There They Go Again - Merck Threatened Legal Action Against Italian Doctor who Criticized Zetia

It seems that when confronted with unfavorable facts or opinions, Merck executives like to threaten legal action, rather than just argue their side of the case.  Last month we discussed how Merck officials used the US court system to try to prevent a physician from publicizing evidence uncovered in prior litigation that suggested Merck employees had concealed the risks of Vioxx from research subjects.

Legal Threats to Shut Up a Critic

Recently, a British Medical Journal news article explained how Merck tried to shut up an Italian physician who dared criticize another of its drugs, Zetia (ezetimibe).

The Italian branch of the drug company Merck Sharp and Dohme (MSD) has stopped a leading public health doctor and administrator from circulating texts to GPs advising them about the use of one of the company’s drugs. 

In the texts, Alberto Donzelli—the head of education, appropriateness, and evidence based medicine at the public health authority of Milan (Milan Healthcare)—had analysed the published evidence on the cholesterol lowering drug ezetimibe and discouraged its prescription in addition to statins.

A letter telling Donzelli to 'cease and desist' was sent in February by MSD’s medical director, Patrizia Nardini, and was cosigned by the company’s director of legal affairs. They accused Donzelli of serious misconduct and a breach of medical ethics and threatened to sue him and Milan Healthcare for as much as €1.3m (£1m; $1.78m).

Dr Donzelli was defended by Dr Roberto Carlo Rossi, the Director of the Order of Physicians of Milan, the local regulatory body,

 Rossi replied in April, declaring that the medical commission had analysed and discussed the issue in depth and concluding that there was no reason to object on ethical grounds to Donzelli’s behaviour.

But,

in late May the company sent a second 'cease and desist' letter to Donzelli 

So,

In mid-June, Donzelli bowed to the request and removed the relevant material from his website....

The Anechoic Effect Trumped

Up to then, the story line was familiar.  We have often noted the anechoic effect, that facts or ideas that offend the rich and powerful in health care often get little circulation, have few echoes.  Health care professionals' may fear that speaking out may lead to great unpleasantness.  Self-censorship may be reinforced by knowledge that the pervasiveness of conflicts of interest in health care means that one's friends, colleagues, family members, or more particularly supervisors are likely to have financial relationships with big health care corporations.  Similarly, those in the media and in the medical and health care scholarly literature may have similar fears, knowing that advertising revenue often comes from health care corporations, and their executives and boards may have their own conflicts of interest.

But in this case, Dr Donzelli was not cowed at first.  Furthermore, neither was the BMJ, and then some people in the media.  Instead of quieting the issue, Merck's legal threats resulted in the BMJ news article.  Then, in short order, the story was picked up by Larry Husten blogging for Forbes, and by Ed Silverman's PharmaLot blog for the Wall Street Journal.  Amazingly, this time it only took Merck one day after this negative publicity to change its position.  Per Matthew Herper, again in Forbes,

Merck says that it 'regrets' using legal threats to push a leading Italian researcher to muffle his public critiques of one of the company’s cholesterol drugs.

Herper was able to get confirmation from Merck spokesman Steve Cragle who said

the physician would be able to post his arguments about the drug, ezetimibe, on his web site again without fear of legal reprisal coming from Merck.

So in this case, sunlight was an effective disinfectant.  Perhaps if some of  the health care professionals who have silently acquiesced to pressure to maintain the anechoic effect decided they would not take it any more, there could be a lot more disinfection.

Note that Merck seems to have a chronic problem with honest discussion about Zetia (as well as Vioxx).  In 2007, we first blogged about reports that Merck had suppressed results of clinical research that showed the drug could cause adverse effects on the liver.  Eventually in 2013, a Reuters article that somehow got by us at the time, but was summarized in FiercePharma, announced that Merck would "pay $688 million to settle two U.S. class-action lawsuits by shareholders who said they lost money because the company concealed the poor results of a clinical trial of the anti-cholesterol drug Vytorin [a combination drug that included ezetimibe]."  Although, "the settlements include no admission of liability or wrongdoing.  'There's probably some merit (to the claims) or they wouldn't have settled for such a large amount,' Judson Clark, a health care analyst with Edward Jones,..."  

Merck managers, like many other health care leaders, got away with making facts and opinions they did not like taboo as topics of conversation for a long time.  Maybe if the health care leaders who are used to producing the anechoic effect for their own benefit saw that doing so will not be so easy in the future, the fog that obscures honest discussion of health care dysfunction might start to lift.  True health care reform would enable such honest discussion, no matter who among the powerful it might offend.  

ADDENDUM (8 July, 2014) - See also comments in the Shearlings Got Plowed blog.  

Shut Up, They Explained (to Ezetimibe Critics)

One of our scouts alerted me to a remarkable editorial just published by Harrison, Brown and Raggi on the ezetimibe controversy [Harrison DG, Brown WV, Raggi P. Enhanced hype. Am J Cardiol 2008; 102: 368-369. Link here, requires subscription.]

We have posted before (as have many others,) about problems with the ENHANCE trial of ezetimibe (Zetia, by Schering-Plough, and one component of Vytorin, by Merck), and how the trial seemed to be designed and implemented so as to increase the likelihood of a favorable result for the sponsors' interests. Particularly controversial was the sponsors' decision to change the definition of the trial's outcome variable after the data was collected, (later reversed after it was publicized.) It also turned out that the supposedly "independent" panel responsible for that decision included a majority of members who had previous financial ties to Merck and/or Schering-Plough.

The ENHANCE trial was not meant to determine whether ezetimibe had any effects on clinical outcomes, that is, whether it made patients feel or function better, avoid morbid events, or live longer. Its focus was on whether the drug reduced the thickness of arterial walls in patients with very high cholesterol levels. The study failed to show even this effect.

Since no previous study had shown that ezetimibe leads to symptom reduction, functional improvement, prevention of morbidity, or extension of life, it was surprising that the American College of Cardiology and the American Heart Association rushed to the drug's defense, counseling physicians not to take patients off it. Why continue to give patients a drug that has never been shown to provide clinical benefit? In this post, we wondered whether this enthusiasm unsupported by clinical research evidence had to do with undisclosed conflicts of interest affecting the defenders of ezetimibe.

Since then, in the continuing absence of evidence about the benefits of ezetimibe, there has been continuing controversy over its use. Harrison, Brown and Raggi continued in this vein. They clearly sided with the American College of Cardiology's statement that physicians should not take patients off ezetimibe, which they contrasted with what they characterized as

hysterical coverage from Web sites, news organizations, and cardiologists who seem to seek high visibility.

So the "hype" and hysteria, according to Harrison, Brown and Raggi, were criticisms of attempts to manipulate the ENHANCE trial, and observations about the lack of clinical evidence supporting the use of ezetimibe. What made their article remarkable, however, was its suggestion that purveyors of "hype" and "hysteria" as defined by Harrison, Brown, and Raggi, should just shut up. First the three authors wrote,

Strong statements regarding guidelines or policy in the use of this drug by cardiologists (with little background in lipid research and atherosclerosis biology) are inappropriate and certainly premature.

Then,

unsupported premature claims regarding a drug’s effectiveness or lack thereof should be conveyed properly, as in the case of the American College of Cardiology’s official statement. There seems to be a recent love affair with the issuance of headline-grabbing statements to the press, and this should be discouraged. When done in haste without proper study and thought, they appear to be self-aggrandizing, and at worse, they are very misleading.

So this editorial is noteworthy not because it defended ezetimibe, or belittled its critics, but because it seemed to question the right to criticize the established dogma.

Obviously, the authors of the editorial have no legal authority to censor those whose views offend them. But even veiled questioning of the right to express dissent are contrary to the core values of science and medicine. For science to advance, open discussion and criticism of methods, results and interpretations is vital. For physicians to take the best possible care of patients, they must have access to the best possible evidence from clinical research, even if that evidence offends the powers that be or those with vested interests.

A clue as to why the authors took such an extreme position may be found in the last sentence of their article,

In the case of ezetimibe, we are concerned that this drug or its makers will be eliminated on the basis of hyperbole, misinformation....

Why would they be so worried as to raise the hyperbolic concern that the controversy over ENHANCE could cause ezetimibe, and even Merck and Schering-Plough to be "eliminated?" A quick Google search revealed disclosed that the authors collectively have multiple relevant financial relationships that they did not disclose.

• Dr David G Harrison is on the scientific advisory board of Atherogenics, Inc.
• Dr W Virgil Brown, according to a financial disclosure statement provided by the National Lipid Association, on whose board he sits, "has advisory relationships" with AstraZeneca, Bristol-Myers Squibb, Merck, Merck Shering Plough, Pfizer, Reliant, Kos, Lilly; has "research relationships" with AstraZeneca, Lilly, Kos, Pfizer, Takeda; has "educational relationships" with Abbott, Lilly; and has "speakers' bureau relationships" with AstraZeneca, Bristol-Myers Squibb, Merck, Merck Shering Plough, Pfizer, Reliant, Kos, Lilly, Abbott, Takeda, Kos.
• Dr Paolo Raggi, according to disclosure statements provided by HDCN for a 2001 meeting, "received grant support and honoraria from Genzyme Therapeutics and is a stockholder in Pfizer Inc;" and according to disclosure statements provided by the Office of Continuing Education for Johns Hopkins University School of Medicine for a 2007 meeting, received an honorarium from Amgen, and received grants, consulting fees, and speakers' honoraria from Genzyme.

Perhaps the authors' financial identification with Merck and Merck Schering-Plough, and with the pharmaceutical and biotechnology industries in general lead to such exaggerated concern. In any case, the authors should have revealed these financial relationships, and allowed readers to decide whether they might have affected their views. Nonetheless, while conceivably such relationships could have somewhat explained the authors' partiality to censorship, it does not excuse it.

As documented on the FIRE web-site, it is now commonplace for academic administrators to try to silence those who disagree with the prevailing campus dogma. This impulse to censor those who provide inconvenient opinions or facts now seems to be extending to the scholarly medical literature. It is ironic that those calling for censorship simultaneously seem loathe to reveal their financial relationships with those with vested interests in maintaining the status quo.

The inconvenient truths that we censor or hide surely will return to afflict us.

ADDENDUM (3 August, 2008) - See also comments by anonymous blogger "PM" on Gooznews.

Lawyers to have cholesterol feast: lawsuits target Vytorin's makers - and, who is responsible for the "confusion?"

In today's news we find that Merck and Schering Plough are coming under lawsuits as a result of the ezetimibe/Vytorin controversy. This was perhaps to be expected:

Lawsuits target Vytorin's makers
Plaintiffs contend the firms knew the drug didn't work.
Sat, Jan. 26, 2008

By Karl Stark
Inquirer Staff Writer

First came the negative publicity, then the lawsuits.

Merck & Co. and Schering Plough Corp., makers of the cholesterol-lowering combination drug Vytorin, are getting hit with a wave of lawsuits asserting the companies knew its product didn't work and delayed telling the public about it.

At least 10 lawsuits have been filed in federal courts, with half the filings in New Jersey, where both parent companies are based. Other federal suits have landed in California, New York, Ohio and Colorado.

The drugmakers "reaped billions of dollars in profits" by failing to release negative results, asserted a class-action complaint filed by a Philadelphia firm on behalf of Lionel D. Galperin of Washington state. The companies also caused patients to spend more money on Vytorin, which sells for more than $100 for 30 pills, compared with a lower-cost generic, the suit alleges.

Here is where I step off the alleged "anti-pharma" bandwagon ... sort of.

While I have criticized Merck's and Schering's mammoth marketing campaign for these drugs here ("Merck and Vytorin ... Who, Exactly, is Confused?") and here ("Full page ads in major newspapers: Does pharma really spend twice on marketing what it spends on R&D?"), I believe lawsuits with the slant of "Bush lied, people died" (i.e., the firms knew the drug didn't work but withheld the information) are both unmerited and especially unhelpful to those attempting to advance medical science.

This claim is in part based on the following:

The companies completed the [Enhance] study [on these drugs] in April 2006 but did not release preliminary results until a press release was issued on Jan 14 [2008]. That was more than a month after congressional investigators had written to company executives, asking about the delay and demanding documents.

The implication is that actual knowledge of the results were withheld from the public to protect the drug. I do not believe this to be the case. I recall genuine excitement at Merck about Zetia's cholesteral-lowering effects, and great confidence that it was a true breakthrough drug that would generate much needed revenue after multiple drug failures and patent expirations. Clinical medicine, however, is full of surprises.

While such excitement could motivate a company to withhold negative new information, I have a different interpretation of why such delays occurred. Pharma is in a state of downsizing. At Merck, a company that carried on a succcesful business for over 100 years without downsizing, the mass downsizing that began in Nov. 2003 and continues to this day was a major cultural "hammer over the head."

Such social changes tend to sink morale very severely. While Catbert the Evil HR Director might find this amusing, most productive poeple do not. It's also something that cannot be "massaged away" with HR propaganda and "employee appreciation days." As I noted in "Happy Accidents in pharma doubtful: Tax Break Used by Drug Makers Failed to Add Jobs" here, the stress of losing a job is like the stress of a death in the family or a divorce, and the stress of fear of losing a job is also pretty darn bad. As the Alaska state government piece on "surviving a layoff" cited in the above posting states, "remaining employees become overworked, burned out, extremely unhappy and put in a position of fear and uncertainty." It doesn't exactly take a rocket scientist to realize this.

Anecdotally, I reside in a Merck community and hear as much about morale from my local car dealer, haircutter, family medicine physician, restaurant waiters, and others. In fact, I don't believe clinical trials information was withheld deliberately. I believe morale is low, departments are understaffed, and people are playing "CYA" like their lives depended on it (as their careers and ability to pay mortgages and support families depends on their jobs, this is actually not unwise).

Taking morale issues into account, and adding in the three late-stage pre-launch drug failures of 2003, resulting cultural shift to mass layoffs, and the Vioxx debacle, extra long "CYA" to make sure the data and conclusions are correct is understandible in context.

In such an environment, where overworked, stressed out people basically give themselves (effectively speaking) hourly pay raises via doing less per hour, and return to seeing jobs as a value-for-value proposition where an employee in a mirrorlike fashion gives a company what it has earned (i.e., deserves) in terms of their committment and willingness to make sacrifices, long delays in handling complex clinical trials results sets - this study, of course, being just one of many - is not at all surprising.

In addition, politics being what they are in any corporate layoff, many good people (the movers and shakers) get laid off, and other good people can't stand the environment and leave for greener pastures. This leaves behind many less capable colleagues to pick up the slack. I believe the cause of the delays in data release are more likely to be found attributable to low morale, a lesser % of "stars" among the workforce than necessary for optimal effectiveness, dysfunctional self protection-style politics, and resultant lowered productivity.

As an aside, it would not surprise me if recent chemical spills of "liquid mustard gas" into the creeks in my community had at its roots a similar cause:

Pharmaceutical giant Merck has agreed to pay $20 million in assorted fines, environmental improvements and cleanup costs to make up for killing untold fish, fouling drinking water supplies and spoiling a season of recreation on the Wissahickon Creek in Pennsylvania with a toxic "liquid mustard gas," the Philadelphia Inquirer is reporting. The massive impact came from an old-school problem: Dumping toxic chemicals down the drain at a vaccine plant, from which they reacted with chlorine disinfectants and washed into the creek, wreaking havoc downstream for miles.

I do not believe the company would deliberately withhold clinical trials data, and therefore do not believe a "deliberately withheld" charge is reasonable with regard to the ENHANCE clinical trial results on ezetimibe (Zetia) and ezetimibe-Zocor(Vytorin) . If there is a good basis for a lawsuit, perhaps the people who should be sued are those in management and in consulting organizations that recommended layoff strategies and stole the soul of such a once-stellar company.

The newspaper also notes the following:

...The drugmakers aren't the only ones facing scrutiny. Both the American College of Cardiology, which represents most cardiologists, and the American Heart Association echoed the companies' assurances and urged patients on Vytorin not to panic after a major test of Vytorin was released on Jan 14. But their stands have drawn criticism from congressional investigators and others because both groups take in substantial sums from pharmaceutical firms.

I'm not going to comment further on this other than to say "that sounds familiar", as the conflict of interest issue affecting medical professional societies has been well addressed by my Healthcare Renewal colleagues.

I will, however, comment on this:

W. Douglas Weaver, president-elect of the cardiologists, echoed those concerns. "We really had huge numbers of patients calling physicians' offices and not knowing how to interpret this information," Weaver said. "People were discontinuing statins because of the confusion."

The unstated but not-so-subtle implication (to those who understand marketing and "spin") appears to be that the big, bad, "anti-pharma" zealots and their allies in the media have gotten the poor public all confused, and the public is stopping their lifesaving meds as a result.

Having been involved in drug nomenclature activities at Merck as well as being familiar with the work of groups such as the Institute for Safe Medication Practices, one major goal in drug naming is to prevent confusion regarding the drug's nature and purpose. One creates drug names to assure that one drug is not confused for another, by healthcare professionals, patients, and others. Information scientists and others work very hard to select names for drugs that do not "resemble" others in spelling, phonetics, etc.

Now, just who is responsible for the confusion among patients "discontinuing statins because of the confusion?"

It seems to me the brainiacs who came up with the marketing scheme of giving a combination drug consisting of a newly-generic drug and a newly-approved one an entirely new name to milk more income out of a drug going generic -- and effectively discourage doctors/patients from simply prescribing/taking two pills (the generic and the new one) -- are largely responsible.

How many patients really understand that their wonder drug has two parts, one old, one new, that they could purchase and take separately likely for less cost than the combination, and that only the "new" part has come under scrutiny? How many understand that if the statin part of the new combination drug doesn't agree with them, they would have to discard the drug instead of simply replacing the statin? In addition, do busy general practice physicians understand this? One wonders.

It therefore seems the marketing folks as well as the drug naming approval organizations and the FDA carry significant blame for the "confusion." Perhaps this is a case of the unexpected (or should I say the predictable but undesired?) happening that provides evidence drug combinations should not be given snappy new names or approved as expensive "new" drugs.

Finally, I cannot but think it ironic that just as VIOXX and other similar drugs may have caused platelets and/or blood vessel walls to become more "sticky" and create vascular side effects, so ezetimibe might cause cholesterol and/or blood vessels to be more "sticky" for reasons not yet understood and negate some of the cholesterol lowering effects. It would be ironic indeed, as the newspaper article suggests by the observation "the combination drug failed to provide any benefit and even performed slightly worse than Zocor alone", if long term studies show ezetimibe to create more harm than good.

However, clinicians, the company and the regulators should be prepared if this occurs to get the data out ASAP when it is available fron ongoing studies - low morale or not.

-- SS

Full page ads in major newspapers: Does pharma really spend twice on marketing what it spends on R&D?

At this post ("Merck and Vytorin ... Who, Exactly, is Confused?") I commented on a full page ad (actually it's a two page ad, where page 2 includes prescribing information) being run by Merck and Schering Plough in the Philadelphia Inquirer to defend drugs Ezetimibe and Vytorin. I predict it is running in other papers in other major markets as well.

I first saw the ad on Tuesday, Jan. 22. It has appeared in the Inquirer every day since, today included. That's at least four days; I don't know when the ad started.

The cost for the ad must be significant. It certainly gives life to the findings that pharma spends twice on marketing what it spends on R&D.

-- SS

Addendum: readers mentioned it also appeared in The Akron Beacon Journal, Boston Globe as well as The Wall Street Journal. I venture is has been in many others as well.

BLOGSCAN - The Sorts of People Who Get to Run Large Health Care Organizations

Back blogging on BrandweekNRX, Dr Peter Rost just posted about the sort of people who now run Schering-Plough, the company that, with Merck Inc, just got a lot of unfavorable publicity after it was involved in delaying the release of results from the ENHANCE trial of ezeimibe (see our last related post here.)

According to Rost, "Sean McNicholas is now Schering-Plough's Senior Vice President, responsible for ZETIA and VYTORIN, reporting directly to [Schering-Plough President] Carrie Cox, who dumped $28 million SGP stock last year." Previously, "Sean McNicholas was Vice President Marketing, Endocrine Care, Pharmacia, responsible for Genotropin marketing until the year 2001." But, "Pharmacia entered into a Deferred Prosecution Agreement with the Government for its illegal promotion of Genotropin for such 'off-label' uses as anti-aging, cosmetic use and athletic performance enhancement...."

Furthermore, "Carrie Cox was Vice President, Women's Health Care at Wyeth, responsible for marketing of Prempro and for Pondimin and Redux, two slimming products.... In September 1997, the FDA requested the withdrawal of Pondimin and Redux [parts of the fen-phen weight loss drug combinations] and Wyeth ended up paying well over $20 billion in class action settlements to women who alleged heart valve damage."

It makes one wonder about the sorts of people who get to run big health care organizations, especially in an environment where there seem to be no negative consequences when top leaders make poor decisions.

Why Should Patients Continue to Take Ezetimibe?: More Fallout from the ENHANCE Trial

We have posted before (as have many others, see below) about problems with the ENHANCE trial of ezetimibe (Zetia, by Schering-Plough, and one component of Vytorin, by Merck), and how the trial was designed and implemented seemed meant to increase the likelihood of a favorable result for the sponsors' interests. Particularly controversial was the sponsors' decision to change the definition of the trial's outcome variable after the data was collected. That decision was then reversed. Later, it turned out that this decision was at the behest of a supposedly "independent" panel, but one which included a majority of members who had previous financial ties to Merck and/or Schering-Plough.

Under intense media pressure, the results of this study were just released. As summarized by theHeart.org, they showed no statistically significant improvement in the thickness of arterial walls for patients who received ezetimibe, and no statistically significant decrease in the rates of revascularization, stroke, myocardial infarction (heart attack), or cardiovascular death in the group of patients given the drug. (The study was not big enough to have much statistical power to detect such an improvement, but the rates of all these outcomes except stroke were actually greater in the ezetimibe group.)

Up until the the release of these results, no study had shown that ezetimibe produces any clinical benefit, e.g., prevents heart attacks or strokes, prolongs life, etc. And the long-delayed results of the ENHANCE trial again showed no such benefit. Thus, why should any patient take this drug? Perhaps there is an argument that patients with pre-existing coronary artery disease with elevated cholesterol and who cannot tolerate a "statin" could use ezetimibe as a last resort, and with caution even then.

So it was surprising to see two major organizations dedicated to fighting heart disease so quickly rush to defend the use of ezetimibe. First, as posted by Ed Silverman on the PharmaLot blog, the American College of Cardiology (ACC) issued a statement that mainly warned physicians not to take patients off ezetimibe nor make "major clinical decisions" based upon the new study.

Soon after the ACC statement was released, Ed Silverman also blogged that the American Heart Association issued its own statement. In it, AHA president Dr Daniel W Jones also warned against precipitously stopping ezetimibe (again, despite a complete lack of evidence that the drug does patients any good.)

Why were both reports so concerned with keeping patients on a drug that had never been shown to be of benefit? The answer is not clear.

However, Ed Silverman also noted that the ACC report "was drafted by an unnamed group of ACC leaders and so-called prevention experts, and approved by the ACC president. Among those involved was Roger Blumenthal, a professor of medicine at Johns Hopkins University, who chairs the ACC’s committee on prevention of cardiovascular disease. However, Blumenthal is also on the speaker’s bureau for Merck and Schering-Plough, and has received unspecified research grants from Merck." There is also evidence that the ACC at least was previously supported by Merck. The Center for Science in the Public Interest reported that the ACC Foundation received $500,000 - $749,999 from Merck in 2002. (So far I have not been able to find any newer information about corporate sponsorship of the ACC or its foundation, one way or the other.)

Furthermore, not acknowledged in the AHA statement was Dr Jones' previous financial ties to Merck. He disclosed in the 2003 JAMA publication of the JNC 7 report that he was a consultant for the company. [Chobanian AV, Bakris GL, Black HR et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560-2572. Link here.] Furthermore, the American Heart Association receives substantial current funding from Merck and Merck/Schering-Plough. In its 2007 report, both corporations were listed as donors in the $1,000,000 -4,999,999 range.

So this case has many lessons. It is yet another reminder of the pervasive web of conflicts of interest that entangles so many physicians, medical academics, physicians' organizations, and other health care non-profit groups.

For the final words, let me quote Dr Stefan Kertesz, who was commenting on the pervasiveness of conflicts of interest affecting the 2004 National Cholesterol Education Panel guidelines that suggested drastic lowering of cholesterol for patients with heart disease and diabetes. (Hat tip for this to DB's Medical Rants.) These controversial guidelines may be one reason physicians feel compelled to use drugs to lower cholesterol which have, like ezetimibe, no proven independent benefits for their patients.

I'm not suggesting that these experts have opinions for sale. The problem is that when data are conflicting, wishful thinking and commercial interests may supplant a rational consideration of the facts.

To protect patients we need to do two things:

We should demand entirely public disclosure of the financial ties for any expert who helps define the standards for quality in health care. And we should demand that at least some of our experts come from outside the industry, altogether.

The point is this: The science of drug development and the science of quality in health care represent two very different enterprises. If we continue to let the drug developers have such a strong hand in defining quality, we will continue to fall prey to conjecture, to wishful thinking and hype. It would be best for our health to keep these two enterprises separate.

Data About Ezetimibe Adverse Effects Suppressed?

Here we go again. Last week, an article by Alex Berenson in the New York Times reported that Merck and Schering-Plough conducted trials of ezetimibe (Zetia, by Schering-Plough, and a component of Vytorin, by Merck) "that raise questions about its risks to the liver," but never publicly reported their results.

Partial results of the studies, alluded to in documents on the Food and Drug Administration’s Web site, raise questions about whether Zetia can cause liver damage when used long term with other cholesterol drugs called statins.

A Schering executive, when asked by a reporter about the unpublished studies, confirmed their existence. But the executive, Dr. Robert J. Spiegel, said the companies had not considered the studies scientifically important enough to publish their findings. Some may eventually be published, he said.

The unpublished Zetia studies, devised as safety tests, would not prove the drug’s effectiveness. But they would give the public more information about Zetia’s potential risks. All the unpublished studies covered periods at least one year in length and were intended to show whether long-term use of Zetia might pose dangers that short-term use did not.

Most of the studies about Zetia in which Merck and Schering have published the results covered periods of only 12 weeks — not enough time for liver problems to develop in most patients.

The unpublished studies, conducted from 2000 to 2003 according to the F.D.A. documents, were not listed on the industry Web sites where companies are supposed to register the results of all drug trials that were ongoing after October 2002. The New York Times discovered references to the studies in briefing papers on the F.D.A. Web site.

Together those studies cover several thousand patients who took Zetia along with statins for one to two years. The statins include Lipitor and Crestor, as well as Zocor, which is usually prescribed generically as simvastatin and is the statin used in the Vytorin pill. Doctors often add Zetia to a low dosage of a statin, because Zetia reduces cholesterol in a different way than the statins do and leads to deeper overall cholesterol reductions.

'We’re pretty comfortable that people don’t have trouble tolerating Zetia,' said Dr. Spiegel, the chief medical officer of the Schering-Plough Research Institute, Kenilworth, N.J.

I agree more with this response by Dr Harlan Krumholz, from Yale.

We keep telling people we want to practice evidence-based medicine, and what we keep finding out is that much of the evidence is obscured.

There is important evidence, but it’s not in public view. It’s hidden from investigators.

As I have noted now it seems ad infinitum, to make the best decisions about patient care, physicians and patients need access to the best relevant evidence from clinical studies. Concealing evidence about, say, the toxicities of a particular drug may lead to bad decisions, specifically, prescribing the drug when its possible harms outweigh its risks.

In addition, suppressing the results of clinical research betrays the trust of human research subjects who were participating because they thought the research might advance science and/or patient care. Obviously, suppressed research can do neither.

This is one more anecdote suggesting that either clinical research sponsored by the companies who make the products the research is meant to evaluate needs much stronger regulation, or such research should be taken entirely out of the hands of the companies who stand to benefit if its results turn out a certain way.

See also comments in the Clinical Psychology and Psychiatry Blog, the Hooked: Ethics, Medicine and Pharma blog (with clinical and clinical epidemiologic background), the Medical Evidence Blog (suggesting a boycott of ezetimibe), and the Scientific Misconduct Blog (warning, contains adult language.)