FDA Scraps Helsinki Declaration on Protecting Human Subjects

In the mid-1990s, the National Institutes of Health ran a clinical trial in Africa testing whether a new antiretroviral drug to combat AIDS worked to prevent mother-child transmission. The trial created an ethical uproar because the control group received a placebo instead of an older anti-AIDS drug called AZT, which had already been proven successful in reducing the number of babies who contracted HIV from their mothers.

To critics, failure to provide a proven therapy to participants in this and similar trials was a basic violation of standards outlined in the Helsinki Declaration on protecting human subjects in research, originally adopted by the World Medical Association in 1964. But to the U.S. Food and Drug Administration and the drug industry, to which it had grown increasingly close over the course of the 1990s, it contradicted its longstanding policy of only requiring trials showing that a new drug was "better than nothing," i.e., better than placebo, to win regulatory approval. If the drug industry were to closely adhere to the Helsinki Declaration, it would always have to run comparison trials if an effective drug were already available.

Rather than accede to international norms, the FDA and the U.S. government in the succeeding years lobbied hard to get the WMA to amend its rules. And it has, several times. For instance, it now allows use of placebo-controlled trials for less serious illnesses. But the basic guidelines protecting human trial subjects' access to best available therapies remained intact.

Why is any of this relevant today? Last week, the FDA formally declared that it will no longer require that clinical trials submitted to the agency to get regulatory approval for a new drug adhere to the Helsinki Declaration. The new rule, which goes into effect next October, was supported by the drug industry but opposed by numerous public interest, patient advocacy, and consumer groups. The new rule requires only that trials conducted abroad by drug manufacturers follow good clinical practices (GCP) and include a review and approval by an independent ethics committee. There's nothing in GCP guidelines that requires patients in the control arm of a trial get access to already proven therapies.

What will this mean for the concept of "informed consent" in a poor country? Imagine for a moment that you live on $2 a day in, say, Tanzania, and have high blood pressure. Since the disease isn't life-threatening, you skip buying the available anti-hypertensives being sold in the village pharmacy because you can't afford it. Now say you learn while visiting the village clinic that an international pharmaceutical company is recruiting patients for a clinical trial testing a new anti-hypertensive drug. If you join the trial, you may only get the placebo. But there's a 50-50 chance you will get the new drug, which hasn't been proven yet, but might work.

Are there risks associated with taking this new drug? Well, so far, none that the doctors think are serious enough to cancel the trial, but it says right on the form that something may turn up in the clinical trial in which you are being asked to participate. You sign up. After all, a 50-50 chance of getting a drug, that has a good chance of working (the drug industry wouldn't be here testing it if it didn't, right?) is better than no drug at all. And how much risk could it be, anyway?

Is that really non-coerced, informed consent?

It's getting tougher and tougher to recruit patients in the U.S. to participate in clinical trials. It's also getting a lot more expensive for drug companies to run them here. The result is that 35 percent of all trials submitted to the FDA in new drug applications now take place abroad. This new rule will only make that number grow.

Moreover, many of those trials conducted abroad (or about 15 percent of all trials) aren't even be registered with the FDA. Unlike trials conducted in the U.S., companies do not have to submit an investigative new drug application (IND) to the FDA before beginning research in foreign countries. The FDA estimates about 575 of the foreign trials submitted to the agency each year as part of new drug applications do not go through the IND process. In other words, the FDA has no records that they even exist.

The FDA is required by law to monitor clinical trials conducted under INDs to protect their human subjects. But an Inspector General's report released last September found that the FDA had no registry of trials (which was rectified by passage of the FDA reform law last October); no registry of the Institutional Review Boards that were supposed to be monitoring trials conducted under its auspices; and independently monitored fewer than one percent of the trials it knew about.

And now it has passed a rule that increases the likelihood that more trials will go abroad and that more of them will not even be registered with the FDA, which makes them all but impossible to monitor.

In the final rule published in the Federal Register, the FDA rejected the notion that adopting the self-regulating GCP standard and eliminating references to the Helsinki Declaration "will hurt subjects in developing countries or result in less protection for subjects in foreign studies." The agency noted that GCP requires trial sponsors closely monitor trial behavior and report adverse events. If I were a headline writer at the New York Daily News, the headline on that story would have been: "FDA to Global Poor: Drop Dead"

What I can't understand is why no one in the U.S. press, including in the medical literature, paid attention to this story in the past year as this change was underway. Even after I wrote about this anonymously in Integrity in Science Watch earlier this week, nobody picked up on it.

Has the U.S. become entirely callous about the impact its ill-conceived policies are having on the rest of the world? Or am I off-base and this stuff really doesn't matter.

Two New Books Well Worth Reading . . .

The New England Journal of Medicine asked Steffie Woolhandler and David U. Himmelstein, long-time advocates of single-payer national health insurance, to review two new books that offer radical prescriptions on two issues that are central to meaningful health care reform: the corporate takeover of modern medicine and the perverse incentives that encourage physicians to overtreat the worried well. You need a subscription to read the review, but needless to say, it was quite positive. Here are the titles, available in finer bookstores or from your favorite online seller:

The Corrosion of Medicine: Can the Profession Reclaim Its Moral Legacy? By John Geyman. 344 pp. Monroe, ME, Common Courage Press, 2008. $24.95.

Worried Sick: A Prescription for Health in an Overtreated America. By Nortin M. Hadler. 353 pp. Chapel Hill, University of North Carolina Press, 2008. $28.

I'll know this blog has made the big time when publishers start sending me review copies in the mail. Ditto to editors looking for reviewers.

Northwest Indiana

As I awaited the results from Indiana last night, I was stunned by the lack of curiosity about Lake County, Indiana shown by the commentators on CNN. I spent a year of my life reporting for the Hammond Times, now the Northwest Indiana Times, so I know a bit about that turf.

The area, fondly known as "the region" to its inhabitants, is a microcosm of American society. Gary, its largest town, is a predominantly poor black city. But the predominantly white counterparts along the southern tip of Lake Michigan to the west -- Hammond and East Chicago -- are also very poor and working class, dilapidated communities that surround downsized steel mills.

But there are about 25 other towns in the county, and the further south you go (Crown Point, the county seat, and my favorite, Merrillville), the whiter and more middle class it gets. In the far south of the county, it is farm country.

I mention this because while awaiting the results, the on air commentators asked no questions about how the "white" areas of the county were voting. When Hammond mayor Tom McDermott was given national air time, all they could ask him about was the delay in reporting the vote. He repeatedly said that he had sent in his vote totals to the county board of elections, and he was upset as anyone that they hadn't been reported to the nation.

But he let slip that Clinton won by 600 votes in Hammond. No one followed up on that comment. 600 votes? There were probably 20,000 votes or so out of Hammond. That means that Obama did very well there. Perhaps the growing black and Hispanic population in that small city accounted for his showing.

Ultimately, Clinton did well enough to hold onto her slim victory in the state. But I suspect it was the more upper middle class areas of Lake County that preserved her margin. Last night's vote in Indiana, and especially in a town like Hammond, suggested to me that white working class Democrats, who have been one of the pillars of the Clinton candidacy, will, in these tough economic times, ultimately support an Obama candidacy.

Steals on Wheels

Medicare recently launched a durable medical equipment competitive bidding program that could save taxpayers and patients $1 billion a year through lower prices on motorized wheel chairs, oxygen tanks and inhalers -- three major Medicare cost centers often associated with aging or disabled smokers and ex-smokers with chronic obstructive pulmonary disease.

Lower prices and lower co-pays through competition? What a radical concept. It was supposed to roll out nationwide next year.

But according to this story in The Hill, which circulates on Capitol Hill, wheelchair and oxygen tank suppliers have launched a furious campaign to get Medicare to drop the program. In traditional inside-the-beltway fashion, they've hired a lobbying/public relations firm, Quinn Gillespie & Associates, to create an astroturf patient group called the National Coalition for Assistive and Rehab Technology to lobby against the program.

If you're a corporation lobbying against competitive bidding, it's probably best if you have people in wheel chairs with oxygen tanks do it.

Folks on the Hill under pressure from these "lobbyists" might want to take a look at this new report, out today from Inspector General Daniel Levinson's office. He found that Medicare's Part B program, which reimburses physicians and some durable equipment manufacturers for drugs administered in their offices or through devices like inhalers, is getting ripped off by certain users of the program.

Three years ago, Medicare switched to a new pricing system that only paid a five percent margin over the drug manufacturer's price for drugs sold under Medicare Part B. It was called the Average Sales Price system, and it pretty much knocked the profit out of drugs administered in doctors' offices.

But the equipment makers apparently are a different story. The OIG looked at all the drugs purchased by Medicare under Part B, and found that 44 were sold to the agency at greater than the five percent margin required by law. In just one quarter, it cost the agency $16 million in excess charges. But just one drug, generic albuterol contained in inhalers, accounted for fully $9 million of those excess charges. That's a cool $36 million a year, or 14 percent of the quarter billion that Medicare spent last year on the drug.

Hill staffers should print out copies of the OIG report. And when those wheelchair-bound ex-smokers on oxygen hit their offices, they should tell them to take it back to Quinn Gillespie. The "lobbyists" should also be instructed to tell the durable equipment makers that it's time to get used to competitive bidding, and to start charging "us" a fair pass along price for drugs.

Huffington's Post

I went to hear Arianna Huffington speak Monday evening, shortly before she made news by claiming in an online column that presumptive Republican nominee John McCain told her shortly after the 2000 election that he hadn't voted for George W. Bush. McCain promptly denied the charge. Given his obvious taste for good looking women twenty years his junior, it isn't hard for me to believe both of them are telling the truth.

But I digress. My real purpose in attending a signing event for her new book, "Right Is Wrong," was to talk about journalism. Her three-year-old online site, The Huffington Post, now has over a half million unique visitors daily. It recently surpassed the Drudge Report in traffic, is chock full of ads (and profitable), and recently began hiring real, full-time journalists.

All well and good. I'm all for entrepreneurial success in journalism, especially when the proprietor isn't Rupert Murdoch.

In her talk, Huffington lashed out at the mainstream press, who "act as if there is no such thing as truth and are more interested in cozying up to those in power than in holding them accountable." Though a frequent guest on talking-head TV, she dismissed the limited reach of cable television's endless chatter. "We have our own platform now," she said, pointing to the success of her own site, Talking Points Memo, Daily Kos and other stars of the leftwing blogosphere firmament.

But add it all up and what do you get? There's maybe 200 jobs that have been created by all the online political ferment on the left. Most of her site is made up of blogs like this one, created by people who have other, full-time jobs who get nothing for their effort. She herself is independently wealthy.

Meanwhile, in the real world of MSM (mainstream media), the Bureau of Labor Statistics will report on its annual job survey later this week. It measures the number of people in each job category. The number out Friday will be for May 2007.

Before going over to hear Huffington speak, I looked up the number of "reporters, correspondents and editors" in the U.S. in May 2006. The total came to a shade under 160,000. In May 2001, the total was a shade under 170,000. Given the accelerating job losses of the past two years, I suspect the total reported later this week will be around 150,000 and the actual number now well below that.

The point is: What will happen when there's no one left in the hated MSM to write the primary dispatches (like that wire copy) that tell us news consumers what's actually happening in the world and gives the endless army of pundits fodder for their commentary? It's great that a tabloid-style news outlet like the Huffington Post can blast away day after day about the Bush administration seeding television news shows with former military men still on the Pentagon payroll. But it took a team of investigative reporters at the New York Times a year to unearth and document that story.

Her response was somewhat heartening. A new round of venture capital financing will allow the Huffington Post to expand its reporting staff. They are forging deals with non-profit investigative outlets like the American News Project and angel-investor-funded start-ups like The Washington Independent, a feisty new voice in the nation's capital edited by Los Angeles Times veteran Allison Silver. The non-profit Center for Public Integrity, started by Chuck Lewis and run now by NPR veteran Bill Buzenberg, is still doing its thing and ProPublica run by former Wall Street Journal editor Paul Steiger has been on a hiring spree. It plans to grow to, gulp, 25 full-time journalists. The Kaiser Family Foundation is about to launch its own primary news service to cover health care issues.

What is most notable about all this activity is that it is non-profit and primarily funded by foundations. Many of these benefactors have agendas. There's nothing wrong with that in and of itself. Most of these new non-profit outlets have gone to great lengths to ensure that there is the same separation between funders and news managers that the MSM always claimed to have between advertisers and its news managers (I say "claimed" because I could tell some hair-raising stories about stories I had spiked because they would have alienated advertisers.)

But will benefactors lose interest? The economics of that model ultimately creates an environment where the primary audience for reporters and editors is their funder, not the public. I have seen this dynamic at work in the non-profit world.

I hope Huffington is economically successful with her online venture and hires a thousand journalists. It will prove that there really is an economy behind the New Economy.

I spent most of my work life in the private sector. In the end, I believe there really is something to be said for creating a product that meets a marketplace test, and that includes the written, broadcast and online word. I suspect the general public will always be somewhat skeptical about journalism that depends on the kindness of strangers.

Doc Pay: Salaries v. Fee-for-Service

Health care reform entails more than health insurance reform, although you wouldn't know it by listening to the candidates of both political parties. Achieving affordable universal coverage will depend on holding down the relentless rise in health care costs, and that will depend on changing the way health care is delivered. Reform must include changing the way physicians are reimbursed.

The current system relies on fee-for-service medicine, which encourages doctors and hospitals to do more services to increase revenue. And its primary beneficiaries are high-paid specialists, who rely on the 21st century equivalent of the time-and-motion studies used by factory engineers in the early 20th century to create compensation schemes for skilled workers.

Under such schemes, the amount of time needed to perform each task in a complicated project (like a tool-and-die maker cutting a new mold for a machine tool) is multiplied by a rating of the skill needed to perform each task. That's then multiplied by the pay scale to come up with the relative value of each worker's time. So in the steel foundry where I worked in the late 1960s, the tool-and-die makers earned 50 percent more than the molders, and twice as much as the laborers.

Medicine uses the same system to determine physician compensation. An American Medical Association committee dominated by high-paid specialists determines the "relative value" of the skills needed to perform, say, eye surgery compared to analyzing a rare eye disease that might be easily treatable with a drug, or shouldn't be treated at all.

The result is wide variability in physician income, and a huge incentive for doctors to enter specialties that not only get high rates for each procedure but can game the system by doing far more procedures than the original time-and-motion studies suggested they could. Sometimes that is a result of improved technology. More often, it is simply the result of ramming more patients through the procedure mill. Today's Wall Street Journal had an enlightening chart showing the resulting disparities in physician income:

Alas, the story offered an inadequate analysis of what needs to be done. Instead of discussing the relative value system and giving voice to critics who suggest scrapping it entirely, the story talked about a looming shortage in sub-specialties that are paid like general practitioners (non-surgical eye specialists in the story). The implication was that insurers need to raise these sub-specialties' relative pay to attract young doctors to the field.

Arnold Relman, the former editor of the New England Journal of Medicine, in his new book "A Second Opinion" offered a different approach. Yes, different physicians have different skill sets and some take longer training than others. That should be recognized in pay scales.

But, he suggests, the more important reform is that physicians be organized into group practices that encompassed all the necessary specialties. And they should be paid not by the number of patients they see or can run through their individual offices, but by skill, experience and their relative importance to improving patients' overall health.

This would give a huge boost to general practitioners and docs who coordinate care. And it would eliminate the perverse incentive that encourages specialists like radiologists and invasive cardiologists to overprescribe many diagnostic tests and surgical interventions.

The Hazards of Secret Science

The development of a blood substitute -- a liquid that has a long shelf life, does not need refrigeration and does not cause infection -- would provide a potentially lifesaving option for surgical and trauma patients with shock from loss of blood. Such a product would be especially in rural areas and military settings.

Most blood substitutes developed to date have been hemoglobin-based products (hemoglobin is the oxygen-carrying protein in red blood cells). Past studies of these blood substitutes suggested that they may be more dangerous than real blood, although the differences have not always been statistically significant.

Charles Natanson and colleagues at the National Institutes of Health teamed up with health advocates from Public Citizen to conduct a meta-analysis of existing trial data on blood substitutes, which was published on-line in JAMA on April 28. By combining the results of 16 trials, they found a 30 percent increased risk of death and an almost threefold increase in risk of heart attack in patients who received blood substitutes, as compared with patients receiving usual care.

The authors call for existing and future blood substitutes to be tested in animals before further clinical trials in humans are allowed to proceed. They point out that if the FDA had conducted a meta-analysis of blood substitute trials by 2000, the increased risks would have become known, and further harm to patients could have been prevented.

Because much of this data was nonpublic, it was impossible for scientists outside the FDA to fully assess the risks. "When 'secret science' is allowed, scientists are unable to build on the successes or failures of other researchers testing similar products, and patients can be repeatedly exposed to risks unnecessarily," the authors wrote.

The authors call for Congress to enact three major changes to the availability of information on clinical trials:

* Reverse the FDA's policy of treating as confidential all corporate materials submitted to it during the product development process, including the investigational new drug application.

* Amend Exemption 4 to the Freedom of Information Act to allow the public interest to be considered when the material sought is considered confidential commercial information.

* Require the results of all clinical trials to be publicly reported, including trials of drugs that have not been approved by the FDA.

-- PM

The Rise of the Uninsured Insured

Today's New York Times leads with a story documenting inadequacies in a growing number of health insurance policies. Rising co-pays, deductibles and caps on coverage are leaving many families with huge and unpayable bills despite thinking they were insured for serious or sudden illnesses. Here's a major anecdote worth highlighting:

Shirley Giarde of Walla Walla, Wash., was not prepared when her husband, Raymond, suddenly developed congestive heart failure last year and needed a pacemaker and defibrillator. Because his job did not provide health benefits, she has covered them both through a policy for the self-employed, which she obtained as the proprietor of a bridal and formal-wear store, the Purple Parasol.

But when Raymond had his medical problems, Ms. Giarde discovered that her insurance would cover only $22,000, leaving them with about $100,000 in unpaid hospital bills.

Even though the hospital agreed to reduce that debt to about $50,000, Ms. Giarde is still struggling to pay it — in part because the poor economy has meant slumping sales at the Purple Parasol. Her husband, now disabled and unable to work, will not qualify for Medicare for another year, and she cannot afford the $758 a month it would cost to enroll him in a state-run insurance plan for individuals who cannot find private insurance.

Here, writ small, is a description of everything wrong with today's insurance market and the conservative approach to health care reform.

* The individual insurance market is notorious for selling inadequate policies that do not cover the true cost of serious illness. Policies that cover just $22,000 of a $122,000 hospital bill aren't insurance in any meaningful sense of that word. They are more properly categorized as a "bait and switch" scheme to defraud the unwary. The Federal Trade Commission should take note.

* Individual "health savings accounts" can never generate enough savings to cover such shortfalls. Moreover, while the newspaper account doesn't reveal how or why Raymond Giarde "suddenly" developed congestive heart failure, HSAs also make it less likely that he would have sought out preventive care long before he developed the disease.

* State programs for the uninsured are far too expensive to provide a meaningful alternative for the uninsured. At $758 a month or $9096 a year, Washington's plan appears to be charging the full cost of family insurance.

Now let's turn to the health care plan of presumptive Republican nominee John McCain annnounced last week and see how it would help this family.

* The $5,000 tax credit for families would not have covered the cost of even the state-run pool for the uninsured, much less a decent family plan. Indeed, it was $250 a month short.

* McCain would expand HSAs, which would be no help to a family like the Giarde's facing a $50,000 hospital bill not covered by inadequate insurance. Given their inability to afford the state plan and the fact their faltering business was already struggling to afford their existing plan, how likely is it that they would have also put aside a few hundred dollars a month for first-dollar coverage decisions like preventive care? Isn't it more likely that, if they had the money, they would have used it to buy adequate coverage for serious illnesses like Mr. Giarde's?

Would McCain's promised Guaranteed Access Plan to make state programs to cover the uninsured affordable have made the difference for this family? His proposal lacks any details. But as I said earlier this week, his advisers' claim that it would cost a maximum of $10 billion nationwide lacks any credibility. That's just $200 per uninsured person in the pool. For every Giarde (someone who suffers from a serious or chronic illness), there would need to be over 600 people who didn't cost the system a dime. How likely is that?

Health Wonk Review

A new one is up at the Medical Humanities blog. Check it out!

HSAs -- Another Wasted Subsidy for the Well-Off

No one should be surprised by the Government Acccountability Office report out yesterday showing that the six million Americans who opened Health Savings Accounts have an average household income two-and-a-half times the national average ($139,000 versus $57,000). The economics of tax breaks compels it.

In theory, HSAs were designed for people with high-deductible insurance plans to cover unanticipated but large medical expenses. But they work like Individual Retirement Accounts (IRAs). The government allows a household to deduct a dollar from income for every dollar it deposits in an HSA.

But high income families benefit much more than low income families from such schemes. Why? Because high income families pay at a higher tax rate. So, if that family with $139,000 in income is in the 31 percent tax bracket, every dollar deposited in an HSA saves it 31 cents in taxes. But if that family with $57,000 in income is in the 15 percent tax bracket, every dollar deposited in an HSA only saves it 15 cents. In that sense, it is like the home mortgage deduction, whose benefits also go disproportionately to people who have the largest mortgages and pay the highest amount of interest on their homes.

Reps. Pete Stark (D-CA) and Henry Waxman (D-CA) are pushing legislation that would require proof that withdrawals from HSAs are actually going for health care. But that wouldn't change the fact that 40 percent of people with high-deductible plans haven't opened these accounts, and won't. For people in the lower middle class or the poor who have to buy a high deductible plan because they work for a lousy employer who either doesn't provide health insurance or only offers high-deductible or high co-pay plans, how likely is it that there will be room in their budgets to also sock away a couple hundred dollars a month for a rainy day health care fund?

HSAs are another gimmick based on the illusion that consumer choice is the best way to rein in rising health care costs. Make patients have "skin in the game," and they will make wiser choices, the theory goes.

Yet as many studies have shown, consumers don't make wise choices when forced to spend their own money on health care. In the short run, they skimp on routine and preventive care, which only makes it more likely that they will develop chronic conditions. And when either chronic disease or a medical crisis occurs, HSAs are quickly exhausted and become irrelevant in determining what kind of care people choose.

HSAs are nothing but another health care plan for the well-off that undermines preventive care. The next Congress should repeal this wasteful subsidy, not tinker with its rules.

McCain's Plan

What was most notable about presumptive Republican nominee John McCain's health care plan unveiled Tuesday was the campaign's unrealistic assessment of its impact on people with life-threatening conditions like cancer, the millions of Americans with chronic disease like diabetics, or preventive care. Instead of promising to expand insurance, as the Democrats are offering, McCain fully embraced the individual private insurance model cooked up by conservative think tanks overly enamored of free market medicine, which no place on earth other than the U.S. takes seriously.

Like President Bush's proposal which the Democratic Congress dismissed out-of-hand, the McCain plan would end the federal subsidy to employers for providing health insurance and give it as a tax credit to individuals ($2,500) and families ($5,000). This is about half what a family plan costs today, leaving the average family of four needing to pay around $400 a month for coverage comparable to what they now have.

You don't have to be a rocket scientist to see that in today's economy, many relatively healthy families who are currently uninsured will choose to underinsure, buying plans without first dollar coverage (whoops, there goes preventive care), with high deductibles and co-pays for routine care (huge extra bills for people with chronic disease), and that limit coverage for expensive cancer drugs (the so-called Tier 4 drugs) and put a cap on total coverage.

The plans authors claimed many employers would continue to provide insurance to retain their best employees. Don't they believe their own free market rhetoric? By removing the tax break, they would create a powerful incentive for even the most well-heeled companies to cap their health care expenses by offering flat payments in addition to the government credit. Over time, as health care costs continued to rise, more and more Americans through their individual choices would find themselves in the chronically underinsured pool.

McCain's answer to the uninsured and underinsured that his plan would leave behind is a new health care welfare system. Er, I mean a safety net. The campaign would create a federal-state program (capped, he reserved his strongest language for his refusal to create an unfunded mandate) that paid for uncompensated care delivered at hospitals. According to the New York Times, McCain's top domestic policy adviser, Douglas Holtz-Eakin, estimated the federal share would be about $7 billion and $10 billion.

I doubt that estimate would fly at the Congressional Budget Office that Holtz-Eakin used to run. With 47 million uninsured, with millions of people already underinsured because of the inadequacies in their employer-provided plans, and with millions more choosing to become underinsured because of the inadequacy of the tax credits offered in McCain's plan, can he really think the federal portion of the safety net will amount to just one-half of one percent of our annual health care bill?

If they actually capped it at $10 billion, that wouldn't be a safety net. That would be Swiss cheese in a sandwich without bread, lettuce or meat.

Merck Effort to Enter Supplement Biz Suffers Setback

Niacin or Vitamin B, commonly available as an over-the-counter supplement, works fairly well to lower bad cholesterol and raise good cholesterol with one major problem -- it causes severe flushing in many people. Merck thought combining it with an anti-flushing prescription drug, laropiprant, would solve that problem, and open a new vein in the anti-cholesterol gold mine for the faltering drug giant. It hoped to generate $2 billion from the drug, called Cordaptive.

The FDA's "not approvable" letter for Cordaptive, issued Monday, struck a blow to those hopes. Merck didn't say what the FDA's concerns were with Cordaptive, but they may center on laropiprant, the long-term effects of which have not been studied. "We plan to meet with the FDA and to submit additional information to enable the agency to further evaluate the benefit/risk profile of (Cordaptive)," Peter Kim, who runs Merck's research labs, said in a press release.

In October 2006, Merck launched a clinical trial in patients with inherited high cholesterol to study Cordaptive's effect on plaque buildup in the arteries. But the company suspended the trial after the unimpressive results of the Vytorin trial (ENHANCE, which also measured plaque) were announced.

Now Merck is studying Cordaptive in a trial called THRIVE, which plans to measure actual outcomes. However, that trial has been criticized on the grounds that it compares Cordaptive to placebo, not niacin (both arms get a generic statin). So clinicians will not be able to know the long-term effects of laropiprant.

That may explain why the FDA questioned this drug. Laropiprant binds to a receptor that some animal studies suggest may have neuroprotective effects, raising the need to evaluate its safety. -- PM

Nothing But Nets

No, this isn't a column about the imminent elimination of my hometown Wizards from the NBA playoffs.

I was remiss last week by not commenting on World Malaria Day. More than a million people around the world die each year from the mosquito-borne scourge, most of them children. International health agencies and foundations are mobilizing resources to combat the disease. As regular readers know, I have written about anti-malarials, especially the artemisinin-based drugs derived from traditional Chinese medicine. But they are just one leg of the three-pronged strategy that can be used to eradicate the disease in an area. The other two are indoor residual spraying (where the quality of housing allows it) and widespread use of bednets.

There are controversies involved in the deployment of bednets in Africa, where malaria prevalence is most pronounced. Should the nets be distributed free, or sold through "social marketing" so that people will value them and help stimulate the local economy? The New York Times this morning didn't address the distribution question, but did note that there is a global shortage of bednets that could be addressed through greater charitable efforts.

Want to help out? I donated $25 last Friday to the Nothing But Nets campaign, jointly sponsored by the NBA and the UN Foundation. Why don't you join me. You can make your own donation by CLICKING HERE.

More Evidence of Our Collapsing Health Care System

If you didn't see the story in yesterday's Wall Street Journal on hospitals demanding upfront payments for cancer treatment, it is must reading. It documents what can happen when individuals have to buy their own insurance and get seriously ill after purchasing "limited insurance" policies.

Is the FDA Getting Tough on Surrogate Markers?

Allow me to introduce readers to PM, who will be guest blogging in this space from time to time. PM follows developments at the FDA closely.

Last week's surprise decision from the Food and Drug Administration that it will require a new cholesterol-lowering drug from ISIS Pharmaceuticals and Genzyme to actually reduce mortality from coronary artery disease may signal a subtle but significant shift in agency policy when approving new drugs that affect surrogate markers.

Cardiovascular (CV) surrogate markers are risk factors like high blood pressure, elevated blood sugar, low HDL cholesterol levels, and elevated LDL cholesterol levels that are associated with increased risk of heart attacks and strokes. In approving new drugs designed to prevent and treat CV disease, the FDA has often relied on improvements in the "surrogate endpoints," not the outcomes patients really care about -- reduced risk of heart attacks, strokes, heart failure and death. 
 
That approach has been unevenly applied over the years. Last month in The Journal of the American Medical Association, Bruce Psaty and Thomas Lumley noted the contrasting paths followed by the FDA with respect to two lipid-altering drugs, ezetimibe (Zetia and a component of Vytorin) and torcetrapib.  In the case of torcetrapib, a drug that raised "good" cholesterol (HDL) and lowered bad cholesterol (LDL), the sponsor carried out the ILLUMINATE trial, in which 15,057 patients with high CV risk were randomized to receive torcetrapib plus atorvastatin (Lipitor) or atorvastatin alone.  Although patients who received torcetrapib had higher HDL and lower LDL than patients who did not, the trial was stopped early because of an increase in the risk of CV events and total mortality in the torcetrapib group.  Pfizer subsequently halted the development of torcetrapib.
 
By contrast, ezetimibe was approved in October 2002 on the basis of its ability to reduce levels of LDL alone.  Clinical trials evaluating ezetimibe's impact on the risk of CV events were slow to start. Indeed, the ENHANCE trial, which evaluated the effect of ezetimibe on atherosclerosis, was not completed until 2006 -- four years after approval -- and the results were not reported until January of thsi year. Guess what? No effect on atherosclerosis was shown.

A large trial, IMPROVE-IT, to evaluate the effect of ezetimibe on CV events will not be completed until at least 2012.  If ezetimibe is ultimately shown to have no benefit for the prevention of CV events, thousands of patients will have been treated with an ineffective drug when more effective drugs were available.
 
Which brings us to this weekend's surprise announcement. Mipomersen, an LDL-lowering drug, is being developed by Isis Pharmaceuticals in partnership with Genzyme Corp.  While the sponsors announced Friday that the FDA was permitting reduction of LDL to be used as a surrogate endpoint for accelerated approval of mipomersen for patients with genetically-inherited high cholesterol (known as homozygous familial hypercholesterolemia or hoFH), the agency will require the companies to conduct a very large clinical trial with real clinical endpoints (heart attacks, strokes, death) if they want to expand its use to the broader population with high cholesterol levels.

It is unclear whether this represents a new FDA approach to approval of lipid-altering drugs when they are first-in-class, or whether the FDA has special concerns with mipomersen. The FDA has asked the companies to include data from two ongoing preclinical studies for carcinogenicity when it submits its filing in 2010, a year later than expected. Whatever the FDA's reason, it's the right approach to take. --PM

Industry Gifts Ban Urged, Speaker Fees "Discouraged"

A task force representing the nation’s 125 medical colleges has recommended a ban on gifts and free meals for students and faculty and stricter regulations of industry visits on campus. But the Association of American Medical Colleges, whose executive council will consider the proposal in mid-June, stopped short of calling for prohibiting faculty members from consulting or speaking on behalf of drug and device companies, or for eliminating industry’s role in financing continuing medical education (CME).

“Clear and well-though-out guidelines will optimize the benefits inherent in the relationship between academic medicine and industry and minimize the risks,” the report said.

The 30-member task force was chaired by Roy Vagelos, former chairman of Merck, and included the CEOs of Pfizer, Medtronic, Amgen and Eli Lilly. The latter two dissented from the report’s recommendations “strongly discouraging” participation in speakers’ bureaus. The report closely followed a proposal made two years ago by Columbia University’s Institute on Medicine as a Profession with one exception. That report called for academic physicians to abandon participation in industry speakers’ bureaus, which it called “an extension of manufacturers’ marketing apparatus.”

Besides banning gifts, the guidelines called for centralized management of free drug samples or, where that is not possible, some alternative that does “not carry the risks to professionalism with which current practices are associated.” Drug and device salesperson visits with individual physicians should be restricted to non-patient areas and by appointment or invitation only.

On speaking and consulting, the report suggested “to the extent that academic medical centers choose to allow participation of their faculty and staff in industry-sponsored, FDA-regulated programs, they should develop standards that define appropriate and acceptable involvement,” which was defined as full transparency and payment “at fair market value.”

Rather than eliminating industry’s role in financing CME, which now accounts for more than half of the $2 billion industry, the AAMC task force recommended that the money be deposited in a centralized fund. It also recommended establishing school-level audit committees to monitor CME activities to ensure they follow conflict-of-interest guidelines established by the Accreditation Council for Continuing Medical Education. At an Institute of Medicine hearing in March, the Center for Science in the Public Interest urged organized medicine to encourage physicians to eliminate the middleman and pay directly for their own continuing education since patients and consumers already paid indirectly for CME through higher drug and device prices.

The version of this story originally appeared in Integrity in Science Watch, a publication of the Center for Science in the Public Interest.

Housing -- Good or Bad Investment for the Little Guy?

With housing prices falling sharply in some areas of the country and stagnant on most others, many people are beginning to wonder if that traditional symbol of achieving the American dream -- home ownership -- is a wise investment. The Washington Post business section on this gray and gloomy Sunday in the nation's capital weighs in with a front page story from which casual readers will draw that incorrect conclusion. It is based on an incorrect assumption: that stocks have provided higher returns than housing over the long-term.

The story is accompanied by a chart from the National Association of Realtors comparing investments of $48,700 in either the median home or a Standard & Poor's 500 index fund in 1978. According to the chart, over the next 30 years that home would have appreciated 347 percent to $218,000. The basket of stocks, on the other hand, would grown a stunning 1,438 percent to $749,000.

That's an average annual return of 5.3 percent for the house, barely ahead of inflation, compared to nearly 10 percent for stocks, according to the chart. Slam dunk for stocks, right?

Alas, the author and the Post editors left out the critical factor in evaluating any investment: how much capital is actually invested to earn those returns. A typical homeowner in 1978 (and we're rapidly returning to those days of typicality as the financial finagling in home mortgage markets gets swept away) put 20 percent down on a home and took out a mortgage for the rest. So for that $48,700 house, the actual amount invested was $9,740; with closing costs, it can be rounded to a neat $10,000.

Let's forget for a moment that this homeowner over the years also got a substantial subsidy from the federal government for the interest paid on his mortgage. Let's also forget about the taxes paid on the dividends and capital gains earned from the stocks. (These factors are mentioned near the end of the story, just like the debt-to-equity issue, but neither are factored into the front-page chart calculation).

If we only look at the return of the house compared to the initial investment, we get a percentage increase of 1,690 percent. That's 200 percent more than the return from stocks.

It's testimony to the power of leverage, and homeownership remains one of the few areas in life where average people get to exert its almost magical powers. (You can buy stocks on margin, too, but few individual investors do since most invest through mutual funds.)

Of course, leverage has an equally powerful effect on the downside. When home prices plunge, equity in a home can quickly be wiped out. That's what happened to families that bought overpriced homes at the peak of the bubble with highly leveraged or no-equity loans.

But that's a relatively small sliver of the market. For most people, homeownership remains their number one source of household savings, and will remain so for the foreseeable future. It's almost shocking that a major American newspaper could so fundamentally misrepresent these basic realities of household finance.

Krugman's Confusion

Paul Krugman of the New York Times is one of my favorite columnists. And even though I voted for Barack Obama in the Maryland primary, I respect his pro-Hillary Clinton drumbeat of criticism aimed at Illinois' junior senator because I believed, until recent weeks, that spirited intellectual competition would sharpen both candidates for the bruising struggle ahead. I want the Democrats to win back the White House in the fall, a must in my view if we're going to get this country back on track. In the end, I'm a Yellow Dog Democrat. I'll gladly vote for either of them over John McCain, who promises us endless war in the Middle East and, on domestic issues, is a transparently duplicitous character getting a free pass from an infatuated national media.

As was apparent from the earliest days of this campaign, Clinton's greatest strength is among working class voters, educated women and older Democratic voters -- all for obvious reasons. The first constituency is crucial, since the others will go Democratic no matter who gets the nomination. The last time workers got a raise in this country was in the late 1990s. We're heading back into tough economic times. I don't think there's a dime's worth of difference between the two candidates on how they'd manage the economy, but trusting someone clearly associated with the last successful Democratic administration seems like a perfectly reasonable response to me.

But in today's column, Krugman attacks Obama for running ads stressing Clinton's support for making purchasing health insurance mandatory, and then suggests Obama's supporters have to be asking themselves "what is this campaign about?"

I don't want to rehash the wonkish debate over mandates. I know a lot about health care. I don't think they're necessary to get to near universal coverage. I think they're a trap politically. And they could be a trap as a system if they're not structured the right away, which is being proved right now in Massachusetts. Why should either Democratic candidate sign on in advance to this particular aspect of health insurance reform? It's precisely what a wonkish candidate who thinks they have all the answers would propose.

But that said, to suggest that there is no rationale for the Obama candidacy, as Krugman did this morning, begs a single word response: Iraq. Not once did he mention that word in his column. Not once did he mention foreign affairs. He only says that the Democrats need to position themselves as the party of prosperity in the fall, and that Clinton is the best candidate to do that.

What he ignores is going to be the main text of this year's fall campaign: What is America's approach going to be moving forward in its relations with the rest of the world? What face are we going to show a world where resources are increasingly constrained yet expectations are rising in its once-poor and still-poor precincts? Over the next couple of weeks, as these two excellent candidates engage in the final rounds of this long campaign, the debate should turn to who is best suited to turning the page on the failed policies of the recent past.

In November, Americans deserve a clear choice on how this country is going to handle Iraq, terrorism, oil, clean energy, and our relations with the developing world. Then, if they choose McCain, at least we will have walked eyes wide open into a future where there are even greater failures and more deaths and squandered treasure to come.

But Isn't That Socialized Medicine?

It was one of those storied occasions impossible to pass up. The President of the United States gathered leaders from both political parties on the White House lawn to honor a true medical genius, Dr. Michael E. DeBakey, the surgeon who was one of the first to conduct coronary bypass surgery. DeBakey, the child of Lebanese immigrants who turns 100 this year, did most of his pioneering work at Baylor in Texas, giving President Bush a few laugh lines at his home state's expense.

But then it was DeBakey's turn. From his wheelchair, he offered these words to the Congresspersons in attendance as they contemplate tackling health care reform:

I want to make a suggestion to the Congress about health care. I know that you have been working on this for many, many years. In fact I was one of President Kennedy's strongest supporters when he came out with Medicare when the medical profession was strongly against. I thought it was a great idea. I still think it's a great idea. Unfortunately, it's practical effect has not been that great. So I know you have sought a better health care plan for the needy. And unfortunately it has been elusive. But there is a model you should look at that I'm thoroughly familiar with because when I was in the military, I was assigned by the Surgeon General to the committee that (Gen. Omar) Bradley and (Rear Admiral Jean Hodgkin) Hawley worked on in fixing up the Veterans Administration. We made many suggestions that resulted in a superb medical service. I've been familiar with the medical services of the Veterans Administration since then. In fact, I developed their research program. I assure you that you can't find a better model. For one thing, its quality of care is superior. And for another, it provides that care at half the cost of other agencies both in and out of government. So you see how efficient it is. So there must be something about what they are doing that we could use to expand our program in health care for the needy.

I wonder what the president thought as DeBakey uttered those words. I wonder if Congress was listening.

Riskless Business

There's still a part of me that's a business reporter, so I couldn't help but notice the profit reports pouring in from drug and device firms in recent days. If I were to write a headline on a round-up story, it would be: "Drug, Device Makers Shrug Off Recession."

Wyeth earned $1.2 billion in the first quarter, virtually the same as a year ago. Glaxo profits were down 14 percent, but that was almost entirely due to a falloff in Avandia sales. Bristol-Myers Squibb saw profits surge 51 percent on a 20 percent increase in sales over a year ago. Boston Scientific beat expectations. AstraZeneca profits were down all of 3.7 percent.

Developing and marketing drugs is a risky business, consumers are constantly told. It takes a billion dollars to bring a new drug to market. Only one in 10,000 molecules make it from the lab to the bedside. That's why they have to charge so much for their products.

But as Stan Finkelstein and Peter Temin write in their new book, "Reasonable Rx," "investing at the drug company level is a good, solid and basically riskless (their emphasis) proposition."

No matter how many times industry analysts warn that a patent expiration is going to make this or that company vanish, it hasn't happened -- at least in the last quarter century. . . A large part of that stability comes from the fact that the industry has figured out how to price its products so companies stay financially healthy."

And, unlike Europe and Japan, there's no one in government to stand in the way. Medicare is prohibited from negotiating lower drug prices, while insurance company co-pays shift more and more of the burden onto consumers, effectively taking them out of the game of negotiating lower drug prices.

Decades ago, investment advisers counseled their clients to shift into consumer non-durable manufacturers like Procter & Gamble to weather a recession. People will always need soap and toothpaste. I suspect these days the word on the Street is to buy drug stocks if you want consistent earnings. Come hell or high water, people will continue taking their meds because there's at least one thing in life that is more precious than cleanliness, and that's health.

McCain on Job Training

So this morning I'm listening to NPR and hear a single soundbite from Sen. John McCain amid all the back-and-forth on the Pennsylvania outcome. It was compelling. He wouldn't promise to bring back the steel mills in Pennsylvania, just like he wouldn't promise to bring back the textile mills in South Carolina (I'm paraphrasing here because I didn't have a pen available to write down the exact quote). But he'd make sure that every displaced worker had access to education and training for the jobs of the future, not the jobs of the past.

So honest. So forward-looking. So, dare we say it, compassionate.

Here's John McCain's record on job training:

* In 2002, McCain voted to kill an amendment requiring the Labor Department to establish a pilot program providing low-interest loans to workers in job training or job assistance programs that would enable displaced workers to continue making their mortgage payments.

* In 2007, McCain said "he would reallocate money spent on existing retraining programs to help pay for his proposal" to create a wage insurance system for laid-off workers, according to the Detroit Free Press.

* In March of this year, McCain skipped a vote on a worker training program, which would specifically "improve the training of manufacturing workers." McCain instead attended a $1,000-a-plate fundraiser in Philadelphia.

In 2000, a Republican candidate running for president told the American people he was a "compassionate conservative" while offering private assurances to religious bigots and economic royalists that he was really one of them. Once in office, it was his private assurances, not his public utterances, that really mattered.

Alas, with the help of the press, it looks like it's going to be "fool me once, fool me every time" from the misnamed "straight talk express." It took me five minutes on the Internet to get the counterfactual from the AFL-CIO and Democratic National Campaign Committee websites (admittedly biased sources, but they referenced the specific votes in Congress). And, anyway, isn't it journalists' jobs to get the other side of fact-based questions, and not rely on campaign-style he said/she said?

Glaxo, the Supplement Maker

GlaxoSmithKline announced late yesterday afternoon that it will acquire Sirtris Pharmaceuticals, the Massachusetts start-up company developing an analog of resveratrol, the chemical in red wine thought to promote longevity by postponing degenerative diseases. To prove this to the Food and Drug Administration's satisfaction, clinical trials involving thousands of people, perhaps even tens of thousands of people, stretching over many years, will have to take place.

Of course, the FDA could abandon its traditional standard and allow Glaxo to market a resveratrol analog as a pricey prescription drug based on lesser studies, which would make it the equivalent of dietary supplement. Since supplements do not have to meet the FDA's scientific standards of efficacy, there are already numerous resveratrol pills on the market. Check out this comment on the Wall Street Journal's Health blog:

According to Wikipedia, Consumer Lab, an independent dietary supplement and over the counter products evaluation organization, published a report on 13 November 2007 on the popular resveratrol supplements. The organization reported that there exists a wide range in quality, dose, and price among the 13 resveratrol products evaluated. The actual amount of resveratrol contained in the different brands range from 2.2mg for Revatrol, which claimed to have 400mg of “Red Wine Grape Complex”, to 500mg for Biotivia.com Transmax, which is consistent with the amount claimed on the product’s label. Prices per 100mg of resveratrol ranged from less than $.30 for products made by Biotivia.com, jarrow, and country life, to a high of $45.27 for the Revatrol brand. None of the products tested were found to have significant levels of heavy metals or other contaminants.

So why would anyone buy this drug? The Glaxo "drug" will be chemically manipulated to be much more potent and more easily absorbed than the natural substance. Is that worth $100 or more a month, the typical price of prescription drugs?

Drug companies are already well down the road to selling drugs that influence biomarkers of disease. LDL cholesterol isn't a disease, but lowering its high concentration in people already at risk of coronary artery disease lowers the incidence of heart attacks and strokes in that population. High blood pressure isn't a disease, but numerous studies have shown that reducing blood pressure correlates with fewer heart attacks and strokes.

Now they're moving into substances that, in their natural form, are good for you. Frankly, I'd rather have a daily glass of red wine. And for $100 a month, I can probably afford better wine than I'm drinking now.

As Longevity Declines in Poor Areas

States Raid Tobacco Settlement Money

Life expectancy is dropping in rural parts of the U.S., a harbinger of what may lie ahead for the rest of the country, according to researchers who published the study in today's issue of PLoS Medicine.

The authors looked at county level data for two broad spans of time: the two decades after the election of John F. Kennedy; and the two decades after the election of Ronald Reagan. Here's what they found (the green areas indicate counties adding life expectancy compared to the national average with dark green being the largest increases; the light orange indicate areas whose life expectancy stayed the same -- which was below the national average, which increased as a whole; and the dark orange indicate areas where life expectancy was falling):

The authors blamed high rates of smoking, rising obesity rates and associated diseases (cancer, chronic obstructive pulmonary disease, Type II diabetes). They also noted that the last two decades of the 20th century marked a period of stagnant wages and rising income inequality, with the hardest hit areas being those left behind what has generally been considered a period of rising prosperity.

The lead author, Christopher Murray, an epidemiologist at the University of Washington, suggested the alarming data called for targeted public health campaigns to combat the physiological causes of declining longevity: smoking, obesity and sedentary lifestyles.

Which brings me to a less reported news item from yesterday: the American Legacy Foundation, which is the national organization that gets money from the 1998 tobacco settlement to run anti-smoking campaigns, will be in court later this week in an effort to stop Ohio from raiding its tobacco settlement trust fund to help balance the state budget. The southern tier of Ohio counties are among those whose life expectancy were either stagnant or declining as its economic fortunes declined.

Most cash-strapped states have already funneled their tobacco settlement money into the general revenue coffers. Only 11 states established trust funds to ensure the money was used for public health. Now Ohio is seeking to become the first to undermine those trusts.

Gov. Ted Strickland (D), who is sometimes mentioned as a potential vice presidential candidate for either potential Democratic nominee, says he needs the money for an economic development program, which, like most such state efforts, is designed to lure business to the state with special incentives. But as Michael Roizen, a nationally known wellness expert at the Cleveland Clinic told an audience at Case Western Reserve University last week, "If you want to do something to help, you write the damn governor and tell him he gets more jobs by keeping the money there and cutting down medical costs so we can afford to have jobs in the state."

So here's what it has come to in the good old U.S.A.: a declining state (sort of like Pennsylvania, where primary voters will be voting today), desperate to attract jobs, takes money away from citizens who are trying to reverse the effects of having no jobs in the first place.

Of course, if the anti-smoking campaign were taking place in Iraq, there'd be plenty of taxpayer money available to do both. On the other hand, when it comes to declining longevity, the Iraqis have a lot more to worry about than their sky-high smoking rates.

JAMA May Penalize Authors Who Hide Corporate Ties

Last week, the Journal of the American Medical Association ran two studies that showed the medical publishing industry has been played like a fiddle by the drug industry. The first revealed that Merck had employed ghost-writers on dozens of published Vioxx studies. A second alleged that a company-funded review of studies involving Alzheimer's and dementia patients had manipulated data to hide the drug’s dangers.

In an accompanying editorial, the editors of JAMA called for steeper penalties on authors who fail to disclose conflicts of interest, hide or manipulate data, or claim to have done work actually done by others. The proposed penalties ranged from requiring public letters of apology to a ban on publishing in the journal.

“When integrity in medical science or practice is impugned or threatened—such as by the influence of industry—patients, clinicians, and researchers are all at risk for harm, and public trust in research is jeopardized,” editor-in-chief Catherine DeAngelis and deputy editor Phil Fontanarosa wrote.

That editorial marks a hardening of attitudes by some journal editors toward repeated failures by scientists to reveal their financial ties to industry. In August 2006, DeAngelis rejected a ban on authors who failed to disclose conflicts of interest, claiming authors would simply seek out other journals. “It cleans our house by messing others,” she wrote then. The shift came just a few weeks after JAMA published corrections involving radiologists who failed to disclose their lung cancer screening study had been funded by the tobacco industry.

Notably absent so far from the debate is the New England Journal of Medicine, which got caught in another scandal last week (it also had not disclosed the tobacco-lung cancer screening connection). This one, revealed in the Wall Street Journal, involved an author of an article claiming tanning improved vitamin D uptake who failed to disclose his ties to the tanning industry trade group.

Portions of this item first appeared in Integrity in Science Watch, a publication of the Center for Science in the Public Interest.

Journalists Slam ABC Debate Tactics

The following open letter was posted on The Nation's website this afternoon. I'm a signatory to the letter:

We, the undersigned, deplore the conduct of ABC's George Stephanopoulos and Charles Gibson at the Democratic Presidential debate on April 16. The debate was a revolting descent into tabloid journalism and a gross disservice to Americans concerned about the great issues facing the nation and the world. This is not the first Democratic or Republican presidential debate to emphasize gotcha questions over real discussion. However, it is, so far, the worst.

For 53 minutes, we heard no question about public policy from either moderator. ABC seemed less interested in provoking serious discussion than in trying to generate cheap shot sound-bites for later rebroadcast. The questions asked by Mr. Stephanopoulos and Mr. Gibson were a disgrace, and the subsequent attempts to justify them by claiming that they reflect citizens' interest are an insult to the intelligence of those citizens and ABC's viewers. Many thousands of those viewers have already written to ABC to express their outrage.

The moderators' occasional later forays into substance were nearly as bad. Mr. Gibson's claim that the government can raise revenues by cutting capital gains tax is grossly at odds with what taxation experts believe. Both candidates tried, repeatedly, to bring debate back to the real problems faced by ordinary Americans. Neither moderator allowed them to do this.

We're at a crucial moment in our country's history, facing war, a terrorism threat, recession, and a range of big domestic challenges. Large majorities of our fellow Americans tell pollsters they're deeply worried about the country's direction. In such a context, journalists moderating a debate--who are, after all, entrusted with free public airwaves--have a particular responsibility to push and engage the candidates in serious debate about these matters. Tough, probing questions on these issues clearly serve the public interest. Demands that candidates make pledges about a future no one can predict or excessive emphasis on tangential "character" issues do not. This applies to candidates of both parties.

Neither Mr. Gibson nor Mr. Stephanopoulos lived up to these responsibilities. In the words of Tom Shales of the Washington Post, Mr. Gibson and Mr. Stephanopoulos turned in "shoddy, despicable performances." As Greg Mitchell of Editor and Publisher describes it, the debate was a "travesty." We hope that the public uproar over ABC's miserable showing will encourage a return to serious journalism in debates between the Democratic and Republican nominees this fall. Anything less would be a betrayal of the basic responsibilities that journalists owe to their public.

Spencer Ackerman, The Washington Independent
Eric Alterman, City University of New York
Dean Baker, The American Prospect Online
Steven Benen, The Carpetbagger Report
Julie Bergman Sender, Balcony Films
Ari Berman, The Nation
Brian Beutler, The Media Consortium
Michael Berube, Crooked Timber, the University of Pennsylvania
Joel Bleifuss, In These Times
Sam Boyd, The American Prospect
Lakshmi Chaudry, In These Times
Joe Conason, Journalist and Author
Brad DeLong, Brad DeLong's Semi-Daily Journal and UC Berkeley
Kevin Drum, The Washington Monthly
Henry Farrell, Crooked Timber, George Washington University
James Galbraith, University of Texas at Austin
Todd Gitlin, Columbia University, TPM Cafe
Merrill Goozner (formerly Chicago Tribune)
Ilan Goldenberg, The National Security Network
Robert Greenwald, Brave New Films
Christopher Hayes, The Nation
Don Hazen, Alternet
Michael Kazin, Georgetown University
Ed Kilgore, The Democratic Strategist
Richard Kim, The Nation
Ezra Klein, The American Prospect
Mark Kleiman, UCLA/The Reality Based Community
Scott McLemee, Inside Higher Ed
Ari Melber, The Nation
Rick Perlstein, Campaign for America's Future
Katha Pollitt, The Nation
David Roberts, Grist
Thomas Schaller, Columnist, The Baltimore Sun
Mark Schmitt, The New America Foundation
Adele Stan, The Media Consortium
Jonathan Stein, Mother Jones Magazine
Mark Thoma, The Economist's View
Michael Tomasky, The Guardian
Cenk Uygur, The Young Turks
Tracy Van Slyke, The Media Consortium
Kai Wright, The Root

Patients Protest Promiscuous Promotion of Off-Label Prescribing

A coalition of consumer groups later today will send a scathing letter to the Food and Drug Administration protesting a proposal to give manufacturers a blank check to promote the off-label use of drugs and devices. The letter, signed by Consumers Union, the Center for Science in the Public Interest, the Government Accountability Project and a half dozen other patient and consumer groups, charges the lenient guidelines will undermine the FDA's authority to regulate off-label marketing and lower incentives for firms to conduct rigorous clinical trials or seek agency approval for the uses to which the drugs are being put.

The guidelines mark a "180-degree reversal of prior practice (by) eliminating Food and Drug Administration review of articles that manufacturers plan to distribute to physicians. As a weak and dangerous alternative, the draft guidance proposes a de minimus self-regulating standard," the letter asserts.

Under the proposal, the only requirements on articles distributed to physicians in their offices by drug industry salesmen is that they come from peer-reviewed journals that have a conflict-of-interest disclosure policy and that they be "well-controlled," which is not defined in the draft guidance. The guidelines would not protect against distribution of ghost-written articles, such as the dozens of studies funded and written by Merck scientists that later appeared in journals under academic physicians' names. Nor would they protect against the mass distribution of so-called seeding studies, which, while peer-reviewed, often are of limited size and do not have statistical significance.

The guidance does not require that the distributed studies reflect the traditional and scientifically valid gold standard of medical research—randomized controlled clinical trials. Despite the best interests of medical research and patient safety, an increasing number of studies that appear in peer-reviewed literature are small in size, without a randomized control arm, or contain an inappropriate control arm (placebo instead of an approved use for that indication). Far too many studies are of limited or even insignificant statistical validity. Indeed, the proliferation of such studies in journals has become so prevalent that one former medical journal editor, Richard Smith of the British Medical Journal, branded medical journals “an extension of the marketing arms of pharmaceutical companies.”

The proposed guidance's conflict-of-interest rule is totally inadequate, the letter noted.

Journal conflict of interest policies are routinely violated by researchers and disclosure offers no protection against ghost-writing by industry paid consultants. Merck had dozens of ghostwritten articles drafted for its infamous pain-reliever Vioxx, according to a recent Journal of the American Medical Association article. Furthermore, what constitutes the weight of credible evidence is itself a contested terrain, with industry underwriting the creation of many evidence reviews and clinical practice guidelines.

"The proposed guidance would allow industry salespersons to distribute literature that industry has largely created under controls that industry has largely underwritten," the letter noted. "The FDA proposed guidance would be in effect a de facto deregulation of the nation’s medical information distribution system that would endanger patient safety."

One in five prescriptions in the U.S. (21 percent) are for uses not approved by the FDA. The majority of these unapproved uses (73 percent) lack any evidence or rigorous studies to support the safety and efficacy for that use, according to the letter.

Historically, the FDA not only reviewed literature distributed by manufacturers to physicians that described off-label use, but limited manufacturers to distributing articles for uses where the companies were at least seeking regulatory approval by running randomized controlled clinical trials -- the gold standard of medical research. The proposed guidance would sharply reduce incentives for manufacturers to complete such trials.

"When manufacturers can market drugs and devices with journal articles, they have an incentive to set up trials with endpoints designed to make their products look good, not meet regulatory standards," the letter stated. "Compared to the FDA approval process, the publication process makes it easier for pharmaceutical and medical device companies to hide information about the shortcomings or risks of their products. Companies will take advantage of the opportunity to delay publication of results they don’t like, as illustrated, for example, by the failure of companies to timely release risk and effectiveness information about Vytorin, Avandia, and Vioxx."

Individuals can issue their own protests before the Monday deadline by going to Regulations.gov and putting the docket number FDA-2008-D-0053 in the search field under the "Comment or Submission" tab. That will take you to “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices,” where you can hit the "submit a comment" button.

The Wall Street Journal ran a story this morning detailing drug companies' push for the proposal. The reporter did not seek a response from any consumer or patient group.

New Health Wonk Review

Want a single place to read about the latest and best of the health care blogosphere? Maggie Mahar of the Health Beat Blog has her excellent take in the latest edition of the Health Wonk Review. Check it out!

Last Night's Debate

I nominate ABC News debate moderators Charles Gibson and George Stephanopoulos for the worst performance by political journalists in a starring role in modern American political history. After 45 minutes of last night's debate, the questions from the alleged journalists had covered bitterness, Rev. Wright, bitterness again, Rev. Wright again, dodging bullets in Kosovo (I guess that passed for equal opportunity bullshit), and then, to top it all off, a question about Sen. Obama's relationship with Bill Ayers, who was a member of a radical fringe group 40 years ago. Then Stephanopoulos, a former Democratic Party apparatchik in the first Clinton administration, bated both candidates to publicly take the "no new taxes" pledge, one year before the Bush administration's massive tax break for the rich (enacted on the eve of war) is about to expire.

Only after the third or fourth commercial break and nearly an hour into the show did the first question come about one of the top three issues on the minds of American voters: Iraq. The economy was passed over quickly to move onto gun control. And unless I missed it while taking a bathroom break, the issue of health care never came up.

I logged onto the ABC News website after the debate and wrote a quick note in their feedback form. I politely informed them that I will never, ever watch ABC News again. Shameful.

FDA Set to Approve Ghost-Writing

All the major newspapers that circulate in the nation's capital (the New York Times, the Wall Street Journal, and the Washington Post) carried stories this morning about a new study in the Journal of the American Medical Association that showed about half of articles that appeared in the medical literature touting Vioxx had been ghost-written by employees or contractors working for Merck, the drug's manufacturer.

What none of those stories or the study mentioned was the regulatory context in which this study (and an accompanying one alleging Merck manipulated the data in one of those studies to hide the mortality risk among Alzheimer's patients who used the drug) appears. The Food and Drug Administration wants to give drug manufacturers like Merck a blank check to distribute to physicians nearly any article advocating off-label use of drugs that appears in the medical literature.

The only substantive criteria in the proposed guidance is that the article be peer-reviewed and reflect "well-controlled" clinical studies. It would abandon the FDA's prior practice of pre-reviewing articles advocating the off-label use of drugs before they could be distributed by industry salesmen. Under this proposal, virtually all of Merck's ghost-written studies could have been distributed. As it was, the company bought nearly a million copies of the seminal study that led to the approval of Vioxx that had appeared in the New England Journal of Medicine.

The draft guidance has already drawn fire from Rep. Henry Waxman (D-CA), and I commented on it in this post, "FDA Proposes Lack-of-Evidence-Based Medicine Policy" when it first came out. Perhaps the best thing that readers of this blog can do at this point is to write to the FDA protesting these proposed guidelines, which you can do by going to the Regulations.gov website, putting in the docket number -- FDA-2008-D-0053 -- and hitting the "submit a comment" button.

Despite a New England Journal of Medicine commentary opposing the guidance last week, there were only 33 comments as of this morning, many of them from industry groups that support liberalizing the reprint policy. A patient and consumer coalition in which I take part plans to file comments before the deadline, which is next Monday. I hope to post those comments in this space later in the week.

You can read the study on ghost-writing here; and the re-analysis of the Merck Alzheimer trial here.

This issues raised by Drs. Bruce Psaty and Richard Kronmal in the Alzheimer's trial are especially disturbing since the company, which ran the trial, did not set up a data safety monitoring committee. Company officials and lawyers quoted in the stories said it wouldn't have made a difference. But Psaty, one of the nation's leading independent biostatisticians, said, "This was a huge safety signal. If this had been made public in a timely fashion, many fewer patients would have used Vioxx, and fewer might have been harmed by it."

The authors conclusions, which go far beyond the ghost-writing issue, are worth pondering:

For sponsors that conduct their own studies or use contract research organizations to conduct studies, it is not clear how transparency in the reporting of results can be achieved if a sponsor chooses to represent its products in the best possible light. The commercialization of clinical trials has neither improved the quality of the science nor enhanced the protection of human research participants.

The findings from this case study suggest that additional protections for human research participants, including new approaches for the conduct, oversight, and reporting of industry-sponsored trials, are necessary. A clinical trials system in which sponsors fund the trials that are conducted by independent investigators would provide additional protections.

Frontline Special: "Sick Around the World"

I had the pleasure of getting to know T.R. Reid of the Washington Post when we were both stationed in Tokyo. Tomorrow night, he presents the first of his series "Sick Around the World" on PBS' Frontline. Check out this trailer, and you'll be sure to watch:

High Biotech Drug Prices = A Failed Industrial Policy

Insurance companies are charging many patients thousands of dollars a month in co-pays for very expensive drugs, the New York Times reported this morning. A quick glance of the list of drugs that the insurance industry funneled onto this so-called "Tier 4" co-pay list are recombinant proteins, products of the nation's biotech industry.

About half of the one dozen drugs highlighted in the graphic accompanying the article are made by Amgen and Genzyme, two of the nation's leading biotech companies. But rather than re-exploring the failures of these biotech industry giants, let's look at Copaxone for multiple sclerosis, which was the drug featured in the lead anecdote in the story and is made by Teva Pharmaceuticals, an Israeli company whose original claim to fame was as a maker of low-cost generics.

From the FDA Orange Book, we learn that the Food and Drug Administration approved this drug in 1996. From the nation's public registry of clinical trials, we learn that the primary approval trial for Copaxone (copolymer 1, a combination of four recombinant proteins) involved about 250 patients with relapsing MS, half of whom were randomized to placebo.

This trial, according to the government, was conducted at the University of Maryland on a National Institutes of Health grant with information provided by the Office of Rare Diseases at the Food and Drug Administration. In other words, taxpayers like you and me paid for the seminal research that brought this drug to market.

According to this website produced by a Brit with MS, we learn that Copaxone reduced the rate of relapses among patients taking the drug by about 29 percent. Subsequent trials, funded by Teva, showed that it was slightly superior or equal to the other drugs for the condition that are on the market (Betaseron by Bayer and Avonex by Biogen, both of which are recombinant forms of interferon). Most of these trials involved just a few hundred patients, and often did not have the statistical power to prove anything in these head-to-head comparisons.

Teva continues to fund research. Again, a quick glance at Clinicaltrials.gov suggests most of these trials compare Copaxone to other drugs for the condition. There are also a few companies seeking to get approval for their own brands of interferon to fight MS, undoubtedly attracted by the high prices set on Copaxone. The government is also still involved. The National Institute of Neurological Diseases and Stroke (NINDS) has financed Dr. Fred Lublin of Mt. Sinai Medical School to test 1,000 patients randomized to either Copaxone, Avonex or placebo. Unfortunately, that trial, which began in 2005, won't be completed until 2012, just two years before Copaxone goes off patent.

Now let's follow the money. A drug company brings a new drug to market based on government-funded research. It charges a huge price for the drug, but since its the insurance companies money, it's everyone's money, which means it's no one's money. So no one complains -- for a while. What does Teva do with the huge cash flow that comes from selling this very expensive drug to a small population of MS sufferers? It funds clinical trials to show it's drug is superior to other in the field, which it shows, sort of. But the trials are never really good enough to prove superiority, just good enough to establish market dominance, which was probably the real goal of the trials. So the government has to sort things out, but it gets back into the game very late and very slowly. The insurance industry, fed up with paying extraordinarily high prices, starts putting the financial onus on patients.

The only justification for the high prices slapped on this government-funded discovery is that it would generate research into new drugs and significant therapeutic insights. Consumers, who paid the tab through their insurance premiums, got neither for their investment. And the government, which could have used that money and much less of it to get started earlier in funding definitive trials, now must come with another huge infusion of cash (a 1,000-person trial will cost at least $10 million) to sort out the mess.

In 1991, when then Secretary of Health and Human Services Louis Sullivan was hauled before Congress to explain why it was paying so much money through the Medicare program for Amgen's Epogen, which is used in dialysis patients, he testified that it was to show Wall Street that this new exciting industry -- biotechnology -- would generate generous returns if it came up with innovative products. Isn't it time to call a halt to this failed industrial policy, especially when it comes to drugs brought to market with taxpayer support? Surely the patients like those now paying 25 percent of the cost these drugs in Tier 4 co-payments deserve better.

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How Not to Run a Comparative Effectiveness Agency

A version of this article first appeared on the Guardian (UK) website.

We live in an age where the answer to many questions is available with the click of a mouse. But when it comes to health care, asking what works best gets a sick person text messages from the Tower of Babel.

If you’re in your 60s and have a slow-growing prostate tumor, should you cut it out, take a drug, stick in a radiating seed, or just watch and wait? Ask a surgeon, a urologist, a radiologist and general practitioner that question, and you might get four very different answers.

As a result, patient care – and cost – varies wildly across the U.S., usually with little difference in outcome and often driven by what local hospitals offer and what physician specialties predominate in an area. Professional medical societies, patient advocacy groups and government agencies publish competing and often conflicting policies to guide clinical practice, while money from companies with a stake in their decisions permeates the entire system, including, all too often, the guidelines offered by the U.S. government.

To cut through the cacophony of competing advice, health care reformers in the U.S. are pushing for a comparative effectiveness agency to provide physicians, patients and insurers with authoritative analyses of what works best in medicine. Much of the oomph behind the push for comparative effectiveness (CE) research is coming from the companies that pay the bills.

And with estimates of waste in the health care system approaching 30 percent (that’s $600 billion annually), who can blame them? It seems like a relatively painless way to convince doctors that they ought to abandon less effective therapeutic approaches that needlessly drive up costs. “Look, here’s what you’ve been doing and its outcomes are not as good as this other (drug, device, procedure, test) that they’re using over here; why don’t you switch to what works best?” an authoritative agency could say. “And if what works best costs less, everyone will be better off.”

Well, not exactly everyone. If your income depends on peddling pricey products and procedures – and that includes many specialist physicians and most drug, biotech, and medical device manufacturers – discovering that an “innovative” new product is no better and maybe even worse than something that is already out there is not in your financial self interest.

Opposition from those groups has usually been enough to kill serious consideration of a CE Agency in the U.S., especially one comparable to the National Institute for Clinical Excellence, which conducts comparative analyses (including cost-benefit analyses) for Great Britain. While NICE has no real power to enforce its findings, it has become the de facto gatekeeper of care standards for the cash-strapped British National Health Service, which must live within government constrained budgets.

But the era where special interests succeed in thwarting the creation of CE agency here appears to be ending. Both Democratic Party candidates have made it a centerpiece of their health care reform strategies. Here's why. Covering all or most of the uninsured without cost controls will add anywhere from $50 billion to $100 billion a year in new health care spending. Under their plans, employers who don’t provide coverage would be subjected to new payroll taxes to cover the uninsured. Unless other costs are controlled, those new taxes would be prohibitively high.

Incorporating CE analyses into coverage decisions would the best way to offset some of those costs, with the savings distributed to everyone who buys insurance. A Commonwealth Fund study released in December estimated the health care system could save $358 billion over ten years by using CE analyses – anywhere from one-third to two-thirds the cost of covering the uninsured.

The movement gained a powerful ally in January when the slow-to-move but prestigious Institute of Medicine issued its own report, “Knowing What Works in Health Care: A Roadmap for the Nation.” It called for a “single entity” to produce “credible, unbiased information about what is known and not known about clinical effectiveness.”

A CE program, the report said, should develop a common standard for evaluating evidence and writing guidelines, and set priorities for conducting its own systematic reviews based on improving health and eliminating “undesirable variation.” It should also consider economic factors, including the cost of treatment.

Unfortunately, when it came to insulating the proposed agency from commercial pressure, the IOM report came up short. The priorities of the CE program should be developed by a committee “chosen to minimize committee bias due to conflicts of interest.” In a separate section on developing clinical practice guidelines, the report called on panels to “include a balance of competing interests and diverse stakeholders, publish conflict of interest disclosures, and prohibit voting by members with material conflicts.”

This is a prescription for paralysis for which disclosure is no cure. If commercial interests have any voice in the design of the studies, the committees' deliberations, or their decisions, it will doom the agency to either issuing innocuous guidelines or risk losing its credibility when affected parties charge bias influenced stronger recommendations.

Powerful forces are already mobilizing to make certain any comparative effective agency established by Congress remains a toothless tiger. When Sen. Max Baucus (D-MT) introduced legislation in March, Pharmaceutical Research and Manufacturers of America vice president Ken Johnson
said the agency should be “structured to promote better patient health and timely patient access to needed therapies, and avoid denying or delaying patients’ access to beneficial care, as what often occurs in Europe and Australia.” The Advanced Medical Technology Association, which represents device makers, insists that “governance of any public-private entity should include representation of all stakeholders.”

This theme was echoed in a recent article in the Journal of the American Medical Association, which likened a potential CE Agency to a Federal Reserve Board for medicine. Its authors – two prominent health care economists and National Institutes of Health bioethicist Ezekiel Emanuel, who also happens to be the brother of a powerful Congressman – also called for putting “stakeholders” on the board and having input into its studies.

This builds what economists call agency capture (when a regulated industry has undue influence over the agency set up to regulate it) into the very structure of the organization. No banks sit on the Fed’s board. And its studies are conducted by researchers who are scrupulously clean of financial ties to the banks they regulate.

It’s one thing to give stakeholders a chance to advice the process – just as they have input through comment and testimony into any regulatory proceeding. But to allow industry representatives to sit on the board, and ask clinicians with conflicts of interest to conduct its studies, would undermine the new agency’s credibility at the start – and doom it to being just another babbling voice in the health care wilderness.