When New Drugs Do More Harm Than Good

Princeton professor Donald Light released a new study at last week's annual meeting of the American Sciological Association that suggests new drugs are twice as likely to cause harm as provide added benefits.

"Systematic reviews indicate that one in seven new drugs is superior to existing drugs, but two in every seven new drugs result in side effects serious enough for action by the U.S. Food and Drug Administration (FDA), including black box warnings, adverse reaction warnings, or even withdrawal of the drug," Light's press release said.

Light also accused the drug industry of designing trials that minimize evidence of toxic side effects by enrolling healthier patients than those who actually take the drug once it's on the market. They systematically exclude patients who are older, poorer or who have multiple health problems, and don't run the trials long enough to detect long term side effects.

“Based on our current system, the designation of ‘safe and effective’ on today’s new drugs could be replaced with, ‘apparently safe based on incomplete information, and more effective than a placebo,’” Light said.

Before you dismiss Light because of his background in sociology, check out this study on Health Affairs' website from Shelby Reed and associates at Duke University's School of Medicine. A frequent consultant for the drug industry, Reed agrees that much larger pre-approval trials can eliminate drugs that wind up -- like Vioxx -- doing more harm than good when used in the general population.

We found that the potential to limit adverse events can be an important consideration in sample-size determinations for preapproval trials. Requiring larger preapproval databases could be a cost-effective means of reducing adverse events in postapproval populations.

But this isn't just about safety. Getting more information both pre- and post-approval is crucial to learning what works in medicine and what insurers, including Medicare, should pay for. That common sense approach is gradually being implemented through Medicare's "coverage with evidence development" program, which got an editorial boost from Stanford University's Alan Garber in the same issue of Health Affairs. A medical economist, Garber also chairs the Medicare Evidence Development and Coverage Advisory Committee. Here's what he had to say about gathering post-approval data to improve both safety and effectiveness of drugs, devices, screening tests and other costly medical interventions:

Under CED (coverage with evidence development), Medicare will, for example, pay for an implantable cardiac defibrillator only if the recipient is enrolled in a registry that collects basic clinical and health outcome data. In other instances, CED means a requirement to participate in a randomized controlled trial. It might mean simply being part of ongoing routine data collection, or a collection of EHRs (electronic health records). The FDA, at least in principle, could adopt analogous approaches to the postapproval evaluation of drugs. But payers may be in a more powerful position to ensure that the data collection actually occurs. One of the most compelling arguments for requiring more preapproval data is that the FDA has so little leverage to enforce agreements after a drug or device is already on the market. Insurers, in contrast, can deny payment for a procedure that was not performed under the terms of an agreement for CED.

Key, of course, is adopting easily transferrable electronic health records. "If EHRs can become a low-cost source of clinically detailed data, the costs of both preapproval data collection and postmarketing surveillance may decline, even for randomized trials. It may become cost-effective to collect much more data--whether pre- or postapproval--if the costs decline," he wrote.

The failure of the medical system, which consumes 16 percent of gross domestic product, to find the resources to rapidly move to electric health records can only be explained by physician and provider reluctance to have anyone peering over their collective shoulders. It's time for their footdragging to stop.

The Rx Industry's Black Box

A drug company gets a letter from the Food and Drug Administration explaining why its application for a new drug approval has been rejected. The company writes a short press release. The company's stock plunges.

As Matthew Herper explains in this interesting Forbes Magazine story, the FDA cannot release the contents of the letter, which Congress, at industry's behest, has deemed proprietary information. The companies rarely release the letter. They only give their brief interpretation of what it said.

Moreover, a month ago, the FDA, again at industry's urging, removed the "approvable" or "non-approvable" labels attached to the rejection letters, according to the story. These FDA pronouncements at least indicated to the general public (and investors) whether the drug, given some additional testing, might eventually pass the regulatory tests for safety and effectiveness.

The story, misheadlined "The FDA's Black Box," concludes with a call for Congress to repeal the law that prohibits the FDA from releasing the letters. I agree. The FDA's analysis of failed drugs can provide important insights to researchers considering similar drugs and to physicians who may be prescribing similar drugs in that class.

But the FDA isn't the only agency with an interest in these matters. Even short of Congressional action, it seems to me that drug companies, at least the publicly traded ones, could be forced to reveal the contents of those letters by the Securities and Exchange Commission. Investors have the right to any information that will have such a material and immediate impact on a company's stock price. Companies should not be allowed to hide such information behind a few phrases in a brief press release.

Merck Consultants: Vytorin Critics 'Hysterical'

The editorialists over at the American Journal of Cardiology who last month attacked Vytorin critics as hysterics must not have heard that there are rules for people who live in glass houses who throw stones: they are required to let readers know when they moonlight for the stone maker.

The editorial by cardiologists David G. Harrison, W. Virgil Brown, and Paolo Raggi supported continued use of Vytorin and criticized the "hysterical coverage [of the ENHANCE trial] from Web sites, news organizations, and cardiologists who seem to seek high visibility." Hmm, I wonder if they were referring to comments that appeared here and here.

Not only were the editorialists upset with critical comments about Vytorin, but they appeared to be discomforted by the very idea of free speech. The last sentence of their editorial stated that "we are concerned that [Vytorin] or its makers will be eliminated" as a result of the press coverage of the ENHANCE trial.

Too bad they failed to point out that each of the editorial's authors has financial ties to either Merck and Schering-Plough, which makes and markets Vytorin, or other companies that make cholesterol lowering drugs.

The AJC wasn't alone in going after Vytorin critics. An editorial in the July Cleveland Clinic Journal of Medicine attacked cardiologists Steven Nissen and Harlan Krumholz for their views on Vytorin and ends with the apocalyptic concern that "unless change occurs, a vibrant pharmaceutical industry with the financial and intellectual capital to find and develop new, more effective treatments will cease to exist." The editorial was written by Michael Davidson, a consultant, speaker, and researcher for Merck/Schering-Plough.

Let's hope that those new treatments will be more effective that Vytorin.

Meanwhile, Ed Silverman on Pharmalot, a blog associated with the Newark Star-Ledger, reports that Rep. John Dingell (D-MI) has sent a letter to the Food and Drug Administration requesting the statistical analysis by Oxford's Richard Peto that dismissed the increased cancer cases and deaths in the SEAS trial and two other ongoing Vytorin trials.

-- PM

FDA Uses New Labeling Authority

The Food and Drug Administration has ordered Amgen and Johnson & Johnson to relabel their anti-anemia drugs Aranesp, Epogen and Procrit over the protests of both firms. The new label says therapy shouldn't be initiated until red blood cell counts fall below 10 grams per deciliter of blood and it will no longer include an upper bound of 12 g/dl, which had been tantamount to declaring the drugs safe at that level for which, as today's New York Times story points out, there is no evidence.

Why did it take since March, when an advisory committee recommended the changes, for the FDA to act? Despite authority in the last year's FDA reform law to order changes without company negotiations, Amgen had been pushing to exclude certain restrictions from the label change, specifically, including a ban on using the drugs for breast or head and neck cancers, which the advisory committee had also recommended. The companies won that battle.

Serendipity and Drug Development

An important perspective on why drug development productivity is declining appeared in yesterday's Financial Times. Authors David Shaywitz and Nassim Talib emphasized the inherent uncertainties of science, and the importance of serendipity in the process (a point made in my book, and what I frequently emphasize in my talks on the subject):

In the face of declining productivity, pharma companies have been trying to boost output by increasing efficiency, narrowing their focus to a handful of disease areas, shelving safe but ineffective compounds without fully exploring their scientific potential and trying to ensure that each project the company is working on is carried out with a clearly defined market segment in mind (emphasis added). Unfortunately, for new medicines in particular, this strategy often fails significantly to reduce exposure to negative uncertainty – all the bad things that can happen during drug development – and eliminates much of the exposure to positive uncertainty (serendipity) that remains so vital.

So intent are managers on maintaining focus that important opportunities for novel discovery are lost, as is the intellectual space for tinkering and capitalising on the chance observations and unexpected directions so important in medical research. Instead, pharma executives are creating an ever-more-rigid environment and then wondering why their productivity is going down, and why they have such difficulty attracting and retaining talent.

Jim Edwards Dissects Bad Math in Kids-on-Drugs Article

We welcome Jim Edwards back to the blogging fray, and note from his bio that he specialized in writing about drug pricing and drug R&D while at Columbia J-School (my own alma mater). Today's excellent post goes through the numbers in a New York Times article on the growing number of kids on drugs due to the obesity epidemic, and finds them implausible. Lesson to young journalists: It never hurts to haul out the back of the envelope and do your own math!

Experts: Vytorin Not a "Front-Line Agent"

As reported earlier this week, the latest trial involving cholesterol-lowering drugs found a troubling increase in cancer cases and cancer deaths in the group that received Vytorin, a combination of ezetimibe (Zetia) and simvastatin (Zocor, a statin). Ezetimibe is a cholesterol absorption inhibitor, a first-in-class drug that operates by a different mechanism than statin drugs.

As previously reported on GoozNews, ezetimibe was approved in 2002 solely on the basis of its ability to lower LDL ("bad") cholesterol, a surrogate endpoint. The FDA did not require Merck Schering Plough (MSP) to conduct clinical trials evaluating ezetimibe's effect on clinical endpoints (heart attacks, strokes, death, etc.), an unfortunate decision that we are still paying for today as millions of people continue to take a drug that may not be benefiting them.

Eventually, under pressure from the medical community, MSP sponsored a trial testing ezetimibe's effect on atherosclerosis -- the ENHANCE trial -- and started three trials testing ezetimibe's effect on clinical endpoints. ENHANCE tested the effect of adding ezetimibe to a statin (as compared with the statin alone) and showed no effect on atherosclerosis from ezetimibe, despite substantially lower LDL levels in the ezetimibe group.

The latest trial, known as SEAS, is the first Vytorin trial since ENHANCE to be completed. Unfortunately, SEAS tested Vytorin versus a placebo, so we have no way of separating out the effect of ezetimibe from the effect of the statin. Vytorin was no better than placebo in reducing the primary combined endpoint of aortic valve and ischemic cardiovascular events and a secondary endpoint of aortic valve events. However, Vytorin achieved a 22 percent reduction in the risk of ischemic cardiovascular events. This positive result was expected, given that Vytorin contains a statin that has reduced such events in other trials. The result, however, is somewhat underwhelming given that the Vytorin group's LDL went down a whopping 61 percent.

No two clinical trials are directly comparable, but as Allen Taylor (head of cardiology at Walter Reed Army Medical Center) pointed out in an interview with heartwire, the 22 percent risk reduction in a high risk population is less than was achieved in two other trials that tested simvastatin versus placebo. "That's actually less relative risk protection than was seen in 4S and the Heart Protection Study, studies using similar doses of simvastatin but with less LDL reduction," said Taylor, "It falls beneath one's expectations."

How ezetimibe works to lower cholesterol and whether it might have off-target effects is a matter of dispute, as discussed in a recent editorial by Allen Taylor that appeared in the Cleveland Clinic Journal of Medicine. That leaves many doctors reluctant to discount the cancer risk. "Obviously, if you see it in one study, even if it's not statistically significant, you've got to be worried," oncologist Ezekiel Emanuel of the National Institutes of Health said in an interview with USA Today. "Maybe this has a biological mechanism we don't know anything about."

"Your first reaction is, 'Is it just a chance finding?' Then you see it in a second trial, and say, 'Whoa, can this be true? What's the science here?'" Taylor told USA Today.

Asked about the results and how they fit into the context of existing Vytorin data, Harlan Krumholz of Yale University School of Medicine told heartwire that SEAS reinforces the message from March when the ENHANCE trial was presented at an American College of Cardiology conference. "This drug does not have sufficient evidence for it to be used as a front-line agent," he said. "Statins are the drugs of choice. The evidence is not even strong enough to say that people who cannot tolerate statins should go on it. It is an option. Right now using it is based on an assumption that you know what IMPROVE-IT will find." IMPROVE-IT is a large clinical trial testing Vytorin versus simvastatin alone, but the results will not be available until 2012, ten years after ezetimibe was approved.

-- PM

Vytorin and Cancer

The news that the cholesterol-lowering drug Vytorin (a combination of Merck's Zocor, a statin, and Schering-Plough's Zetia) didn't reduce heart valve disease but raised the risk of cancer sent the stocks of both companies plunging yesterday. I don't have much to add to the basic story. The New York Times got it right. Headline: "Trial Intensifies Concerns About Safety of Vytorin."

The trial's sponsors brought in Richard Peto of Oxford to explain away the cancer results, which, while small, reached statistical significance. Of the 1,900 people in the four-year trial, "102 patients taking Vytorin developed cancer, compared with 67 taking the placebo. Of those, 39 people taking Vytorin died from their cancer, compared with 23 taking placebo," according to the paper.

Said Peto, who compared those results to a still uncompleted set of trials of the combination drug: “I think we should not be diverted by fears of cancer.” His argument? It triggered many different types of cancers, not just one type. So it couldn't have been the drug.

What kind of science is that? According to Times reporter Alex Berenson, the cancer signal reached the 95 percent level of certainty, the benchmark used by medical researchers as statistical significance. You don't get to move the goal posts after the ball is kicked, in this case, away from where the data landed.

I guess I shouldn't be surprised. Though Peto has been a leading voice in the crusade against second-hand smoke, the last time we heard from him was when he explained away the late Richard Doll's undisclosed conflicts of interest with Monsanto. The two men issued a famous report in the early 1980s that downplayed the environmental causes of cancer.

He's always claimed to be a great stickler for the sanctity of the data. This appears to be a case where he should have let the data speak. If those larger trials come back without a cancer signal, then the famed epidemiologist (or others) can do a meta-analysis (a pooling of all the data) and say the risk is not statistically significant. But as of now, it would appear that this combination pill, still taken by millions of people, raises the risk of cancer.

Giving Up on Small Gifts

The Pharmaceutical Research and Manufacturers Association this morning will unveil a voluntary code asking member companies to give up the practice of showering drug logo-bearing small gifts like mugs, pens and mousepads on physicians. Both the New York Times and Wall Street Journal report that the code won't limit the consulting and speakers fees earned by so-called key opinion leaders who encourage other doctors to use particular pharmaceuticals.

Critics, while welcoming the move, will continue to push for the Physician Payments Sunshine Act, which requires disclosure of such gifts, according to the story. It seems to me that PhRMA's endorsement of a ban, while voluntary, should embolden the bill's sponsors to include that more far-reaching step, at least on small gifts.

But even if the chotzkes disappear from physician offices (as I write this, I'm staring at the Vioxx-labeled reflex hammer that a physician-friend gave me as a present a few years ago), this PhRMA guideline doesn't get at the most significant ways that drug companies (and medical device and biotechnology companies, who aren't covered by this voluntary guideline) influence medical practice.

Doctors in community practice take their cues for the most part from their professional societies, from the leading journals in their fields, from their annual continuing medical education classes, and, most importantly, from what will be reimbursed. With that thought in mind, here's a starter list of items that ought to be banned:

* Clinical practice guidelines that are written by physicians who double-dip on industry's payroll;

* Clinical practice guidelines that are underwritten by professional societies that accept cash from firms with a stake in the outcome;

* Continuing medical education classes that are underwritten by the drug and medical device industries (Pfizer recently announced it would stop underwriting CME at for-profit CME providers, a start);

* Medical journals allowing industry-funded physicians to write reviews and conduct meta-analyses that outline the "state of the science" in their medical fields; and

* Reimbursement guidelines that rely on compendia that are written by clinicians with financial ties to firms whose products they are evaluating.

The True Costs and Benefits of Avastin

The New York Times on Sunday revisits the escalating controversy over the high cost of cancer care with a major story on Avastin, Genentech's blockbuster drug for colon, lung, and breast cancer that is already generating $2.3 billion a year for the firm.

The story points out that "many patients with cancers other than those of the colon, lung or breast are taking the drug, even in cases where there is no compelling evidence that it can help." And now that the Center for Medicare and Medicaid Services has allowed oncologists to use the National Comprehensive Cancer Network compendium to justify payment for many more off-label uses, many of which have very weak evidence behind them (see this GoozNews post), you can be assured costs to patients and taxpayers will only grow in the years ahead.

The Times story asks all the right questions:

What does it mean to say an expensive drug works? Is slowing the growth of tumors enough if life is not significantly prolonged or improved? How much evidence must there be before billions of dollars are spent on a drug? Who decides? When, if ever, should cost come into the equation?

I addressed many of them myself last July in this GoozNews post.

Alas, the Sunday Times story provides no real answers. At the least, the story could have raised an idea that I addressed last February (in this GoozNews post). All results from the on- and off-label use of anti-cancer drugs like Avastin should be registered in a publicly available database so that researchers can later conduct studies to see how well they actually worked. This has been done for years in the Children's Oncology Group, and has resulted in tremendous improvements in the protocols for treating pediatric cancers. (I highly recommend clicking on that story and reading the comments if you're interested in this subject.)

Since the central motif of the story involved the high cost of the drug vis-a-vis its marginal utility, allow me to add a few facts to one misleading paragraph that some may interpret as justification for the drug's high cost. It was buried deep in the story and was couched in the journalistic phraseology reserved for "scoops":

Genentech, which has never before revealed what it spent to develop Avastin, now says that it and its partner Roche have spent more than $2.25 billion starting with Dr. Ferrara’s original work. The figure includes research, clinical trials and filing for regulatory approval and is well beyond what was spent by the federal government, which conducted important clinical trials of Avastin. Through May 2006, the government had spent $44.6 million on Avastin trials and related laboratory work, according to figures obtained from the National Cancer Institute by Consumer Watchdog, an advocacy group.

Here's what that paragraph doesn't include. First, it doesn't include the support the National Cancer Institute gave to Judah Folkman, the recently deceased scientist whose pioneering work on angiogenesis (blood vessel formation) gave Genentech and other firms developing vascular endothelial growth factor inhibitors a target to aim at. In just one year (1992, the first in an easily accessible database that I could turn up in two minutes of Internet searching), NCI awarded Dr. Folkman $1.1 million. The agency supported his work for over 30 years until he passed away in January (see this GoozNews obit).

It also doesn't include the $250 million a year that NCI spends (see this NCI budget) on maintaining groups like the Eastern Cooperative Oncology Group, which conducted three of the first four major third stage clinical trials that led to Avastin's approval for colon, breast and lung cancer (see this NCI fact sheet).

It also fails to put the $2.25 billion that Genentech spent in its proper context. That money was spent over many years. Every year, that money was a cost of doing business for the firm. That means, from an accounting standpoint, it was paid for by current consumers, i.e., you and me as patients and taxpayers.

Last year, Genentech took in $2.3 billion from the drug -- almost exactly what it spent over its 15 years of development. It accounted for about a third of its total revenue. How much did actually cost to make the drug? The cost of sales (i.e., manufacturing) came to just $1.6 billion for all its drugs or about 17 percent of sales. That means the gross profit margin on Avastin recoups the entire amount spent on its R&D over 15 years within 15 months.

It's also useful to compare that R&D cost to Genentech's pre-tax income, which was $4.2 billion, or its after tax income, which was $2.8 billion. Assuming that Avastin accounted for about a third of each, that means the company generates earnings equal to its entire R&D investment in less than three years.

The anecdotes of patients, taxpayers and insurers paying through the nose for the chance of extending lives for a few months are heartrending. As the story quotes former Merck ceo Roy Vagelos saying, the national debate on the wisdom of paying exorbitant prices for so little medical return is about to begin. Let's just make sure that all the facts are on the table as we have that debate.

Haste Still Makes Waste

Corrections in the press or scientific literature usually involve author backpeddling and gracious apologies. But that's not what Harvard researcher Daniel Carpenter offered after the Food and Drug Administration criticized his study showing that new drug approvals made on the eve of deadlines set by the Prescription Drug User Fee Act had a 14 percent likelihood of later getting a black box warning because of safety concerns. After reviewing the data (and making adjustments for new information that the FDA had not posted on its website), Carpenter concluded: "we found more modest but still significant associations between just-before-deadline approvals and safety problems."

Rx Industry Marketing in the News

A couple of major stories yesterday took aim at the drug industry's direct-to-physician marketing. BusinessWeek reveals how several doctors "routinely" failed to tell their patients about payments they took from Pfizer while prescribing Chantix, the company's smoking cessation drug. CBS News uses the death of a pre-teen girl who'd been prescribed Zoloft for minor anxiety to highlight the parents' anger that they had never been told their doctor was taking payments from the manufacturer, also Pfizer.

Both stories touted Sen. Charles Grassley's Physician Payments Sunshine Act, which would require that any payment to physicians greater than $500 be reported on a publicly available database. I'm all for it, but ask yourself this: next time you're at your doctor and he/she prescribes a drug, are you going to go online to look up whether they took money from the manufacturer (first you may have to look up the name of the manufacturer, since that is usually not clearly marked on the prescription or the label) before filling that prescription? And if they did, will you not fill it?

The estimated cost of direct-to-physician marketing has now reached $57 billion annually, according to the story (this is taken from a recent estimate that appeared in PLoS Medicine). It's not just direct payments, it's advertising, journal reprints, free samples, trade show exhibits, a sales force (about 90,000 reps at its peak) that alone must cost $10 billion a year in salaries.

Transparency is good. But wouldn't a total ban on such payments and tighter restrictions on the rest be better?

Testing Drugs on Vulnerable Vets

Last week, ABC News and the Washington Times reported that hundreds of veterans with post-traumatic stress disorder (PTSD) have been enrolled in Department of Veterans Affairs (VA) studies testing smoking cessation drugs, with 143 of these veterans taking Chantix, a drug that has been linked to severe psychiatric symptoms (see posts here, here, and here. The veterans are paid $30 a month for participating.

According to the ABC News/Washington Times report, the VA became aware in November that Chantix had been linked to psychiatric side effects, but waited over three months to notify the veterans of the potential danger. Late last week, the VA disclosed that 26 Serious Adverse Events (SAEs) had occurred during the Chantix study, including 10 of a psychiatric nature.

The ABC News/Washington Times story describes the case of James Elliott, a decorated Army sharpshooter with PTSD who started taking Chantix in November and soon started experiencing hallucinations and suicidal thoughts, unaware that Chantix might be causing them. In February, Elliott was tasered by police who were called to his home after he became confused and psychotic. "Lab rat, guinea pig, disposable hero," said Elliott in describing how he felt he was treated by the VA.

Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania, said the VA's behavior violated basic protections for humans in medical experiments. "When you're taking advantage of a very vulnerable population, people who have served the country, and the agency that's responsible for their welfare isn't putting their welfare first, that's a pretty serious breach of ethics," he said.

Caplan, who reviewed the consent and notification forms for the study at the request of the Washington Times and ABC News, said the VA deserved an "F" and that it has an obligation to end the study, given the vulnerability of veterans with PTSD and the known side effects of Chantix. "Continuing it doesn't make any ethical sense," he said.

Late last week, the VA announced that the study would continue but that it would send a letter to all 32,000 veterans who are taking Chantix, warning them of possible side effects, including suicidal thoughts and behavior. "Our first responsibility is to our veterans," said Veteran Affairs Secretary James Peake, who said he has asked VA doctors to review "the communications process" involving all VA studies using veterans who are suffering from PTSD.

-- PM

BMJ Takes on Key Opinion Leaders

This morning's British Medical Journal slams the drug industry's practice of hiring "key opinion leaders" among academic physicians, whose job is to promote sales of individual products with company-dictated presentations to practicing physicians. Australian journalist Ray Moynihan includes a revelatory interview with an 18-year veteran drug representative, who candidly admits "if that speaker didn’t make the impact the company was looking for, then you wouldn’t invite them back."

To read the interview, and see a video clip, click here.

What Took So Long?

The Food and Drug Administration on Monday slapped stronger warnings on anti-psychotic medications because they raise the risk of death in the nursing home-bound, slightly demented patients for whom they are often prescribed off label. In this fine blog post, my former colleague at the Chicago Tribune, Judy Graham, asks, "What took so long?"

Glaxo's Delay on Restless Legs Drug

GlaxoSmithKline is complaining that the Food and Drug Administration delayed in approving its once-a-day version of its Parkinson's disease drug, Requip (ropinirole). The drug, which mimics dopamine in the brain, has primarily been promoted as a treatment for restless legs, a disease invented by the company's marketing department.

According to this morning's Wall Street Journal, company executives told an investors conference that the FDA failed to give the drug priority status, which resulted in the drug coming to market after its patent on the thrice-daily version expired. The FDA is giving short shrift to drugs that are not innovative, the story suggested.

Let's explore this one a bit further. A once-a-day version of a drug that substitutes for a thrice-daily version isn't hard to make (it usually involves a minor modification of the original molecule that makes it harder to metabolize without detracting from its effectiveness). And, while it won't win anyone the Nobel Prize, a longer-lasting version does offer some benefit to patients in terms of convenience and increased compliance (patients are more likely to remember to take their pill every morning than every morning, noon and night).

So do companies rush to bring this level of "breakthrough" to market? No they don't. Whether it is for a phony disease like restless legs or a significant use like Parkinson's, they keep the long-lasting version in the wings until the patent expires on the original drug. In fact, they try to time their passage through the FDA so that it arrives in the marketplace just a few months before the old patent expires. This marketing-driven strategy seeks to wean physicians (and their patients) off the soon-to-expire patented drug by getting them to prescribe the newer version (using increased compliance as the selling point).

How long does it take to get regulatory approval for the newer version (including the necessarily clinical trials)? Hard to say, but obviously a lot shorter than the 10 to 12 years that it takes to get the original molecule approved. Five years is not an unreasonable estimate (only 12 to 18 months of which is after the completed application and data are submitted to the FDA for non-priority drugs).

A quick check with the Orange Book (the FDA's listings of medicines and their approval and patent expiration dates) shows that the original Requip was approved in 1997. Its key patents expired last year and in May of this year.

Glaxo knew the minute the drug came on the market that it could develop a version that only needed to be taken once a day. But did it rush into the lab to develop this innovation? Or did it slow its development program so that it could be marketed in time to replace the old drug when the patents expired? The evidence clearly suggests the latter.

So who is really to blame for the "delay" in getting Requip XL (the name given to once-a-day ropinirole) to market? Is it the FDA, or a corporate strategy that would sacrifice patient convenience and compliance in the name of bolstering the bottom line?

NCCN to Reveal Oncologists' Financial Ties

The National Comprehensive Cancer Network late last week announced that beginning in July it would reveal the financial ties to drug companies of oncologists who write its clinical practice guidelines. The change came in response to a Center for Science in the Public Interest campaign to force NCCN to open the books.

“Historically, the NCCN has disclosed the names of companies with whom there are relationships,” said Dr. William McGivney, CEO of the NCCN said in a press release. “We now will apply that to individuals so that the public may better use the scientific, evaluative information that we provide.”

Last Friday, the Center for Medicare and Medicaid Services gave oncologists the okay to begin using the NCCN compendium, which is drawn from its guidelines, to justify payment for the off-label use of anti-cancer drugs.

While the change in NCCN's disclosure policy is a victory for transparency, it doesn't change the underlying reality that many of the drug uses listed in the compendium do not have much evidence to back their inclusion. Cancer clinical trials often show that drugs like Avastin slow the amount of time before tumors begin growing again, but just as often there is no significant reduction in the time to death. Yet these trials are routinely used to justify that particular use in the NCCN and other compendia.

For the war on cancer to progress, the public needs better information about the outcomes from the use of these drugs in very sick and dying patients. CMS should consider requiring physicians to electronically report the outcomes of their chemotherapy regimens, especially when they involve the off-label use of drugs.

Independent epidemiologists and biostatisticians (perhaps working at a comparative effectiveness agency?) would then have a powerful database for analyzing the outcomes from the use of these drugs. While such analyses will not have the same predictive power as controlled clinical trials, it would give researchers and practicing oncologists valuable insights into what really works and what doesn't when it comes to treating the more than 100 forms of the dread disease. Patients' health, and the nation's fiscal health, deserves nothing less.

Adverse Events Reports Soar

The number of individuals who report negative side effects from taking prescription drugs has soared in the past decade, and now almost equals the number of adverse events turned in by physicians and pharmacists, according to newly released statistics from the Food and Drug Administration.

In 2003, the year before the Vioxx scandal broke, there were just under 50,000 such reports from consumers, about what it had been for the previous four years. But by 2007 that number had more than tripled to 174,206 adverse event reports. Over the same period, reports from providers rose 42 percent to 202,686 reports.

It is well-known that the FDA's adverse events monitoring system misses most unwanted and dangerous side effects because it relies on self-reporting by physicians and consumers/patients. That's why Congress last year voted more money to beef up the nation's post-market surveillance system. The FDA is currently hiring new biostatisticians to conduct epidemiological analyses of insurers' databases of patient outcomes like the one done by David Graham that proved just how dangerous Vioxx was.

But even when those new employees are in place, adverse events reporting by individuals, physicians and pharmacists will remain an important part of the system. Such reports alert regulators to the possibility that something may be wrong with a drug that was never noticed or was too rare to be picked up in the original clinical trials that led to the drug's approval. They are the clues that tell the biostatisticians where to look.

What these data clearly show is just how important consumer awareness is in generating those reports. The Vioxx headlines are fading. To help keep consumers vigilant, the FDA should move rapidly to put a prominent warning label on every drug container and package. It should state that the drug may cause unwanted and as yet unidentified side effects, and it should provide a 24-hour 800 number to call should such events occur. A similar warning should be contained on every direct-to-consumer print and broadcast ad.

Such labels cost manufacturers nothing. But they will generate additional anecdotal evidence that could help regulators identify the hidden dangers in some prescription drugs.

Pfizer's Study Raises Issues with Chantix

Last Thursday I discussed the recent Institute for Safe Medication Practices report showing a high level of serious adverse events associated with Chantix (varenicline). Since then I became aware of a Pfizer-funded study comparing the safety and effectiveness of Chantix and nicotine replacement therapy in the form of a patch.

The study, published online in Thorax in early February, was a 52-week randomized trial in which participants received either Chantix for 12 weeks or a nicotine patch for 10 weeks. Participants (376 in the Chantix group and 370 on the patch) received counseling at every telephone and clinic visit. Persons with a history of depression or other psychological disorder and a host of medical conditions were excluded.

The self-reported "continuous abstinence rate" (CAR), confirmed by measuring exhaled carbon monoxide, for the last 4 weeks of treatment was 55.9 percent for Chantix (weeks 9-12) and 43.2 percent for NRT (weeks 8-11). CAR through week 52 was 26 percent for Chantix and 20 percent for NRT, with the difference just missing statistical significance. Since all participants in the trial received intensive counseling to help them stop smoking, these percentages are higher than what can expected in the real world.

Adverse events were experienced by 84.8 percent of the Chantix group and 70.3 percent of the NRT group with severe adverse events were experienced by 9.8 percent of the Chantix group and 7.3 percent of the NRT group. Two patients in the Chantix group experienced serious depression or suicidal ideation.

This study was too small and excluded too many categories of patients to give a full picture of Chantix's side effect profile. Some general observations seem warranted, however.

1. Patients in the Chantix group experienced significantly more side effects, including serious side effects.

2. At the end of 12 months, the advantage in effectiveness for Chantix was relatively minor.

-- PM

Conflicted Judges Give Merck Another Victory

Judging by the pattern of courtroom decisions, you'd think Vioxx was a safe drug.

A three-judge panel in Texas today overturned a jury decision awarding $26 million to the widow of a man who had died from a blood clot eight months after he began taking the drug in 2001. It was Merck's second big victory of the day. Earlier a New Jersey appeals court reversed most of a $13.9 million settlement won in a non-fatal case.

If you're into keeping score, that's 11-3 in favor of Merck in individual cases that have made their way through the court system to final jury or appeals court decisions. Does that mean that juries and judges, once they hear all the evidence, generally conclude that Vioxx is a safe drug?

Hardly. Here's one confounding variable. In Texas, the appeals court judges who ruled in the drug company's favor were elected, and in recent campaigns had received contributions from the law firms representing Merck. "Outrageous," plaintiff lawyer W. Mark Lanier told the Associated Press.

The New Jersey decision, on the other hand, gives some hope to those fighting efforts by the drug industry to use federal regulation (or the lack thereof) to preempt state product liability laws (and a tip of the hat to Ed Silverman's Pharmalot blog for pointing the errors of news accounts; he reprints the court decision here). Though the decision overturned the punitive award, the compensatory damages (about a third of the total) were left in because of a traditional product liability claim that the company had failed to adequately warn its users about potential risks.

It's unlikely this decision will affect the business-friendly Supreme Court, which recently ruled in favor of preemption in a medical device case and will hear a similar drug case next fall. The prospects for injured patients keeping their right to sue are slim.

Merck lawyers have already effectively admitted some responsibility for the Vioxx disaster. Last November the company set up a $4.85 billion pool to settle personal injury cases that involved heart attacks, strokes or death. Some 45,000 people enrolled for payments as of March 31. FDA safety expert David Graham has estimated anywhere from 40,000 to 120,000 people died from Vioxx between 1999 and 2004 before Merck voluntarily withdrew the pain reliever from the market.

Taking Chantix to Stop Smoking? Proceed with Caution

Pfizer is launching an advertising and public relations campaign to reassure the public that taking Chantix, the anti-smoking drug now approaching a billion dollars a year in sales, is safe, the Wall Street Journal reports this morning.

The drug industry giant needs to counter the recent Institute for Safe Medication Practices (ISMP) report showing a high level of adverse event reports associated with the drug. The ISMP based its report on consumer and physician complaints filed with the Food and Drug Administration.

The report included 988 serious adverse events (SAEs) during the 4th quarter of 2007, including accidents and injuries, heart rhythm disturbances, heart attacks, seizures and abnormal muscle spasms or movements, high blood glucose and new onset diabetes, aggression, psychosis, suicide, severe skin reactions, and vision disturbances.

In response to the ISMP report, the Federal Aviation Administration said it would no longer permit pilots or air traffic controllers to use Chantix, and the Federal Motor Carrier Safety Administration advised medical examiners to not qualify anyone currently using Chantix for a commercial motor vehicle license. The Chantix label includes a warning that Chantix may impair driving ability.

The FDA recently issued an alert about psychiatric symptoms linked to Chantix and requires pharmacists to distribute a medication guide with Chantix prescriptions, warning of potential psychiatric side effects.

Chantix, which was approved in May 2006, is thought to achieve its effect in smoking cessation through partially blocking and partially stimulating a type of nicotinic acetylcholine receptor. Acetylcholine receptors play many roles in the brain and body and are central to muscle contractions, including voluntary movement as well as heart muscle contractions and the tone of the smooth muscles that line blood vessels.

Chantix is thought to be most active against a particular receptor that affects the release of dopamine in the brain. Dopamine plays a major role in addiction, mood, and muscle movement. Chantix was derived from cytisine, a smoking cessation drug that has been used in Europe for decades. Of note, cytisine is contraindicated for patients with hypertension and advanced atherosclerosis. The author of a 2006 meta-analysis on cytisine stated that studies of cytisine's toxicity in humans conducted by Sopharma, the manufacturer of cytisine, were not published in scientific journals and Sopharma did not provide him with copies when he requested them.

ISMP identified the "safety signal" for Chantix through monitoring the flow of quarterly adverse event reports to detect changes in the numbers of serious events and other trends. In the 4th quarter of 2006, Chantix appeared for the first time among a small group of drugs that accounted for 100 or more reports of serious injury during the quarter. By the 2d quarter of 2007 it ranked third among all drugs in the United States. By the 4th quarter of 2007 Chantix accounted for more reports of SAEs in the United States than any other drug.

The ISMP report notes that adverse event reports do not establish causality, and the authors recommend additional research to resolve questions about the safety of Chantix. In the meantime, the authors recommend that doctors and patients exercise caution in the use of Chantix and consider alternative methods of quitting smoking.

The federal clinical practice guideline on treatment of tobacco use and dependence, adopted in 2000 and updated this month, recommends that all smokers who wish to quit be treated with drugs, unless medically contraindicated. The guideline recommends the use of Chantix, buproprion, and nicotine replacement therapy. The guideline-writing panel, chaired by Michael Fiore, has been criticized (see this February 2007 Wall Street Journal article, this post by Roy Poses at Health Care Renewal Blog, and this post by Michael Siegel on The Rest of the Story Blog) for the ties of some of its members to the makers of stop-smoking products. Fiore, a strong advocate of the use of smoking cessation drugs, is the holder of a chair endowed by GlaxoSmithKline, the manufacturer of bupropion and various nicotine replacement products.

Michael Siegel, a physician with 20 years experience in tobacco control, recently stated that the guideline "overestimates the benefit of drugs in smoking cessation and overlooks population-based evidence showing that most people who quit smoking do so without pharmaceutical aids." According to this Associated Press article about the guideline, Lois Biener, a researcher on tobacco use and control at the University of Massachusetts in Boston, said there was little evidence that smoking cessation drugs are superior in the long run to quitting cold turkey, and that while a few studies have shown some benefit, it's "way less than what is claimed" by medication advocates.

-- PM

Conflicted Guideline Writers Pushed Dangerous Anti-Bleeding Drug

What were they thinking?

Early last year, a task force of thoracic surgeons and cardiovascular anesthesiologists met to write new clinical practice guidelines for how to conserve blood and prevent blood transfusions during heart surgery. Just a few months earlier, the FDA had learned that Bayer, the maker of Trasylol (aprotinin), a blood-clotting drug used in surgery, had hidden results of its own study of the drug from the FDA and from an FDA advisory committee. The story made national headlines.

The hidden data showed that patients who received aprotinin were at increased risk for death, kidney failure, congestive heart failure and stroke compared to patients who received other anti-bleeding drugs. Yet here is what the guideline, published in The Annals of Thoracic Surgery in May 2007, recommended:

1. High-dose aprotinin to reduce blood transfusions, blood loss and the need for followup surgery to stop internal bleeding in high-risk heart surgery patients. (The guideline notes that the benefits of use should be balanced against the increased risk of kidney dysfunction.)

2. Low-dose aprotinin to reduce blood transfusions and blood loss in other patients having heart surgery.

3. Lysine analogues to reduce blood transfusions and blood loss in patients having heart surgery. The guideline states, however, that the safety of lysine analogues "is less well studied compared with aprotinin."

The recommendations are labeled "Class I" (the classification for treatments for which the benefit clearly outweighs the risk) and "level of evidence A" (meaning sufficient evidence is available from randomized trials or meta-analyses). The authors rejected the safety concerns with aprotinin that had been raised by Dennis Mangano and colleagues in a 2006 study published in the New England Journal of Medicine.

A subsequent study published by Mangano's group in the Journal of the American Medical Association in February 2007 was not discussed. It is unclear whether the JAMA study, which found that aprotinin raises the risk of death over five years after surgery, was available at the time the guideline was being written. If not, one wonders why such important information did not merit an update or revision.

The votes on the three recommendations were 15 to 2, 15 to 2, and 16 to 1. Eight out of 17 of the guideline authors disclosed ties to Bayer in the form of lecture and consulting fees and/or research support. Would the outcomes of these votes been different if so many of the authors had not had ties to the maker of aprotinin? If the guidelines had not endorsed continued use of aprotinin, could lives have been saved?

On November 5, 2007, the FDA requested a marketing suspension of aprotinin in response to preliminary results of a trial showing an increased risk of death in patients receiving aprotinin. A week later -- more than nine months after the JAMA study, the Society of Thoracic Surgeons finally announced that the portion of the guideline relating to use of aprotinin was under review.

--PM

BusinessWeek's Interview with FDA's Richard Pazdur

Here's some must reading this morning.

Anyone interested in the cancer drug approval process at the Food and Drug Administration should read this interview posted yesterday on the BusinessWeek website. Richard Pazdur, chief of the FDA's oncology drug division, has some interesting things to say about the differences between big and small companies that are trying to get new cancer drugs approved, and his emotional response to desperate cancer patients who want access to unproven experimental therapies.

But most importantly (from a scientific point of view), here's what he had to say about efforts by some companies to salvage drug candidates that have failed in achieving their primary endpoint, which is usually prolonged survival:

One of the problems we've had is people coming to us after a drug fails because they've invested millions and millions of dollars into a drug; and then it's, "How can we salvage this?" In other words, failing your primary endpoint and then trying to salvage a trial by looking at subgroups of patients. That's akin to shooting an arrow and having it land on a wall and then drawing a target around it. It's an attempt to resurrect a trial that has failed.

Pazdur has been a frequent target of Wall Street Journal editorials, whose editors seem to have one ear permanently cocked in the direction of the cancer quackery that has always flourished on the fringes of modern medicine. It's nice to see that he hasn't lost his bearings, or his courage in standing up for scientific principles at the FDA.

Is It Really the End of This Bloody Mess?

I suspect the trial lawyers will still have something to say about that.

A large clinical trial published Thursday in the New England Journal of Medicine confirmed that Trasylol (aprotinin), an anti-bleeding medication designed to reduce major bleeding during heart surgery, significantly increased the risk of death compared to two lysine analogues, which are much cheaper alternatives. The trial was stopped last October when it became apparent the drug was killing some people unnecessarily.

Patients on the slab for heart surgery were given aprotinin to reduce the need for blood transfusions. But, as this latest trial (called BART) found, they had a 50 percent higher risk of death in the first month after the operation. In an accompanying editorial, Wayne Ray and C. Michael Stein concluded that "in all likelihood, this is the end of the aprotinin story."

If so, this final chapter closes the book on a story largely written through the courageous and pioneering work of Dennis Mangano of the California-based Ischemia Research and Foundation, whose data-mining research and epidemiological review of outcomes among post-operative patients first brought the dangers of this drug to light. His story was featured on 60 Minutes earlier this year.

(And for some more background on how Bayer HealthCare, the drug's manufacturer misled the FDA, see this GoozNews post and this New York Times story.)

In the wake of this latest trial results' publication, the FDA announced that Bayer had notifed the agency that it would begin removing the remaining aprotinin stock from the U.S. market. Currently, the FDA limits access to aprotinin to investigational use according to procedures described in a special treatment protocol. The FDA also said that it is reviewing the BART data to reassess the appropriateness of this special treatment protocol.

In the editorial, Drs. Ray and Stein suggested that the aprotinin controversy lasted as long as it did because other trials of the drug tested it against a placebo instead of other available drugs. They also pointed out that although blood loss during surgery is of undisputed clinical importance, it is a surrogate endpoint.

They stated that, as with many other drugs, evaluation of anti-bleeding medications must include effects on death and other clinical endpoints, and not rely on surrogate endpoints (for more on that issue, see this GoozNews post.

Meanwhile, the results of the POISE trial, published online May 12 in The Lancet, call into question current guidelines that recommend use of beta blockers preoperatively in patients undergoing noncardiac surgery. These guidelines were based on previous studies that were small and showed conflicting results, but nonetheless adherence to the guidelines is used in quality assessments and hospital rankings.

In POISE, 8351 patients with cardiovascular disease or at high risk for cardiovascular disease were randomized to Toprol (metoprolol), a beta blocker, or matching placebo, given 2-4 hours before surgery and continued for 30 days. The patients who received metoprolol had fewer cardiovascular events but more deaths and strokes than the placebo group (all-cause mortality 3.1 percent vs. 2.3 percent, stroke rate 1 percent vs. 0.5 percent).

"What POISE says is that in the dosing we used, we see beta blockers have substantial risk in the perioperative setting," lead researcher Dr. Philip Devereaux told Heartwire, "and until someone demonstrates with a clear and large randomized controlled trial that an alternative dose is both effective and safe, it's just not rational, not in people's best interests, to be assuming -- that's how we got into this trouble in the first place."

He points out that if even 10 percent of physicians followed the guidelines, the POISE results mean that in the past decade 800,000 people have died and 500,000 have had a major stroke because they were given preoperative beta blockers.

In the cases of aprotinin and beta blockers in noncardiac surgery, many patients died or suffered injury because a drug or class of drugs were used without sufficient evidence, in the form of large randomized trials, showing that the benefits outweighed the risks that didn't show up in the limited clinical trials given to the FDA at the time of the drugs' approvals. Physicians need to weigh the strength of the available evidence carefully before adopting the latest new drug or treatment strategy.

-- by PM

FTC Wants to Waylay 'Pay to Delay' Deals

A few months back, the Federal Trade Commission sued Cephalon for paying four generic drug makers to refrain from selling generic versions of the anti-sleepiness drug Provigil until 2012. Each of the four companies had challenged the only remaining patent covering Provigil (modafinil), which is taken by people with sleep apnea, narcolepsy, and shift-work sleep disorder.

U.S. sales of Provigil totaled $800 million in 2007, and accounted for more than 40 percent of Cephalon's total revenue. The prospect of generic versions of Provigil entering the market posed a major threat to the company.

The saga began in 2002 when the four generic companies submitted applications with the Food and Drug Administration to begin marketing generic versions of Provigil. Each company had either designed around, or challenged the validity of, the only remaining patent on Provigil. Cephalon sued them all. In late 2005, with the companies nearing FDA approval, Cephalon agreed to pay the companies more than $200 million to stay out of the market.

Despite its losing streak in such cases, the FTC filed suit, accusing Cephalon of engaging in anticompetitive practices and abusing its monopoly power.

Two federal appeals courts recently upheld similar "pay for delay" settlements. Not surprisingly, these favorable rulings caused the frequency of such settlements to increase. In fiscal 2006, half of all pharmaceutical patent settlements (14 of 28) contained such payments. Such deals cost consumers millions of dollars by keeping lower-cost generic drugs off the market.

So what's behind the current case? It's clear that many FTC officials are tired of seeing their authority eviscerated by the courts (see this Washington Post op-ed by FTC commissioner Jon Leibowitz). By bringing the action against Cephalon, it appears the FTC is hoping to create a "circuit split" that could lead eventually to Supreme Court review. Of course, it's not likely the super-business-friendly Roberts court would side with consumers, either.

That's why the FTC is also supporting legislation pending in both houses of Congress that would ban the payoffs. Alas, that faces tough sledding, too. An Associated Press analysis of lobbying reports for fiscal year 2007 showed that about 12 generic and brand-name drug makers and industry trade groups spent $38.8 million on lobbying Congress.

"Lobbyists have a lot of influence in Washington," said Sen. Herb Kohl (D-WI), who sponsored the Senate bill. "If we can just get this to a vote, it will be pretty hard for people to vote against it. A vote against this is a vote against consumers."

-- by PM

Who Stopped the FDA Effort to Curb Procrit Ads?

The Food and Drug Administration held off ordering Johnson & Johnson to pull controversial Procrit ads in 2002 after the Office of the Chief Counsel, then headed by attorney Dan Troy, intervened. Five years later, Troy, now representing J&J from the corporate law firm of Sidley & Austin, emailed former colleagues at the OCC while the agency was considering slapping a black box warning on the drug to "make sure that people understand the limits of their authority."

The email revelations were contained in documents released last week during a House Government Oversight subcommittee hearing on the negative effects of direct-to-consumer (DTC) advertising. They were republished on The Cancer Letter website over the weekend.

It's not clear from the emails if Troy was directly involved in getting the FDA to retreat from pulling the Procrit ads in 2002. Nor is it clear that Troy's efforts to influence the agency in 2007 involved DTC, since the ads had already stopped running.

Still, Scott Amey, general counsel for the watchdog group Project on Government Oversight, called for the FDA to "investigate whether any employee involved in formulating the advertising policy is now working for the other side." Federal revolving door rules prohibit former officials from lobbying on "particular matters" on which they participated "personally and substantially."

In the intervening years, studies have concluded that high doses of Procrit and the other red blood-cell promoting drugs (Aranesp and Epogen by Amgen) may make cancers worse. The FDA last year slapped a black box warning on the drugs.

The Procrit ads, which ran from 1998 to 2005, promoted the idea that taking the drug would give cancer chemotherapy patients "strength for living." The FDA staff that reviewed the DTC ads in 2001 and 2002 called that claim "misleading." The claims "have not been demonstrated by adequate and well-controlled clinical trials," the agency said.

Those protests were overruled by the Office of the Chief Counsel, according to notes from a May 29, 2002 meeting.

During the hearing, investigations subcommittee chairman Bart Stupak (D-MI) grilled J&J's Kim Taylor, who heads its Ortho Biotech division, about the ad campaign's misleading claims. While the drug was approved for treating anemia associated with chemotherapy, it had never been proven to reduce chemo-related fatigue.

FDA staff letters as early as 1998 sought to get the company to modify its ads. "Procrit is intended, among other things, to treat anemia associated with certain chemotherapeutic regimens, not 'tiredness' in general," the agency wrote. In December 2001, it escalated its concerns, branding the advertising slogan "strength for living" as "misleading."

Taylor told Stupak that "we had a reassurance that during the period concerned, the FDA was satisfied that we complied with regulations." That reassurance appears to have come from the Office of the Chief Counsel, not the office that regulates DTC ads.

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. 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.

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.

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

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

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.

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.

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.

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.

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.

Celebrex Increases Heart Attack Risk, Too

With all the attention at yesterday's American College of Cardiology meeting in Chicago focused on the Merck/Schering-Plough Vytorin fiasco (Sen. Charles Grassley, R-IA, yesterday demanded more documents on the companies' withholding data), reporters largely ignored another damning study on Pfizer's Celebrex.

A pooled analysis of clinical trials of the last Cox-2 inhibitor on the market showed that patients already at risk of heart disease who take high doses of Celebrex tripled their risk of potentially lethal heart attacks and strokes. Even at the more common dose of 200 milligrams twice a day for chronic arthritis pain, the risk nearly doubled, from 6.9 events among 1,000 patients not taking the drug over the course of a year to 10.8 events for every 1,000 patients taking the drug for a year.

The statistical meta-analysis, conducted on a National Cancer Institute grant by researchers led by Scott D. Solomon of the Harvard Medical School, suffered from the trials it had to work with: all the trials used a placebo as the comparison and used fairly high doses of Celebrex. Had it used a drug like naproxen (sold over-the-counter as Aleve or Naprocyn) as the comparator, the results might have been similar to the Vioxx-naproxen trial that doomed that drug. And the high doses used in the pooled trials allowed Pfizer to dismiss the new analysis as not typical because it exceeds the labeled use, which already carries a black box warning about the heart attack risk at high doses.

But are people prescribed this painkiller heeding the warnings on the label? According to Pfizer's latest Securities and Exchange Commission filings, sales of its anti-arthritis medications rose to $2.9 billion in 2007 from $2.7 the previous year and $2.4 billion in 2005, the first year after the black box warning got slapped on the drug. How could sales of this drug be rising? Between April and July of last year, the company launched a massive direct-to-consumer advertising campaign to "clarify misperceptions among arthritis sufferers." It was so successful, they reprised the campaign starting in November.

On the American Heart Association website, where the trial got major billing, past AHA president Ray Gibbons suggested physicians pay close attention to their patients' underlying cardiovascular risk when considering using the drug. "Patients at the highest risk should be the most cautious," he said.

Yes, but when serious arthritis or back pain hits, or an aging Baby Boomer is about to go out and play 18 holes of golf, they're likely to grab a couple of those 200-milligram pills; and they'll take a few more when they get home. And if they do that repeatedly and they're already at risk of a coronary (overweight? diabetic? got a family history?), this latest analysis suggests they've unwittingly put themselves at much greater risk.

Newer Anti-Cholesterol Drugs Strike Out

The final version of the study that sank Vytorin and Zetia appeared in the New England Journal of Medicine over the weekend after its presentation at the American College of Cardiology conference in Chicago. (You can see a summary of the study here.) The take away lesson for consumers? When new classes of medicine come on the market to treat something for which there is already something available, stick with the older medication as long as it works, especially if it is a generic. That the two drugs generated over $5 billion a year in sales for Merck and Schering-Plough is testimony to the power of marketing, and the poverty of medical and regulatory science.

For a dispassionate review of the issues, or if you still have questions about whether you should be taking these drugs, I suggest you read this analysis by Dr. Harlan Krumholz, which was published yesterday on the Journal Watch website.

SEIU Disavows Lipitor Promotion

The Service International Employees Union issued the following statement in response to the Health Beat Blog article, which was reprinted on this website.

Recently, a letter appearing to endorse a well-known pharmaceutical was circulated by the International Association of EMTS and Paramedics, an affiliate of the National Association of Government Employees (IAEP/SEIU).

SEIU does not endo