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.

Merck and Vytorin ... Who, Exactly, is Confused?

Treating the number rather than treating the patient is usually bad medicine.

In today's Philadelphia Inquirer and probably a number of other papers, a full page ad appeared with the following in a huge, Victory-in-Europe-WW2-is-Over!! font:

Are you taking Zetia (ezetimibe) or Vytorin
(ezetimibe/simvastatin)?

Then the following statement is made in a large bold font, smaller than the headline's but still very large (ellipsis in the original, but bolded emphasis mine):

If so, you may be worried about recent news stories questioning the benefit of these medicines ... on the basis of a single study that has generated a lot of confusion.

The font size goes down another notch with this:

In fact, ZETIA and VYTORIN have been proven to lower LDL (bad) cholesterol along with diet in multiple clinical studies involving thousands of patients. Both the American College of Cardiology and the American Heart Association agree that lowering bad cholesterol is important.

The font then goes up a notch in size once again:

All of us at Merck and Schering-Plough proudly stand behind the established efficacy and safety profiles of ZETIA and VYTORIN.

If you have high cholesterol, follow your doctor's recommendations on eating right, staying active, and taking your prescribed medicines.

The ad is signed by Richard Murray, MD, VP, External Medical and Scientific Affairs at Merck, and Robert J. Spiegel, MD, FACP, Chief Medical Officer, Schering-Plough Corp.

I cannot help but be touched by this ad. It is factually accurate, gives good medical advice about following your doctor's recommendations and taking your meds, and appeals to the authority of the very prestigious ACC and AHA.

Here's the catch. In the "Important Information" column below the above material, along with contraindications and possible side effects, the statement is made that (bold in original):

"Zetia has not been shown to prevent heart disease or heart attacks."

In which case, I'm not sure who, exactly, is "confused" by the "single study."

The ad calls for treating the number, perhaps in the hope that it is treating the patient. However, hope and wishful thinking are not the tools of science. Roy Poses provides more detail on this issue here:

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.

I understand the rationale behind the new ad -- an attempt to keep sales of Zetia and Vytorin up to prevent yet another drug from failing in the setting of a thin pipeline of drugs ready for launch and looming patent expirations. I do not envy the difficult position these executives, trying to keep their businesses healthy, are in. However, I consider the ad to be bad spin, the kind in which politicians engage, not biomedical scentists and organizations. The real issues are:

Why should consumers and insurers spend extra on a drug like Zetia, which also can cause additional side effects, if it is shown to lower cholesterol but not shown to prevent heart disease or heart attacks, one of the major (if not the predominant) reason people take cholesterol-lowering drugs? Why "treat the number?"

I believe there is good evidence that many of the statin drugs do lower the risk for heart disease. If zetia does not, then why assume the expense and/or take the risk until meaningful clinical benefit to the patient, if any, becomes clear?

Other recent widely-publicized drug debacles have certainly given support to "erring on the side of caution."

That would seem to be the "un-confused" approach.

In fact, massive full page ads that cost a lot of money like this one may "treat the pharmaceutical company", but likely generate even more skepticism about the industry among the lay public and among critical-thinking clinicians.

I also add that the creation of a "new" drug (Vytorin) via the combination of two existing drugs (statin and ezetimibe) is likely a sign of a company trying to "do business from an empty wagon." It's regrettable when a company that had done as well as Merck in the past in creating truly "breakthrough" drugs has had to resort to such repackaging to stay financially viable.

I spent much effort at Merck to increase access to important informatics tools by drug discovery scientists to which access was rationed, an accomplishment I am proud of, but probably would not have had to perform if the industry understood the priorities for long term survival and research creativity better. This seems unlikely in a pharmaceutical industry dominated by non-scientist/clinician, quarterly profit-oriented, management fad-centric businesspeople at the helm.

Perhaps if as much resource and energy had been devoted by the pharma industry to R&D as to marketing (recent studies show a 2-to-1 overspend on the latter), and less had been spent on bureaucracy, the need for "repackaging" and "spin" by the industry would not exist - they'd be selling good drugs. And, I might still be employed in the industry, rather than part of the 4,400 laid off in 2003 when several other new drugs failed to make it into the sales wagon.

-- SS

Addendum: the above full-page ad has now appeared for the third straight day in the Phila. Inquirer. Perhaps there were better uses for the money spent, such as R&D, or the postmarketing drug surveillance that pharma often skimps or simply reneges on?

Most post-market studies funded by industry are intended specifically to expand the market for a drug, and such studies are usually not undertaken unless the calculated probabilities indicate that the study will yield a positive financial return [1]. In approving a new drug, FDA may demand that a company conduct additional safety trials after release to the public, but the agency can't enforce these post-approval studies, which are tedious and expensive, as FDA has “limited authority to require that sponsors conduct post-market safety studies [2]. More than half of those agreed to by manufacturers never occur, according to a Department of Health and Human Services report in the March 15, 2004 Federal Register [3].

1. Preventing Medication Errors: Quality Chasm Series. Committee on Identifying and Preventing Medication Errors, Board on Health Care Services (Aspden P, Wolcott J, Bootman JL, Cronenwett L, editors), Institute of Medicine, National Academies Press, 2007 (prepublication copy), p. 238 (quoting Tunis et al., 2003).

2. Drug Safety: Improvement Needed in FDA’s Postmarket Decision-making and Oversight Process. p. 11, United States Government Accountability Office, Washington, D.C., March 2006, http://www.gao.gov/new.items/d06402.pdf

3. Dangerous Practices: Critics see flaws in drug-safety monitoring. Science News, Week of Feb. 5, 2005; Vol. 167, No. 6 , p. 90, http://www.sciencenews.org/articles/20050205/bob10.asp

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.