from: http://mercola.com/2000/oct/1/fda_drug_approvals.htm

FDA Advisers Tied to Industry

More than half of the experts hired to advise the government on the safety and effectiveness of medicine have financial relationships with the pharmaceutical companies that will be helped or hurt by their decisions, a USA TODAY study found.

These experts are hired to advise the Food and Drug Administration on which medicines should be approved for sale, what the warning labels should say and how studies of drugs should be designed.

The experts are supposed to be independent, but USA TODAY found that 54% of the time, they have a direct financial interest in the drug or topic they are asked to evaluate. These conflicts include helping a pharmaceutical company develop a medicine, then serving on an FDA advisory committee that judges the drug.

The conflicts typically include stock ownership, consulting fees or research grants.

Federal law generally prohibits the FDA from using experts with financial conflicts of interest, but the FDA has waived the restriction more than 800 times since 1998.

These pharmaceutical experts, about 300 on 18 advisory committees, make decisions that affect the health of millions of Americans and billions of dollars in drugs sales. With few exceptions, the FDA follows the committees' advice.

The FDA reveals when financial conflicts exist, but it has kept details secret since 1992, so it is not possible to determine the amount of money or the drug company involved.

A USA TODAY analysis of financial conflicts at 159 FDA advisory committee meetings from Jan. 1, 1998, through last June 30 found:

At 92% of the meetings, at least one member had a financial conflict of interest.

At 55% of meetings, half or more of the FDA advisers had conflicts of interest.

Conflicts were most frequent at the 57 meetings when broader issues were discussed: 92% of members had conflicts.

At the 102 meetings dealing with the fate of a specific drug, 33% of the experts had a financial conflict.

"The best experts for the FDA are often the best experts to consult with industry," says FDA senior associate commissioner Linda Suydam, who is in charge of waiving conflict-of-interest restrictions.

But Larry Sasich of Public Citizen , an advocacy group, says, "The industry has more influence on the process than people realize."

Number of drug experts available is limited

By Dennis Cauchon, USA TODAY

In October, pharmaceutical giant Johnson & Johnson sent a team of executives to a Holiday Inn ballroom in Silver Spring, Md.

Their job: persuade the Food and Drug Administration's panel of independent experts that an expensive antibiotic, Levaquin, should be the first drug approved to treat penicillin-resistant pneumonia.

For Johnson & Johnson executives, the FDA's Anti-Infective Drug Advisory Committee included some familiar faces. At least two of the experts were paid consultants to the drug company and had worked on the very same medicine that they were being asked to evaluate for approval in an important new market.

The expert panel's "consumer representative," whose assignment is to defend consumers' interests, had the most extensive financial relationship with Johnson & Johnson. Keith Rodvold, a pharmacy professor at the University of Illinois-Chicago, serves on a company anti-infective drug advisory board, according to Johnson & Johnson spokesman Marc Monseau. Rodvold advised the company on how to design and analyze the clinical trials that got the drug approved. In 1999, he designed a study to measure how Levaquin is absorbed in the lungs. The company also uses him regularly as an consultant on a variety of issues, Monseau says.

Rodvold declined to discuss his relationship with Johnson & Johnson and his work on Levaquin. The company declined to say how much Rodvold had been paid during the five years he has consulted for it.

The case of Levaquin reveals how deeply pharmaceutical industry money and influence penetrates the drug approval process. FDA advisory committees consist almost entirely of pharmaceutical industry consultants and researchers. Even consumers' and patients' representatives on the committees often receive drug company money.

At least one committee member had a financial stake in the topic under review at 146 of 159 FDA advisory committee meetings, according to a USA TODAY study of advisory committee meetings held from Jan. 1, 1998, through June 30, 2000. At 88 of those meetings, at least half the advisory committee members had financial interests in the topic being evaluated.

Powerful panels

Eighteen FDA advisory committees play a crucial role in nearly every major decision on drug regulation. They help decide what drugs should be approved and how the pharmaceutical industry should be regulated. In recent years, the FDA has followed every advisory committee recommendation to approve or reject a medicine - except once, FDA spokeswoman Susan Cruzan says. (The FDA approved the flu drug Relenza in July 1999 despite an advisory committee voting 13-4 against approval.)

Investors follow advisory committees closely. A committee vote can add or subtract hundreds of millions of dollars from a drug company's stock market value.

The FDA is required by law to screen all committee members for financial conflicts. The law says members have conflicts when committee action could have the "direct and predictable effect" of causing the member a financial gain or loss. The federal agency is forbidden from using experts with financial conflicts unless a waiver is granted, usually on the grounds that the experts' value outweighs the seriousness of the conflict. The FDA grants these waivers routinely.

In the period analyzed by USA TODAY, the FDA granted 803 conflict-of-interest waivers. Seventy-one other times, members had financial conflicts that were voluntarily disclosed but did not require a waiver. In the 746 other member appearances on the committees, there was no conflict of interest.

The FDA says granting waivers lets it tap the nation's leading researchers, most of whom do work for the pharmaceutical industry.

"The system is designed to bring together the best scientific experts we can find," says FDA associate commissioner Linda Suydam, who approves waivers.

She says conflict-of-interest waivers go through as many as eight levels of review before they are granted. But Larry Sasich, a pharmacist who works for the Ralph Nader-founded Public Citizen's Health Research Group, says, "It is outrageous that the pharmaceutical industry's influence is so great that even some consumer representatives are on drug companies' payrolls."

Sasich says it might sometimes make sense to let experts with financial conflicts participate, but "it should be rare and that person should not be allowed to vote."

Financial conflicts were most common when committees considered broader issues, such as warnings labels for pregnant women or how cancer studies should be designed. At the 57 meetings on regulatory policy, committee members had conflicts 91% of the time.

At the 102 meetings involving specific drugs, 33% of committee members had a direct financial stake in the outcome.

It is impossible to determine how advisory committee decisions might have been influenced by the financial relationships its members have. The FDA stopped making details of financial conflicts public in 1992, after controversies about whether the financial interests of committee members had biased decisions on breast implants, Prozac and a drug to treat Alzheimer's disease. The FDA says it stopped releasing details on conflicts because of concerns about violating the privacy rights of committee members, not because of the controversies.

Types of conflicts

Financial conflicts include stock ownership, consulting fees, research grants, a spouse's employment and payments for speeches and travel. The conflict could be a tie to the company whose drug is under consideration or to a company that sells a competing drug.

Many financial conflicts are considered too small to require disclosure or a waiver and were not counted in USA TODAY's study. For example, a committee member can be paid up to $50,000 a year by a drug company without any financial conflict being disclosed if the work was on a topic other than what the committee is evaluating, according to FDA guidelines. Committee members also can own up to $5,000 in stock in the company appearing before the committee.

Advisory committees include many of the nation's leading researchers. The pay is not high considering the stature of many members: about $400 a day for meetings, plus travel expenses, and nothing for work done outside a meeting. However, the assignments are prestigious, and committee members, whose terms last four years, are in heavy demand as industry consultants.

Conflicts are most common on the committees that consider heart drugs. Forty-eight percent of experts had financial conflicts when considering the worthiness of specific heart medicines.

"The greater degree of expertise, the greater the potential for conflicts," says Milton Packer, chairman of the Cardiovascular and Renal Drugs Advisory Committee.

Packer is a good example. He is a leading figure in cardiovascular research and has helped pioneer the development of drugs to treat congestive heart failure. Last year, he led an effort by 150 leading cardiac researchers to establish consensus guidelines on how to treat congestive heart failure, which is suffered by 5 million Americans.

But his work with pharmaceutical companies creates many financial conflicts. The FDA granted him a waiver that allowed him to participate in a meeting May 2 on the drug Refludan, which treats clotting. (Packer says he doesn't recall what the conflict was.) And Packer did not participate in a meeting May 1 on the heart drug Altace because of a financial conflict. (He declines to say what the conflict was.)

Packer says consolidation in the pharmaceutical industry has increased the potential for conflicts because there are fewer companies and nearly all have heart drugs.

Financial conflicts are so common that eight of 10 members who evaluated the drug Aggrastat, made by Merck, had conflicts of interest.

Packer says he doesn't believe that financial conflicts distort the recommendations of advisory committees: " There are so many checks and balances, it would be almost impossible for a single individual to steer the committee."

At the meeting on October 20, 1999, on Levaquin, the chairman of the committee and one other member stepped aside because of financial conflicts.

Of the 10 members remaining, four had received conflict-of-interest waivers from the FDA.

In addition to Rodvold, New Jersey physician Carl Norden had consulted for Johnson & Johnson in 1997 on the design of Levaquin studies for illnesses other than the treatment of penicillin-resistant pneumonia, the company said.

Johnson & Johnson says having its consultants on the advisory committee didn't create bias.

"We don't believe (advisory panel members) would let a consulting arrangement compromise their reputation and stature in the medical community," says Monseau, the Johnson & Johnson spokesman.

The advisory committee voted unanimously to recommend that Levaquin, an $8-per-pill antibiotic, be approved for treatment of penicillin-resistant pneumonia. The FDA ratified the decision in February. Levaquin has been on the market since 1997, but the FDA's action allows Johnson & Johnson to market the medicine as the first antibiotic approved for the more than 25% of pneumonia cases that are resistant to penicillin.

Industry influence on advisory committees will increase later this year. As required by a law approved in 1997, the FDA will add official industry representatives to the committees. The industry officials will participate in deliberations, but they will not be allowed to vote.

These articles originally appeared in the USA TODAY September 25, 2000 edition on-line.

FDA under pressure for rehab Scrutiny after Vioxx focuses on turf battles, independence

By Laura Gilcrest, CBS MarketWatch Last Update: 5:12 PM ET Dec. 7, 2004  WASHINGTON (CBS.MW) -- The recent fiasco over the Vioxx recall has exposed the U.S. Food and Drug Administration to broad-based charges that the agency is less an independent regulatory body than an old-guard bureaucracy where senior officials snuff out dissenting voices among its scientific staff members. With prescription drug safety under renewed scrutiny following the recall of the painkiller by Merck & Co. (MRK: news, chart, profile), pressure is mounting in Washington to revamp an agency accused of making its rank-and-file scientists tow the party line. "If you're not with the wagon riders, you're outside looking in," said Larry Pilot, a former FDA official who now represents drug companies doing business before the agency. "In a bureaucracy [like FDA], it's easy to push people aside and keep them quiet." At stake is the future of an agency overseeing an industry with annual revenues exceeding $200 billion. The FDA handles dozens of applications for new drugs each year, any one of which could turn into a treatment with blockbuster sales potential. However, some critics say that when FDA officials find an approved drug may need to be pulled off the market, their conclusions get swept up in turf battles inside the agency's sprawling Center for Drug Evaluation and Research. Moreover, some observers believe that the bureaucracy is underfunded and overly reliant on a budget backed by industry-paid fees. In late 2002 and 2003, the agency approved 55 new drug applications that were submitted sometime during 2002. Last year, the FDA received 113 applications. Since 1990, 14 approved drugs have been taken off the market for safety reasons, according to Public Citizen, the Washington watchdog group. But as in the Vioxx case, it's usually the pharmaceutical companies themselves, not the FDA, that take the drugs off the market. If follow-up tracking by companies points to a problem with a drug, the companies consult with the FDA and then call for a voluntary recall. Outside agency? A number of reform scenarios are being debated. One option could be to create an independent body charged with monitoring drug risks after they hit the market, an idea supported by Sen. Charles Grassley, R-Iowa, chairman of the Senate committee that heard Graham's testimony, and the editors of the Journal of the American Medical Association. Currently, the Office of Drug Safety, a unit of the FDA's powerful Center for Evaluation of Drug Research, monitors potential post-market risks or problems that went undetected in clinical trials. The concept of a new oversight arm gained momentum after an Office of Drug Safety whistleblower's widely publicized testimony on Capitol Hill last month laid bare divisions within the bureaucracy that employs more than 9,000 people. Having FDA officials review the safety of drugs that are already on the market creates a conflict of interest, the plan's proponents say. It means the agency must second-guess its own initial findings that a drug is safe. Agency critics including Sidney Wolfe, director of health research at Public Citizen, say top FDA officials have failed to back up findings of the Office of Drug Safety when its staff people raised red flags over risks of certain pharmaceuticals. Whistle-blower In the most explosive such charge to date, David Graham, associate director of science and medicine at the Office of Drug Safety, went before Congress last month to declare that the agency's structure isn't equipped to protect the public from another Vioxx debacle. Graham reportedly could face retaliation for speaking out on Capitol Hill, and higher-ups quickly sought to undercut his testimony, Graham had led an FDA post-market study of Vioxx and first warned of the drug's link to an increased risk of heart attack and stroke with long-term use. "One employee in the agency was saying that something needed to be done," Pilot said. "You must pay attention to these messages." Mark Mansour, another Washington, D.C.-based regulatory attorney, said dissenting opinions at the agency often don't see the light of day. "I've seen that with less important situations and I wonder if it represents something broader," he said. The Vioxx affair was only the most recent case in which minority voices were drowned out by a consensus view that a new drug was safe for the marketplace. Earlier, an agency staff member had tried to warn superiors after a new class of antidepressants -- known as selective serotonin re-uptake inhibitors -- was linked to an increased risk of suicidal behavior in children, Pilot noted. "There was one voice crying in the wilderness [but] FDA didn't listen," he said. "It's another black mark on the agency." Industry lobbyists say that although creating a new independent agency might increase oversight, they worry about adding another layer of red tape to the existing bureaucracy. And there's nothing to prevent bias in what is supposed to be an independent agency, they say. "The notion that something is structurally wrong [with FDA] is fundamentally misguided," said Stuart Pape, a lawyer who represents drug companies. Balancing act Pape says to separate pre-market drug review from post-market drug monitoring would dismantle the classic risk-benefit analysis, the underlying balancing act at the heart of every drug safety assessment. Taking the post-market monitoring function out of the FDA's hands would result in a lopsided analysis that focuses on a drug's risks without considering its benefits, he contended. In monitoring a drug after it's on the market, the agency determines whether its risk-benefit profile has changed since it was first approved, which is often the case as new side effects emerge that were not seen in the drug's clinical trials. Pape said. On the other hand, the FDA could do a better job of scrutinizing marketed drugs, especially the ones that turn out to be more widely prescribed than originally contemplated, he added. Public Citizen's Wolfe said that whether post-market drug monitoring is taken out of FDA altogether or merely split off from the agency's Center for Drug Evaluation and Research and given a separate office, the real issue is one of power. "There's an extraordinary imbalance of power at FDA," he said. As it now stands, the agency doesn't decide that a particular drug poses a problem until thousands of people are injured or killed, Wolfe said. A separate drug-oversight arm won't make any difference in public safety if the Center for Drug Evaluation and Research can still trump its decisions about marketed drugs, he said. What's really needed is more congressional oversight of FDA and an end to the drug review system's reliance on industry-paid fees, Wolfe argued. "The power of CDER is funded in large measure by industry," he said. Drug act Under the Prescription Drug User Fee Act of 1992, drug companies pay pre-set fees with new drug applications that help FDA speed application review times by, for example, hiring additional medical reviewers. But while the law has cut drug review times significantly, groups like Public Citizen claim the law actually allows industry to trade cash for favorable decisions on new products. Wolfe said that FDA's mission in ensuring drug safety is too important to be left to industry funding, and should instead be adequately funded by Congress. At the very least, many observers say, the FDA needs to strip away redundant layers of bureaucracy that hinder communication and give its dissenting scientists more say about a particular drug's safety. Pilot, who worked as a special assistant to FDA commissioner for 10 years, said it should foster an atmosphere where scientists know they'll get a fair hearing when they express minority views about a drug. "Why be frightened of the possibility that maybe there was a mistake made?" he said. from: http://www.billingsgazette.com http://www.billingsgazette.com/index.php?id=1&display=rednews/2004/12/08/build/nation/40-heart-drug.inc Billings Gazette Last modified December 8, 2004 - 12:35 am   FDA to warn against heart drug after delay Knight Ridder News WASHINGTON - After a delay of more than a year, the Food and Drug Administration has approved publication of new patient warnings for a potentially risky heart drug that millions of Americans are taking. Patients taking amiodarone can read the new warnings on the Internet at www.wyeth.com beginning next week and will soon start receiving paper copies when they get or refill prescriptions. The FDA's action comes two weeks after Knight Ridder reported the delay, prompting an outcry from readers who said they've lost loved ones or suffered side effects from the drug, and as the agency is under fire for failing to protect consumers from dangerous drugs. FDA officials had no comment Tuesday. The agency hasn't responded to Knight Ridder's repeated requests for information about why publication of the amiodarone medication guide - planned since October 2003 - has taken so long. The guide is undergoing a final edit and will be posted on the Web sometime next week, said Chris Garland, a spokesman for Wyeth, the drug maker assigned to write it. Details of the guide's contents weren't available Tuesday. In general, such guides contain detailed warnings about potential side effects, how the drug should be used and what conditions the FDA has approved it to treat. Amiodarone, also sold under the brand names Cordarone and Pacerone, has numerous serious and fatal side effects, including lung toxicity, thyroid problems and liver damage. Because of its dangers, the FDA approved amiodarone only as a drug of last resort for specific life-threatening heart rhythm conditions, called ventricular arrhythmias. But over time, it's gained favor with cardiologists as a treatment for atrial fibrillation, a common and less serious heart rhythm condition it was never approved to treat. According to recent pharmaceutical industry data, doctors wrote more than 2 million prescriptions in a single year for atrial fibrillation and other heart conditions that the drug wasn't approved to treat. For the year ending July 31, 2003, 82 percent of the drug's retail sales were for unapproved uses, a Knight Ridder analysis found last year.