Crisis of trust in doctors, drug companies & the FDA

I heard this report on Marketplace Radio this evening, FDA works on transparency.

Here's the summary: "In the wake of growing conflict-of-interest criticism, the FDA today announced it will spell out how and why it grants waivers to outside experts and allows them to serve as FDA advisers. Hillary Wicai reports."

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This is a May 20th NYT article titled "Unease on Industry's Role in Hypertension Debate:"

The dinners promoting a new definition of high blood pressure illustrate connections — among the pharmaceutical industry, academic physicians and societies that formulate opinion — that can ultimately affect patient treatment. And the dispute within the society reflects a growing unease that industry money is influencing scientific discourse in medical societies and elsewhere.

At a recent speech before another society, the American College of Cardiology, its new president, Dr. Steven E. Nissen of the Cleveland Clinic, suggested that the medical profession had become addicted to industry money just as the nation was addicted to foreign oil.

After months of controversy within the American Society of Hypertension that included accusations of industry influence, the society's president, Dr. Thomas D. Giles, said yesterday that the group's leadership would be required to disclose more details about the money they receive from industry.

Dr. Giles said the organization had always maintained a firewall between its activities and industry funding. "We don't take money that has strings attached to it," Dr. Giles said, emphasizing that its industry grants are not earmarked for any specific purpose.

The added disclosure had been sought by a board member, Jean E. Sealey, a biochemist and a longtime blood pressure researcher affiliated with Weill Medical College of Cornell University, who was among those also involved in a leadership struggle within the organization.

Dr. Alderman, a professor of medicine and epidemiology at the Albert Einstein College of Medicine in the Bronx, is one of several doctors who withdrew from a group formed by the society to write the new blood pressure definition.

He complained that the definition was derived from a hodgepodge of opinions not supported by hard science, and also questioned whether the society of 1,600 could insulate itself from the drug company donations it used to operate.

Controlling blood pressure has long been a mainstay of the pharmaceutical industry. About 65 million Americans have high blood pressure under the current definition and they help fuel a $17 billion annual market in drugs for hypertension. But another 59 million people are on the borderline, and many doctors believe the new definition of hypertension could make drugs a standard treatment for many of them, drastically expanding the potential drug market.

Dr. Giles of Louisiana State University's medical school in New Orleans was the driving force behind the new definition. The work of the group that developed it was financed by $75,000 in unrestricted drug industry grants from Merck, Novartis and Sankyo, according to Susan Rood, a spokeswoman for the Society of Hypertension. Ms. Rood also confirmed that the dinners were financed by $700,000 in grants, also unrestricted, from the same companies. The new definition that resulted was written by some of the leading experts in blood pressure medicine.

Pre-hypertension has been considered a blood pressure reading of 120/80 to 139/89, according to guidelines developed by a National Institutes of Health panel, which first identified the pre-hypertension category in 2003. Currently, pre-hypertension is generally not treated with drugs.

The new definition proposes assigning some of the people with pre-hypertension to a new category called Stage 1 hypertension. Hypertension is currently defined as blood pressure readings of 140/90 and above.

Dr. Giles estimated that the proposed definition would move half of those whose blood pressure readings are currently considered pre-hypertension to the Stage 1 hypertension category.

That determination would be based not just on their blood pressure readings, but also on other risk factors.

The proposed definition makes no specific treatment recommendations. But some specialists who have read the proposed definition say it is a short step from labeling someone with high blood pressure to prescribing pills. And they predict that if the new definition is embraced, it will expand the use of medications.

Dr. Curt D. Furberg, a professor of public health science at Wake Forest University, who was among those who withdrew from the writing group, citing concerns that its work was not evidence-based, said, "The industry wants to sell drugs and to as many people as possible."

But Dr. Giles said it was possible that the use of medication could actually contract under the new definition, with some doctors recommending lifestyle modifications rather than medication. And he said industry money or influence did not play a role in the proposed definition, which he said reflected a concern that too many people with diagnoses of pre-hypertension ended up having strokes.

"I will tell you that if you've ever sat there and watched patients in the prime of life get a stroke or a heart attack, it's heart-wrenching," Dr. Giles said last week.

The recommendations by Dr. Giles and his group are considered influential in the evolving thinking over what constitutes high blood pressure. In addition, the discussion about whose blood pressure should be treated is also being driven by a new study that concluded that a drug called Atacand by AstraZeneca could reduce the risk that people with pre-hypertension will develop hypertension.

Treating pre-hypertension was among the topics at a meeting this week of the society at the New York Hilton. The meeting ends today.

The debate is in some ways similar to questions about changing thresholds for defining high cholesterol, diabetes and obesity — areas where accusations have been leveled in the past that the pharmaceutical industry has tried to exert influence.

"All of this has got the ring of seeming to be of great benefit to the pharmaceutical industry without clear evidence that it's going to be the same benefit to the public," Dr. Alderman said recently

In statements, spokeswomen for Merck and Novartis confirmed that their companies had helped finance the society's work, but said that they had no influence over the outcome of the new definition or the content of the dinner briefings held last fall in seven cities.

Sankyo did not return calls seeking comment.

Of the seven doctors who wrote the proposed new definition, six have said that they served as consultants and speakers for pharmaceutical companies that make blood pressure medications. The seventh is a consultant and stockholder in a company that markets a diagnostic method to measure damage to blood vessels.

Such industry affiliations are not unusual among prominent doctors at academic research centers. And for years, the American Society of Hypertension, known as ASH, has operated with industry support.

But some members of ASH have become vocal critics of the influence wielded by the drug industry, including the person who was next in line to become the society's president, Dr. Sealey, who has been embroiled in a longstanding dispute with the organization's current leadership over that and other issues.

"The truth of the matter is that we have many members who are leaders in our society who are making well into the six figures from their pharmaceutical-company-supported activities," Dr. Sealey, a research biochemist and physiologist, said in an interview two weeks ago.

But many members of the society have taken umbrage at suggestions that their work for drug makers affects their scientific independence.

"There are those who accuse us of being nothing more than shills of industry; a lot of us take pretty great offense at that," said Dr. Joseph L. Izzo, a professor of medicine at the University of Buffalo who was part of the group that developed the new definition. "We've basically devoted our careers to researching this disease and how to treat it."

Dr. Sealey's assertions had fueled dissension within the society and were among the reasons that a vote to block her presidency had been expected at yesterday's business meeting of the society.

Instead, an agreement was forged under which Dr. Sealey gave up her term as president and, according to written statements circulated among those attending the meeting, the organization's leadership agreed that its board would soon submit detailed financial disclosure forms, which Dr. Giles said had been in development for more than a year.

Dr. Giles said those disclosures would go beyond the affiliations that were currently disclosed and would require leaders of the group to state how much they received, in broad categories.

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Finally, from the AARP:
FDA Woes

The FDA's job is to protect the public from unsafe drugs, faulty medical devices and contaminated food. But many doctors, consumer groups and lawmakers worry that the FDA is becoming less effective.

Last September an advisory panel voted 8-1 to recommend that the Food and Drug Administration approve a new drug for diabetes even though the risk of heart attack and stroke doubled among patients in clinical trials. The only cardiovascular expert on the committee didn't attend the panel's meeting because he had performed work for the drug manufacturer. But then, so had the committee's chairman, who did attend and in fact ran the meeting.

Some of the nation's leading cardiologists were upset by the recommendation. Writing in the Journal of the American Medical Association a few weeks later, they called on the FDA to reject muraglitazar because Bristol-Myers Squibb and Merck, its manufacturers, had failed to provide an accurate measure of the medication's risk.

"I'm increasingly concerned that these panels have become unbalanced," says Steven Nissen, M.D., of Ohio's Cleveland Clinic, a co-author of the JAMA article and former chair of the FDA's cardiovascular drugs advisory panel. "We have to make certain we have a balance of experts, [including] people who deal with the complications and side effects."

"There's too much bias toward bringing new treatments to market," adds Art Levin, director of the Center for Medical Consumers in New York and the consumer representative on the FDA Drug Safety and Risk Management Advisory Committee.

The FDA regulates companies that account for 25 percent of the U.S. economy. Its job is to protect the public from unsafe drugs, faulty medical devices and contaminated food. But 100 years after the birth of this federal agency, many doctors, consumer groups and lawmakers worry that the FDA is becoming less effective in carrying out its mission.

The hazy relationship between the FDA's advisory committees, such as the one for the diabetes drug, and the companies the agency regulates is just one issue raising concerns about the effectiveness of the FDA, which is still considered the gold standard among food and drug regulators around the world. Two other issues are a reported backlog of more than 800 generics awaiting approval and what the FDA acknowledges is the lax monitoring of drugs after they are approved and on the market.

"A lot of people are nervous about what's in their medicine cabinet, and for good reason," says Sen. Chuck Grassley, R-Iowa, a leading agency critic on Capitol Hill. "[The FDA] has become too cozy with the industry it regulates ... That's not a recipe for full trust and faith among consumers."

Acting FDA Commissioner Andrew von Eschenbach, M.D., the director of the National Cancer Institute who has been nominated to head the FDA permanently, insists the agency is working to protect the public. "We are making a tremendous commitment to the whole area of drug safety," he told Congress in March.

Serious questions about conflicts of interest at the FDA arose in 2004 when the painkiller Vioxx was taken off the market because it increased the risk of heart attack and stroke. Concerned that similar drugs might pose the same risk, the FDA convened a special advisory committee to evaluate the evidence. The agency almost always follows the advice of advisory panels, whose members are usually drawn from prominent medical institutions outside the FDA. Critics say most of the outside advisory panels include scientists with ties to the firms whose products are under agency review.

Should This Drug Be Kept on the Market?
The FDA’s drug safety and arthritis drugs advisory committees met to consider whether Vioxx and two other drugs in its class were safe. At least 10 of 32 voting members had received fees, research funds or other benefits from Merck and Pfizer, the drugs’ manufacturers. Here’s the vote:
Vote of Full Committee Vote When Members With Conflicts of Interest Were Excluded
Vioxx 17 YES 15 NO 8 YES 14 NO
Bextra 17 YES 13 NO 8 YES 12 NO
Celebrex 31 YES 1 NO 21 YES 1 NO
Source: Gardiner Harris and Alex Berenson, “10 Voters on Panel Backing Pain Pills Had Industry Ties,” New York Times, Feb. 25, 2005.

The panel that analyzed Vioxx, Celebrex and Bextra voted in February 2005 to keep them on the market, even though Vioxx had already been pulled. Only later did the media report that nearly a third of panel members had ties to makers of the drugs. Had their votes been excluded, the drugs would not have gotten a positive vote.

An FDA spokesman says advisory panelists are screened to "carefully weigh any potential financial interest with the need for essential scientific expertise" to protect public health.

"One of the conundrums," says Carl Peck, former director of the FDA's Center for Drug Evaluation who now heads the Center for Drug Development Science in Washington, is that the scientists "who are capable of making an informed decision are the very ones who typically are called on by drug companies and FDA to advise." He argues that limiting advisers to those who've never had research or consulting agreements with drugmakers could reduce the pool of qualified experts.

But Eric Topol, M.D., of Ohio's Case Western Reserve University disagrees. He says it's "essential for the 'jurors' to have no conflicts. There are many people who would qualify who have absolutely no ties to industry."

After the Vioxx decision, the FDA pledged to tighten its review process by creating an internal Drug Safety Oversight Board. The group has come under fire for meeting in secret, but the FDA says information from the companies involved is confidential. Peter Gross, M.D., outgoing head of the FDA's drug safety advisory committee, has urged more transparency, with "public representatives" named to the board.

The FDA gets more than 20 percent of its $2 billion annual budget from industry user fees, which are paid by companies seeking the FDA's OK to market new products. The fees, which account for nearly half of the new-drug office's budget, were mandated by law in 1992 to speed up the approval process by enabling the FDA to hire more reviewers.

"That's the problem," says Nissen of the Cleveland Clinic. "It would be smarter if we funded the FDA through public dollars. In terms of our national budget, it's trivial."

"I understand the importance of bringing new medications to market," he says. "But I just want to make sure we've appropriately balanced risk with benefit."

Meanwhile, just under 3 percent of agency funds is devoted to monitoring drug side effects. The FDA recently reported that drugmakers failed to begin two-thirds of post-approval studies it had requested. The agency has hired a consulting firm to assess the problem.

"The greatest flaw in our post-marketing system," Peck says, "is that it's voluntary by physicians and patients. This needs to be fixed."

He adds, "Everything needs improving, all the time."

Merrill Goozner, author of The $800 Million Pill, directs the Integrity in Science Project at the Center for Science in the Public Interest, an advocacy group in Washington. Bulletin staff contributed to this report.