from its use.”

Several major insurance companies contacted Friday said they were reviewing their positions on Avastin in light of the FDA’s revocation.

The decision was praised by many others, including several leading breast cancer advocacy groups and experts who said it was important for the agency to base its decisions on the results of careful clinical studies, not emotional appeals, especially when lives are at stake and controlling health-care costs is so crucial to the nation’s economy.

“We should be using our time and resources to find drugs that work. It is unfortunate that Avastin does not,” said Fran Visco, president of the National Breast Cancer Coalition, a patient advocacy group. “Marketing campaigns and appeals by the public devastated by breast cancer cannot change that. These women deserve drugs that well-designed research tells us will prolong their lives. Let’s focus our attention on making that happen.”

Among the costliest

The FDA is not supposed to acknowledge cost in drug approvals, and officials have stressed that the price was irrelevant. But coming amid a continuing national debate over President Obama’s health-care overhaul, the fight about Avastin has become entangled in the politically sensitive struggle over medical spending and effectiveness.

“The fact remains that thousands of women today depend on Avastin as a vital tool in their fight against breast cancer, and the FDA should not have taken that option off the table by rationing access,” said Sen. David Vitter (R-La.)

Avastin is among the costliest of a new generation of anti-cancer medications that appear to offer some patients perhaps a few extra months of life. It was the first drug designed to fight cancer using a new strategy – inhibiting blood flow to tumors – and was approved for treating several malignancies. Evidence is much clearer that the approach is effective for colon, lung, kidney and brain cancer.

Avastin for breast cancer has been controversial since its approval in 2008. Only one study found that the drug appeared to slow the growth of an advanced breast tumor, delaying progression by about 5¹ / ₂ months. It remained unclear whether patients lived longer or enjoyed a better quality of life. So the FDA authorized Avastin under a special program designed to make advances in treatment available to patients quickly. The deal was that Genentech must validate the risk-benefit ratio with additional studies.

The agency moved in December to revoke the approval based on a July 2010 advisory committee conclusion that the new studies had not shown that the drug extends life and had indicated that it slowed tumor growth for far less time – perhaps as little as a month.

At the same time, the drug increased the risk for life-threatening bleeding and hemorrhaging, heart attacks, heart failure, severe high blood pressure and perforations in different parts of the body, including the nose, stomach and intestines.

Genentech immediately challenged that decision. That led the agency to convene a two-day meeting in June, which was marked by unusually tense exchanges between representatives of Genentech and agency officials. In the end, the six-member committee concluded that the drug was doing more harm than help.

New research vowed

On Friday, the company vowed to start a new study of Avastin in combination with another drug in metastatic breast cancer patients to “evaluate a potential biomarker that may help identify which people might derive a more substantial benefit from Avastin,” Arnold said.

Before the FDA announced initial plans to revoke Avastin’s approval for breast cancer, the drug was being prescribed annually to about 60 percent of the 29,000 U.S. women with breast cancer who were eligible. Globally, Avastin had annual sales of about $5.5 billion in 2010, making it the world’s best-selling cancer drug and one of the top-selling products for Genentech and Roche, its Swiss owner.

Genentech has waged an unprecedented campaign to keep U.S. approval of the drug for breast cancer. But as questions have been raised about its safety and effectiveness, sales and use of the drug have dropped significantly for breast cancer in the United States, falling to about 20 percent of eligible women, according to Genentech.

“The science is clear: Breast cancer patients are more likely to be harmed than helped by Avastin,” said Diana Zuckerman, president of the National Research Center for Women & Families. “The risks of the drug are very substantial and can be fatal, killing patients long before they would otherwise die from the disease. FDA made a scientific decision, and it was absolutely the right decision.”

Staff writer N.C. Aizenman contributed to this report.

The government delivered a blow to some desperate patients Friday as it ruled the blockbuster drug Avastin should no longer be used to treat advanced breast cancer.

Avastin is hailed for treating colon cancer and certain other malignancies. But the Food and Drug Administration said it appeared to be a false hope for breast cancer: Studies haven’t found that it helps those patients live longer or brings enough other benefit to outweigh its dangerous side effects.

“I did not come to this decision lightly,” said the FDA’s commissioner, Dr. Margaret Hamburg. But she said, “Sometimes despite the hopes of investigators, patients, industry and even the FDA itself, the results of rigorous testing can be disappointing.”

Avastin remains on the market to treat certain colon, lung, kidney and brain cancers. Doctors are free to prescribe any marketed drug as they see fit. So even though the FDA formally revoked Avastin’s approval as a breast cancer treatment, women could still receive it — but their insurers may not pay for it. Some insurers already have quit in anticipation of FDA’s long-expected ruling.

However, “Medicare will continue to cover Avastin,” said Brian Cook, spokesman for the Centers for Medicare & Medicaid Services. The agency “will monitor the issue and evaluate coverage options as a result of action by the FDA but has no immediate plans to change coverage policies.”

Including infusion fees, a year’s treatment with Avastin can reach $100,000.

The ruling disappointed patients who believe Avastin is helping to curb their incurable cancer.

“It’s saved my life,” said a tearful Sue Boyce, 54, of Chicago. She’s taken Avastin in addition to chemotherapy since joining a research study in 2003. Her breast cancer eventually spread to her lungs, liver and brain, but Boyce says she is stable and faring well.

“So I’m hoping the insurance company will grandfather me in to continue taking it,” she said.

The Avastin saga began in 2008, when an initial study suggested the drug could delay tumor growth for a few months in women whose breast cancer had spread to other parts of the body. Over the objection of its own advisers and to the surprise of cancer groups, FDA gave Avastin conditional approval — it could be sold for such women while manufacturer Genentech tried to prove it really worked.

The problem: Ultimately, the tumor effect was even smaller than first thought. Across repeated studies, Avastin patients didn’t live longer or have a higher quality of life. Yet the drug causes some life-threatening risks, including severe high blood pressure, massive bleeding, heart attack or heart failure and tears in the stomach and intestines, the FDA concluded. In two public hearings — one last year and one this summer — FDA advisers urged the agency to revoke that approval.

“The science is clear: Breast cancer patients are more likely to be harmed than helped by Avastin,” said Diana Zuckerman of the National Research Center for Women and Families in Washington.

Genentech had argued the drug should remain available while it conducted more research to see if certain subsets of breast cancer patients might benefit, and some patients and their doctors had argued passionately for the drug.

“There certainly are patients who benefit tremendously,” said Boyce’s oncologist, Dr. Melody Cobleigh of Rush University Medical Center. “We’ll just be battling with the insurance companies.”

“For those not fortunate enough to be on Medicare or an insurance plan that covers it, it’s a death sentence,” Christi Turnage of Madison, Miss., said of the FDA’s decision. Her breast cancer had moved into her lungs before she began Avastin three years ago and the spreading stopped, but Turnage said her insurer is ending coverage and she will seek financial help from Genentech’s access program.

Hamburg said that she considered those arguments but that scientifically there are no clues yet to identify who those rare Avastin responders would be — putting a lot of people at risk in order for a few to get some as-yet-unknowable benefit. She urged Genentech to do that research, saying the FDA “absolutely” would reconsider if the company could find the right evidence.

Genentech, part of Swiss drugmaker Roche Group, pledged to begin that research.

“We are disappointed with the outcome,” said company chief medical officer Dr. Hal Barron. “We remain committed to the many women with this incurable disease and will continue to provide help through our patient support programs to those who may be facing obstacles to receiving their treatment in the United States.”

The breast cancer organization Susan G. Komen for the Cure said that it respected the FDA’s decision and that it was time for researchers to concentrate on finding so-called biomarkers that would tell which drug is right for which patient.

“Each type of cancer is very different from another in important ways, and in the end it’s no surprise that Avastin’s effectiveness may not be equivalent against all types of cancer,” said Dr. Neal Meropol of University Hospitals Case Medical Center in Cleveland, who has long used Avastin for colon cancer.

Associated Press writer Marley Seaman in New York contributed to this report.

Copyright © 2011 The Associated Press. All rights reserved.

Anna Yukhananov, Reuters: August 31, 2011

U.S. health regulators said they would consider setting up a registry that tracks safety problems with breast implants, after too many patients dropped out of company-funded studies.

But the U.S. Food and Drug Administration emphasized on Wednesday that silicone implants were safe and would stay on the market, despite calls for their removal by consumer groups.

Expert advisers who held a two-day meeting to discuss post-approval safety studies for silicone implants urged the FDA to establish a registry.

“We believe it’s a good idea to have a conversation about a breast implant registry. … (But) we believe implants are safe and effective and should remain on the market,” Dr William Maisel, deputy director of the FDA’s devices division, told reporters after the meeting.

In 2006 the FDA approved silicone gel-filled breast implants sold by Allergan and Johnson & Johnson’s Mentor unit on condition both companies follow 40,000 women for 10 years to look at safety issues, as well as extend smaller pre-approval studies.

So far, Allergan has collected preliminary two-year data for 60 percent of participants, while Mentor has collected three-year data for only 21 percent — well below the 65 percent the FDA said would be acceptable.

“It’s very inefficient to enroll 40,000 patients, and only get data on 400 on them (for rare symptoms). So having registries is a much more high-value approach,” said Jason Connor, a biostatistician on the advisory panel.

There were almost 400,000 breast enlargement or reconstruction procedures in the United States in 2010, according to the American Society of Plastic Surgeons. That includes silicone and saline implants.

In June, the FDA said the risks of breast implants are well understood, after looking at the companies’ results as well as reports of negative events and scientific literature. It said women who get silicone implants are likely to need additional surgery within 10 years.

The agency had banned silicone implants for most U.S. women in 1992 after some said the devices leaked and made them chronically ill.

The companies and FDA advisers said patients and their doctors may not have enough incentives to stay in the company-funded studies, especially if they have to fill out a 27-page questionnaire every year, or do expensive medical procedures such as MRIs that test if their implant has ruptured.

A registry, which would track any patient who has had a breast implant, can provide broader data, making it easier to identify any complications, such as rupturing of the device.

Panel members said women should be encouraged to enroll in the registry by linking participation to the warranty on their devices, or to their surgeons’ certification.

Maisel also said it was important to involve different groups, including advocacy groups and physicians, to make sure patients understand the benefits of sharing information about their implants.

“What we’ve heard over the last two days is that it takes a whole community,” Maisel said. “You can have the most well-meaning company, but if the patients don’t want to participate in the study, that’s out of their control.”

However, some groups said the agency was letting manufacturers, especially Mentor, off the hook.

“You can’t ignore the fact that Allergan has three times more patients participating than Mentor. You can’t not hold Mentor responsible for that,” said Diana Zuckerman, president of the National Research Center for Women & Families.

Officials Say They Will Work With Companies to Improve Follow-Up Rates