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

Government Health IT Webcast featuring MedInformaticsMD: The Problem With EMR's

Readers of Healthcare Renewal know of my views on Healthcare Informatics and clinical IT such as electronic medical records. I am a passionate supporter of clinical IT, but believe the industry is still immature, employing a leap of logic - faith? - that impairs results. Namely, the almost religious and mostly unchallenged belief that the leadership, assumptions, culture and methodologies of what I call "business computing" or M^3 computing (M cubed - management, mercantile, and manufacturing) computing are appropriate, if not the only approach, to the computing subspecialty of clinical computing.

In postings here and here I wrote on my concerns about an "irrational exuberance" over EMR's that seems to be sweeping the healthcare industry. The former post, I believe, caught the attention of an editor at Government Health IT. The end result of our conversation was a webcast in which the editor interviewed me on the issue.

You can listen to the webcast here. It is entitled "The Problem with EMRs."

So far, I've had a number of positive responses and a few speaking engagement invitations. I have not yet been called a luddite or technophobe. Considering my website on health IT difficulties has been viewed 500+ times via a link the Government Health IT story, I consider this a minor miracle.

-- SS

Lux et Veritas, or Trust But Verify? Yale discovers eDiscovery

Recent amendments to the Federal Rules of Civil Procedure concerning the discovery of “electronically stored information” have created headaches for organizations that rely extensively on digital information and communication technologies (ICT's). Which includes most organizations in the 21st century. No fooling.

Roy Poses has written about conflicts of interest and other forms of ethical problems in academic medical centers in posts such as here, here and here.

Add Yale to the list. Further, add Yale to the list of organizations discovering the eDiscovery is no laughing matter. In this presentation (Powerpoint .pps file) by Yale's Information Technology Services entitled "What The New e-Discovery Rules Mean to Me", we discover that Yale has perhaps discovered the wages of professorial sin.

Those wages are June 26, 2006 subpoenas from HHS, NIH, DoD, NSF, and NASA regarding all information related to 47 grants from 13 departments. The FBI was involved, with FBI agents going at night to faculty and staff homes and to one vacation destination for questioning (that must have been worthy of scenes for a movie). The investigations are apparently still underway.

The issues include allocation of research expenses, reporting of faculty effort devoted to grants (i.e., claiming 25% of time is devoted to five grants), and numerous matters relating to grant administration including: cost transfers, allocation of expenses, effort, administrative charging and subaward monitoring, and conflict of interest.

Of note is a Feb. 2006 HHS audit of a Yale subcontract from UMass Medical School causing $194,000 of a $572K NIH award to be disallowed due to irregular cost transfers, effort % allocation, and cost allocation methodology. This may have been a trigger for further inquiry.

For starters, 600+ individuals were named as "people of interest", 400+ accounts were put on legal "hold" status, 100 individuals's disks were 'captured.'

In an example of the perils of eDiscovery and unethical people, an altered email was discovered. A reference to "spending down" a subgrant that was soon to expire had been deleted.

Yale president Levin wrote in the Yale Daily News that "the amount of documents that have been requested by the federal government amounts to ... hundreds of thousands, even millions of pages." An entire floor of class A office space was reserved for the auditors and lawyers reviewing documents.

The IT department actually ran out of tape and disk storage in backup system servers (probably due to legal hold requirements), people became afraid to delete anything, and of course there was "tension" between faculty and administration regarding mandatory faculty training in research administration and in actually obeying the directives for document preservation and retention in fulfilling the federal subpoenas ("Faculty Object to Searches, Yale Daily News, Feb. 2, 2007):

As a federal investigation into possible mismanagement of grant monies at Yale enters its eighth month, some professors are speaking out against what they say is an inappropriately invasive response from the University.

At a faculty meeting Thursday, some science professors said the University is impinging on privacy and academic freedom by copying documents from professors’ hard drives and requiring faculty members to undergo mandatory training or supervision in the grant administration process. But administrators said they have already addressed one of the faculty’s concerns about the training, and that they have simply taken steps required by government subpoenas.

Imagine that, tenured Ivy professors having to undergo mandatory training in how to administer federal money appropriately and turn over records. The horror! Must be a Karl Rove/Joe McCarthy/David Horowitz plot to destroy academic freedom!

The resources required for production are perhaps yet another cost of doing academic business "the old fashioned way."

It is amazing that this story has received precious little coverage nationally. The NYT had a brief article in 2006. I only heard about this recently, from a former colleague. Perhaps this is another example of the Anechoic Effect.

Yale's clinical operations have seen federal investigation once before. See "Insufficient IT Management Depth Results in Justice Dept. Investigation, Millions of Dollars in Fines."

That story was more about incompetence rather than malfeasance, however. Ironically, when I was Yale School of Medicine junior faculty in Yale Center for Medical Informatics, I was charged with teaching postdoctoral fellows about NIH ethics guidelines. The tenured senior faculty I was working for just didn't have the time. See "Anti-social informatics at Yale" for a flavor of Yale kultur:

At that link is a detailed case example from the late 1990’s of impaired efforts to implement clinical information technology via wasted resources and opportunity, attempted misappropriation of intellectual property by prominent tenured faculty for private use, unauthorized practice of law in the Office of the General Counsel, blacklisting, extortion, and retaliation treated with a blind eye and silence by university officials at this prominent university.

I am not at all sorry to see this latest investigation. I believe Yale needs a house cleaning. I am going to attempt via the FOIA to find out who, if anyone, has been found to have been "naughty" via the federal investigations.

While I am perhaps experiencing a degree of Shadenfreude, the current situation is very unfortunate for society, of course. Time and effort that could have been spent improving society is being spent trying to uncover and correct behaviors of the privileged and protected involving taxpayer money -- at taxpayer expense, of course. Let's hope Yale can live up to its motto of "Lux et Veritas." My experiences showed that motto to ring just a bit hollow (or, perhaps a better metaphor would be that the motto was just a bit transparent).

Finally, by way of speculation, the DoD has also had its issues with Yale. Payback time, perhaps?

-- 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.

Logical Fallacies and the Discussion of Health Care Policy: Examples Courtesy of DrugWonks.com

On the DrugWonks blog, blogger Robert Goldberg seemed terribly perturbed about Health Care Renewal, and me in particular. In the last week, he devoted two posts to disagreeing, to use a polite term, with me and this blog, and threw in parenthetical comments about me and this blog in two other posts. It is not exactly clear what I wrote that set him off. He never linked to particular posts, or quoted anything I actually wrote. My best inference is what most recently raised his ire was this post about conflicts of interest related to two public pronouncements by influential health care not-for-profit organizations urging patients and physicians not to abandon Zetia and Vytorin.

His posts are entitled "Beware of All Innovations, Especially New Ones," "Sanctimony About Vytorin's 'Secret' Panel,", "Everyone has a right to their own opinion as long as they agree with me," "Why the Media and Pharma Blogsphere Fails to Get Personal."

We have previously posted about op-eds in the mainstream media written by Robert Goldberg, and his boss, Peter Pitts, which have also featured logical fallacies (here, here, here, and most recently here.) Goldberg also once used DrugWonks as a platform to try to discredit Health Care Renewal, again making use of logical fallacies (see post here).

We have noted before that Goldberg works for the Center for Medicine in the Public Interest, whose president, Peter Pitts, is Senior Vice President for Global Health Affairs at the big public relations firm Manning, Selvage and Lee. Manning, Selvege and Lee has many big pharmaceutical accounts, as listed on the CommuniqueLive.com site. Furthermore, in a post on Drugwonks, Goldberg acknowledged "CMPI accepts grant from drug companies -- and we do so proudly because they actually invent things that help people." In the op-eds noted above, neither Pitts nor Goldberg acknowledged their relationships to the pharmaceutical industry, giving us reason to label their writings in the media stealth health policy advocacy.

Goldberg's latest set of writing are notable mainly for their creative use of multiple logical fallacies. So to try to make some lemonade out of the lemons he has provided, let me respond to some of his points sorted by the kind of fallacies they represent, with discussion of the definition of these fallacies and how they were deployed. All definitions used here were from the Nizkor Project.


A Squadron of Straw-Men

The straw-man argument seems to be a favorite of Goldberg's. One working definition of the straw-man fallacy is: "The Straw Man fallacy is committed when a person simply ignores a person's actual position and substitutes a distorted, exaggerated or misrepresented version of that position." Here are some examples, in the order they appeared in his posts.

• "the Poses postulates" - In "Beware of All Innovations...," Goldberg invented a set of exaggerated postulates purportedly for the use of pharma-skeptics. They begin with "don't trust Pharam research or the researchers they pay," and go downhill from there to "don't use any drugs...." Obviously, the first could conceivably be an exaggeration of some things I have written, and the last is plain ridiculous. Also obviously, I never proposed anything remotely like these. So this is a quintessential straw-man fallacy. Goldberg has simply made up words and then attributed them to me.
• "this also should apply to Zocor," - In "Sanctimony About Vytorin's...," a post which starts by criticizing me as "insufferable," Goldberg seemed to imply that I suggested "people should stop taking SSRIs, Avandia, and Vytorin." He then added "now I guess this should also apply to Zocor." I have criticized the suppression and/or manipulation of clinical research about SSRIs, Avanda, and Vytorin, and noted that it is not clear that the benefits of the latter two drugs outweigh their harms. I have never had reason to directly discuss Zocor (simvastatin, by Merck), a commonly used statin lipid-lowering drug. I certainly never suggested that it not be used.
• "anyone who consults for drug companies is a prostitute and endangers the public health," - Also in "Sanctimony," Goldberg suggests I expressed this extreme sentiment. I surely have written about concern that medical academics who also have financial ties to commercial health care firms are hard pressed not to be influenced by such ties. But I never used the p-word in this context.
• "And he presumes that the only source of bias that affects the public health adversely - mostly without empirical evidence - is financial inducements from drug companies," - In "Everyone has a right...," Goldberg directly misrepresented my position as above. If he bothered to read Health Care Renewal, he would find that I (and our other bloggers) have been equal opportunity offenders, skewering deceptive marketing, conflicts of interests, and other such practices involving all sorts of health care organizations, not just pharmaceutical companies.
• "By his standards, Gertrude Elion, Louis Pasteur, Josh Lederberg, Joseph Goldstein, Phil Sharp, Nobel Laureates all, are untrustworthy tools while Poses is the trusted one...," - This appeared in "Everyone has a right...." To be concrete, I don't think I have ever mentioned any of these luminaries in Health Care Renewal. More importantly, all these scientists were best known for basic research, and they all did their major work before the rise of pharma as a major sponsor of clinical research. All I have written about conflict of interest, research manipulation, and research suppression has been about clinical research, that is, research on intact human beings. I have been most concerned with influence by the manufacturers of particular products on human research that tests the products they make. The issue has never been commercial funding of basic science. So Goldberg's assertion in this case was certainly the biggest collection of straw so far.
• "So obsessed is he with the fear of pharma infiltration of medicine and science that he casts a blind eye towards other sources of conflict." - Again, in "Everyone has a right," Goldberg demonstrates that he is not a faithful HCR reader. As noted above, we have criticized all sorts of conflicts of interest, involving not just pharma, but device, biotechnology, managed care, hospital suppliers, etc, etc. More straw piled on the camel.
• "And who said the conclusion of ENHANCE was to lower cholesterol at all costs? Roy Poses?" - This was in "Why the Media...." Of course, I didn't say that. Enough straw-men to break any camel's back.

Accusations of Guilt by Association

A working definition, "Guilt by Association is a fallacy in which a person rejects a claim simply because it is pointed out that people she dislikes accept the claim."

• "There is no doubt Poses is part of the 'I hate Pharma' crowd...." - Goldberg wrote this in "Everyone has a right...," This has elements of a straw-man too, since, as noted above, I have written quite a lot about health care organizations outside of pharma. Clearly, though, Goldberg has lumped me into an amorphous group whose existence is as plausible as Hillary Clinton's "vast right wing conspiracy."
• "the failure of the I hate pharma crowd in the media and blogsphere...." - This was in "Why the media...." See comments above. I guess Goldberg doesn't think I'm in with the in-crowd.

Down the Slippery Slope

A working definition, "The Slippery Slope is a fallacy in which a person asserts that some event must inevitably follow from another without any argument for the inevitability of the event in question. In most cases, there are a series of steps or gradations between one event and the one in question and no reason is given as to why the intervening steps or gradations will simply be bypassed. " Goldberg tended to employ slippery slopes in conjunction with straw-men.

• "the Poses Postulates" - Again, as noted above, these were certainly not my postulates. The postulates themselves were a fairly classic slippery slope, starting with exaggeration, "don't trust Pharma," proceeding through this dubious reasoning, "Don't trust the drugs they produce or market since the FDA is nothing but a tool of pharma," and ending with the ridiculous, "don't use any drugs...."
• From "any financial ties is a conflict," through "people should stop taking SSRIs, Avandia, Vytorin. Now I guess that should also apply to Zocor." Again, this was noted above as a case of a straw-man fallacy. Goldberg constructed his straw-man so as to slide down a slippery slope.

Fishing for Red Herrings

Working definition: "A Red Herring is a fallacy in which an irrelevant topic is presented in order to divert attention from the original issue. The basic idea is to 'win' an argument by leading attention away from the argument and to another topic."

• "Poses has also remained silent about the rash of websites that have popped up urging people to sue Merck and Schering for false claims, to stop taking Vytorin and switch to 'natural' cholesterol lowering products that they sell, etc." - Goldberg wrote this in "Everyone has a right...." Obviously, whether or not such web-sites exist, whether or not they are abusive, and whether or not I have noticed or commented on them has no bearing on whatever I wrote about ezetimibe, clinical research on it, etc that so offended Goldberg. (Goldberg actually never clearly referred in any of these posts to anything specific that I wrote, so what so offended him was never clear.)
• Goldberg wrote two paragraphs about alleged conflicts of interest affecting the Prescription project, then "Should Poses be suspicious about the choice of drugs made by the Prescription Project based on their source of funding? Not a peep." - This again was in "Everyone has a right...." Again, this is irrelevant to the ezetimibe controversy. I have tangentially referred to the Prescription Project on this blog, but not in a way that is relevant to anything else Goldberg was talking about.

For Latin Lovers, Ad Hominem Tu Quoque

This may not be the most well-known fallacy, but its working definition is: "This fallacy is committed when it is concluded that a person's claim is false because 1) it is inconsistent with something else a person has said or 2) what a person says is inconsistent with her actions. "

• After making the straw-man argument that I would have labelled a host of Nobel Prize winning basic scientists as untrustworthy, "while Poses is the trusted one because they take or took drug money or worked for drug companies while he Poses [sic] just got one Merck grant back in 1997-1999 (which he never declared in his blog.)" - This appeared in "Everyone has a right...." The argument seems to be that anyone who ever had a relationship with a pharmaceutical company of any type can never criticize anything to do with such relationships. (In a funny way, Goldberg thus seemed to be making an argument for how conflicts of interest do influence what people say and do.) I freely admit I was the Principal Investigator of a grant sponsored by Merck, and paid to the hospital which employed me. Why that singular relationship ten years ago should discredit my current arguments about conflicts of interest, arguments which Goldberg never directly addressed, is, to be charitable, not obvious.

Joe Collier wrote succinctly in the British Medical Journal, [Collier J. The price of independence. Br Med J 2006; 332: 1447-9.] "In my experience, people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult." Goldberg's latest writing seem to demonstrate this well.

The writings of Goldberg and Pitts probably inadvertently have provided a great set of teaching cases about how logical fallacies can be used in persuasive writing to put forward dubious, and conflicted postulates. A working knowledge of logical fallacies should help readers separate the wheat from the chaff in the cacophonous clamour about the current crisis in health care. Some useful web-sites for those interested in logical fallacies are the Nizkor Project: Fallacies, LogicalFallacies.info, and the Fallacy Files. (I'm sure there are others.)

ADDENDUM (28 January, 2008) - Goldberg has also taken issue with Dr Howard Brody (of the Hooked: Ethics, Medicine and Pharma blog) and Dr Daniel Carlat (of the Carlat Psychiatry Blog), and then with Dr Aubrey Blumsohn (of the Scientific Misconduct Blog). See if you can spot the logical fallacies in Goldberg's pieces. Then see Dr Brody's reply here.

BLOGSCAN - Conflicts of Interest, CME, and MECCs

On the Carlat Psychiatry Blog, Dr Daniel Carlat reported an alternative take on the Macy Foundation report which called for the abolition of commercial funding of continuing medical education (CME). (See Dr Carlat's earlier post on this report here.)

In a seminar on medical ethics, Harvard University's Neurologist-in-Chief, Dr Martin Samuels, trashed the Macy report on the basis of, you guessed it, conflict of interest. He charged that one of the members of the conference that produced the Macy report was a top executive of UpToDate, a medical education and communication company (MECC) that makes its money by selling subscriptions, not from drug companies. Meanwhile, Dr Carlat also reported that Dr Samuels was praising yet another MECC, Pri-Med, for which he happens to direct a neurology course.

You can't tell the conflicts of interest without a scorecard. This story does seem to underline, in my humble opinion, the need to disclose all conflicts of interest, and the need to develop a structure for medical education (undergraduate, graduate, and continuing) that somehow avoids conflicts due to relationships with any organization, drug company, managed care organization, MECC, for-profit, not-for-profit, whatever that have vested interests other than discovering and disseminating the truth in a spirit of free enquiry (that is, the fundamental educational mission.)

We physicians also ought to remember the oaths we once swore, and stop trying to figure out clever deals to make more money on the side.

Variations on a Theme of Sleaze

VARIATIONS ON A THEME OF SLEAZE

A few days ago I posted on corrupt reports in two medical journals, where key opinion leaders (KOLs) and corporate employees misrepresented the potential of Janssen’s atypical antipsychotic (AAP) drug risperidone for depression. One of these reports appeared in a general medical journal, Annals of Internal Medicine (AIM), which confirms the designs of the corporate marketers: by volume, treatment of depression now is centered in primary care. Considering the weak efficacy data, the dubious risk-benefit profile, and the inferiority of AAP drugs to other options, there is no justification for the broad and early adjunctive use of these agents for depression in primary care. The Eli Lilly Company, which markets the combination of olanzapine and fluoxetine in a single pill (Symbyax), has the same objective. Other companies are moving rapidly into this market space.

Combining AAP drugs with antidepressants takes us back to the bad old days of antidepressant-antipsychotic drug combinations like Triavil in the1960s and 1970s, when we learned that depressed patients are especially susceptible to a serious adverse event known as tardive dyskinesia (TD) caused by antipsychotic drugs. While the risk of TD is less than with the early antipsychotic agents, it is still unacceptably high with AAP drugs for patients who are unlikely to show meaningful clinical benefit, as I detailed earlier. In adult patients with schizophrenia the risk of TD with olanzapine treatment is about 2.5% at 1 year. In children and adolescents treated with AAP drugs for 6 months the risk is an alarming 6% (Wonodi I et al Movement Disorders 2007; 22: 1777). In patients with mood disorder, these figures are likely to be higher. And this is before one even begins to factor in the metabolic toxicity of AAP drugs (weight gain, obesity, insulin resistance, and Type II diabetes mellitus)! Patients are not well served when AAP drugs are pushed for treating depression in primary care.

Medical journals are not the only compromised medium. Continuing Medical Education (CME) is a second front in the campaign to expand the AAP drug market. The standard formula calls for corporate sponsorship channeled through an “unrestricted educational grant” to a medical education communications company (MECC). The MECC employs writers to prepare the “educational content,” and academic KOLs are recruited to deliver this content. The KOLs are chosen for their willingness to be “on message” for the corporate sponsor. If they go “off message” they know they will not be invited back. The talk of “unrestricted grants” is window dressing. The MECC also secures the imprimatur of a nationally accredited CME sponsor, typically an academic institution. The sponsor is paid to certify that the CME program meets the standards of the Accreditation Council on Continuing Medical Education (ACCME). Everybody turns a buck: the MECC and its staff are handsomely paid (CME is now a multi-billion dollar business); the KOLs are generously rewarded with honoraria and perquisites; the academic sponsor is well paid by the MECC; the ACCME receives dues from the academic sponsor; the audience obtains free CME credits rather than having to pay for these required educational experiences; and the corporate sponsor gets what it considers value for its marketing dollar.

ACCME standards include clear identification of off-label drug use; full and fair disclosure of clinical trial results, warts and all; and clinical guidance to the audience about risks, benefits, and treatment options. It is not an exaggeration to say that these standards are more often honored in the breach than in the observance. That is because CME events have been degraded to little more than thinly veiled advertising, built around promoting a product rather than around education. So corrupted has the process become that the Macy Foundation recently recommended that industry financing of CME be ended, “whether such support is provided directly or indirectly through subsidiary agencies.” See Daniel Carlat for more on this topic. Is this position alarmist? Consider the following examples of corruption in CME.

A widely advertised CME program appeared on-line 6 November 2007, titled Treatment-Refractory Depression: Is there a Role for Atypical Antipsychotics? Note the leading question and the product category focus. The program was developed by the MECC PeerView Institute for Medical Education, and it was sponsored by the Semel Institute for Neuroscience and Human Behavior at UCLA, which certified CME credits. Like the journal articles I discussed last week, this CME program is marked by a concatenation of deceits. The major messages were, augment earlier rather than later; AAP drugs are “an emerging therapeutic option” for augmentation (note the branding language); and AAP drugs are efficacious. None of these messages is based on credible evidence.

The first sleight of hand was the leadoff presentation, which featured the STAR*D study results concerning remission and response rates to adjunctive treatments or switching after various levels of treatment failure. The data naturally suggest unmet needs in treating depression (a favorite theme of marketers). The unspoken implication of this academic veneer is that the later studies described in the CME program were comparable to the STAR*D study in terms of case material, which is not so. Recruitment to STAR*D was explicitly different from recruitment to the usual experimercial sponsored by a drug company, where many cases come from contract research organizations, not from clinical referral streams. Moreover, STAR*D was a purely descriptive study that by design could not identify specific treatment effects.

Charles B. Nemeroff, MD, PhD from Emory University (yes, the same) discussed short term use of AAP drugs. His presentation is a model of being economical with the truth. Dr. Nemeroff has clearly mastered the art of accommodating his many corporate clients. He discussed 4 atypical antipsychotic drugs as augmenting agents for nonresponding depression. When discussing olanzapine he went beyond his short term remit to suggest that long term treatment is efficacious, yet he neglected to address the neurological or metabolic toxicity of long term olanzapine. When discussing risperidone he did not disclose that he was senior author of the major report he described and cited; he neglected to disclose the retractions he and Mark Rapaport from Cedars-Sinai Medical Center had been obliged to publish; he neglected to disclose that treatment with risperidone beyond 6 weeks was no more efficacious than placebo. That aspect was discussed by another speaker, who repeated Dr. Nemeroff’s now-retracted and discredited claims for significant long term preventive efficacy of risperidone in a subgroup of patients. Dr. Nemeroff made further claims about risperidone improving sexual function in patients receiving an SSRI antidepressant but he failed to disclose that beyond 6 weeks risperidone impaired sexual function in women who were receiving the SSRI; he backed up his claims about risperidone and sexual functioning by citing his publication in his own journal Neuropsychopharmacology that contained no data whatsoever on the matter; and he neglected to address the metabolic toxicity of risperidone that the corporation disclosed on ClinicalTrials.gov. He also falsely stated that the short term efficacy of risperidone in nonresponding depression was demonstrated in a controlled study, citing his own open-label study. These problems were called to the attention of the Semel Institute for Neuroscience and Human Behavior at UCLA. In response, the CME program was revised on January 11, 2008. Dr. Nemeroff’s material now contained a different citation that again contained no data concerning sexual side effects. They removed the claim that the short term efficacy of risperidone had been established in a controlled trial (although by then the problematic report of this very issue in AIM had been published for over 2 months). The inadequate discussion of the toxicity of risperidone in Dr. Nemeroff’s trial was unchanged, and another speaker continued to repeat the retracted and discredited claims of Dr. Nemeroff for significant long term preventive efficacy of risperidone in a subgroup of patients. No explanation of the changes made on January 11, 2008 in the on-line materials was provided by UCLA to CME readers who had studied the erroneous and biased material for more than 2 months. Other speakers made passing reference to the metabolic toxicity of AAP drugs but only in a perfunctory way that had no educational value, like what we see in direct-to-consumer advertising. Nobody mentioned the risk of TD.

As the Macy Foundation report makes clear, CME providers are expected to give learners guidance on the risk-benefit balance of new treatments. It is disingenuous of Dr. Nemeroff to talk up risperidone for short term treatment of these difficult depressions by exaggerating the benefit, downplaying the risks, avoiding comparison with alternative treatments, and glossing over the problem of longer term loss of efficacy. These are clear violations of ACCME principles.

When discussing aripiprazole for nonresponding depression, Dr. Nemeroff once again was economical with the truth. Note that Bristol-Myers Squibb, the marketer of aripiprazole, sponsored this PeerView/UCLA program. To document his claims about aripiprazole, Dr. Nemeroff cited one Abstract from the American Psychiatric Association meeting in May 2007. That does not meet ACCME standards of documentation for learners, most of whom would be unable to access the cited Abstract (not that it would tell them much even if they could). For some reason, Dr. Nemeroff did not inform learners that the complete report of the aripiprazole study had appeared in June 2007 (Berman RM et al. J Clin Psychiatry 2007;68: 843-853), fully 5 months before the CME event went on-line. From that readily available report it is clear that the Number Needed to Treat (NNT) for response with aripiprazole is 10, which compares unfavorably with a NNT of 4 for lithium, the best established augmenting option in placebo-controlled trials. A NNT of 10 means a clinician would need to treat 10 patients with aripiprazole before obtaining one remission that would not have occurred anyway with placebo. That does not constitute compelling clinical benefit. Dr. Nemeroff did not candidly discuss these troubling data. Dr Nemeroff provided his CME audience none of the remission or response data from the published aripiprazole study, though these data were readily available. These omissions of published, highly relevant information signify disrespect for his audience by Dr. Nemeroff, incompetence by the MECC, and failure of due diligence by the accrediting institution, UCLA, to ensure that accurate, balanced information and adequate documentation are provided. Likewise, no substantive risk-benefit analysis was provided to guide CME learners, and there was no meaningful discussion by Dr. Nemeroff of the metabolic toxicity of aripiprazole. The published report tells us that 7.1% of patients treated with aripiprazole gained more than 7% body weight, a very significant difference (p < 0.01) from the placebo treated patients (1.2%). Dr. Nemeroff did not share that information with the CME audience. Instead, he slyly minimized the appearance of the problem by showing a mean weight gain of only 2 kg with aripiprazole. In addition, the neuromotor toxicity of aripiprazole was remarkable (23.1% akathisia and 27.5% extrapyramidal symptoms). Dr. Nemeroff gave the CME audience no guidance about that problem or about its unblinding effect in the trial. Why do highly paid KOLs behave in this way? Do they think nobody will notice?

A final insult to CME learners in this program was the disclaimer that “The Semel Institute for Neuroscience and Human Behavior at UCLA is responsible for the selection of this report’s topics, the preparation of editorial content, and the distribution of this report” but “No responsibility is taken for errors or omissions in these reports.” Well, then, who is responsible? Why not UCLA, considering the ACCME standards and the fees UCLA received for sponsoring this CME activity through an “educational grant” from Bristol-Myers Squibb Company? Overall, it is difficult to avoid the impression that this so-called CME activity is a meretricious infomercial for Dr. Nemeroff’s corporate clients rather than a balanced educational event that aims to give practitioners considered guidance on a difficult clinical problem.

Will these revelations slow the marketing-inspired momentum for use of atypical antipsychotic drugs in depression? Not likely. Indeed, a new road show is right now getting under way, bringing the good news about atypical antipsychotic drugs in depression to CME audiences in Miami, San Francisco, Los Angeles, Chicago, Boston, and New York. Why now? Has some new insight been achieved that requires urgent communication to physicians? No. The road show has been launched now because aripiprazole was recently approved by the FDA for the secondary indication of adjunctive treatment in depression. It’s all about marketing. The faculty speakers are the usual suspects – KOLs and KOL wannabes who enjoy cozy or nepotistic relationships with the chairman. The funding is through another “educational grant” from the marketers of aripiprazole. The CME sponsor is an outfit in Texas that knows how the CME game is played. And the chairman of this new enterprise? Why, none other than the compromised Dr. Charles Nemeroff from Emory University. Why are we not surprised?

UMDNJ Monitor Alleged "No Research Compliance Capability"

We have done a long series of posts about the troubles at the University of Medicine and Dentistry of New Jersey (UMDNJ), the largest US health care university. The university now is operating under a federal deferred prosecution agreement under the supervision of a federal monitor (see most recent posts here, here, here, here and here.)

We had previously discussed allegations that UMDNJ had offered no-bid contracts, at times requiring no work, to the politically connected; had paid for lobbyists and made political contributions, even though UMDNJ is a state institution; and seemed to be run by political bosses rather than health care professionals. (See posts here, and here, with links to previous posts.) A recent development (see post here with links to previous posts) was that UMDNJ apparently gave paid part-time faculty positions to some community cardiologists in exchange for their referrals to the University's cardiac surgery program, but not in exchange for any major academic responsibilities. Another was some amazingly wasteful decisions by UMDNJ managers leading to spending millions of dollars for real-estate that now stands vacant (see post here). Another was the indictment of a powerful NJ politician for getting a no-work job in the system, and the indictment of the former dean of the university's osteopathic medicine school for giving him the job (see post here). Most recently, we found out that UMDNJ had named one of its teaching hospitals for a pharmaceutical company in 2001 (see post here), that the federal monitor accused the dean of one of the UMDNJ campuses of fixing students' grades (see post here), and that the monitor found even more bizarre financial practices at the university (see post here).

All things must pass, so UMDNJ no longer has a federal monitor. Apparently, the publicly released version of the monitor's final report noted a number of positive changes at the university. However, a Newark Star-Ledger story revealed that even this report described contained yet another heretofore unknown problem.

Hundreds of millions in federal grants could be at risk because of lax research oversight at the state's medical university, according to a previously undisclosed portion of the federal monitor's report.

The new material, whose conclusions University of Medicine and Dentistry of New Jersey officials vigorously disputed, found the school had 'no research compliance capability' -- jeopardizing future funding, as well as the health of patients in clinical studies.

At issue is the university's problem-plagued Office of Ethics and Compliance, and UMDNJ's ability to audit research spending and report violations of clinical studies' guidelines to the federal government. The confidential portion of the report found the ethics office, whose director recently resigned and is missing other key personnel, had failed in performing critical oversight of federal research grants.

'UMDNJ admittedly has no research compliance capability at all and none is anticipated,' the monitor stated in the report.

University officials vehemently challenged the assertions.

'We have a significant amount of research compliance. We have over 20 years of history of research compliance at this university,' said Denise V. Rodgers, executive vice president of academic and clinical affairs. 'Do you think people ... would risk their reputation coming to an institution if there was no research compliance? Not a chance.'

U.S. Attorney Christopher Christie, who was briefed on the compliance findings, called it a 'serious matter' that seemed to have started long before UMDNJ came under the scrutiny of his office in 2005.

'It's always a problem when you don't have sufficient internal controls on any program. It is even a greater problem for an institution like this,' he said, citing UMDNJ's well-documented troubles with patronage, no-bid contracts and violations of Medicare and Medicaid laws.

In the public version of his final report, the monitor found UMDNJ had significantly improved since the string of scandals that nearly shut down the $1.6 billion university. However, he singled out UMDNJ's ethics and compliance office for criticism. The university's chief ethics officer, Michael R. Clarke, resigned last month after less than 18 months on the job, saying he wanted to return to the private sector. The university is now searching for a successor.

Stern's rebuke of the compliance office was far more harsh in the full report not released to the public. It alerted UMDNJ to failures that investigators only recently began looking into before the deferred prosecution agreement that led to the monitorship termination in December.

All of the monitor's reports released to the public have been edited to omit details of any ongoing investigations, and the final report cited 42 open investigative files based on 'allegations of legal and ethical breaches or conflicts of interest.'

Rodgers attributed the monitor's findings to a 'misunderstanding' over the fact that the university has not yet hired a research compliance officer. She said research at UMDNJ comes under multiple layers of oversight, including an Institutional Review Board; a Human Subjects Protection office; an office of research, as well as an institutional compliance officer and other academic officials.

'This university has over ($115 million) in grants from NIH,' she said. 'You can believe that if they had big concerns that we had no research compliance we would have not been able to get that money?'

I would note parenthetically that the rebuttals by UMDNJ officials seem to be based on logical fallacies, and therefore do not seem very convincing.

The officials first seemed to deliberately interpret the monitor's report in a very concrete way, that it alleged the university literally had not compliance efforts whatsoever. Then, they tried to rebut this straw-man argument by saying that yes, UMDNJ actually has an IRB, a human subjects protection office, etc. In fact, the report did not deny the existence of a compliance structure, it just somewhat sarcastically denied the structure was functional.

The officials then asserted that if the University had no functional non-compliance mechanism, someone ought to have already figured this out, and punished the university for it. This appears to be a version of a logical fallacy called an appeal to consequences of a belief (if X were true, there would be bad consequences. There have not been bad consequences, so X must not be true.) Why the particular problem mentioned in the report, a non-functional research compliance system, should have been more obvious than all the other problems at UMDNJ is not clear.

It's amazing how often the issues discussed on Health Care Renewal inspire health care organizational leaders to creatively use logical fallacies to defend their organizations and prior actions.

Unfortunately, this latest report reinforces the notion that the UMDNJ administration was a poster-child for poor management of an academic health care institution at multiple levels and in multiple spheres. Let's hope that things really are getting better there.

BLOGSCAN - Deftly Dissecting Dubious Defenses of Research Suppression

On the Clinical Psychology and Psychiatry blog, this post notes how a recent article about the effect of suppressing clinical research on SSRI (selective serotonin reuptake inhibitor) anti-depressants brought out some curious defenses of not publishing research results. The anonymous Clin Psych blogger deftly dissects these dubious defenses of research suppression.

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.

The Business-Think Rationale for In-Store Clinics

An urban legend that has haunted health care in the last 20 years, to its great detriment, is that the application of business-like thinking, business-think for short, to health care (not just financing health care), will yield enormous improvements.

One of the latest health care fads generated by business-think appears to be in-store clinics. We have blogged several times, (most recently here, here, here, and here) about these clinics. Such clinics are situated in retail stores, such as drug stores, staffed by nurse practitioners, but usually not doctors, and claim to treat a limited number of ailments quickly for reasonable prices. They have been touted as the latest business-like solution to the decline of primary care.

My biggest concern is that these clinics may fail to provide good care to some of their patients, particularly patients who have more serious problems masquerading as or accompanying one of the limited ailments which the clinics claim to handle.

KevinMD just put it more graphically.

I've said it before and my stance hasn't changed. In their zeal for speed, convenience, and profit, someone will screw up.

A 'bronchitis' will actually be a PE [pulmonary embolism]. Chest pain caused by an 'anxiety attack' will be an MI. The inevitable malpractice suits against a retail clinic will no-doubt put a damper on things. Bet on it.

I am afraid that the people touting in-store clinics and similar business-think based fads are too preoccupied with the brilliance of their business models to appreciate how the health care context may make the model unworkable. For example, I noted that the initial designs of the MinuteClinics proposed for Massachusetts including no plumbing in or adjacent to the clinics. No doubt eliminating plumbing would cut construction and maintenance costs. However, in an era when practitioners are urged to always wash their hands to prevent the spread of new, contagious, and treatment-resistant infectious diseases, neither practitioners nor patients in these clinics would have easily been able to wash their hands. And some of these nasty new contagious diseases could masquerade as some of the limited ailments the clinics claim to handle.

The Boston Globe just published a commentary by Steve Bailey that (probably inadvertently) disclosed some more of the fallacious thinking used to justify the concept of in-store clinics. Selective quotes from the article are below, in sequence, and I don't believe out of context,

In the business schools, the personal computer and Southwest Airlines are taught as case studies of what has come to be known as 'disruptive innovation.' Now, with CVS Corp. poised to open as many as 30 medical clinics in their stores in the Boston area alone this year, local primary care doctors and neighborhood health clinics worry they could be next. They may be right.

America spends more money per capita on healthcare than any nation, but continues to lag behind many less affluent countries when it comes to benchmarks like infant mortality and life expectancy. The problem, says Harvard Business School professor Clay Christensen, is that so much of the money goes to maintain the status quo because it is given to organizations wedded to their current solutions, including the old delivery models.

Christensen literally wrote the book on the kind of disruptive innovation that the PC and Southwest Airlines represent. His landmark 1997 book, "The Innovator's Dilemma: When New Technologies Cause Great Firms to Fail," turned Christensen into a rock star of the start-up revolution during the dotcom boom. Now in a book due out in August, Christensen and coauthor Jason Hwang examine how the disruptive innovation model can be used to cure what ails our healthcare system.

CVS's MinuteClinics get an entire chapter in the book. Physicians' associations typically oppose MinuteClinics on patient-safety grounds, Christensen and Hwang write. In about half the states, the business model is illegal because regulations mandate that doctors supervise nurse practitioners and physicians' assistants. But the regulations haven't caught up with the science, they say. Today, the diagnoses for a host of illnesses - from sore throats to ear infections to the flu - are precise and the therapies predictably effective.

'These regulations now trap care in high-cost models when there are much more affordable and accessible business models available,' they write. 'About $15 billion is spent each year in high-cost physicians' offices for the care of acute, rules-based disorders. Delivering even half of this care through a disruptive business model such as the MinuteClinic could easily save $7 billion a year. . . . A billion here and a billion there soon amounts to serious money.'

Maybe it is too snarky to being a "rock star" of the dotcom boom, which became, of course, the dotcom bust, does not seem to be a good credential to tout as a redesigner of health care.

Moreover, the commentary exposed Christensen's fallacious thinking: in-store clinics are a disruptive innovation that will improve quality and save money by using the latest cutting-edge technologies that are not available in old school physicians' offices.

His notions of the capabilities of the latest cutting-edge technologies, however, are seriously misguided. Christensen declared that the diagnoses of illnesses such as sore throats, ear infections, and influenza are "precise" and their treatments are "predictably effective." That's plain wrong.

One reason medicine is still a challenging profession is that the situation is exactly the opposite. There are no practical, quick and accurate diagnostic methods for these diseases.

Let me use sore throat as an example. Most sore throats are are self-limited, and are probably due to a variety of pathogens, most viral. Streptococcal pharyngitis ("strep throat") is caused by a specific bacteria, can last longer, and rarely can produce severe complications. There is no way to quickly and accurately diagnose strep throat. Signs and symptoms do not clearly differentiate strep. Using multiple signs and symptoms in a statistical diagnostic model (most notably the "Centor model") can categorize patients by their risk of strep, but can neither rule it in nor rule it out. The various rapid strep tests are not very accurate. The throat culture is generally thought to be specific, but it takes at least 24 hours to provide results. (References for all the above provided on request.)

Similarly, there are no quick, practical, accurate ways to diagnose bacterial ear infections There are rapid tests that can diagnose influenza, but they have variable and imperfect sensitivity and specificity.

Furthermore, there are no "predictably effective" treatments for sore throats, ear infections, or influenza. Antibiotics at best may shorten symptom duration and decrease the likelihood of complications from strep throat, but have side effects. There are no specific treatments for "viral" sore throats, or most ear infections, or "flu-like" illnesses. The newer antiviral agents for influenza can shorten symptom duration, but only on average by one day.

I'm sure such details about the imperfections of existing diagnostic and therapeutic technology might seem tedious to a "rock star" like Christensen. The sort of business-think he embraces seems to demand a big-picture view that neglects all the devils lurking in the details. But his notion that in-store clinics will bring miracle technologies to "customers," that the dinosaur physicians in their offices do not use is just nonsense, to use the most polite term.

I still hope that exposing the dubious logic and evidence underlying the in-store clinic movement will slow it down before, as KevinMD feared (see above), the malpractice suits start.

After Firing Dean, UCSF Stalls Release of Audit

We previously posted about the firing of Dr David Kessler as Dean of the University of California -San Francisco (UCSF) medical school, after he complained about financial irregularities at the school. UCSF top leadership had countered with their own claims that internal reviews and an independent audit of its finances found no serious problems.

The San Francisco Chronicle just reported that UCSF is stalling the release of the independent audit.

In response Tuesday to a Public Records Act request by The Chronicle, UCSF officials released information from two internal reviews, but declined to release the independent financial review or the name of the firm hired by the university for $165,000 to carry it out.

UCSF spokeswoman Corinna Kaarlela said the contract does not allow UCSF to release that information without permission of the firm, and the accounting firm has yet to grant it.

Citing similar objections from the accounting firm, UCSF also refused to provide a copy of the contract itself.

Given that UCSF is a public institution, the delay in producing this report created concern, if not outrage.

Reached Tuesday, Kessler said he wants the independent report released. It is essential,' he said.

State Sen. Leland Yee, D-San Francisco, who authored a new law to require the University of California to be more open to the public, said UC should release the documents immediately.

"They are the ones receiving the services," he said. "If they want to give out the audit, they can. They are the holder of it because they purchased it."

A number of consumer advocates and experts in public records law agreed.

"It is an absolutely outrageous, high-handed abuse of the public's right to know what is going on with its money," said John Simpson, of the Foundation for Taxpayer and Consumer Rights in Santa Monica. He said the public has a right to see the documents and know the terms of the contract.

Peter Scheer, a lawyer and executive director of the California First Amendment Coalition in San Francisco, said it is common for private consulting firms to require confidentiality to protect what they consider proprietary techniques or trade secrets. It often costs more, he said, to retain the services of a firm without that secrecy requirement. However, he contends that does not release a public agency from state public access laws.

"The mere fact that they have agreed to that isn't the end of the matter. It is possible that that promise is simply one that they cannot keep," Scheer said.

This case is far from resolved, but if nothing else, the latest developments demonstrate how opaque the management of many respected health care institutions has become. And the more efforts the leaders of health care organizations make to hide information, the more questions ought to be raised about why they want to hide it.

ANTIPSYCHOTIC DRUGS FOR DEPRESSION?

Readers concerned about commercial influence know that the Devil is in the details when it comes to recognizing and exposing distortions like spin, bias and shills in journal publications. One guiding observation is that “For private companies, publication and a positive press have cash value…” (E.W. Campion, New England Journal of Medicine, 2004).

With an eye to the sly details, this posting will describe a current campaign to promote the atypical antipsychotic (AAP) drug risperidone as an augmenting agent in nonresponding major depression. The campaign aims to shape a favorable climate of opinion for the drug through experimercials (commercially strategic clinical trials) and journal publications that are really infomercials. The stakeholders are some major corporations, “key opinion leaders” (KOLs), leading medical journals, and several million patients who suffer from nonresponsive depression in the US. The winners are the KOLs and the corporations, while the big losers are the patients.

We begin with the November 2006 report of an experimercial testing Janssen’s AAP drug risperidone for nonresponding depression, published in the journal Neuropsychopharmacology (NPP). This is the house journal of the American College of Neuropsychopharmacology (ACNP), which aspires to be the premier organization in its field. Bottom line: short term, open label, uncontrolled use of risperidone appeared to be helpful, but placebo-controlled continuation beyond 6 weeks was not effective in preventing relapse. The lead author was Mark H. Rapaport, MD from Cedars-Sinai Medical Center in Los Angeles. A co-author was the controversial Martin Keller, MD from Brown University, and the senior (last) author was Charles B. Nemeroff, MD, PhD from Emory University, who was also editor in chief of the journal.

Dr. Nemeroff’s is a long-time KOL for Janssen’s efforts to create a favorable climate of opinion for risperidone in depression. He fronted for the company in presentations of the risperidone infomercial at the ACNP meeting in 2004, in a Janssen-financed journal supplement in 2005, and in co-authoring the 2006 infomercial in his own journal, NPP. Readers will recall that Dr. Nemeroff ran into problems in 2003 for failing to disclose his financial conflicts of interest in a Nature publication, and again in 2006 for failing to disclose his commercial ties in a review article he co-authored favorable to the Cyberonics vagus nerve stimulation (VNS) device for depression (also published in the journal he edited). As a result of that episode, Dr. Nemeroff resigned as editor of NPP, but not before publishing the infomercial mentioned above on risperidone in depression. One wants to ask whether these publications that he co-authored went through a credible peer review in Dr. Nemeroff’s journal. One also wants to ask whether Dr. Nemeroff abused his position as editor to give product placement to his corporate clients Cyberonics and Janssen. And one wants to ask why the risperidone infomercial was published in NPP, given that the data had already been published by Dr. Nemeroff himself in another journal, in a special supplement financed by Janssen. This prior publication of the risperidone trial, that by journal policy should have precluded publication in NPP, was not revealed (cited) by Dr. Nemeroff and his co-authors. Did they think nobody would notice?

The main outcome of the risperidone trial reported in NPP was negative: long term use of risperidone did not prevent relapse. By assiduous secondary analyses and data mining, the authors found something positive to salvage their effort. They claimed by two analyses that risperidone was effective in preventing relapse in a subgroup of patients. In short order, however, they qualified the original report. First they belatedly disclosed the authors’ commercial ties to Janssen. A second Corrigendum retracted one of the claims of efficacy: by some process of Immaculate Conception, an “error” had occurred whereby a p value of 0.4 was transformed into a p value of 0.05, first in the text and again in the Abstract. This retraction occurred only because alert readers asked probing questions of the lead author, Dr. Rapaport. No author took responsibility for this compound misrepresentation in NPP. The “error” was so obvious that all authors and any conscientious reviewer should have seen it. You begin to see the picture: we have the appearance of editorial self-dealing, including product placement for a corporate client of the editor; an incompetent or possibly dishonest journal review process; and the appearance that somebody went out of his way in two places to insert a false claim of efficacy into the report of a negative clinical trial. Finally, we have reasonable cause to suspect that the KOLs did not actually read the article they were credited with authoring. For busy KOLs, tradecraft is a thing of the past.

Soon, more questions arose. In a letter to NPP published in 2007, I challenged the second claim of efficacy for risperidone in preventing relapse in a subgroup: the claim made in the journal and in two of Dr. Nemeroff’s prior publications did not match the corporation’s analysis reported on ClinicalTrials.gov. Rapaport, Keller and Nemeroff had “nudged” the statistical result of Janssen’s analysis from borderline to unqualified statistical significance. My letter also detailed how these KOLs downplayed the disturbing data on metabolic toxicity (weight gain): the raw data were stated but the unfavorable statistical analysis of those data that appeared on ClinicalTrials.gov was suppressed. The KOLs chose not to reveal that patients who received risperidone gained significantly more weight than those who received placebo. The appearance of bias and spin was unmistakable. In response to my letter, the lead author, Mark H. Rapaport, MD, who seemed to have been deserted by his KOL colleagues, abjectly disowned any claim of efficacy whatsoever for risperidone, while being nonresponsive to the charge that they had manipulated the risk-benefit profile of the drug. So now we have high profile academic KOL authors putting lipstick on the pig with both false and exaggerated claims of efficacy in a negative study, misstating the results of statistical analyses, and “burying” inconvenient toxicity analyses. Were the reviewers for NPP so incompetent that they could not see what any reader could see? One wants to ask whether this report, with the editor in chief as senior author, received any review at all.

So far so good: with Dr. Rapaport’s latest retraction, Janssen and its hired KOLs now disown any claim that risperidone is effective in long term prevention of relapse in nonresponding depression. What about short term treatment? The infomercial in NPP contained only uncontrolled, open label data on the short term efficacy of risperidone. That is the weakest level of evidence, even though it was touted by the KOLs with the message that many patients responded “rapidly and robustly.” Inconveniently, many of them relapsed even with continuation risperidone therapy. So much for robustness.

As luck would have it, Janssen reported a placebo-controlled short term study of risperidone in nonresponsive depression in the November 6, 2007 issue of Annals of Internal Medicine (AIM) (Mahmoud RA et al. Ann Intern Med 2007; 147: 593-602). The authors are Janssen employees who had been co-authors with Rapaport, Keller and Nemeroff on the now retracted NPP report. (Possibly in response to static over the earlier report, Nemeroff and Rapaport plus a few other KOLs were simply acknowledged as advisors instead of receiving co-author status on the AIM report).

The bottom line? Though there were some statistically significant differences favoring short term risperidone over inactive placebo by conventional rating scales, evidence of clinical utility was underwhelming. Once again, Janssen’s presentation of the results was biased: the authors used completer data for efficacy, which improved the appearance of benefit for risperidone, whereas they used Intent to Treat (ITT) data for toxicity, which minimized the apparent metabolic adverse effects of risperidone. Dr. Ralph Koek and I pointed out in an on-line response to the journal that when ITT data are used consistently the Number Needed to Treat (NNT) for remission was 15.6 at 4 weeks and 10.2 at 6 weeks. Those NNTs do not indicate compelling clinical benefit for risperidone: an NNT of 15 means one would need to treat 15 patients with risperidone to obtain 1 remission that would not have occurred anyway with placebo. Moreover, the metabolic toxicity of risperidone (weight gain) was significantly increased over placebo, but the authors downplayed that problem by keeping it out of the Abstract, and it did not appear in the “Summaries for Patients” posting by the journal. Once again, Janssen used questionable manipulations to maximize the appearance of efficacy while minimizing the apparent risk of risperidone in nonresponding depression. This is called “augmenting” the risk-benefit profile.

So now there is evidence from two controlled trials that risperidone confers little significant benefit and has a dubious risk-benefit profile either in short term use or in longer term use for nonresponsive depression. In light of this evidence it is difficult to justify the broad and early use of risperidone or, probably, any other atypical antipsychotic drug in such patients. Richard Shelton, MD from Vanderbilt and George Papakostas from MGH concur with this conclusion, in a thoughtful review article that has just appeared on-line in Acta Psychiatrica Scandinavica. These two investigators conducted several of the early trials of other AAP drugs in depression. They gave a timely warning about the late-appearing but often devastating side effect of tardive dyskinesia that can result from exposure of depressed patients to AAP drugs. Needless to say, that tissue was not addressed in either of the Janssen publications talking up risperidone for depression.

Studies of this issue routinely take the de minimis approach of testing AAP agents only against an inactive placebo, ignoring the problems of unblinding that occur when these sedating agents are used, and avoiding comparisons with other options. Quite possibly, any sedating or anxiolytic agent like off-patent trazodone would have effects indistinguishable from risperidone. The corporation’s goal is not to answer such important clinical questions, however, but only to clear the regulatory bars needed to expand the market for its drug. Patients lose out when an expensive atypical antipsychotic drug with an NNT of 10-15 is promoted while an inexpensive option like lithium augmentation, which has an NNT of 4, is ignored. But, as these experimercials are driven by marketing rather than by scientific or educational goals, the evidence that risperidone is inferior to lithium, the best established augmenting agent, is routinely ignored in the clinical trial reports.

So, here is the litany of sly tactics used by Janssen with the willing cooperation of KOLs like Nemeroff , Rapaport and Keller. Remember, these KOLs are paid directly or indirectly by Janssen for their association with the marketing campaign: design a clinical trial in which unblinding is guaranteed and ignore this confound which favors the drug; secure high profile product placement in a journal like NPP, with the cooperation of the editor; make false claims of efficacy in a negative trial report; when challenged, lamely try to pass off this compound misrepresentation as an “error” for which nobody accepts responsibility; take self-serving liberties with the results of statistical analyses so as to claim efficacy where none exists; suppress inconvenient statistical analyses of toxicity; manipulate the apparent risk-benefit profile of the drug; constructively plead nolo contendere to the charge of manipulating key data analyses; focus on the statistical significance of psychometric outcome measures while ignoring clinimetric measures of usefulness like NNT; bias the analysis of efficacy by using completer data; bias the analysis of toxicity by using ITT data; and ignore existing data that suggest the corporation’s drug is inferior to established alternatives.

Any one of these sly tactics might be viewed individually as an unfortunate slip, for which some will incline to give the authors the benefit of the doubt. The concatenation of deceits, however, speaks for itself. Readers ought never to underestimate the cunning and the venality of marketeers and their co-opted academic KOLs in corrupting the medical literature. In a future posting I will continue this sordid tale with illustrations from the equally compromised world of CME programs.

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.

Who Will Monitor the Monitors?

We have discussed deferred prosecution agreements involving a number of notable US health care organizations, e.g, a hospital (Roger Williams Medical Center), health care university (University of Medicine and Dentistry of New Jersey), not-for-profit health care insurer (Blue Cross Blue Shield of Rhode Island), pharmaceutical company (Bristol-Myers-Squibb), and multiple medical device companies (Biomet, DePuy, Smith and Nephew, and Zimmer).

Deferred prosecution agreements may be made between federal prosecutors and corporations, including not-for-profit corporations. I am not a lawyer, but my best interpretation is that pursuant to these agreements, usually the corporation involved agrees to specific compliance measures, often including the appointment of a "monitor," and in return, the prosecutor agrees not to prosecute the corporation for crimes it was alleged to have committed as long as it continues the compliance measures.

The Washington Post reported that such agreements, which have become a more frequently used tool in the US against white-collar crime, are generating more controversy. According to the Post,

The number of corporate monitors has risen more than sevenfold since 2001, researchers said, a move that reflects a shift from lodging criminal indictments against businesses for fear they will collapse and cost employees their jobs. Instead, the government has taken a different path: forcing companies to submit to outside oversight at their own expense as a condition of settling fraud and corruption cases. Major companies from AOL and Bristol-Myers Squibb to Merrill Lynch have yielded to such oversight after recent financial scandals.

The arrangements all but give prosecutors a seat in the corporate boardroom. The arrangements are spelled out in contracts and vary depending on the company and its problems. Generally, though, monitors enjoy wide latitude to interview employees, sift through business contracts, uncover legal violations and mandate that companies change their ways. In recent years the overseers have made recommendations to hire and fire workers, enlisted high-priced accountants and consultants to review corporate operations, and blown the whistle to prosecutors if the company fails to respond to their concerns. The monitors typically send private reports to update prosecutors several times a year -- and send their bills to the companies.

The controversy seems to be about who gets appointed to be the monitors.

A consulting firm led by former U.S. attorney general John D. Ashcroft recently won an assignment, valued at more than $25 million, to ensure that a medical equipment maker [Zimmer, and see coverage in the NY Times here] stops paying kickbacks to doctors who use its products. Other former government officials with ties to the Bush administration have secured similar deals, which are paid using corporate funds and entail few, if any, checks on spending.

One particular example was the monitor for Bristol-Myers-Squibb,

The deals now drawing sharp outside criticism involve [New Jersey District US Attorney Christopher J] Christie, a GOP fundraiser who has served as New Jersey's top federal prosecutor since 2001.

One of the steps that Bristol-Myers Squibb took to resolve accounting charges was an endowment to create a job "dedicated to the teaching of business ethics and corporate governance" at Seton Hall University's law school, Christie's alma mater. That came on top of more than $300 million in criminal penalties and millions more in fees that the drugmaker paid to corporate monitor Frederick Lacey, a retired federal judge and New Jersey U.S. attorney under President Richard M. Nixon. Lacey played a role in the ouster of Bristol's chief executive two years ago. He did not return calls placed to his law office.

So,

The chairmen of the House and Senate Judiciary committees last week demanded that Justice Department leaders provide a list of all such deals and the fees they have generated. The Project on Government Oversight watchdog group has questioned whether the agreements reward 'cronies' who share political affiliations or backgrounds with the U.S. attorneys handing out the deals.

The arrangements raise alarms about 'potential favoritism and political interference that can undermine our judicial system,' said Rep. Frank Pallone Jr . (D-N.J.). Pallone has been critical of U.S. Attorney Christopher J. Christie, the New Jersey prosecutor who chose Ashcroft and a possible GOP gubernatorial candidate in the state.

Concerns were also raised by Republicans,

Richard C. Breeden, a former Republican chairman of the Securities and Exchange Commission, engineered a nearly complete overhaul at WorldCom after its top executives faced criminal charges in one of the largest fraud schemes in the nation's history. After being appointed by a federal judge from a different political party, Breeden and his team helped reshape WorldCom from its board of directors to its executive ranks, before guiding the telecommunications company, which emerged from bankruptcy protection as MCI, into a 2006 merger with Verizon.

'People should be very careful to make sure that monitorships do not become political plums,' said Breeden, who stressed that he was not speaking about specific cases. 'The key is the person who is monitor has to have a very good understanding of the business they're dealing in.'

The rising number of deferred prosecution agreements involving health care corporations has been at least an indicator that white collar crime involving large health care organizations is getting more attention.

I am certainly no expert in the legal issues involved, but it does seem that whether deferred prosecution agreements are good deterrents of misconduct by corporate executives, particularly in health care, deserves discussion.

However, there has been precious little discussion of these agreements in the health care context. Searching Medline for the term "deferred prosecution" yielded a single article, on the prosecution of driving while intoxicated, but absolutely nothing on white collar health care crime. I suspect that the best collection of discussion of deferred prosecution agreements in health care is right here in our Health Care Renewal archives.

So we end with another example of the anechoic effect. Misconduct by the leaders of health care organizations in general remains a taboo topic. As long as we are afraid to even discuss it, we will come no closer to a solution.

ADDENDUM (18 January, 2008) - See also comments by Joe Paduda in the Managed Care Matters blog, and by Matthew Holt in the Health Care Blog.