One in ten

David Graham's study will finally see the light of day Wednesday when the Journal of the American Medical Association publishes his analysis of the dangerous side effects of statins.

Graham, a top medical officer in the Food and Drug Administration's drug safety office, along with several colleagues reviewed a quarter million HMO records of patients, many elderly and diabetic, who took statins to lower cholesterol in the late 1990s through 2001. Besides Lipitor and other leading statins, the study looked at Bayer's Baycol (cerivastatin), which was withdrawn from the market in late 2001.

The shocking numbers: for every ten persons treated with Baycol and a fibrate (generics used to lower triglycerides, another lipid that in excess can cause heart problems), one came down with the debilitating muscle wasting disease, rhabdomyolysis.

The other leading statins were much less dangerous. If one looked at patients who only took statins, one in 20,000 patients taking the leading brands for a year would wind up in the hospital with rhabdomyolysis. But for those taking Baycol, it was 10 hospitalizations for every 20,000 users.

No wonder the FDA has been trying to shut him up and denigrated his study. With that kind of comparative risk profile, how did Baycol ever get approved? And what does it say about the state of post-marketing surveillance at the FDA if the agency allowed it to stay on the market for nearly two years?

As the accompanying commentary (which received widespread press coverage when it was released early) pointed out, putting companies in charge of collecting adverse events reports is a flagrant conflict of interest. The time has come for an adequately funded office of drug safety that is independent of the section of the agency that approves new drugs.

Meanwhile, a tip of the hat to Sen. Chuck Grassley (R-IA) for going to bat for Graham after he testified at the Vioxx hearing two weeks ago. Grassley wrote the FDA this week to warn its leaders not to punish Graham for going public.

Attorney Tom Devine of the the non-profit Government Accountability Project also has been doing yeomanlike work defending Graham. After Graham called him up seeking whistleblower protection, some higher-ups at FDA tried to scare Devine off the case by making anonymous phone calls and casting aspersions on Graham's work. Devine checked his caller i.d., saw the calls were coming from inside the FDA, and leaked the cad-like behavior to the Washington Post.

Fun with numbers at the Vioxx hearing

At least one Food and Drug Administration official revealed her deep-seated pro-industry bias today at the Senate hearing on Vioxx.

Sandra Kweder, the acting director of the Office of New Drugs in the Center for Drug Evaluation and Research, which is responsible for approving new drugs, dismissed concerns about the heart problems associated with the drug. They were "numbers on a spread sheet," she said.

She added that the safety concerns raised by internal reviewer David Graham had ignored the benefits of the drug -- the reduced gastrointestinal distress that occasionally results from taking too many aspirin or ibuprofen.

Here are the numbers on that spreadsheet that show the benefits and risks of Vioxx, taken straight from the clinical trials:

If 1,000 people take Vioxx every day for a year, about 6 will get gastrointestinal complications such as ulcers or severe gastric distress. That's a small but noticeable improvement over the 14 that might suffer those fates while taking ibuprofen, naproxen or other non-steroidal anti-inflammatory drugs (NSAIDs).

As you can see, the problem Vioxx was meant to solve is fairly minor (the FDA label states about 2-4 percent of patients on NSAIDs may suffer gastrointestinal side effects). None of the people in the clinical trial died from their ulcers. And while industry-funded studies have suggested 16,500 people die per year from NSAIDs, that estimate is wildly overstated. The latest statistics from the Center for Disease Control show that fewer than 5,000 people die each year from all stomach acid disorders and most of those deaths have nothing to do with taking pain pills.

If that's the benefit, what's the risk? The latest trial of Vioxx (to see if it reduced colon polyps) was halted because for every 1,000 people who took the drug for a year, there were 6.3 additional heart attacks compared to the group on a placebo.

So now let's do our risk-benefit analysis. For every million people put on this drug (and this was a multi-billion dollar blockbuster), the head of the FDA's drug approval unit thinks it is worth risking 6,300 heart attacks in order to prevent about 8,000 ulcers.

Which do you think will cost the health care system more -- the heart attacks or the ulcers? Which do you think will lead to an excess of deaths?

And what choice would most Americans make if they knew the real numbers? Would they continue plunking down $90 a month for Vioxx (plus the cost of the doctor visit) and risk that heart attack? Or would they choose going to the drug store where for $15 they can get a month's supply of ibuprofen, which works just as well for pain and runs the minor (and roughly comparable) risk of getting an ulcer?

Footnote: Two months ago, I had a brief email exchange with Dr. Eric Topol of the Cleveland Clinic after he published a hard-hitting editorial in the New England Journal of Medicine calling for Congressional hearings into the FDA's malfeasance in the Vioxx case. I ran these numbers past him. He wrote back: "Your math is pretty close to what we've got."

FDA To Reconsider Furberg Role on Safety Panel

They're backtracking at the Food and Drug Administration.

Dr. Curt Furberg was notified Tuesday that the agency is still considering appointing him to the advisory committee that will evaluate the safety of all Cox-2 pain relievers. Furberg's tentative appointment had been summarily withdrawn last week after he told news reporters that his analysis of clinical trials showed Pfizer's Bextra may have the same heart problems as Merck's Vioxx, which was withdrawn from the market in late September.

Sandra Kweder, acting director of the FDA's Center for Drug Evaluation and Research, told the press in the wake of Furberg's dismissal that his remarks showed he was biased.

According to Furberg, the FDA official in charge of advisory committees, Igor Cerny, called him Tuesday to apologize for the agency's actions. "He told me someone took action without following proper procedure," he said. "He said this was a mistake."

Furberg is one of the nation's leading drug safety experts and a frequent industry critic. He is also a permanent member of the FDA's drug safety advisory committee. He and another drug safety expert had been invited to take part in the arthritis drugs advisory committee meeting in February that will evaluate the safety of Cox-2s.

At the last meeting of the arthritis committee, which took place in June, 7 of 12 outside experts reported financial conflicts of interest that had to be waived before they could sit in on the meeting. Financial conflicts of interest are cause for dismissal from a federal advisory committee unless the agency issues a waiver based on needing the scientist's expertise.

The FDA's bumbling on Furberg's appointment couldn't have come at a worse time for the agency. The Senate Finance Committee on Thursday will begin its investigation into the FDA's handling of Vioxx.

Besides testimony from Merck chairman Raymond Gilmartin, the hearing will focus on efforts by FDA higher-ups to delay publication of an internal study by David Graham that showed an excess of heart attacks among people taking Vioxx. Graham's study will be published in this week's Lancet, a leading British medical journal.

The change of heart on Furberg may also have been helped along by inquiries from the Office of Government Ethics (OGE), which oversees federal agencies' compliance with conflict of interest laws. An OGE official on Tuesday called the FDA to get the internal handbook that contains guidelines for handling potential conflicts of interest and bias on advisory committees.

Those guidelines list the steps agency officials can take to manage bias such as not allowing a biased member to dominate the discussion. None of the steps include dismissal since the law requires that bias be balanced, not eliminated. "Sometimes people use the broad phrase conflict of interest to cover a multitude of things, but it doesn't cover intellectual bias," said an OGE official.

Double Standard Rules at FDA

The Food and Drug Administration advisory committee that met last September to consider approving AstraZeneca’s new anti-clotting drug Exanta had two major issues on its agenda. Did it work and did the occasional case of liver poisoning make Exanta unsafe?

A key expert sitting on that panel was Dr. Paul Watkins, a liver toxicity expert at the University of North Carolina. He took part in the discussion, but could not vote. The FDA limited his role because he sits on the advisory boards of two competing firms, one of which paid him more than $50,000 a year, according to a transcript of the meeting posted on the FDA website.

Watkins was not alone. Of the 14 members holding the fate of Exanta in their collective hands that day (the FDA almost always follows the advice of its advisory committees), ten disclosed relevant conflicts of interest at the meeting. None of the other nine were denied a vote.

They ranged from chairman Dr. Jeffrey Borer, who serves on the steering committee of a competitor, to University of Minnesota heart specialist Dr. Alan Hirsch, who listed eight corporate consulting and speaking relationships, several of which were with AstraZeneca’s competitors. “That was about the longest conflict of interest statement I can remember,” joked Borer, whose day job is at the Weill Medical College of Cornell University.

The Watkins case is the most significant, however, because it highlights inconsistencies in how the FDA evaluates conflicts of interest and bias among the scientists sitting on its dozens of advisory panels. Industry critics are being held to a higher standard than physician-scientists who frequently consult for industry.

Last week, the agency bounced Dr. Curt Furberg of Wake Forest University from a meeting that will take place next February to evaluate whether all Cox-2 pain relievers cause the same heart problems that forced Merck to withdraw Vioxx from the market. Furberg, a well regarded drug safety expert and a frequent industry critic, had been quoted in the New York Times a day earlier suggesting his analysis of Pfizer’s Bextra trials showed it may cause the same heart problems as Vioxx.

The FDA’s acting chief for drug evaluation, Sandra Kweder, in ordering his removal claiming Furberg’s comment indicated he was “biased.” Adding insult to injury, she invited Furberg to present his evidence to the committee, but precluded him from taking part in the discussion.

The agency’s treatment of Furberg stands in stark contrast to its treatment of Watkins only two months earlier. Watkins has a long history of bringing an industry-oriented bias to FDA proceedings.

Watkins is typical of many of the physician-scientists who sit on FDA committees. When he sits on a committee, he has his numerous conflicts of interest waived. And whether he’s sitting on the committee or appearing before it as an expert witness, he brings a distinct point of view to the committee’s deliberations.

In March 1999, for instance, Watkins, then at the University of Michigan, appeared before an FDA advisory panel as an expert witness to argue that the liver toxicities associated with the diabetes drug Rezulin were rare and usually associated with other conditions. One of the two patients who died in clinical trials drank 12 beers a day, he pointed out. “It’s reasonable to assume that both patients probably had underlying liver disease that reduced their ability to survive the drug related injury,” he said.

The client sponsoring his appearance before the committee was the drug’s manufacturer, Warner-Lambert. A year and over 60 deaths later, the FDA pulled the drug from the market.

Watkins stuck to his theme of individual susceptibility during the September meeting considering AstraZeneca’s anti-clotting drug Exanta, whose generic name is ximelagatran. Claiming that 13 of 16 drugs withdrawn by the FDA in recent years for safety problems involved potentially predictable susceptibilities, Watkins told his fellow committee members that the liver problems that popped up in the ximelagatran trials “suggest to me a genetic component.

“I would applaud any efforts the company would do either retrospectively or prospectively to get genomic DNA to help us get some of the answers to these questions,” he said. At the end of the day, the committee – its voting members, that is – elected to send the drug back for more data after concluding its toxicities outweighed its benefits.

Meanwhile, the FDA’s action in Furberg’s case went beyond the requirements of the law. The Federal Advisory Committee Act prohibits scientists with conflicts of interest from serving on the more than 200 science advisory committees sprinkled across the federal government. The law does allow agencies to waive those conflicts when a scientist’s expertise is needed to fill out the committee. That exemption is routinely invoked by the FDA.

There is nothing in the law, however, that prohibits “biased” scientists from serving on advisory committees. It only requires that scientists who have strong points of view be balanced by someone reflecting an alternative perspective.

“FACA requires that federal advisory committees be fairly balanced in terms of the points of view and the functions to be performed, and the courts have interpreted this requirement as providing agencies with broad discretion in balancing their committees,” the Government Accountability Office wrote in a report last April. “It is important that committees are perceived as balanced in order for their advice to be credible and effective.”

Ironically, Furberg and Watkins have served on an FDA advisory panel together. In 2002, both men played important roles on a committee evaluating whether unintentional overdoses of some over-the-counter pain killers like acetaminophen cause liver problems. At the outset of the meeting, its chairman waived a reading of all the participants’ conflicts of interest. “Because general topics impact so many institutions, it is not prudent to recite all potential conflicts of interest as they apply to each participant,” Louis Cantilena, chairman of the nonprescription drugs advisory committee, said.

Indeed, the law covering conflicts of interest is much less strict when it is applied to advisory committees that are discussing broad issues rather than individual companies' products. But that technicality seems to have been overlooked in the Furberg case.

The FDA’s drug safety committee that meets in February will be evaluating the safety of all Cox-2s, not just Vioxx or Bextra, which was the subject of Furberg’s most recent study. A close reading of Furberg’s comments in the original Times story indicates he was only referring to one drug – not the entire class. “Basically, we showed that Bextra is no different than Vioxx, and Pfizer is trying to suppress that information,” Furberg was quoted as saying after reporting his study’s results to an American Heart Association meeting in New Orleans.

Furberg sounded a conciliatory note after Kweder announced his removal. He wouldn’t object “if it’s the same rule they apply to others."

Furberg booted from FDA panel

The Wall Street Journal reports this morning that the Food and Drug Administration removed Dr. Curt Furberg of Wake Forest University from the panel that will evaluate the safety of Cox-2 painkillers next February. Sandra Kweder, the acting director of the agency's Center for Drug Evaluation and Research, claimed he was biased because he was quoted in a New York Times article suggesting that all Cox-2s may cause heart problems. Merck's Cox-2 Vioxx was pulled from the market late last month, prompting next February's meeting.

The significance of this move can't be overstated. Dr. Furberg is the one of the nation's most independent, judicious voices in drug analysis. He was the intellectual godfather of the ALLHAT trial, which showed that generic diuretics were just as good as premium medicines for combating high blood pressure. That he would be booted from a panel for a single comment represents the height of hypocrisy by the FDA. The agency routinely grants conflict-of-interest waivers to industry-funded researchers so they can sit on panels evaluating medicines.

More on this issue later . . .

What will the progressive 527s do now?

Here's one suggestion:

Turn up the heat on Republican Senators from blue states. Much has been made of President Bush's popular majority and the 55-45 margin the GOP won in the Senate. But many of those Republicans hail from states with healthy Democratic majorities. Three of them -- Lincoln Chafee (RI), Olympia Snowe (ME) and Rick Santorum (PA) -- are up for reelection in two years. Another four -- Norm Coleman (MN), Susan Collins (ME), Gordon Smith (OR) and John Sununu (NH) -- are up in four years.

Every time one of these politicians indicates they might vote in favor of privatization of Social Security, or contemplates consenting to a ultra-conservative Supreme Court justice, or hints they'll vote to impose further restrictions on a woman's right to choose, the 527s should run vicious attack ads in their home states telling their constituents what they're contemplating doing.

Republican front organizations have been doing it to moderate Democrats in swing states for years. It's allowed them to rout decent Democrats like Tom Daschle from office and achieve policy goals far beyond their numbers.

There is only one way to beat the Republican's mendacious attack machine. That's to build one of your own. Right now, the Republicans have a majority in the Senate because progressive states have repeatedly elected moderate Republicans to office who cave in to their hard right leaders at crunch time.

We're seeing the game plan in action again this week. Sen. Arlen Specter (R-Pa) is under attack for a stray comment that suggested he holds moderate views on selecting Supreme Court justices. He's slated to take over the Judiciary Committee, where he may be able to temper Bush's ability to ram hard right nominees through the Senate.

It's still possible the religious fundamentalists' allies in Congress will deny it to him. Earlier this year, they tried to unseat Specter in the primary. Now the right wing direct mail machine is flooding Capitol Hill with faxes, emails, phone calls and letters demanding his scalp. The conventional wisdom is that he'll survive and assume the seat his seniority has earned him. But I wouldn't hold my breath.

Isn't it time that the moderate Republicans in Congress start hearing from the other side of the political spectrum -- from the voters who gave John Kerry a clear majority in their home states? Perhaps if they hear from enough of them (amplified, of course, by those 527s), maybe they'll find the political courage to buck their right wing leaders. Maybe a few of these Blue Dog Republicans will even switch sides.

From Mencken to Machiavelli

A reader sent these in:

"There's no underestimating the intelligence of the American public."
-- H.L. Mencken

"If you have a weak candidate and a weak platform, wrap yourself up in the American flag."
-- Matt Quay, 1886

"If you tell a lie big enough and keep repeating it, people will eventually come to believe it."
-- Joseph Goebbels, German Minister of Propaganda, 1933-1945

"Politics is the conduct of public affairs for private advantage."
-- Ambrose Bierce, The Devil's Dictionary

"The Prince must seem to be religious."
-- Machiavelli

"You can fool too many of the people too much of the time."
-- James Thurber

The Election

The big shocker from yesterday's vote: The idea that a big turnout equals a big Kerry victory turned out to be incorrect.

It would appear that the lower middle/working classes of America, living in ex-urbs, driving hours to work in a gas guzzler, shopping at Wal-Mart and attending the evangelical mega-church on the outskirts of cities large and small, is just as much a forgotten group as the inner city/immigrant/working poor scattered everywhere that the Democrats put at the center of their get-out-the-vote strategy. Bush won his forgotten group bigtime. Until the Democrats and liberals discover how to reach this crowd, there's no hope of resuscitating progressive politics in America.

Tom Frank asked the right question. What is the matter with Kansas? Why when times are rough do so many Americans throughout the heartland turn to God, guns and disgust of gays, pregnant teenagers, the advanced degree crowd and anyone who tries to tell them that melting polar icecaps and traces of arsenic in the water are somehow more important than putting the bible at the center of one's life?

Kerry may yet win Ohio, although the latest numbers suggest all those challenged voters have to break his way for it to happen. The fact is there is no consolation in this fiasco. Bush won a clear majority of the popular vote because in huge swaths of the south, lower midwest, great plains and mountain states, which are the growth areas of this country, the Democrats are not competitive and do not even have a language for appealing to voters there.

Over the next four years, the last remnants of social democracy in America will be challenged and perhaps overturned. The universality of Social Security, Medicare and even the pretext of everyone having health insurance -- the elements of the social contract that remind us that we are in fact one people and have a common responsibility, expressed through the government, to take care of one another -- may be jettisoned.

The only thing I'm sure of is that in the every man for himself world that may come, it is the very people who voted for this administration and a Republican Congress who will fall through the cracks.

One final thought: Bush and the Republican majorities in Congress may not have a chance to move on all the issues listed above. Over the next two months, his administration will have to face the monumental disaster in Iraq. They need more troops on the ground to hold the election they're planning; they need $100 billion in a supplemental appropriation to pay for it; and the military is woefully stretched thin.

Bush and his narrow group of advisers didn't have an exit strategy when they went in. I doubt they've spent the past three months developing one. Indeed, there wasn't much advice offered by the Kerry campaign.

If I were a callous person, I'd say that the one consolation from yesterday's vote is that it's still their quagmire. But that is no consolation at all. Because when it comes to the war, all I can think about is the thousand dead, those dying every day, the tens of thousands of dead Iraqi civilians and the permanently maimed and scarred. Those are the ultimate victims of George W. Bush's policies. And it is to those issues that I suspect we'll be increasingly paying attention in the weeks and months to come.