Thursday, December 27, 2012

Just What is the APA Thinking These Days?

This is a little story about the American Psychiatric Association, based on a recent article by Peter Whoriskey in the Washington Post:

Whoriskey tells us how this past month, an APA committee writing a guideline--I assume as part of the revisions for the forthcoming DSM-V--decided to eliminate an old provision that urged psychiatrists to be wary of prescribing antidepressants for patients having grief reactions. The vast majority of the psychiatrists writing the guideline had financial ties to the drug industry. Since grief is very common, and most grieving people have at least some depressive symptoms, this could be viewed as an invitation to prescribe antidepressants much more widely, which wouldn be hard to do since today, almost everybody and his duck is already taking them.

Still following Whoriskey, the APA guideline panel appealed to a few studies of antidepressants in grief, and indeed the author of one such study (funded by GlaxoWellcome) was selected by the panel to write the scientific rationale for the new guidelines. Now, if I wanted to, I could challenge the science on which the guidelines are supposedly based. For example, the study by guideline writer Sidney Zisook was an open-label, uncontrolled study of bupropion (Wellbutrin). Only 22 subjects were followed for 8 weeks. Now, when I was a young lad in training, I was told that the main reason you did not want to treat grief with medicines was that grief had to work itself out normally, and if you medicated the patient all you did was produce a prolonged grief reaction later on. That may be valid or it may be nonsense, but the fact is that an 8-week follow-up period is far too short to see if there are any negative long-term consequences of treating grief with an antidepressant. Plus we've seen a lot of evidence lately of the serious adverse effects of these drugs, including addiction-like syndromes, and 8 weeks may also be much too short to detect those adverse consequences. In short, a study of 22 subjects for 8 weeks, with no control group, unblinded, is nothing but a scientifically worthless infomercial for Wellbutrin, and anyone who publishes such a paper should be ashamed to pose as a member of a scientific guideline writing committee.

So if I wanted to I cound write about the shaky science, but I won't. I am perfectly willing at this point to make a generous assumption that there may be some evidence to support using antidepressants in at least some patients. Grief and depression are both very common conditions and there has to be a wide area of overlap, so saying as dogma that no patient with grief should ever, ever be treated with medication is surely silly.

Since I am not going to challenge the science, what I want to challenge instead is the APA's posture of choosing a bunch of docs with obvious conflicts of interest to write such a guideline. Assuming that the guideline is indeed scientifically valid, why would you choose such a strongly conflicted panel and imagine that the general public and other phyicians are going to believe a word they say? Whoriskey talked to the chair of the panel, Dr. Jan Fawcett of the University of New Mexico. Here is what Dr. Fawcett told the Post reporter:

“In choosing people, I wanted some people who see patients, not just academics,” Fawcett said. “I wanted some people who were visionary and some people who are conservative and data-driven.”

Their financial ties to the industry were not a consideration, he said.
“I wanted them for their quality,” he said. “I knew whether they had integrity or not.”
Long ago, when he was serving his residency as a doctor, he recalls being a “rebel” for believing in medications — at the time, counseling was more in vogue. But then came the revolution in psychopharmacology, which made clear to him that there was a place for drugs as well as psychotherapy.
“I’m still working at 78 because I love to watch patients who have been depressed for years come to life again,” Fawcett said. “You need those medicines to do that.”
In recruiting panelists, Fawcett said he had to inform candidates that they would have to disclose their industry ties and give up any industry income over $10,000 a year. He likened the financial restrictions to “a financial colonoscopy.”
Some DSM panel members had to give up “significant” income in order to serve, he said.
Fawcett, for example, who testifies on behalf of pharmaceutical companies in suicide lawsuits, had to give up three cases, he said.
He was skeptical of efforts to reduce the financial ties to industry.
“It has gotten to be a witch hunt,” he said.
“Most academics have taken money from pharma if they’re successful,” he explained, noting the limits on government research funding. “If you want to get any studies funded, where are you going to go? How are you going to do it?”
For example, in one of his disclosures filed with the courts in 2007, when the committee’s work was beginning, Fawcett indicated that he had served as an investigator for Bristol Myers, Eli Lilly and Abbott Laboratories. His 2011 disclosure with the APA indicated that he was working for Merck on its diagnosis manual....
“I don’t think these connections create any bias at all,” Fawcett said. “People can say we were biased. But it assumes we have no intelligence of our own.
“There has to be some cooperation between academia and pharma if you want to make any progress. People need to realize that.”

In short, why should physicians and the public trust what this panel says?  Because the chair of the panel, who also has his hand deep in the drug company till, says they are all people of integrity. Besides, everyone does it, at least everyone with any brains, and if you oppose it, you're engaged in a witch hunt.

I am sure reporter Whoriskey thinks he wrote a totally factual story, but I think I discern in his piece the narrative of a sort of morality play, with the APA arrayed on one side and the Institute of Medicine on the other--the IOM being the source of recent strict guidelines on avoiding conflicts of interest in medical education and research. (Full disclosure--I am an IOM member though I had nothing to do with writing the COI guidelines.) When Whoriskey has to cite an expert calling for eliminating COI from clinical guidelines, he usually cites an IOM source.

So, given the fact that the IOM guidelines on COI are widely known and have been out now for some time, what can you say about Dr. Fawcett and his protestations on behalf of his panel? I must be frank and say that this sort of commentary is increasingly Neanderthal in this day and age. It ought to be pretty embarrassing to the APA that one of their main spokespersons should talk to the press in this fashion.

So now I come to what I mainly want to say, which is to offer several hypotheses as to how to explain this behavior on the part of the APA.
  • The not-too-bad is the enemy of the better: As I have covered in previous posts, the APA has actually taken important steps to free itself from drug money influence. Whoriskey reports that they currently take about 14 percent of their operating revenue from drug firms, when the figure used to be around a third--that's a significant change. Whoriskey quotes the APA's CEO, James H. Scully Jr., several times expressing pride in the organization's progress away from COI. So I wonder if part of this is that they legitimately feel good about what they have done so far, and so are much less inclined to look themselves in the mirror and realize they still need to come a lot farther. (After all these panelists, says Dr. Fawcett, had to give up a lot of income just to sit on the panel in accord with current APA rules--even if the result fell far short of what the IOM calls for.)
  • They just don't get it: If, after all the ink spilled and voices raised about COI, Dr. Fawcett can say all the things he said and still keep a straight face, then maybe the bottom line is that he, and by extension much of the APA leadership, remains clueless about the real issues here. They have accepted all these new COI rules, but in their heart of hearts they see no reason for doing so and think the whole thing is ridiculous. The idea that this has anything seriously to do with science and public trust has never penetrated. After all, they know that they are people of integrity; how could anyone else doubt that was true? And they know that they are rational, objective scientists and so mere money could never sway their opinions.
  • The corporate culture of entitlement: Here I'll channel our good friend Dr. Roy Poses at Health Care Renewal blog. Dr. Poses, I am guessing, would point to the sort of culture that exists today in corporate board rooms across the USA. Execs feel as if they are a breed apart, superior to all other humans. They can run their companies into the dirt and still expect a multi-million-dollar end-of-year bonus, plus the golden parachute when they leave. Right-of-center commentators commonly bemoan our entitlement society and entitlement culture, but they have it quite wrong about who that consists of; it's not the poor but the rich who are prone to act entitled. Now, as corporate money has flowed into big medical societies and health care firms, this same corporate mentality is now to be found among execs in health care and organized medicine. As Dr. Poses has documented thoroughly, one commonly sees the same people on the board of the corporations and on the boards of the local hospital. So no surprise that this gang sees the world in the peculiar way that they do, that corporate COI is no problem and that anyone who claims it is is some sort of out-of-touch whiner.

I'll just lay out the options this time; you can take your pick.

Zisook S, Shuchter SR, Pedrelli P, et al. Buproprion sustained release for bereavement: results of an open trial. Journal of Clinical Psychiatry 62:227-30, 2001.

Monday, December 24, 2012

Yet Another Silly "Integrity"" Agreement: Amgen and Aranesp

Okay, now we can go back to the standard form:

Company: Amgen
Drug: Aranesp (darepoetin alfa)
Offense: Marketing drug for off-label uses (anemia in all cancer patients when approval only for patients receiving chemotherapy)
Amount of settlement: $762M (including both criminal and civil penalties)
Settlement is what percentage of annual revenues from drug sales: 38%
Did company admit wrongdoing: Yes, pleaded guilty to one misdemeanor account

The facts are summarized in the usual insightful post by Dr. Roy Poses at Health Care Renewal:
--which in turn cites the New York Times:

All this is same song, third verse for readers of this blog who might remember these previous two posts:
--on which more in a minute. Basically, drugs to treat anemia in both cancer patients and kidney dialysis patients have been pushed heavily by drug companies, despite evidence (that was successfully hidden for some years) that higher doses of these meds, leading to higher blood counts, actually caused more patient deaths by leading to blood clotting. Aranesp is one of this family of drugs (generally referred to as epoetins). While as a technicality Amgen was nailed on off label marketing for claiming that all cancer patients, and not just those on chemotherapy, needed their red blood cells boosted up with this medication, the real offense was aggressively pushing the drug despite risks of harm.

Now, as the older of the two previous posts made clear, the blame for this sad state of affairs only partially lies with the drug firm, though they clearly did everything they could to milk extra profits even over the bodies of dead patients. The other part of the puzzle is the crazy way the Feds have reimbursed kidney dialysis and cancer docs. They are virtually the only physicians paid on commission for prescribing either more expensive drugs, or higher doses of drugs. So when Amgen came to these docs and said, your patients have this terrible anemia, use our expensive drug to boost their red cell count, and don't worry about those nasty rumors about lack of safety when you use the highest possible doses, they were preaching to the choir, as these docs pocketed extra money both for using the drug in the first place and also for using more of it. As I said in the original post, how anyone could be so insane as to imagine that such a system would result in high-quality patient care truly amazes me, and I'm pretty much beyond being amazed.

As is his constant refrain, Dr. Poses notes that no one at Amgen is doing any jail time, or even is worried about it, after the company pleaded guilty to criminal charges. When the drug, even now that docs have finally been warned and are using less of it, sells $2B worth every year, the company can easily afford a $700M settlement. In the face of these business realities--just pay your fine and go your merry way, and no company executive will ever suffer personally--then the fact that Amgen signed a "corporate integrity agreement" as part of the settlement remains nothing but a really bad joke. It was only as short time ago that we (thanks again to Dr. Poses) noted the repeat offenses of another company that has now signed enough corporate integrity agreements to paper the CEO's suite:

Tuesday, December 18, 2012

A Major Figure in Pain Medicine Recants--Partially

Thanks to a post at Health Care Renewal by Dr. Roy Poses:
--I was guided to a recent Wall Street Journal piece by Catan and Perez (subscription required) that addresses an issue I have previously blogged about at some length:

My own take on this issue differs a bit from Dr. Poses' so I refer the reader to the earlier posts in which I state my basic sympathy with the goal of treating chronic pain aggressively, with narcotics if other modalities don't work and if the patient seems a suitable candidate and is carefully monitored.

In taking that position over many years of (former) practice, however, I must admit that I was heavily influenced by the writing of one person, Dr. Russell Portenoy, who became head of pain medicine at Beth Israel Medical Center in New York. Dr. Portenoy was an early advocate of much liberalized use of narcotic medications for chronic pain, basically saying that one could take the same lessons learned in treating terminal cancer patients and apply them to the much larger population of adults with chronic non-cancer pain. Traditional physicians cried wolf when hospice first came on the scene, warning that liberal use of opiate drugs would kill cancer patients from depression of their breathing and turn all of them into addicts. When the drugs did neither, some of us concluded that a general "opiophobia" among physicians and nurses might be standing in the way of rational practice more generally. Dr. Portenoy was a leader in applying that logic to chronic pain.

It is therefore painful (no pun intended) for folks like me to read in this article that in a recent interview, Dr. Portenoy freely admitted that the advice he handed out back then was probably wrong-- particularly, that narcotics are much more dangerous and addiction-prone than he made out to be. This generally more  cautious attitude is mirrored in what studies have recently become available on the topic--for example, this study by Dillie and colleagues:
--looking at the association between dosage and reported quality of life in chronic pain, opiate-treated patients and showing that the better quality of life was related to lower and not higher dosages of the medication.

Dr. Poses correctly notes that there was not, when Dr. Portenoy began his campaign, nor is their today, any solid high-quality evidence that narcotics work effectively and safely in treating chronic non-malignant pain. I would simply ask one to consider what it would take to launch a definitive randomized, controlled, double-blind trial to answer this question, and I don't think it's a great surprise that there have been no such studies. This is especially the case since there is very limited NIH support for studies of pain generally.

OK, so all this is very disppointing when it comes to treating chronic pain. The aspect that especially concerns us in this blog is the role of conflicts of interest and industry funding. The WSJ article makes clear that Portenoy accepted huge sums of cash from the drug companies that make opiates, especially the problem-prone OxyContin manufactured by Purdue Pharma, the now-infamous "hillbilly heroin." The old excuse we heard from the pain docs and pain associations is that they had no choice but to accept industry money if they wanted to get any research done at all, given the dearth of federal funds. This article (and others in the previous posts) show that it was not just a matter of research funds; many of these docs became high-rolling "key opinion leaders" feathering their own nests with dollars not intended for research at all. And as was usually the case back then, articles they wrote for medical journals, or guidelines they authored for various national organizations, seldom if ever disclosed those conflicts.

Here is where Dr. Portnenoy's mea culpa hardly extends far enough. He seems to have learned that the safety profile of opiates is not as rosy as he made it out to be 10 and 20 years ago. But he does not seem to have gained any perspective on the dangers of being bribed by industry. He told the interviewer, "My viewpoint is that I can have those [financial] relationships, they would benefit my educational mission, they benefit my research mission, and to some extent, they can benefit my own pocketbook, without producing in me any tendency to engage in undue influence or misinformation."

Well, since Dr. Portenoy began his career, new evidence has emerged about the efficacy and safety of narcotics in chronic pain. New evidence has also emerged about the degree to which docs are influenced by Pharma money, even if they deny it. Dr. Portenoy seriously needs a refresher course in the latter body of evidence, just as he seems to have had some helpful re-education regarding the first.

Catan T, Perez E. "A Pain-Drug Champion Has Second Thoughts." Wall Street Journal, Dec. 15, 2012, P. A1.

Monday, December 17, 2012

Doing It Again, After Promising Not To--Pfizer's Amazing Record

Once again I can kick back and let the nice folks over at Health Care Renewal do all the heavy lifting:

I want to highlight several things reported in that post that pick up on themes previously discussed here.

Dr. Roy Poses tracked down a couple of recent Federal settlements involving Pfizer. These settlements did not get much media attention--in one case Dr. Poses could not even find any details about what the company supposedly did wrong--and the amounts of the settlements are chickenfeed compared to earlier numbers, less than $100M each. So I won't even go to the trouble to do my usual scorecard of latest Pharma fraud judgments.

What does matter, and as Dr. Poses noted, was not mentioned at all in the very limited media coverage, was Pfizer's overall track record of paying settlements due to alleged or admitted illegal behavior. As he has reconstructed it, and he admits he might have missed a few things, it looks like this since the turn of the century:
  • 2002: Pfizer and affiliates Warner-Lambert and Parke-Davis, $49M, failure to pay proper federal and state rebates for Lipitor
  • 2004: Pfizer and affiliate Warner-Lambert, $430M, off-label promotion of Neurontin
  • 2007: Pfizer and affiliate Pharmacia & Upjohn, $35M, illegal kickbacks to promote Genotropin
  • 2009: Pfizer, $2.3B, illegal marketing of Bextra
  • 2010: Jury finds Pfizer guilty of violation of anti-racketeering statute for marketing of Neurontin, assesses $142M damages
  • 2010: Another case, no details provided
  • 2011: Pfizer affiliate Pharmacia, settlement with New York for overcharging
  • 2011: Pfizer and affiiliate Quigley settle class action suit for $265M over asbestos exposure
  • 2011: Pfizer, $14.5M, illegal marketing of Detrol
  • 2012: Pfizer, $60M, allegations of subsidiaries bribing foreign government officials
  • 2012: Pfizer and subsidiary Wyeth, $55M, illegal marketing of Protonix
  • 2012: Pfizer, $43M paid to 33 states, illegal marketing of Zyvox and Lyrica

As Dr. Poses (and previous posts here) have noted, several of these settlements involed promises by Pfizer that it had learned its lesson and would not do those sorts of things again. They obviously did learn their lesson, which is that you can do these sorts of things again, pay your fine, and keep merrily toting up all the profits.

Dr. Poses then appropriately juxtaposes these recent small-potatoes judgments against Pfizer with two larger events. The one you may have heard of is the scandal involving the monster British bank HSBC, found to have laundered money for Mexican drug cartels, and to have helped numerous bad guys around the world dodge international sanctions. As the New York Times opined in an editorial:
--the Feds's failuire to indict any top executives of this bank shows that "the government has bought into the notion that too big to fail is too big to jail."

The other event that you probably never heard about was the 15th International Anti-Corruption Conference, sponsored by Transparency International, in Brasilia, which led to the Brasilia Declaration decrying the failure of governments to properly punish corrupt officials. Without such punishment, said the group, don't expect any reduction in corrupt practices:

As I have previously blogged:
--it's naive to imagine that corruption is something that happens in poor nations on the other side of the globe, when we have splendid examples of corporate corruption cropping up all over the US and Europe. So the rules for what needs to be done to thwart corruption should be applied here first and foremost.

Tuesday, December 11, 2012

Obama's FDA-- Same Ol', Same Ol'

No one was surprised when under the Bush Administration, FDA's leadership took a decidedly pro-industry tilt. There was briefly some hope when Obama's people took over that a new breeze might be blowing there and that positive changes were underway--such as:

Therefore an article published back in March in BMJ:
--by Drs. Lisa Schwartz and Steve Woloshin of Dartmouth represents very depressing evidence that nothing really has changed and that the FDA remains the lapdog and not the watchdog of Pharma.

The background you need to know is that donepezil (brand name, Aricept, manufactured by Eisai and marketed by Pfizer) is one of several drugs intended to slow the progress of Alzheimer's disease, but that have never been shown to work very well. In research studies, the drugs will improve thinking, memory, or function by a few points on some measuring scale, but typically the patient or family cannot detect any real improvement. People feel obliged to use these drugs anyway since Alzheimer's is such a bad disease and we have nothing better to offer.

OK, so it's 2010, and Aricept, previously made in 5 and 20 milligram doses, is about to go off patent, and sales will be lost to the generic makers. How to evergreen this drug? Eisai apparently took a page from Abbott Labs' experience with fenofibrate:
As we've discussed here and in HOOKED, the more usual evergreening process (extending the patent life of a drug to keep profits rolling in) has involved going into the chemistry lab to tweak the drug molecule in some minor way, then claiming that one has discovered a new miracle breakthrough drug. But why bother even to go into the lab if you can con the regulators to allow you simply to make a new dosage form of the drug, then claim that it's a brand new drug and deserves patent protection?

So Eisai went to the FDA with a new, 23-milligram form of Aricept with studies purporting to show that it was safe and effective. The FDA's own staff, as Schwartz and Woloshin tell the tale, said this was garbage--the study failed to show that the new dose was any more effective than the old 10 mg dose in global disease improvement. (There was a statistically significant, but clinically tiny improvement in cognitive function.) The staff also noted that when you upped the dose, guess what, patients suffered a lot more side effects--and side effects in the frail elderly can be nothing to sniff at. The chiefs of that section of the FDA overruled the staff and approved the "new" drug.

Eisai-Pfizer then launch a huge ad campaign aimed at both the general public and at docs. The campaign for the public transmitted the message that if you don't beg your doctor to prescribe this new wonder drug for Grandma, then obviously you don't love her. The ad for docs blatantly misrepresented the study data and claimed that the new dose form had been shown to be superior on global measures to the old one--and soft-pedaled the evidence for worse side effects.

When various do-gooders pointed out this lie, the FDA looked into it and discovered that they could not legally fault the company for the ads, because the ads contained the same information as was in the official FDA-approved product label. Apparently when the company sent in the proposed text for the new label, the FDA goofed and approved the incorrect language, despite their own in-house evidence that the labelling was false. Eventually the FDA fixed both the label and the ad campaign--only 18 months and 68,000 prescriptions after the ad campaign started.

In short, if this one instance is any clue, it's business as usual at the FDA, and it doesn't seem to matter who's in the White House.

(Hat tip to Drs. Rick Bukata and Jerry Hoffman of Primary Care Medical Abstracts for alerting me to the Schwartz-Woloshin paper.)

Saturday, December 8, 2012

What To Do about Worthless Guidelines

While I have been getting behind in my posting, our friends at Health Care Renewal have been on a tear, including this useful piece:

The post summarizes (and also links to) a recent study showing that the majority of clinical practice guidelines fall woefully short of the standards recently recommended by an Institute of Medicine report. I should add here that what the IOM did was not exactly rocket science; they pretty much summarized earlier thoughtful recommendations. So no one could claim that the IOM report came from out of the blue with a bunch of wild and crazy criteria.

What HCR is especially concerned about, suitable for our own purposes in this blog as well, is the frequency of conflicts of interest among guideline writers and chairs of panels, and the general failure of the guideline-sponsoring societies to police or even to disclose such conflicts.

As usual the HCR post makes a number of good points, but I would add a comment on what needs to be done about all this. HCR bemoans the fact that right now, no one has any interest in cleaning up the mess; everyone involved is looking for a way to use guidelines to make a buck. As my friend Dr. Jerry Hoffman of Primary Care Medical Abstracts likes to say, our current fetish for pay-for-performance makes the job of the drug companies and their ilk easy. They used to have to find a way to bribe 800,000 docs to write prescriptions for their pills. Now all they have to do is find a way to bribe about 1000 docs--the ones charged with writing the practice guidelines. Then the P4P folks will tell the rest of the 800,000 that they won't get paid unless they follow the guidelines, and the industry can laugh all the way to the bank.

So what to do if no one has an interest in cleaning up the mess? We have to turn back the clock a bit and recall the history of the Federal agency now called the Agency for Healthcare Research and Quality (AHRQ) which in olden days was the Agency for Health Care Policy and Research (AHCPR). In its AHCPR days, the agency gained a reputation for writing the best clinical practice guidelines around. They usually spent $10M per guideline and the result was highly respected by experts.

One result, however, was not highly respected by one group. The lower back pain guideline that said that surgery was hardly ever warranted as treatment upset a few well-heeled orthopedists, and these guys just happened to have some good friends in Congress. Thanks to that cabal, the next thing you knew, there was an action in Congress to eliminate all funding for AHCPR. AHCPR just barely squeaked by and survived with a major budget cut. But as part of that whole deal, they agreed to stop writing practice guidelines.

AHRQ is now the host of, a central respository where you can find just about any clinical practice guideline written by any group for any disease. Also, if you look at the inclusion criteria at, you'll see that AHRQ exercises virtually no editorial control whatever over the content of the guidelines. So long as some document is the guideline equivalent of a warm body that has a pulse, it goes on the site. And that makes good political sense if you don't want some other influential group of rich docs, who think you're robbing them of their cash cow, lobbying Congress to revoke your funding.

What has to happen, given the widespread promulgation of guidelines that fall abysmally short of any decent standard of quality? Somebody in government has to run interference for AHRQ and have the spinal fortitude to assign them the task of applying all the IOM criteria to each guideline. Now, so far as I care, can stay as it is and collect all guidelines in one handy location; but there then needs to be an inner circle of the real guidelines that actually meet a reasonable subset of IOM quality criteria. The guidelines with the seal of approval have to be carefully labeled and distinguished from the rest. Then maybe the other players in the game, especially the medical specialty societies which are currently among the worst offenders, will finally have an incentive to produce quality products instead of the current drek.

Full disclosure department: I am a member of IOM and spent the year 1993-94 as a visiting scholar at AHCPR.

Minimizing Side Effects at Merck--the Old Paycheck Effect

One of the more enthusiastic members of my very small fan club kindly sent me this link:

Now, I don't want to make too much of this post from a clearly biased source, and the incendiary part of the post is obviously the idea that the big drug company would not only cause terrible side effects in patients who take their drugs, but then proceed to heap scorn on the patients who report the side effects. But what seems mainly to come through loud and clear is the simple refusal on the part of supposed scientists working for the company even to see the link between the drug (alendronate) and the adverse reaction (destruction of the jawbone following dental procedures), despite a large accumulation of both animal and human data pointing toward the connection. So somehow, if you give an animal that drug and you see jawbone destruction, suddenly that animal is no longer a reliable experimental model and the results don't count.

If you ever had occasion to doubt if author Upton Sinclair was on to something when he wrote, "It is difficult to get a man to understand something when his salary depends upon his not understanding it," this little anecdote about Merck staffers might shed some light.

Friday, December 7, 2012

US Appeals Court: It's Free Speech, Not Off-Label Marketing

I've been out and about lately and have gotten behind on posting, but before addressing any backlog I have to refer to today's news:

A 2-1 majority of ta panel of the 2nd Circuit Court of Appeals (Manhattan) dismissed the conviction of a drug rep for off-label marketing on the grounds that he was simply exercising his free speech rights. The government will appeal, first to the entire Appeals court, and next to the Supreme Court if that is unsuccessful.

If you have been following our numerous posts about criminal settlements of big drug companies with the Feds in recent years--most recent example:
--then you know that when the Feds manage to catch the companies doing shady marketing, almost always the regulation that's violated has to do with off-label marketing. We have long had the apparent paradox that while physicians can legally prescribe any drug for whatever purpose, despite what the official FDA-approved label says, companies can only legally market the drug for approved uses. This has become the principal tool by which the regulators can rein in the excesses of the industry. So if this ruling were to stand, the entire landscape of drug regulation in the USD would shift radically.

As the one dissenting judge stated the obvious, the ruling undermines the entire system of FDA regulation, since if companies can freely market drugs for off-label uses, they have no reason to go to the FDA to seek approval for any use except the most minimal required to get the drug onto the market at all. That means no need to submit any data to show that the drug is safe and effective for its various recommended uses.

As somebody concerned about ethics and logic I can say what I think of this ruling, quite apart from how it stands as a bit of legal reasoning based on case law and precedent. The logic part comes in when we ask how drug reps are trained by the companies and assigned to their jobs. Last I heard, the companies spend a lot of time and money to assure that their reps don't speak freely. They are trained to be consistent, reliable mouthpieces for the industry marketing message. Now, if a drug rep had been fired by industry for telling docs that a drug made by his company was unsafe or ineffective, and he sued to keep his job, and the court had ruled that he should keep his job because the company decision violated his free speech rights, then I might believe that the court was perhaps really serious about applying the doctrine of free speech to the relationship between drug rep and doctor. As it stands, to put what the drug rep did in this case by telling a doc (apparently one wearing a wire as a Federal informant) about off-label uses of the drug under the category of "free speech" is simply a bad joke.

Monday, November 12, 2012

Corporate Integrity? Professionalism? Give Us a Break

"The rich are different from you and me."
"Yes, they have less integrity."

I'll return at the end to this exchange that never happened between F. Scott Fitzgerald and Ernest Hemingway. The thread begins, however, with this post by our friend Dr. Roy Poses on Health Care Renewal:

Dr. Poses reviews the recent legal difficulties of the firm Orthofix, which seems to be headquartered down in my neck of the woods, in Lewisville, TX. Orthofix makes stuff that orthopedists implant in patients and so getting surgeons to choose their products over competitors' is huge for Orthofix profits. Some of the wrongdoing occurred in a subsidiary company, Blackstone Medical, which Orthofix bought out in 2006.

Some of the legal issues, in four separate legal actions, are summarized in a Bloomberg News release:
Others came from an SEC news release that Dr. Poses quotes.

Not to get overly fancy about which legal action is which, basically Orthofix was implicated in all of the following:
  • Having to pay a total of $121.4M to the Feds in all the actions combined
  • Paying docs sham consulting fees and kickbacks for using Orthofix products
  • Paying bribes to Mexican government officials to obtain sales contracts with Mexican government-owned hospitals
Health Care Renewal has made a big deal of how drug and device companies repeatedly are caught violating laws and committing fraud, but they pay fines that amount to small percentages of their total take on the products they were peddling illegally, and have no real financial incentive not to do it again, which they then routinely do. Dr. Poses has stated that until executives of these companies do jail time we can expect this behavior to continue. So it is therefore worthy of particular note that in this case, the behavior was apparently so egregious that 5 Orthofix employees, including a vice president, have pleaded guilty to criminal charges in the kickback allegations.

What do we mean by "egregious"? Well, even if you are now jaded by all the repeated accounts of company wrongdoing, this stuff may get your attention. Here's the partial rundown:
  • Docs were paid as much as $8000/month under fictitious consulting agreements, and some were awarded phony research grants for up to $18,000
  • Blackstone sales tactics routinely included wining and dining docs, taking them to strip clubs, and paying for prostitutes
  • One Blackstone female sales manager was urged by two surgeons whom she took to a strip club to disrobe and join the strippers on stage--after she complied, she was demoted but not fired
  • The bribes paid to Mexican government officials were referred to in Orthofix documents as "chocolates," but consisted of cash, laptop computers, TVs, and appliances given directly to the officials or via front companies
Somewhere in the mix of all the legal actions back and forth, there was mention of Orthofix being forced to agree to a corporate integrity pact with the Feds. One has to wonder what possible meaning an "integrity" agreement could have in this type of situation. It is sort of like going to the local garbage dump and getting them to sign a "smell nice"" agreement.

That brings us back to the non-quote with which I began. We would like to talk about corporate integrity, on the industry side, and professionalism on the physicians' side. What does corporate integrity mean when companies act in the way that Orthofix has--apparently as a standard business arrangement? What does professionalism mean when a company offers strippers and prostitutes as well as funny money to surgeons, and expects that this will gain them points with their customers, instead of enraging and offending the surgeons? ("We've already established what you are; we're just haggling over the price"?) And what does professionalism mean when a company assumes that surgeons will find these offers attractive and acceptable--and the surgeons, in fact, do accept them, eagerly?

Well, it turns out that one problem we may be facing here is that both the corporate leaders and their surgeon-customers are wealthy. And going back to Health Care Renewal again:
--we're reminded that there is starting to be a body of experimental and survey literature that documents a general trend of rich folks to be less honest and more likely to feel entitled to bend the rules in their favor than average people.

This is the opposite of what the popular political discourse proclaims. When we hear mention of "entitlement programs," we are not likely to think of corporate welfare for the rich, but rather of programs that aid the poor and middle class, and make those nasty people into bad folks who feel "entitled" to things they did not properly earn. But the available research suggests that it's rather those who grew up under privilege that somehow are conditioned to believe that they earned every bit of that advantage and that they can expect it to keep rolling in. (Which is what F. Scott Fitzgerald, in the legitimate quote, actually did say about the rich.)

So I conclude that for some corporations to develop integrity, and for some physicians to develop professionalism, would require a dose of anti-entitlement pills. The drug company that seeks to market that particular product might get my blessing.

Wednesday, November 7, 2012

A Non-Psychiatrist Dares to Comment on Psychiatry

I have occasionally posted about the controversy aroused by the American Psychiatric Association's (APA)forthcoming DSM-V classification of mental illnesses, for example:

I will now offer a further comment based on two posts, first, Dr. Bernard Carroll over on Health Care Renewal:
--who in turn cites the 1 Boring Old Man blog run by a retired psychiatrist:

The short form of these two posts is that the APA has antagonized so many folks with the way they have mishandled the DSM-V business that they risk making both DSM-V and themselves irrelevant to mental health, and that smart people will ignore DSM-V and turn elsewhere for classifications of mental illness.

What follows is my attempt to synthesize some important ideas from these two recent posts, and I'll use the excuse that even though I am not a psychiatrist, the other two bloggers are, and so I am simply trying to pass along what they have said.

1 Boring Old Man recalls what it was like to practice psychiatry in the 1970s and 1980s. He recalls that a thousand flowers bloomed. There were many disparate, incompatible theories and schools of psychiatry--and that was good. Psychiatrists read Freud and benefited from the reading, but very few were the cardboard-caricarture Freudians that now are derided and are trotted out as the excuse as to why psychiatry had to reform itself. When the DSM-III (the first modern version) came out, most psychiatrists realized why it had been created, and basically supported the idea that some sort of standard diagnostic approach was necessary; but hardly anyone found it clinically useful. The eclectic mix of disparate schools and theories was confusing to the statisticians and epidemiologists, but a rich mine ideas for the psychiatrist who had to confront a wide variety of symptoms in a wide variety of people. The eclectic mix gave them the freedom to do what worked best under any given circumstance.

This state of affairs, these psychiatrists say, has evolved from toolbox to straitjacket as the new DSM-V seems a further attempt to impose a rigid orthodoxy on the field that stresses brain biology and drug treatment--so much so that many are now saying they'll have none of it and the APA can go take a hike.

Okay, now I'll add my own ideas. When eclecticism is working for a field, and people decide to throw out the eclecticism and replace it with something clinically much less helpful, that's bad. What this blog is mostly concerned about is the impact of industry-driven commercialization on medicine. So the next question is, how much of this bad stuff can be traced to drug industry influence.

In a previous post:
--I recounted journalist Robert Whitaker's history of the APA (in his Anatomy of an Epidemic) giving the specific dates (between 1974 and 1980) when the APA decided they had major problems on their hands, that those problems could be solved by a big influx of Pharma dollars, and that their policies therefore should shift to make APA an extremely Pharma-friendly venue. The above-listed posts further document how the new DSM-V appears to be an even bolder move toward allowing the Pharma fox to guard the psychiatric-diagnosis henhouse, in ways that maximize industry profits and the drugging of patients with even mild symptoms.

So does this shift in the DSM, that results in a further flight from clinical utility, have something to do with Pharma influence? Yes.

Monday, November 5, 2012

Let's Do It Again: Latest Federal Settlement (Boehringer Ingelheim)

We are back to our standard form, to report the latest incident of a drug firm settling with the Feds over alleged lawbreaking:

Drug company: Boehringer Ingelheim
Drugs involved: Combivent (ipratropium/albuterol), Micardis (telmisartan), Aggrenox (aspirin/dipyridamole)
Amount of settlement: $95M
Settlement equals what percentage of one year's sales of the drug?: I could quickly locate annual US sales figures only for two of the drugs in 2010, Micardis and Combivent; the settlement amount is 4% of that combined figure.
Did the company admit wrongdoing? Yes/No: Of course not
Link to detailed news coverage:

This is such small potatoes in the balance sheet of a big drug firm, less than $100M, that it's hardly worth even mentioning, except that the Feds claimed that besides evidence for off-label promotion which amounted to lying about the drug's effectiveness, the company also engaged in paying kickbacks to docs for prescribing the drugs. Not surprising to any regular readers of this blog, the kickbacks consisted of payment for serving on advisory boards, speaker panels, speakers' training programs, and consultancies.

The company, in denying any wrongdoing, commented that industry standards had recently changed, that the company was cooperating fully, and that they had entered into a supposed integrity agreement. Given the frequency with which other drug companies in the past have entered into such agreements and then repeatedly re-violated, one can be forgiven for skepticism that this amounts to any significant deterrent.

Hat tip to our Health Care Renewal friends for tipping us off:

Saturday, November 3, 2012

Roses (and Thorns) by Any Other Name: ACRE's New "Guidelines"

I have blogged at length about the Association of Clinical Researchers and Educators (ACRE), the primary outlet for pharmapologist sentiments, for example:

ACRE has now come out with what seems alternatively to be called either a "statement" or "guidelines" on "relationships between physicians and industry":

(Side note: I looked for this statement first on ACRE's own website and found that their latest posted news release was dated mid-2011, so I'm not sure what's up with them, but for all I can tell this statement is legit.)

If you want to cut to the chase and read the statement directly, not the summary of it in the press release, you can go to:
The summary says that this is to be published in the journal Endocrine Practice, which is not exactly a high-impact journal, but leave that aside. Corresponding author is Dr. Michael A. Weber of SUNY-Downstate, with our old friends Drs. Tom Stossel, Avi Markowitz, and philosopher Lance Stell among the writing committee.

OK, so why should a pharmascold blog like this one devote (virtual) ink to anything coming out of ACRE? I decided it might be instructive to see what happens when this organization attempts to be positive and actually issue a set of practical guidelines. Think of an analogy with the Romney campaign. Romney had it easy early on when all he had to do was attack "Obamacare." Then things got tougher when unkind folks asked him what his own health plan consisted of. When forced to come up with concrete policy proposals, Romney suddenly discovered that he actually agreed with some parts of the Affordable Care Act. So one might ask whether any similar "aha" moments might emerge from ACRE's recent efforts.

Let's quickly review ACRE's track record. Perhaps guided by in-house philosopher Stell, ACRE has never been content to quibble about the details of the ethics of the Pharma-medicine relationship. They have always gone for the jugular, attacking the core assumptions of the pharmascold position (if I may caricature it that way for brevity).

What are those assumptions? Folks like me always start with a collection of ideas:
  • Conflict of interest
  • Professionalism
  • Trust (alleging that conflicts threaten patient and public trust in medicine)
ACRE's previous publications take aim at every one of these, as we've reviewed in previous posts. There are no worries about financial conflicts of interest, because COI is ubiquitous in science and medicine so no reason to worry about one form of it. Professionalism is an outmoded sentiment. There's no empirical evidence that anyone's trust in medicine is diminished when docs fill their pockets with industry cash.

So, having trashed all the more usual ethical assumptions on which one could base guidelines for physician-industry interactions, and which in fact were relied on by folks like the IOM, NIH, and AAMC in their proposed guidelines, what can ACRE come up with?

Their summary statement seems to be: "While there may be strengths and weaknesses to [current] approaches [to regulate these relationships], the best course is a middle road: one that values transparency of such relationships, but does not harm patients or slow innovation in the process."

They then begin their statement with a substatement: "The vast majority of collaborations between physicians and industry has added considerably to improved patient care.  Moreover, these collaborations have been conducted with integrity and commitment.  Critics of these collaborations have raised concerns, largely speculative and theoretical, that have created complicated and counterproductive regulations and rules regarding these relationships."

This sounds like the old ACRE, trashing the pharmascold position as based solely on theoretical concerns when everyone knows that in the real world, nothing but benefits flow from the exchange of cash between docs and industry. And in fact, a good deal of the verbiage in the actual statement consists of a long list of all the advantages to science and patient care provided by industry and strong relationships between medicine and industry. But wait...

Here are some comments culled from the summary review, which reflect the language in the statement itself:

On medical societies: "Accordingly, ACRE recommended that leaders of medical societies have a strong obligation to create internal operational procedures ... to ensure corporate support does not create inappropriate endorsements of industry products.  ... societies should be proactive in protecting themselves and their corporate supporters against the appearance of inappropriate endorsements."

On CME: "Faculty should create their own talks"

On publishing: "Cannot prevent or delay publication of unfavorable results... Begin before outlines of article or any drafts are written ... 'ghostwriting' should be avoided and the use of external writing agencies or 'editorial assistance' should be undertaken with great care..."

On travel expenses for meeting attendance: "Travel support to attend a meeting as a member of the audience, not the faculty, should be declined...Acceptance of travel support must not be linked in any way to prescribing performance or other support of the sponsor’s products"

On consulting/advising: "Avoid giving the impression of primarily defending industry interests"

  • As I noted, ACRE's past publications have ruthlessly trashed the ideas of COI, professionalism, and concern about public trust. But their new statement/guidelines offers no alternative set of principles on which ethical conclusions might be based. And many observers would note that the above-quoted recommendations make no sense at all unless one implicitly assumes concerns about COI, professionalism, and breaches of trust.
  • Put another way, whenever the principal actors in ACRE have allowed us to peek behind the curtain to see what basic philosophy motivates them, we see some version of economism, or a faith that the unregulated free market will solve all human problems (see This proposed set of guidelines is inconsistent with that philosophy. If the market did not want ghostwriting to exist, it would not be so profitable and hence so commonplace. So the guidelines represent a tacit admission that the marketplace cannot solve all these problems on its own, and that the unregulated marketplace indeed creates problems for medicine.
  • ACRE's champions have always insisted that pharmascolds have blown a very few anecdotes way out of proportion, to claim that problems at the Pharma-medicine interface are serious and widespread. But if you look at what this blog has repeatedly documented, and then look at what ACRE's guidelines call for, you see that behavior that their own guidelines criticize occurs commonly. So these guidelines represent a tacit admission by ACRE that their past dismissal of these problems is ill-founded.
 ACRE ends this new statement by saying that while they agree with transparency and disclosure (again, why, if they reject concerns such as trust, professionalism, and conflicts of interest): "ACRE rejects the terms 'conflict of interest' [and] 'competing interests'...ACRE strongly believes that 'acknowledgement of support' is more appropriate and should be used in making disclosures of financial relationships by physician educators and researchers." All right, so they want to call it by that name, but the ethical concerns seem to be pretty much the same when you drill down. 

Monday, October 29, 2012

When the Marketing Tail Wags the Research Dog: More on Medtronic and InFuse

I have posted a number of times on the case of Medtronic, its payments (bribes) to spine surgeons, and its product BMP-2 or InFuse:

Our good friends at Health Care Renewal now inform us that the staff of the Senate Finance Committee has issued a report on this whole episode:

The Senate staff report itself can be found at:
I'd caution you that the entire report is over 2300 pages, of which 22 pages is the report itself and the rest is "exhibits." (More on that later.) I am not sufficiently dedicated to have read all 2300 pages so what follows is based on the HCRenewal summary plus the first 22 pages of the Report proper.

The committee, no doubt at the urging of Sen. Grassley of Iowa, demanded internal documents from Medtronic regarding its clinical trials of InFuse, which is a biological product that makes bone grow. The basic idea is that when a surgeon wants to do a spinal fusion, in which two vertebrae are more or less glued together to stabilize the back, you can do it in two ways. You can take a graft of bone from the patient's hip and use that to bridge the two vertebrae; or you can use InFuse, put into a special metal cage made for the purpose, and it causes bone to grow in the same area and fuses the vertebrae. The problem is when InFuse makes bone grow where you don't want it, or escapes from its cage, or causes a variety of untoward reactions. The earlier posts describe the problems with InFuse, Medtronic's initial efforts to hide the problems, and the exhorbitant sum it paid to spine surgeons who did its bidding; the later posts show how Medtronic has changed its tune and promised a full and neutral investigation.

Now enter the Senate Finance Committee. They plowed through all those documents and concluded that Medtronic exerted an undue influence over the clinical studies and the way they were reported in scientific journals. I'll focus here on one specific anecdote included in the report, that probably add the most to what we have long known about how Pharma allows its marketing apparatus to control the scientific branch.

One study compared the use of InFuse with the standard hip bone graft method. The authors of the study first reported, "12 months after surgery, the patients [sic] graft-site pain had resolved...and no patients complained about the graft-site appearance." Medtronic employee Neil Beals, assigned to manage marketing programs and initiatives for biologic products like InFuse, inserted a comment in the draft: "ALTHOUGH THE PATIENTS DID NOT COMPLAIN ABOUT THE APPEARANCE DIDN'T SOME STILL EXPERIENCE PAIN AT THE DONOR SITE? SEEMS LIKE RESIDUAL EFFECTS OF DONOR SITE SHOULD BE NOTED." The supposedly "scientific" authors then dutifully inserted a sentence: "...even at the 24-month follow-up assessment, some patients continued to experience residual pain at the donor site, and rated the appearance of the site as only fair."

This seems quite a blatant example--the clinician-scientists report that pain and appearance of the donor site are not a problem. The marketing dude back at the company, who probably never laid eyes on a single patient, says, that can't be right, we'll never sell a lot of product that way. So the scientists meekly buckle under and change their report to make it come out like the marketing guy wanted. When you read further that one of the authors of this study was paid $22M in so-called consulting fees by Medtronic between 1997 and 2010, you might hazard a guess as to why the authors were so malleable.

Now let me switch-hit and say a word for the other team. If indeed the Senate Finance staff plowed through 2300 pages of documents, and the worst dirt they could find against Medtronic was the few anecdotes in the brief report, then maybe things were not all that bad. (Except, if you read my previous posts, they were.) But as I say I am not just now about to read all 2300 pages for myself, so we'll just have to leave it there.

Thursday, October 25, 2012

Against Capitalism?

One of my most faithful pen-pals (if such a term can be applied to people who send me e-mails) shipped over this link:

Briefly, this blog post recounts the history of an exchange between Dr. Ben Goldacre, a British physician/journalist and author of a new book called Bad Pharma, and a dissident economist, Harry Shutt. Goldacre's book appears based on what I've heard so far to be same ol', same ol' for readers of this blog--he nails the drug industry and its medical hangers-on for their addiction to profits over science and health. Shutt's criticism was that all Goldacre calls for is improved regulation of the industry. How, he asked, can you assume that's any sort of adequate measure, when you've just compiled this huge body of evidence that the industry snaps its fingers at all the regulation previously put in place? Goldacre first sent a wimpy reply back, then ceased to respond at all as Shutt pressed him further.

This exchange points out a basic feature of my book HOOKED as well as of this blog. I'm guilty as Goldacre is charged. I have clung to the position that I accept that we live in a capitalist society and that the drug industry is going to continue to be run as a for-profit endeavor. I have called for a lot of changes in how the industry, medicine, and government all do business, but have not called for nationalization of the industry or making it a public utility.

I may be accused of similar wimpiness in my recent book, The Golden Calf (see I there attack economism, the belief in an unregulated free market as the solution to all human social problems. But to the extent that I offer a vision for an improved future, it's largely a return to the capitalism of the 1950s where the power of government and organized labor helped balance out the excesses of big business, and not the overthrow of capitalism.

I cannot honestly report that I have a deep philosophical commitment to capitalism, though I am persuaded by authors such as economist-philosopher Amartya Sen that basic respect for human rights and human liberty has to include respect for rights to participate in fair markets. My overall goal has been strategic rather than philosophical. I am trying to get the attention of readers, most especially my fellow physicians and health professionals. If the position from which I started is anti-capitalist, I could expect that hardly any of them would read beyond the first sentence. If I stay under the capitalist big tent and specifically detail the problems with medicine and Pharma, maybe at least a few more of them will pay attention.

Is that a coherent and responsible position to take? The beauty of a blog is that y'all get to decide.

Wednesday, October 24, 2012

Yet More from the Belly of the Beast: Pfizer's Campaign to Market Neurontin Off-Label

Thanks as so often to Dr. Roy Poses over at Health Care Renewal--
--we are alerted to the recent publication by S. Swaroop Vedula and colleagues:

These authors were part of the team that testified in lawsuits brought against Pfizer related to the drug Neurontin (gabapentin). As a result they had access to a trove of internal e-mails and documents. Here they report their analysis of these documents, from two separate legal actions in 2004 and 2008, providing a longitudinal account of how the company approached publication of clinical trial data on gabapentin for off-label uses. (The drug was approved by the FDA for two relatively narrow indications, epilepsy and post-herpetic neuralgia;and the company wanted to extend sales by showing that it worked also for migraine, bipolar disorders, neuropathic pain, and nociceptive pain.)

First the authors documented: "For each of the four off-label indications we included in our study, a document titled ‘marketing assessment,’ designed to examine the financial impact of seeking FDA approval for a new indication versus other methods of increasing sales for the indication, preceded clinical trials sponsored by Pfizer ..." That is, before the company or independent academic scientists had a go at designing and conducting a clinical trial, the marketing people already had their innings and decided on the overall strategy. In this instance, the key decision was not to try to gather data that would allow an aplication to the FDA to expand the approved indications for Neurontin, but to find data that would support off-label prescribing for that usage. And that key decision was made not based on the scientific results of clinical trials, but before the clinical trials were even begun. A critical difference is that if the company had approached the FDA, they would have been legally required to hand over all study results, both favoring the drug and not; while by going the off-label route, they could cherry-pick what they published, as we'll come to. (Reminder: a company cannot legally market a drug for off-label use directly, but its physician "key opinion leaders" are free to recommend off-label use so long as it seems to be at arm's length from the company. Today, drug reps can also hand out trial report reprints that support off-label use, hence the need to publish trials that are favorable.)

The other main reason, besides more control over publication, was that the patent on Neurontin was about the expire and it made no business sense for the company to expand its use just as the drug was about to go generic. In one instance, the decision as to publication of negative results seems to have been driven by the form's "evergreening" strategy, which was to roll out the "new" drug pregabalin as a me-too drug to replace gabapentin as their expensive, heavily-marketed brand-name drug. As pregabalin was about to be launched, the company may have wanted negative trials published about Neurontin, so as to lay the groundwork for later being able to claim that pregabalin was really head and shoulders better than its predecessor.

The next major finding from the authors was, "According to the internal company documents, 'affiliate-driven manuscripts' were written for Pfizer ... by [Medical Action Communications, a medical communication company] and sent to the authors for approval. Each article was coordinated by a manuscript team, consisting of representatives from the medical and marketing divisions of the company." This suggests that ghostwriting--having paid writers spin the research papers the way the company wanted them, and only then letting the scientific "authors" see the drafts of the papers--was simply standard operating procedure within the company. The entire process showed that Pfizer, and especially its marketing division, kept everyone involved in the publication of a paper on a short leash.

Finally, the authors demonstrated that the journals in which papers were published, and the timing of publication, were also chosen for maximum marketing impact--for instance, with positive results published in high-impact journals and published quickly, and with negative results showing up in low-circulation journals years later.

As the authors summarize: "In this study we also observed that publication occurred in journals with higher or lower circulations related to statistical significance of findings; delay in publishing statistically non-significant findings; tailoring of publication content to reflect key marketing messages; adding spin to scientific publications such that conclusions favoring gabapentin were emphasized and conclusions that did not favor gabapentin were explained away; and indicators of ghost authorship. Each form of bias, and spin, on its own, could be seen as a relatively minor issue. The value of our findings is in the overall picture that emerges from what appears to be the simultaneous use of many forms of reporting bias and spin, all within the context of a pharmaceutical company’s publication strategy, implemented for marketing purposes."

So-- it's all about the marketing, and not about the science. No big surprise here, but further documentation of what we've had reason to believe from all previous reports of this type.

Now, I sort of hate to keep beating up on editor Jeffrey Drazen of the New England Journal:
--who as previously reported said we should not judge articles based on who sponsored the research but on the quality as depicted in the published paper. What Dr. Vedula and colleagues show us is that if a paper that's positive about a new drug shows up in Dr. Drazen's high-impact journal, we can be reasonably sure that there are 3-4 other studies with much less impressive, or even negative results, which are kept aside to be not published at all, or else published in much-lower-circulation journals many years later--or at least that's the standard business plan within the industry. And of course there's no way on this green earth that even the most fastidious reader of NEJM could ever know that. So much for being able to read a paper in the journal and then draw your own conclusions.

Friday, October 12, 2012

More on Sponsorship of Studies in Medical Journals

In my last post:
--I took off after an editorial in the New England Journal defending industry sponsorship of trials, saying that you should decide whether a trial is trustworthy based on reading its methods, not based on who sponsored it. My rebuttal is that many of the features that make results untrustworthy simply cannot be gleaned from reading the published report in the journal.

Here's the other side of the coin--things that make results untrustworthy that the alert reader can spot.

Again tipping my hat to Rick Bukata and Jerry Hoffman's Primary Care Medical Abstracts, I come across a study by Drs. Michael Hochman of UCLA and Danny McCormick of Harvard:

These guys looked at several ways of reporting results that overestimate benefits:
  • Reporting relative vs. absolute risks
  • Reporting surrogate endpoints rather than significant changes in health
  • Reporting composite endpoints instead of reporting each endpoint of interest separately
  • Reporting only disease-specific mortality instead of all-cause mortality
If people write in and request I'll explain why each of these overestimates benefit from drugs.

Drs. Hochman and McCormick then compared how likely it was that a study would report results in these ways, based on who sponsored the study. They found significant differences in two categories. Exclusively industry-sponsored studies were more likely than studies with at least some non-commercial support to report surrogate endpoints (45% vs. 29%) and disease-specific mortality (27% vs. 16%).

Now, if you wanted to defend the NEJM editorial position, you could say that readers of studies can readily see how the data are reported according to these criteria and can be wary of any study, regardless who funds it, that reports data in the less desirable way. But let's give the last word to Drs. Hochman and McCormick, in their final recommendations: "These findings highlight the need for educational efforts to ensure that readers understand the complexities of these endpoints and of relative risk reporting. ... In addition, Institutional Scientific Review Committees and regulatory agencies (e.g. the FDA) must closely examine the endpoints used in clinical trials and discourage the inappropriate use of surrogate and composite endpoints, and endpoints involving disease-specific mortality. Finally, medical journals may consider instituting editorial policies mandating the reporting of results in absolute numbers."

In other words, rather than asking readers to sift through whether the results are reported in a useful and valid fashion, medical journals like NEJM could simply refuse to publish papers that don't adhere to the highest standards. Of course, if they did, they might lose revenue as drug companies would not buy so many expensive reprints of papers that are really useful for marketing drugs--which may be one of the roots of the problem.

Thursday, September 27, 2012

NEJM: Overly Defensive, or Just Naive?

The Sept. 20 issue of the New England Journal of Medicine featured a study ( by Dr. Aaron S. Kesselheim and colleagues, of Harvard (where else?), a part of Dr. Jerry Avorn's pharmacoepidemiology & pharmacoeconomics operation. The study addressed how practitioners judged research articles based both on methodological quality and industry sponsorship.

They showed 503 internists fake abstracts that they had manipulated according to the study variables. The good news was that these internists knew quality when they saw it; they were less willing to prescribe a new drug as the rigor of the study design diminished. The part of the study that forms the remainder of our discussion was that independent of study quality, the internists were less likely to prescribe a new drug (by a factor of about half) if the study was labeled as industry-funded compared to NIH-funded.

This latter finding unloosed an editorial from NEJM Editor-in-Chief Dr. Jeffrey M. Drazen, somewhat ominously titled,"Believe the Data" ( Dr. Drazen took serious issue with the idea that one should judge an article based on who funded the study: "A trial's validity should ride on the study design, the quality of data-accrual and analytic processes, and the fairness of results reporting. Ideally, these factors — not the funding source — should be the criteria for deciding the clinical utility." Just in case we were not sufficiently impressed, he then pulled out the moral trump card: "Patients who put themselves at risk to provide these data earn our respect for their participation; we owe them the courtesy of believing the data produced from their efforts and acting on the findings so as to benefit other patients." That is: If you decide to question the results of a study because it's industry-funded, you're being disrespectful of the patients who agreed to participate in the research.

All of which shows that Dr. Drazen is not a regular reader of this blog. Let us take just a sampling of past posts, starting with the most recent one:

(In the last-mentioned post, see the sub-entry, "Data Dredging: Which Studies Do It the Most?")

I could have listed a lot more, but the ones that I've shown basically tell the following story:
  • Research studies paid for by industry commonly distort findings so as to favor their products.
  • As a rule, the journal reader cannot tell how the results have been distorted. (As the latest entry showed, to find out what was misleading about a study that occupies 7 pages in a journal might require wading through 8500 pages of data.)
  • These distortions occur in all medical journals and if anything are even more prevalent in the top-tier journals. (Probably not because these journals are badly edited, but because it's so much more of a coup if the company can land their research findings in those top journals.)
Bottom line-- if the reader is automatically more skeptical of a study because it's industry sponsored, there is good reason for that skepticism. Naturally Dr. Drazen does not want to admit this, as editor of what many regard as the premier medical journal in the world (or at least the US). Sadly, it requires an ostrich-like posture to disagree with those conclusions.

Now--let's address Dr. Drazen's moral trump card. The issue he raises about respect for research subjects is indeed an important issue. It just has nothing to do with whether the reader should be suspicious of a company-sponsored study. The real question is: when are we going to demand that truly "informed consent" for research subjects in industry-sponsored trials include disclosure of when the trial is not designed for scientific purposes and is instead designed for drug marketing purposes?

Wednesday, September 26, 2012

More on Tamiflu: The Challenges of Getting Good Evidence

I posted some time back on oseltamivir (Tamiflu) and the Cochrane systematic review that concluded that there's no good evidence that this drug prevents serious complications of influenza (despite international public health bodies having spent billions to stockpile it):

Earlier this year, the BMJ published a further commentary from the Cochrane team, explaining further their difficulties in getting credible evidence to do their review:

Doshi and colleagues noted that after a good deal of fussing around, they were able to get their hands on portions of the clinical study reports from a number of trials of oseltamivir. They admitted that when this all started, they had no idea of what a clinical study report was. A clinical study report is the province of regulatory agencies; it's what the FDA looks at, for example, when deciding whether to approve a drug for marketing. Academic investigators, by contrast, including the Cochrane folks, generally deal with published study reports in medical journals. The difference can be seen when they noted, "For example, the published version of one cardiac safety trial of 400 patients is seven pages long... compared with 8545 pages for the full clinical study report."

Depite still being unable to get their hands on all the materials from all of the studies, the Cochrane team found temselves the proud possessors of 22,000 pages of documents giving highly detailed information about each study. As a result, "Our new Cochrane review update of oseltamivir engaged the equivalent of two whole time researchers (a junior and a senior) for 14 months."

In short, this account presents a sobering picture of how much we still don't know about the evidence for and against a drug even after reading what purports to be a thorough, well-done systematic review based on published studies. It probably goes without saying that very few academic teams have the resources to let two people spend all their time for 14 months reviewing a single study question.

Since I learned of this paper via the services of Primary Care Medical Abstracts, I also had the advantage of Dr. Jerry Hoffman's trenchant commentary. Jerry asked how likely it was that of the research data that remains unpublished and thus far unanalyzed, any of it supports the wider use of oseltamivir for influenza. If the world were just, there'd be roughly a 50-50 chance that any unpublished data leaned for or against the drug. Based on what we know from past experience, if a study was done and there was any way at all that the results could be spun in a manner that produced positive marketing for Tamiflu, it would probably have taken the drug company (Roche) about 7 nanoseconds to arrange for the data to be published and widely disseminated. So we have good grounds to believe that the unrevealed data is not very friendly to Tamiflu.

Nonetheless, another point that Doshi and colleagues noted in their paper is that the various government agencies cannot see eye to eye on the current data:

"In December 2009, we expressed serious doubts about the credibility of the evidence for oseltamivir because of the inaccessibility of these unpublished trials. Nevertheless, influential organisations such as the US Centers for Disease Control and Prevention (CDC) and European Centre for Disease Prevention and Control continued to cite the Kaiser et al meta-analysis....[a company sponsored study supportive of the drug] Neither agency seems to have done an independent analysis of all available evidence, even after Roche’s public offer to provide full clinical study reports. Their stance is more worrying given that another US agency unambiguously holds the opposite opinion. The FDA, which has reviewed the oseltamivir trial programme in perhaps more detail than anyone outside of Roche, states that “Tamiflu has not been shown to prevent such complications [serious bacterial infections].”... The FDA even sent Roche a warning letter in 2000 instructing it to “immediately cease dissemination of promotional materials” containing “false or misleading” claims, including statements about a reduced risk of influenza complications.... The FDA has, however, not challenged the CDC’s claims."

The Deja Vu Fan Club out there might be commenting at this point that the oseltamivir story seems to be a retread of the reboxetine story:
--in which only one-fourth of the study data on a new antidepressant was published, with that one-fourth favoring the drug, and the 3/4 that remained unpublished showing that the drug was both ineffective and less safe than comparable drugs.

Tuesday, September 25, 2012

Another Example of Industry Spreading Non-Facts: Health Information Technology

While I try not to tread on the territory of our friends over at the Health Care Renewal blog, and keep this blog devoted to pharmaceutical and device industry issues, I've had occasion in the past to mention the good work of Dr. Scot Silverstein (see for example Dr. Silverstein is a highly informed critic of the bad sorts of electronic health records and other uses of health information technology (HIT), which unfortunately today may be the majority of uses. This has put him in the unhappy position of being blasted by the many hyperenthusiasts of HIT within medicine, as well as the industrial providers of HIT. As Dr. Silverstein has documented liberally in his posts, if you dare to suggest that HIT is anything less than perfection itself, the response of the enthusiasts makes the extremist-fundamentalist Muslim reaction to the recent idiotic anti-Mohammed video look like a friendly conversation over coffee.

In the recent post in question:  Dr. Silverstein mentions a recent column in the Wall Street Journal (no need for a separate link as he repeats virtually the entire opinion piece) by Stephen Soumerai and Ross Koppel, two similarly distinguished experts. In turn Soumerai and Koppel refer to a recent study out of McMaster University:

Cutting to the chase in all this, the bottom line is that when the politicians jumped on the bandwagon and called for massive Federal outlays to support and encourage quick adoption of HIT, they were motivated a little bit by promises that electronic records would make medical errors disappear, but no doubt even more by promises of cost savings--even to the point that they fondly imagined that they could spend billions buying HIT systems that would in the end pay for themselves in reduced costs. Just to add a personal note, if I ever believed that electronic records would save mioney, I stopped believing it after attending a meeting of department heads at my own medical center. One head estimated that the faculty now spent an extra 30% more time just completing the required electronic record tasks, and no one else disputed that estimate. I concluded that any technology that reduced physician productivity by 30% was unlikely to be a big money saver overall. (And our medical center owns one of the supposedly better HIT products.)

So the new study by O'Reilly and colleagues at McMaster looks specifically at drug ordering systems, and reviewed 31 research studies that in one way or another addressed the economics of the systems. The conclusion was that while a few studies suggested possible cost savings, the general quality of the research was poor, and one would have to conclude from the overall pattern of what us now known that there's no good evidence that electronic records save money with regard to drug ordering. Soumerai and Koppel, and Silversteion in turn, generalize this to HIT across the board and claim a lack of evidence that any of these promised cost savings are coming to fruition. Given hyped-up predictions of up to $100B in annual savings from wide adoption of HIT, this is indeed (as they used to say on the old TV sitcom) a revolting development.

What we see in the HIT industry seems to emulate a pattern we've seen many times in Pharma. A new drug is rushed onto the market because of some presumed advantage that puts it way ahead of existing drugs. (Think glitazones for diabetes, or COX-2 for arthritis.) As soon as careful studies can be carried out, the supposed advantages of the new kid on the block turn out to be illusory, and the downside starts to become glaringly apparent. But the industry is raking in too much cash to let that negative message get out, and so does its best to stonewall any disclosure of the new information. In the process it calls upon all of its lackeys inside medicine, who use their big university credentials to bolster the industry cause. In the case of Pharma, it seems usually to be the case that these "key opinion leaders" have simply been bought. HIT is different in that the issue seems to be genuine enthusiasm (not to say zealotry) among the early adopters, who then would look so silly if they admitted the validity of the new data that they dig in their heels and attack the messengers.

Dr. Silverstein repeats as often as anyone will listen that HIT holds great potential promise and that he's not against HIT. He's against poorly tested HIT that's rushed into use when it should still be considered experimental. Again, sadly, that seems to be most electronic record products now in use in the US, with more coming on line every day due to the Federal stimulus support and the Affordable Care Act.

Wednesday, September 12, 2012

Inverse Benefit in the Trenches: Primary Care Providers Treat Chronic Illness

My esteemed anthropologist colleague, Dr. Linda M. Hunt, and her graduate student Meta Kreiner at Michigan State University set out to do a study of how concepts of race influence physicians' treatment of patients with common chronic illnesses like hypertension and diabetes. Along the way they became so impressed with issues they were seeing about how drugs are prescribed that they chose to report a separate study on that latter topic. Recognizing the relevance of my own work on the Inverse Benefit Law (, they very kindly invited me to participate in the final data analysis and discussion, with the results just now appearing in the Annals of Family Medicine (

Hunt and Kreiner interviewed 58 clinicians and 70 patients at 44 primary care clinics in Michigan, oversampling clinics treating low-income and minority patients. They also observed 107 office visits. What did they find?

First, they noted that their sample mirrored CDC data reporting that 40% of people over age 60 now take 5 medications or more; the average prescritions per patient in their sample was 4.8. While one might imagine that providers in low-income, minority-serving clinics might be a model of enlightened social awareness, they found that 72% of the clinicians they talked to had regular contact with drug reps and 62% saw more than 10 reps each week. While protesting that they always were alert for commercial bias, 77% reported finding the information they received from the reps useful.

These clinicians were basically sold on the standard practice guidelines that set target numbers for blood pressure and blood sugar, and were unfazed by the likelihood that patients would need to be on multiple medications to reach the targets--as one family physician said: "I tell most new diabetics that the sad news is that they’re going to be on 5 meds…. That’s just what’s going to happen because their cholesterol parameters are lower [and] their blood pressure parameters are lower…. It’s usually a pretty frank talk: 'You have a deadly disease and it’s going to kill you. How long you have it is up to you.' (Laughs)"

Many of these clinicians are being reimbursed in ways that include pay-for-performance bonuses for meeting targets, and this influences their practices: "I was being a little bit lackadaisical with the A1c goal as 7.0[%] or less. I wouldn’t really like to admit it, but the insurance companies making a financial carrot is probably one impetus for really cracking down on my diabetics to get them 7.0[%] or less. 7.1[%] don’t cut it…anymore. It has to be 7.0[%] or less."

Time out--a while ago I blogged about a study ( that showed that there's reasonable evidence that patients with diabetes do well when their glycohemoglobin (A1c) level is around 7.5%, and that trying to get it super-low down to 7.0% actually does harm to patients. I also have blogged repeatedly about studies that show that diabetics are not any healthier, in the long haul, with tighter control of their blood sugar or A1c levels ( Despite study after study on this topic, the drug companies continue to push drugs that lower blood sugar but fail to improve long-term outcomes; groups dependent on drug company money like the American Diabetes Association continue to promulgate guidelines that stress strict control of blood sugar; and as this study shows, physicians in practice toe the line--especially when paid to do so.

Back to the Hunt-Kreiner findings. What happens when you throw a lot of medicines at patients with diabetes and hypertension, trying to make their numbers look good in the chart? At least three bad things. First, their drugs cost a lot and some of the patients go crazy trying to pay for them. Second, the patients get a lot more adverse reactions. Third, the prescribing cascade kicks in--physicians either don't recognize the adverse reations as due to other drugs, or else feel they have no choice but to prescribe those drugs because of the guidelines; and so even more medications are then prescribed to treat the side effects of the first medications, which further raises cost and risk of side effects, and so on: "A number (24%, 14 of 58) discussed the challenge of managing multiple medications, pointing out adverse effects of common medications that may worsen other conditions, requiring even more drugs, for example, β-blockers aggravating asthma symptoms, or antipsychotics elevating blood sugar. When discussing these complicated issues, only 1 clinician mentioned prescribing fewer drugs; all the rest focused on reaching goal numbers by either adding or changing medications."

The impact this had on patients is dramatic, as one fairly typical case report showed: "Her diabetes medications cause diarrhea and bouts of hypoglycemia, which interferes with her ability to leave her home because she must eat and go to the bathroom so frequently. She also had 5 visits to the emergency department in 1 month for excruciating headaches, before they were determined to be an adverse effect of the additional hypertension medication she had been prescribed after her diabetes diagnosis. ... At her most recent appointment, her physician happily told her: 'Your blood pressure is 130/78 [mm Hg], your A1c is 7.0[%], and your cholesterol was normal. Very good!'"

As Hunt and Kreiner comment, "On the basis of current standards, the clinician classified this patient as healthy, a success story; however, this classification does not address the broader question of her well-being. Getting test numbers into the stipulated range jeopardized her employment and led to repeated hospitalizations and serious financial burden." And, I would add, with precious little evidence that at least some of these medications were improving the patient's long-term health.

Sadly, these hard-working, dedicated, and undoubtedly smart clinicians seemed both puzzled and resigned in the face of these outcomes: "I’ve got patients on 4 different medications and their blood pressure is still uncontrolled. We try sending them to the cardiologists, and they say, 'Just keep adding stuff because there’s really nothing we can do about this.'…Some people whose blood pressure that we do get normal again, they don’t function very well at all. I’m not sure why."

After all the usual warnings about not generalizing qualitative studies beyond the small sample included in the research, I worry that this peek into the trenches of clinicians actually caring for patients with common problems strongly validates the worries I have expressed in this blog in more theoretical form, especially in The unholy alliance of drug company marketing, pay-for-performance, and unrealistic and commercially biased practice guidelines are ganging up on these patients to make them sicker rather than healthier--and the clinicians seem helpless to do anything about it.