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. They only need receive the standard of care in that country.

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, Zimbabwe, 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 them and none are on the national formulary. Hence, there is no local standard of care.

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 there 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 record 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. 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.

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.

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.

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.

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.

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.

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

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?

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.

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.

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

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.

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