Von Eschenbach's Two Hats

Let's see if I have this right:

The Bush administration, under fire for appointing incompetent cronies to key positions, learns late last week that the Food and Drug Administration commissioner owns stock in a drug distributor. A high administration official calls Lester Crawford and asks him to resign. He does.

This same official or group of officials gets on the phone to Dr. Andrew von Eschenbach, who runs the National Cancer Institute after a long career at the Houston-based M.D. Anderson Cancer Center. He has no particular experience in evaluating the safety of food, drugs, medical devices, or dietary supplements, the primary job of FDA. However, he does serve with George (Sr.) and Barbara Bush on the board of C-Change, a partially industry-funded advocacy group for speeding the pace of cancer drug approvals. He gets the interim job at FDA.

However, von Eschenbach insists on keeping his NCI post, where his mission is to run an agency charged with developing new drugs to treat cancer. Moreover, while in that position he has developed deep ties with the drug industry. He advocates for relying on new and untested markers for measuring drug effectiveness. He sets a goal of turning cancer into a manageable disease by 2015, which causes many oncologists to cringe.

There was immediate and bipartisan outrage at the administration's inability to perceive that this appointment, even on an interim basis, was a blatant conflict of interest. Senators Ted Kennedy (D-Mass.) and Dick Grassley (R-Ia.) immediately condemned the von Eschenbach choice.

A prediction: The Bushies, reeling in the polls, will move quickly to find a permanent replacement for Crawford. The von Eschenbach appointment, made in haste, is a liability they just don't need at this point.

The Crawford Resignation Mystery

True to form, the administration picked late Friday afternoon to announce that Food and Drug Administration commissioner Lester Crawford resigned. The veterinarian in charge of the world's premier food and drug safety agency, who was confirmed for the job just two-and-a-half months ago, cited his age. He is 67.

The Saturday morning papers (the least read of the week; that's why troubling announcements get released late Friday) gave no clues as to what drove the decision, although both the New York Times and the Washington Post hinted broadly that he was forced out. But why? It couldn't have been the postponement -- again -- of approving Plan B, the morning after contraceptive pill. Crawford was doing the administration's bidding on that issue.

One possible clue to the administration's thinking comes from the appointment of Andrew von Eschenbach, head of the National Cancer Institute, as acting commissioner. Von Eschenbach, who previously ran the M.D. Anderson Cancer Center at the University of Texas, has been touting the new generation of targeted cancer drugs and in recent speeches has been confidently predicting that cancer would become a manageable disease -- like AIDS -- by 2015.

The Post story mentions that many oncologists have criticized von Eschenbach for overpromising, but ignores the back story. His prediction and embrace of the latest drugs has been prominently featured by the conservative Manhattan Institute, whose work on FDA and medical issues is conducted at its Center for Medical Progress. The Center is funded by the drug industry.

In the world of journalism, the Wall Street Journal's editorial page has been touting the new cancer therapies even when the clinical trial evidence shows they don't work or help as few as 10 percent of patients (and even then only for a few months). The Journal has been on the warpath against Richard Pazdur, who runs the FDA's oncology bureau, claiming he has slowed the pace of drug approvals.

Paul Goldberg's influential "Cancer Letter" pointed out in its August issue how a right wing "insurgency" is pushing for early approvals of cancer drugs. The insurgency includes Michael Milken (who has been treated for prostate cancer) and an all-star cast of conservative think tanks like the Manhattan Institute, the American Enterprise Institute, the Cato Institute, the Competitive Enterprise Institute, the Washington Legal Foundation and a cancer patient advocacy group known as the Abigail Alliance.

Grabbing a page from the AIDS activists of the early 1990s, their slogan is early access to experimental cancer drugs for the dying. If they can get the FDA to approve early access based on experimental data that suggests a new, experimental drug may affect the disease (usually based on some surrogate marker like tumor shrinkage, which can have no relationship to survival), they can then force insurance companies, Medicare and Medicaid to pay for the treatments.

That would be a godsend to the drug industry, which has invested billions in searching out cancer cures with marginal success. The new targeted therapies can cost anywhere from $4,000 to $10,000 a month. No wonder it has financially supported many of the conservative groups in the coalition.

Pazdur, who also came to the FDA from the M.D. Anderson Cancer Center, has fought to hold the line for the agency's traditional standard that a drug be shown to be effective before getting approved. His staff has also done a good job assessing whether a new drug's usually marginal benefits outweigh the substantial side effects and risks that are often associated with cancer therapies, including the newer targeted therapies. Just yesterday Genentech announced it had to stop a trial of its new drug Avastin for ovarian cancer after 11 percent of patients began developing holes in their stomachs and intestines.

There is a serious discussion that needs to take place at the FDA about how companies with new therapies can be encouraged to collaborate to see if in combination these drugs can have a major impact on cancer. But sophisticated scientific discussions and breaking the entrenched habits of competitive drug firms is not what the ideologues behind the anti-Pazdur campaign have in mind.

If von Eschenbach forces his former colleague out and appoint someone more malleable to run the agency's oncology division, we'll know the real reason why Crawford resigned.

Senate Backs Watered Down Version of FDA Bill

The Senate late Tuesday passed an amendment that will create greater transparency when the Food and Drug Administration puts scientists with drug industry ties on its advisory panels. While this measure doesn't go as far as the bill the House passed last June, which would ban the practice, it is a step in the right direction.

The legislation, sponsored by Sen. Richard Durbin of Illinois, requires that the FDA post the names of scientific advisers granted waivers for their conflicts of interest on their website at least 15 days before an advisory committee meeting. It also requires that the FDA simultaneously publish the nature of those conflicts on its website.

Currently, the public has to file a freedom of information request to get the names of the companies involved and the amounts paid to those scientists for consulting, speaking, doing studies and the like. Anyone who has ever filed a FOIA request with FDA (or most other agencies in this administration) knows that the process can take years.

There is one final element to the Senate bill. The FDA will have to document its efforts to find unconflicted scientists every time they create a new advisory panel. While this in itself doesn't change anything, it creates an incentive for the agency to at least try to find unconflicted scientists since the alternative is to file blank reports.

Removing the ban on conflicted scientists that was contained in Rep. Maurice Hinchey's amendment, which passed the House 218-210 last June, rendered the Senate version "virtually noncontroversial," according to Sen. Robert Bennett (R-Ut), chairman of the Appropriations Committee. "It is important that we do not enforce the conflict-of interest issue with such difficulty that ultimately the pharmaceutical companies are cut off from any opportunity of ever consulting with the best experts in the field because those experts want to also remain available to the FDA," he said.

Let's follow Bennett's logic for a moment. He fears leading physicians across the country will drop those $10,000 and $20,000-per-year consulting gigs in order to serve on FDA advisory committees, where they get plane fare, a hotel room and lunch in exchange for several days wrestling with an FDA briefing book and sitting through a daylong meeting.

Put that together with the FDA's claim that "everyone who is anyone consults for industry" and you have the most persuasive case yet for why the conference committee should pass the Hinchey version of the bill. It will get at least a few leading physicians off industry's payrolls and onto the public's side!

Conflicts of Interest at the FDA

When the Food and Drug Administration (FDA) evaluates a new drug or medical device, it often faces a terrible dilemma. In an era when many new therapies offer at best marginal improvements for most patients, evaluating a new drug can turn into an agonizing balancing of relative risks and benefits.

Take the latest cancer drugs, for instance. Many offer benefits that are measured in months of additional life – not years – and often at terrible physical toll. Drugs for some common conditions like allergies or depression offer relief at a rate that is barely distinguishable from placebo. Other new drugs are no more effective than medicine already on the market, yet come with substantially greater risk. The Cox-2 painkillers like Vioxx are a tragic example of this phenomenon.

It’s the FDA’s job to calculate these tradeoffs. Moreover, it must do so with limited data that is usually derived from clinical trials sponsored by the firm that manufactures the product.

To sort through this evidence, the agency relies on hundreds of outside scientists who sit on its 30 advisory panels. The agency almost always follows their advice. So the make-up of these panels is crucial. Should they be comprised of doctors who work every day with patients suffering from the disease and have collaborated the maker of the drug or one of its competitors? Or should the panels contain scientists and clinicians who know the disease and can interpret clinical trial data, but are not involved in any way with firms that have a financial stake in the outcome of the committee’s deliberations?

In recent months, a slew of high-profile drug-safety disasters have brought this issue to the forefront. Scientists with direct financial ties to drug companies have been allowed to sit on panels evaluating whether antidepressants cause suicides in teenagers; the magnitude of the heart attack risk from big-selling painkillers known as Cox-2 inhibitors; and the long-term safety of silicon gel breast implants.

In at least one case – involving the painkillers sold by Merck and Pfizer – the FDA advisers with financial ties to the drug makers held the swing votes on the committee and voted in favor of continued marketing of the drugs. The FDA staff later overruled its own advisory committee’s recommendations – an almost unheard of event.

In June, the House of Representatives moved to rectify this situation by approving a rider, sponsored by Rep. Maurice Hinchey (D-NY), to the FDA appropriations bill that would prohibit the agency from placing scientists with conflicts of interest on its advisory panels. The notion is simple: outside advisers should be expert, of course; but they also must be scrupulously objective. Allowing advisers with financial ties to firms with a stake in the outcome to remain on a committee would inevitably taint the public’s perception of the process and potentially skew the results.

The Senate will soon consider a similar measure sponsored by Richard Durbin (D-IL). In recent presentations on Capitol Hill, the FDA is fighting against this commonsense approach. Commissioner Lester Crawford raised similar objections during his nomination hearings.

They claim that in many medical fields, there are almost no experts who don’t have ties to companies producing products for that specialty. Moreover, to deny such experts a role in the FDA process would deny the public the best advice since it is inevitable that both industry and the government turn to the same key thought leaders in any particular medical field. As a result, the FDA granted special conflict-of-interest waivers to one of every eight scientists who served on FDA advisory committees over the past several years with some committees dominated by conflicted scientists.

The FDA is wrong on both counts. Their protests that there aren’t highly qualified, non-conflicted scientists to fill these slots is a terrible insult to the thousands of physician-scientists at the nation’s 125 medical schools, not to mention foreign experts, who have chosen not to work with industry on clinical trials. Some turn to government to fund their clinical trial work. Others rely on institutional support or concentrate on researching the basic science of the disease while monitoring the latest medical advances reported in the literature. Many would leap at the opportunity to serve the public as objective arbiters of the latest advances in medicine.

And that, in the end, is what is at stake in this relatively simple reform. In the increasingly blurry world of advancing medical technology, Congress must insist that the FDA’s decisions be informed by a scientific jury whose only loyalty is to the best interest of patients. The alternative is to turn advisory committees – a vital piece of the regulatory system for protecting public health – into another partially-owned subsidiary of the pharmaceutical, biotechnology, and medical-device industries.

Iraq update: Time for an exit strategy

Adil Shamoo, a professor of ethics at the University of Maryland School of Medicine, has collaborated with me on a number of pharmaceutical-related issues. But he is also a native of Iraq. Today, he posted a heartfelt commentary on the Foreign Policy in Focus website. You can also read it here:

Despite increased U.S. military operations and the stepped-up training of Iraqis, the Iraq insurgency continues to be deadly—nearly 3 U.S. soldiers died per day in August. Dwarfing that number are Iraqi deaths as a result of the fighting which average 34 every day.

Iraqis, the U.S. public, and now even members of the U.S. Congress are calling for an exit strategy. It’s time for President Bush to hear these calls of the people and explain what the plan is and when U.S. troops will come home.

Twelve Days

There's nothing quite so depressing as a day spent with the Food and Drug Administration's Oncologic Drugs Advisory Committee. On Tuesday, ODAC, as it is fondly called by its denizens, approved a new drug for pancreatic cancer that extended patients' lives by an average of 12 days while subjecting them to sometimes fatal side effects.

But don't think the ODAC is without standards. The 10-2 vote in favor of OSI Pharmaceutical's Tarseva came right after the committee unanimously rejected Abbott Lab's prostate cancer drug. Xinlay, as it is known, failed to extend life at all.

Thirty five years into the war on cancer, here's where we're at on pancreatic cancer. If you get it, you're a dead man walking. Take the best chemotherapy drug now on the market, Gemzar by Eli Lilly, and you'll live an average of 5.95 months. Add OSI Pharmaceuticals' newly recommended Tarseva to the mix and you've got 6.37 months. I'll do the math for you. It's about 12 days. The FDA usually follows the advice of its advisory committees.

Of course, the dying patients on Tarseva will have to put up with severe diarrhea, various other complications and an increased risk of stroke. Indeed, seven percent of several hundred patients in the trial on the new drug died of those complications, compared to none from Gemzar alone. By the way, no patients in either arm survived the trial, which lasted less than two years.

Clearly, Gemzar was no great breakthrough either. When it was approved in 1996, it increased the median lifespan of its trial enrollees from 4.2 months to 5.7 months. Put these two new drugs together and the cancer industry has added an average of two pain-wracked, chemo-tortured months to patients lives.

Abbott Labs, meanwhile, showed it obstinacy by even bringing its drug to ODAC. Its own data monitoring committee had ordered the trial stopped midstream when it became clear that no one was benefiting from the drug. But Xinlay had an intriguing scientific concept pushing it forward (the academic researcher who discovered the mechanism also conducted the clinical trial). Once prostate cancer spreads to surrounding bones, it triggers out-of-control bone deposits, which causes the unbearable pain of end stage prostate cancer (95 percent of patients spend their last days on opiates).

Xinlay was designed to interfere with the bone deposition process. And apparently it worked if all you considered were pictures of patients' bones. Unfortunately, no ones life was extended by taking the drug. And the FDA reviewers said the differences in reported pain among patients on the drug versus those not on it were minor and suspect because it was based on a subjective survey. All the patients knew they were on the drug.

So, I'm afraid I must report there was not much good news for people struck by these two major killers (most of the prostate cancer patients were 70 or older, but over half of the pancreatic cancer patients, evenly divided between men and women, were under 65). But it was good news for OSI. The company expects sales of $150 million a year within a few years.

Meanwhile, thalidomide's comeback continued today when ODAC approved Celgene's Revlimid, which is a chemical cousin to the once notorious drug. The new drug will be used against a mild form of leukemia called myelodysplastic syndrome.

This disease requires a blood transfusion about every month. But by taking Revlimid, about two-thirds of these patients became transfusion free for an average of 7 months. Celgene anticipates at least $500 million a year in sales and perhaps three times that amount if doctors begin using it for more serious forms of the leukemia.

That sounds like a pretty good deal: take an oral drug to stay off transfusions for more than half a year. But Dr. Richard Pazdur, head of the FDA's oncology branch, warned the company that it would have to make sure pregnant women didn't take the drug. Thalidomide, sold in Europe in the late 1950s to ward off morning sickness in pregnant women, caused severe birth defects in their unborn children.

No-Bid Contracts to the Usual Players

From today's Wall Street Journal:

"The Bush administration is importing many of the contracting practices blamed for spending abuses in Iraq as it begins the largest and costliest rebuilding effort in U.S. history.

"The first large-scale contracts related to Hurricane Katrina, as in Iraq, were awarded without competitive bidding, and using so-called cost-plus provisions that guarantee contractors a certain profit regardless of how much they spend.

"Contracts for temporary housing have been awarded to politically connected companies like Fluor Corp. and Bechtel National Inc., a unit of Bechtel Group Inc., leading congressional Democrats to renew charges of cronyism they first leveled when the firms won lucrative work in Iraq."

FDA Once Again Packs Its Advisory Committees

The Food and Drug Administration yesterday and today held advisory committee meetings to discuss the safety and efficacy of two new drugs for diabetes. In each case, one-third of the committee's nine members had financial ties to the drug manufacturers that submitted the new drug applications, or their competitors.

Why does the agency persist in inviting conflicted scientists to serve on its panels? Last June, Rep. Maurice Hinchey (D-NY) attached a rider to the FDA appropriations bill that would ban the practice. Nearly three dozen Republicans joined with most Democrats to pass the measure 218-210. The bill is slated to come before the Senate, probably next week. Aides to Sen. Richard Durbin (D-IL), its sponsor, hope that the concern on both sides of the aisle about the agency's safety record will translate into a positive vote.

This week's sorry performance suggests that despite the political pressure the agency still doesn't get it. At today's advisory meeting, for instance, which considered a Bristol Myers-Squibb/Merck oral drug for diabetes, the agency appointed a University of California at San Francisco endocrinologist named Thomas Aoki to serve on the panel. Aoki, who hasn't published an article in the medical literature since 2001, has a patent on a technology that's been licensed to several start-up firms that would make insulin easier to use and potentially more effective. This would obviously undercut the market for oral drugs, which don't work as well as insulin. Obvious conflict, right? They appointed him anyway.

Yesterday, the agency allowed three scientists with direct ties to Pfizer or Nektar Inc. to evaluate those companies' joint application for an inhalable form of insulin (Nektar makes the inhaler). Again, this would give diabetics a much easier way to use insulin (what would you rather do, inhale or give yourself a shot?).

Sounds like a real breakthrough, right? Unfortunately, there are serious safety concerns for many diabetics who might use inhalers. Smokers wind up inhaling much more of the drug per dose. Some people lose breathing capacity. Existing lung diseases can be exacerbated. Clearly, if you've got an ax to grind for or against Pfizer/Nektar's petition, you could easily find data to support your case.

In the end the final vote was 7-2 in favor of the inhaler with one of the three conflicted scientists voting against. The Bristol-Merck drug got an 8-1 positive vote, with Aoki voting along with the majority. So it can't be said that the conflicts of interest determined the ultimate outcome.

But the public's faith in the integrity of the entire process is undermined when the FDA persists in appointing scientists with ties to industry to its advisory panels. How will this week's appointments look if the inhaler turns out to be the next Vioxx? Congress would be well advised to pass its measure and force the agency to mend its ways.

The Post on the Army Corps -- again

Got to give the devil his due. Michael Grunwald and the Washington Post headline writers weighed in with a decent analysis this morning of the Army Corps' failure to shore up the New Orleans levees. I had criticized Grunwald a few days ago for his previous series on Army Corps pork, my argument being essentially that his award-winning series of a few years ago failed to separate the wheat from chaff when discussing infrastructure projects.

Today's headline, "Money Flowed to Questionable Projects: State Leads in Army Corps Spending, but Millions Had Nothing to Do With Floods," summed up the situation.

When Congress sits down to apportion the Army Corps pie, they think up all kinds of phony justifications for dubious projects that have little to do with improving the nation's economy. Using specious cost benefit analysis, they are able to justify an Alaskan bridge to a virtually uninhabited island, or, in the case of New Orleans, a series of expanded locks for grain barges that never come.

But this is only half an analysis. The press is still remiss in failing to hammer at what needs to be done to begin correcting the collapsing infrastructure in the U.S., from levees in New Orleans to bridges falling down on Connecticut interstates. Our infrastructure is falling apart after decades of neglect. The billions that do get spent go to projects that pad the bottom lines of special interests who either benefit from building a project or benefit from its completion.

Even with these misplaced priorities, we shouldn't be surprised that Louisiana leads the nation in scoring Army Corps projects. The Mississippi Delta drains the water system for nearly two-thirds of the U.S. land mass. We are just beginning to hear about the havoc the destruction in New Orleans will play with U.S. farm exports. The Gulf region produces two-thirds of our domestic oil and natural gas.

Yet protecting the infrastructure for these crucial industries depends first and foremost on protecting the city and region they called home. But instead of insisting on that basic maintenance, the oil and ag-barge lobbies connived with local politicians to spend the money on their own narrow interests. Low-income neighborhoods in New Orleans were the last things on their minds.

I'm sure they'd all agree now that theirs was a rather short-sighted view.

Army Corps Out of Action

Rep. Henry Waxman, the ranking Democrat on the House Government Reform Committee, today posed this question:

"Could the New Orleans levee system have held? The budget of the Corps of Engineers for construction projects in New Orleans district was cut by over 40% between 2001 and 2005, apparently to free up funds for the war in Iraq and homeland security projects. In 2004, for the first time in 37 years, the Corps halted all work on the New Orleans levee system."

He wants Congress to hold hearings. Don't hold your breath.

Politics As Usual

From this morning's New York Times:

Top of story: President Bush's top two political advisers, Karl Rove and Dan Bartlett, are orchestrating a campaign from inside the White House to shift blame for the slow relief effort to Louisiana state officials.

Further down: "One Republican with knowledge of the effort said that Mr. Rove had told administration officials . . . that the administration should not appear to be seen now as being blatantly political."

Comment: Dante could not imagine a circle of hell deep enough to deserve these people.

Swept Away

The media, like President Bush and the government, were slow to respond to the devastation caused by Hurricane Katrina. But once the press mobilized, they've done a remarkable job bringing us news about the human cost and insight about the neglect that led up to the tragedy. Moreover, as media critic Tim Rutten outlined in today’s Los Angeles Times, the press in hindsight also did a fine job in sounding early warnings about the potential crisis.

“Three years ago, New Orleans' leading local newspaper, the Times-Picayune, National Public Radio's signature nightly news program, "All Things Considered," and the New York Times each methodically and compellingly reported that the very existence of south Louisiana's leading city was at risk and hundreds of thousands of lives imperiled by exactly the sequence of events that occurred this week,” Rutten wrote. “All three news organizations also made clear that the danger was growing because of a series of public policy decisions and failure to allocate government funds to alleviate the danger.”

Note that one important media outlet didn’t make it onto that list. Unfortunately, it was the one that most politicians in Washington read to gauge what’s really important. That outlet is the Washington Post.

Where has the Washington Post been on the question of crucial water control projects? Over the past several years, the paper has run story after story attacking the Army Corps of Engineers for wasteful government spending, often to the cheers of public interest and environmental groups.

Reporter Michael Grunwald took the lead with a June 2002 attack on the Everglades restoration project, which was portrayed as a gift to Gov. Jeb Bush and nothing more than a pro-development project to deliver more fresh water to greedy housing developers.

There are plenty of reasons to oppose the way most shoreline and inland water projects are handled – from how they treat the environment to how they wind up benefiting wealthy property owners and developers. But when reporters go after these aspects of the projects, they often wind up painting the entire concept as a boondoggle. There's no room for nuanced coverage -- ugh, how boring -- in the press.

Here’s how Grunwald described the Everglades project in his "nut graf" (news-speak for the paragraph that signals what the story says and why it's important): “Most of the plan's ecological benefits for the Everglades are riddled with uncertainties and delayed for decades, though it delivers swift and sure economic benefits to Florida homeowners, agribusinesses and developers.”

And here’s how he introduced that nut graf: “The plan is already the national model for future restorations, from a $ 15 billion proposal for Louisiana coastal wetlands to a $ 20 billion plan for California rivers and deltas.”

Yes, politicians ignored warnings in the media about what could happen to New Orleans after a direct hit by a major hurricane. But the capital’s paper of record was sending them a very different message, one that was music to the ears of the Republicans in power. That message said: All government spending on infrastructure is wasteful.