Wednesday, December 23, 2009

NPR: How Osteopenia Became a Treatable Disease

Alix Spiegel at NPR did a fabulous story on drug treatment for osteopenia:

The story lays out the history of how Merck addressed the problem it first faced with its new drug, alendronate (Fosamax): It seemed to be a breakthrough drug for treating osteoporosis and preventing hip and spine fractures in post-menopausal women; but sales were very slack.

So they brought in a marketing whiz named Jeremy Allen. And he did nothing less than invent the medical industry of bone mineral density (BMD) testing.

When Allen came along, there were very few BMD testing machines, because the machines were huge and expensive, and tests cost a lot and were not reimbursed by Medicare.

Allen's first response was to create an organization called the Bone Measurement Institute. Its board included 6 highly respected osteoporosis investigators. Its physical plant consisted of Allen's desk at Merck. Its funding was all Merck money.

Eventually Merck went so far as to buy out a medical device company to prove that it could make cheap BMD testing machines that would easily work in a physician's office, and do screening tests at reasonable cost. Merck claims that these smaller machines are effective. The device companies that make the bigger machines protested that the smaller machines were not accurate because they did not measure density at the hip and spine, but rather measured limb bone density, which research has shown change at different rates from the sites of the worst fractures. (Spiegel's story does not go this way, but please read John Abramson's excellent chapter on osteoporosis in his book, Overdo$ed America, explaining why drugs like Fosamax may make BMD numbers look great without doing anything really to reduce risk of fractures in most cases--especially in osteopenia.)

The Bone Measurement Institute eventually lobbied Congress to pass a law to get Medicare to pay for BMD scans. It now was profitable for docs to buy smaller machines for their offices and to offer the tests widely to patients.

Once patients began getting the tests wholesale, they saw that a paper printed out with three colored zones, green, red, and yellow. Green was normal and red was osteoporosis. Yellow was a thing called osteopenia which women had never heard of. When the term was formalized at a 1992 scientific meeting in Rome, it was seen simply as a name for the statistical condition of not-quite-osteoporosis, and not as a diagnosis, certainly not a disease that needed drug treatment. But the women who saw the yellow zone worried about their higher risk for fractures and started to demand that their doctors do something. Thus was born the widespread pharmaceutical therapy for osteopenia, which according to most research is essentially useless.

The dynamic at play here is the classic "disease mongering" as publicized by Ray Moynihan, the Australian journalist. It also highlights how often the best way to sell drugs is to sell screening instead.

Here's a good summation from Spiegel's article:

"I get a great sense of satisfaction that I was able to rejigger the marketplace so that women could be treated for osteoporosis before it got them," Allen says. "That was a good episode of my life."
From Allen's perspective, by making a treatment for osteoporosis widely available, he helped save millions of lives.
But [Richard] Mazess, from the Lunar Corp., [a maker of large BMD machines], doesn't see it that way. "He was complicit in a plot to misdiagnose American women," Mazess says of Allen.
From Mazess' perspective, millions of women with osteopenia are now needlessly exposed to the risks of a medication that may not ultimately help them.
The paradox of our health care system is that both of these men are probably right. That is, drug companies produce incredible drugs that can greatly relieve suffering. But one way they profit from those drugs is to extend their use to as many people as possible, which frequently means that medications are used in populations with milder and milder versions of a disease, so that the risks of medicating can come to outweigh the benefits.

This morning my e-mail included no less than two notices about how physicians should be prescribing statin drugs for healthy people with normal cholesterol but with some heart-disease risk factors. Jeremy Allen at work behind the scenes again?

Monday, December 21, 2009

OIG-DHHS: Pooled funding for CME

If that alphabet soup is perplexing, folks in the Office of the Inspector General, Department of Health and Human Services, commented on funding for physicians' continuing medical education (see below for cite, subscription required).

Lewis Morris, JD and Julie K. Taitsman, MD, JD include the obligatory Federal disclaimer that they do not speak on behalf of the OIG-DHHS. But they do remind us that their office wields a sizeable stick, having, for example, been involved along with Department of Justice in the recent criminal charges against Pfizer and Warner-Lambert over off-label promotion of Neurontin, which ended in a $430M settlement.

Morris and Taitsman begin by explaining that it is in the public interest to reduce the bias introduced into CME by commercial sponsorship, which now accounts for more than half the total costs of CME in the US. They stress that even if no specific drug is being shilled for at a CME program, commercial sponsorship still skews the content of CME toward drug treatment and the like, and away from equally important topics such as prevention and patient education. They also suggest that current guidelines that supposedly limit commercial interference in the choice of topics and speakers are relatively easy to get around.

They then list several strategies that might be employed to limit undesirable commercial bias in CME programming: avoid commercial funding entirely; insist that companies pay into a common funding pool and then have a neutral third party give CME programs grants from that pool on a competitive basis; accredit specific programs rather than CME providers so that individual programs come under closer scrutiny; and eliminate some types of CME providers who currently receive funding almost solely from commercial sources (medical education and communications companies). The authors' personal choice is for the pooled funding mechanism.

This paper is a good summary of the pitfalls in the current state of CME funding and gives us a hint as to where the Feds are going to be looking for future violations. As we saw in a previous post, others--specifically the IOM--have been less reticent about proposing the full elimination of commercial CME funding as the best option for the future:

Morris L, Taitsman JK. The agenda for continuing medical education--limiting industry's influence. New England Journal of Medicine 361:2478-81, December 17, 2009.

Sunday, December 13, 2009

More on Hirsch/Lanier Diatribe in Mayo Proceedings

Back in September I blogged about an article and editorial in the Mayo Clinic Proceedings: (see Sept. 1 post-- for some reason I cannot get the copy/paste function to work here to provide the link!)

That post was very long and I went into laborious detail about both the article by Laurence J. Hirsch and the accompanying editorial by William L. Lanier, with some not very complimentary comments on each--so no point now repeating all that.

I did however want to note that the Chronicle of Higher Education has now reported on the resulting controversy, which apparently has continued to simmer. If you believe the Chronicle, the focus of the fracas has been on what I identified as the one apparently valid point in a rambling and illogical attack on Pharmascolds generally--the argument that we should be as suspicious about those who take a lot of money from Pharma foes as we are about those who are in the back pocket of Pharma.

The article provides an opportunity that eluded me at the time I first posted--to get the facts straight (or at least straighter) about the actual sums made by the two Pharmascolds singled out by Hirsch, Dr. Harlan M. Krumholz of Yale and Dr. David S. Egilman of Brown. According to Hirsch, as a result of their work for plaintiffs' lawyers suing drug and other companies, the former had pocketed a total of $300,000 and the latter as much as $25M. The sums according to the Chronicle are respectively $200,000 and $2M. (Yeah, I know, those pesky decimal points--funny how they jump around all over the place when you're not looking.) On the one hand it is a further point against Hirsch's article that he was so inaccurate in naming the proper sums. On the other hand, the sums are still substantial, and I agree that anyone who makes that sort of money as a result of being paid by X (whoever X might be) is at high risk for coming to the conclusion that X is a really fine institution and that the causes undertaken by X are especially noble causes; and that those who say nasty things about X are not nice people.

So, memo to the drug industry--if you don't want the likes of Drs. Krumholz and Egilman telling the world what they think of you and your research endeavors, then in the future, be more transparent in your activities, so that we can find out about you via some route besides the legal discovery process when you are sued big time for your misdeeds. That way we would not have to depend on plaintiffs' expert witnesses, who have been paid to do the sorry job of slogging through thousands of pages of internal e-mails and memos, to tell us what you have really been up to.

Basken P. "Ex-Merck Spokesman Points Finger at Paid Consultants in Drug Lawsuits." Chronicle of Higher Education, Dec. 13, 2009 (subscription required to access on-line).

Thursday, December 10, 2009

How Not to do PR for your Drug Firm

If you have been thinking about going into business as a public relations flack, and hoped to do a lot of work with drug and biotech companies, here's a few tips on what not to do.

The New York Times:
--has noted the questions raised by a cancer drug called Folotyn, manufactured by Allos Therapeutics. The drug received FDA approval back in September and the company plans to start marketing it in January. It was approved for a very rare cancer, peripheral T-cell lymphoma, which currently has no effective treatment, and that affects about 5600 Americans annually.

The company plans to charge $30,000 a month for this drug. Commonly used cancer drugs such as Avastin and Erbitux, for example, also accused of being over-priced, cost $8800 and $10,000 a month by comparison, respectively, says the Times. Moreover, the drug has been shown to shrink tumors but not to have any impact on mortality statistics.

The Times quotes James V. Caruso, chief commercial officer at Allos (whatever that is--do companies have non-commercial officers?), as defending the price by saying among other things that the cancer is so aggressive that no patient will be taking it for that many months, anyway.

So now we come to our lesson in PR strategies. If they ask you to defend the exhorbitant price of your cancer drug...

Do say:
"Our treatment costs about the same as other treatments for other cancers."
"Many millions of dollars were spent doing the research needed to develop this drug."
"It's hard to put a price tag on hope as we continue to wage the war on cancer."
"This particular cancer is very rare and so the only way to bring the drug to market was to increase the price per patient, much as we hated to do that."

Do not say:
"Our drug is such a rotten drug, and people die so quickly with it, that they won't be around to spend that much money for very long anyway."

Hat tip also to PostScript and Jonas Hines for the original news and his own wry comment.

Wednesday, December 9, 2009

BMJ: Medical Research is Broken

A set of articles posted yesterday on the BMJ website seems to have attracted next to no attention among the mainstream media, but raises a set of serious concerns about the integrity of medical research. Probably the most convenient entry point is via this editorial (subscription needed to access full text):

The key article in terms of the origin of the dispute is:
--which is an update of a Cochrane Collaboration review of the usefulness of oseltamivir (Tamiflu) for the prevention and treatment of influenza. The review (by Tom Jefferson and colleagues) differs from a 2005 review, that had viewed the drug as helpful for preventing serious complications of influenza. A Japanese investigator had alertly noted that the positive conclusions were apparently based on a single meta-analysis, but that the component studies on which the meta-analysis was based were not publicly available for review. So he questioned the earlier findings, and the Cochrane investigators decided that the only way they could respond to the question was by fully reconstructing the earlier meta-analysis.

Trying to summarize a very complex story (so complex that BMJ ended up teaming with Channel 4 News in the investigation), Jefferson et al. went back both to the company that sponsored all the studies (Roche, maker of Tamiflu) and to the named investigators who authored the reports of that research. The investigators did not have the original data and referred Jefferson et al. back to Roche. At least one purported investigator of a study said he never conducted that particular study. Roche first refused to provide any data, then provided partial summary data, and finally said they could not provide full data because a rival meta-analysis group was reviewing all the data. (Roche provided its side of the debate and it is printed in the same collection of BMJ articles.)

In the end, Jefferson et al. had to conclude that there are no available data to confirm the value of oseltamivir in preventing the complications of flu. Notice that governments around the world have spent billions of dollars stockpiling oseltamivir specifically under the impression that it is proven to prevent serious flu complications, and so represents a major public health response to pandemic influenza. (In yet another article, the BMJ concludes that observational studies supplied by Roche to supplement the published clinical trials also fail to demonstrate any more than a very small effect of the drug on preventing flu complications.) It now turns out that there is no well-established scientific basis for having spent all this money and having made this supposed investment in a public health response.

Fiona Godlee and Mike Clarke, the BMJ editorialists, are careful to note, "In being less then forthcoming with the raw data, Roche has done nothing wrong by current standards and even less by standards of 10 years ago. It has done exactly what the current system allows."

That leads them to the same conclusion that I proposed in HOOKED now nearly 3 years ago-- that we somehow need to unlink the machinery of medical research from commercial sponsorship of drug trials by individual drug companies, paying grants directly to individual investigators.

The BMJ series tends to support the comments of Roy Poses over at the Health Care Renewal blog (see, commenting in turn on an article published in last week's BMJ by Graf et al, proposing new standards for "good publication practice" on behalf the medical communications industry (the nice folks who bring you ghostwriting). Dr. Poses suggests that these guidelines provide a telling perspective on how the industry views research. From a typical academic-medical standpoint, a research study has a principal investigator or PI. The PI "owns" and accepts full accountability for the study. She gets the grant to fund the study; she oversees the conduct of the study and the analysis of the data; and she is chief author of the eventual publication. The buck stops with the PI. From an industry standpoint, no one owns and is accountable for the study. (The drug company may think it owns it but, as we saw with Roche, seems to run the other way when accountability is called for.) Who happens to be managing it at any point in time is a hireling who can be replaced at any instant, and the hireling who, say, authors the eventual paper may have no connection with the hireling who managed the study data collection, did the statistical analysis, or whatever. These are simply functions on an assembly line. What that means for the integrity of scientific research is something we can discuss.

Addendum 12/10: I noted in the original post that the mainstream media in the US did not seem to glom onto this story. I have since seen that AP and Yahoo did pick it up:
The news story adds the info that the WHO disputes the BMJ and says that it has a lot of faith in Tamiflu's value. There's a bit of conflict of interest here as the WHO has been one of the great promoters of the drug and has been behind a number of governments deciding to buy huge quantities for their national stockpiles. You can see how it would now be very embarrassing for them to have to admit that maybe the drug was oversold. If the WHO is so convinced that Tamiflu works, on what basis are they convinced; and why were the Cochrane reviewers unable to locate that evidence?

Tuesday, December 8, 2009

The AAFP-Coca-Cola Deal: A Letter to a Member

I have now posted several times regarding the deal struck between my own medical specialty society, the American Academy of Family Physicians (AAFP), and Coca-Cola to fund patient education materials on obesity, most recently:

As a dutiful AAFP member I sent a letter to the President, Dr. Lori Heim, and the Executive Vice-President, Dr. Douglas Henley, raising the same concerns about conflict of interest and public trust in organized medicine that I did in my blog postings.

I have now received their reply. I have not yet formally resigned but the chances of my remaining an AAFP member do not look good.

There is no hint of any retreat from the stance taken by AAFP at the start, that this relationship is to be commended and not condemned--despite the fact that in the interim, the editor of one of the major family medicine journals, Dr. Jeff Susman of the Journal of Family Practice, wrote an editorial sharply critical of the AAFP's position (Susman J. Do things really go better with Coke?

Some samplings from the AAFP letter (which I assume was mostly a form letter sent to all members who complained): "As a long-time member..., you certainly must appreciate the fact that the AAFP has been managing relationships with outside funders successfully for many years. The Academy has then highest standards and rigorous rules...and rigorous firewalls are in place to assure the separation of editorial and policy decisions from funding considerations."

Comment: It is true that people like me have been very lax in the past. It seems the AAFP has been happily taking funds from a variety of commercial interests, and that Coke is only the latest in the series. Shame on us family docs for not objecting loudly before this. But past actions of a questionable nature certainly don't justify future actions even more discreditable.

"Your comparison with the AMA's Sunbeam situation is a false product endorsements are expressed or implied...our board of directos has been kept fully informed at every stage of development...Our Board took the lessons of Sunbeam very seriously in our deliberations and took pains to avoid all those traps."

Comment--points well taken. In the various ways listed, the AAFP did not act exactly like the AMA. They do indeed seem to have learned all the lessons of Sunbeam except the final, and most important one: don't let the dollar signs blind you to how bad you're going to look when the deal becomes known to the wider public.

"The argument voiced by many is that even the appearance of a confliict means that a conflict exists and that it is irresolvable. The AAFP has never accepted this line of thinking. Conflicts need to be disclosed and then dealt with. Again, the AAFP has been very successful in disclosing and managing any potential conflicts..."

Comment: This is indeed a possible ethical position. It is, for reasons I discuss at length in HOOKED, a highly unsatisfactory one. It is also not the dominant position taken in the medical literature with regard to professional societies and their responsibilities to set the highest professional tone for their members. (For just one recent example see Rothman DJ, McDonald WJ, Berkowitz CD, et al. Professional medical associations and their relationships with industry: a proposal for controlling conflict of interest. JAMA 301:1367-1372, April 1, 2009.)

"In a world of complex relationships, when tensions are high and society is so polarized, there are two approaches an organization such as ours can take. One is a strategy of engagement, whereby we choose to work together with organizations different from the AAFP in areas of mutual interest to advance the greater good and build trust and influence to help change behavior. One example of this...involved the Coca-Cola Company a few years ago, when the Robert Wood Johnson Foundation, the William J. Clinton Foundation, and the American Beverage Association worked together to address the issue of suragy soft drinks sold in school vending machines. ... The other strategy is not to collaborate at all with such organizations..."

It was Arthur Schafer at Manitoba who first noted how quickly, in the minds of industry apologists today, "engagement" and "collaboration" somehow automatically segue into "taking a lot of money from." The AAFP leadership here poses an utterly false dichotomy. None of the AAFP members who are up in arms over the Coke deal are complaining because AAFP saw fit to engage with Coca-Cola.

Summary: The leadership of the AAFP appears to have elected to turn a blind eye toward the controversy sparked by the Coca-Cola deal and has apparently wrapped itself smugly in its assurance that it can do no wrong. This certainly leaves members like me in a bind, which sadly appears resolvable only by us parting company. If the AAFP decides that this means I am no longer willing to engage with them, I guess they will have to be of that mind.

Sunday, December 6, 2009

A Solicitation to Ghost/Guestwriting, and More on Commercial Contamination of the Medical Literature

There's a small flap going on over at Dr. Danny Carlat's Psychiatry Blog that is quite instructive for our purposes:

Dr. Carlat received from a colleague a letter from a medical communications company, BlueSpark. There are two ways to interpret the letter to the colleague. Dr. Carlat favors the interpretation that the letter is an invitation to put one's name as guest author on an article that will be ghostwritten by BlueSpark. He contacted BlueSpark who, not surprisingly, vigorously denied this interpretation. They pointed to stipulations in the letter that required a phone conference between the colleague and their staffer; approval by the colleague of a detailed outline before a draft is completed; and final editing of the draft. They also added that if the role of their own writer met the official criteria for authorship of the medical journal editors' organization, then the staff writer's name would appear as a co-author.

To which Dr. Carlat replied that of course, in this day and age, no one is going to write a letter and say flat out, "Wanna put your name, for pay, on an article that somebody else actually wrote?" He suggested that by reading between the lines, one could discern the clues that this was in fact an invitation to participate in a ghostwriting venture.

All of this is sort of fun and entertaining, but in my opinion it is not the heart of the matter. To fully understand what is going on here you have to know psychiatry the way an expert like Dr. Carlat does (and admittedly I certainly do not). You have to know that BlueSpark has a contract with Sanofi-Aventis and that they are makers of a "brand new" antidepressant, which is really nothing more than a once-a-day version of an old standby generic antidepressant, bupropion. You need to know that bupropion is indeed well regarded as a useful and effective antidepressant, but that the older generic forms are dirt cheap compared to the nearly incredible price tag of this new drug form (would you believe $5.58 a dose, compared to 28 cents for the generic?). For this extra price you get exactly one benefit--if you need to take the highest daily dose of bupropion, instead of having to take two pills once a day, you can now take one pill once a day.

So the really critical point is this (from Dr. Carlat): "[L]et’s face it. No psychiatrist is going to wake up in the morning and say, 'I think today is the day I’ll work on a review article on bupropion and depression and how awful it is that the tiny number of patients who require the maximum dose have to take two pills in the morning instead of one. Yes—this will be a significant contribution to the medical literature.' This would never happen, because there’s nothing new or interesting in this topic. We know that bupropion works well for depression, and we’ve known it even since it was approved by the FDA in 1985.
No, the only reason a psychiatrist would get motivated to write such an article is if a cold-call email solicitation from BlueSpark gets pas[t] the spam filter. I’m guessing that BlueSpark hopes that eventually they will find an uncreative, mid-level academic who is treading water professionally, and who will jump at the chance to pocket a little extra money while simultaneously padding the resume with a publication that will require essentially no work to produce. ...
Whether or not this meets the formal definition of ghost-writing, it is clearly a manipulation of the medical literature, a kind of plastic surgery of science. The articles may look impressive, and they may look real, but in fact they will be phony."

I actually made a somewhat similar point in an earlier post:
(On that occasion, the utterly artificial excuse for writing an article about an antidepressant was to celebrate its birthday! Even I, as a nonexpert in psychiatry, could figure out that was scientifically bogus.)

Monday, November 30, 2009

Two-for-One Special over at Health Care Renewal

Roy Poses over at the Health Care Renewal site has been blogging up a storm. Rather than try to summarize or encapsulate, I'll simply point toward two valuable posts:

On yet more evidence of systematic suppression of negative study data regarding antidepressants:

On the question of why Genzyme can charge $160,000 a year for its drug to treat Gaucher's disease, and pay its CEO $50M a year, but cannot manage to get its factory to turn out non-contaminated supplies of the drug:

Beware the CER Trojan Horse in Senate Reform Bill

I'm a bit late picking up on this important Perspective in the New England Journal:

The co-author is long-time Pharma watcher Alastair J.J. Wood whom many think ought to have been FDA commissioner, if the drug industry did not traditionally have so much veto power over that post.

Selker and Wood basically warn us that there's a serious discrepancy between the House and Senate health reform bills regarding comparative effectiveness research (CER) which could easily be missed since both allocate about the same amount, $600M/year, to CER.

The House went about things in the standard way. The responsibility for CER would be handed over to the Agency for Healthcare Research and Quality (AHRQ), which has a long history of dedication to strict policing of conflicts of interest and following the academic peer review process for funding research. The Senate, however, influenced by drug industry lobbyists, calls for the creation of a new body for CER, with 3 seats on its 15-member governing board being reserved for industry representatives. The industry folks would also have representation on the board's methodology subcommittee.

Most worrisome, as Selker and Wood explain:

"The Finance Committee bill also includes language requested by industry lobbyists (pages 1138–1139) that threatens to withdraw federal funding for 5 years from any investigator who publishes a report on research funded by the proposed institute that is not 'within the bounds of and entirely consistent with the evidence.' Determinations regarding such consistency would be made by the newly created research entity, which would have industry involvement both in its governance and in study design. To allow scientists — and their institutions, which receive the support for the conduct of research — to be punished for the publication of work that is not approved by this entity is essentially to cede authority over the dissemination of government-funded research to a body that is at least partially controlled by persons with a potential commercial interest in its outcome. This move would be a major retrograde step that would both inhibit the conduct of CER and call its integrity into question. In addition, because researchers and their institutions will seek to avoid such punishment, this provision is likely to result in prolonged arguments, taking place out of public view, regarding which data are acceptable to publish, thereby impeding and delaying publication. The American public, which would be paying for this research, deserves better."

If anyone has been following the CER debate, it seems clear that there is no reason to favor the features that have popped up in the Senate version that were not in the House version, except to give industry assurances that no research or guidelines will be published that might put a serious crimp in its profits. For example, why set up a completely new agency to do CER when AHRQ is all ready to hit the ground running? The prospects of a gag order on any scientist who disagrees with the governing board about what the evidence says is an especially worrisome sign.

See also Roy Poses' commentary on this same issue in his "Health Care Renewal" blog,

Friday, November 27, 2009

Another Example of Spin in Published Results of Industry-Sponsored Clinical Trials

Long-time readers of this blog may want to skip this post; but starry-eyed optimist that I am, I continue to believe that a new reader or two may show up once in a while, and so it may be worth adding further examples of how carefully you have to read published reports of clinical trials in medical journals to detect marketing spin in industry-sponsored research. I was alerted to the present study thanks to the good offices of "Primary Care Medical Abstracts," aka Drs. Rick Bukata and Jerry Hoffman.

Tapentadol (Nucynta) is one of the newest analgesics to be discovered and tested. The article by Kleinert and colleagues claims that it is special in having two mechanisms of action--it affects the mu-opioid receptor as does morphine and the other opiates; and it also has norepinephrine-reuptake-inhibition properties. The present study was a double-blind controlled trial of a single oral dose of various medications to treat pain following extraction of a wisdom tooth. The investigators compared 5 different doses of tapentadol to 60 milligrams of morphine (a good sized dose ordinarily, but with a proviso we'll get to in a minute); 400 milligrams of ibuprofen (two over-the-counter Motrin); and placebo.

The pain outcomes were measured using the 100-mm visual analog scale, asking people to mark on a 10-point, 100-mm line where their pain was at any given time and then measuring to the nearest mm. To interpret such a study you need to know the relationship between a statistical drop in pain and a clinically important drop in pain, when you combine the scores of many research subjects in a trial and get a numeric average. This has been looked at repeatedly and it is generally agreed that a drop in pain of 13 mm is the minimum pain relief that a patient can actually detect as a clinical response. That is, if you do a study of a drug and the result is that the drug reduced pain by 10 mm, you can say that this drug is clinically worthless as it did not reach the threshold where a patient could tell the difference.

So when Kleinert et al. report the results for their 399 subjects, the first thing it is logical to do is to compare these reuslts to the clinical threshold. It turns out that of all the doses and drugs tested, only 3 turn in a degree of pain relief on the primary outcome measure that surpasses the minimum threshold--the highest dose tested (200mg) of tapentadol (15.3), morphine (13.8), and ibuprofen (17.9). Notice that in this situation morphine just barely sneaks past the threshold limit. Dr. Hoffman suggests in his commentary that this can be explained by the rapid rate at which oral morphine is metabolized by the liver when one receives a single dose. Also note that none of these numbers is all that much over the threshold so as to make the results worth writing home about.

So how would a strictly honest scientist report these findings? The most candid report would probably be, "In this study, none of the drugs at the dosages tested produced substantial, clinically important pain relief."

What Kleinert and colleagues reported was, first, that tapentadol was obviously better than placebo (which came in at a measly 4.7 mm); and second, that the highest dose was better than morphine. As they say in the abstract (which is all that most readers will bother to read of the article), "Pain relief scores with morphine sulfate 60 mg were between those of tapentadol HCl 100 and 200 mg....These data suggest that tapentadol is a highly effective, centrally acting analgesic..."

Now, note what they also could have said if they were reporting honestly: "The pain relief achieved with the very highest dose of tapentadol was less than what you can get with cheap over-the-counter ibuprofen 400 mg." The way that they handled the inconvenient comparison between ibuprofen and their own drug was to finesse it out of the picture. They explained that ibuprofen, being both analgesic and anti-inflammatory, is a "gold standard" drug for treating dental-extraction pain. In their study, ibuprofen was superior to placebo. This fact, they proclaimed proudly, "established the sensitivity of the model." It was as if the only reason they included the ibuprofen in the study was to show that their experimental model worked. The fact that ibuprofen then outperformed their own drug was conveniently ignored.

If you are interested in the details of the cost issue, I'll report that on, 90 pills of 100 mg Nucynta costs $269.95, coming in at just $3.00 per tablet. Since to get the relief superior to morphine you had to take 200 mg in the study, that would be $6.00 per dose. You might walk into your local pharmacy with six bucks and see how many generic ibuprofen you can buy with that cash.

All of this reminds me of a joke from the old days during the depts of the Cold War, when Soviet propaganda often reached absurd extremes in trying to prove to the average Russian citizen that the USSR was truly better than the US. An auto race was held as match race between two vehicles only, an American and a Russian car. Thje Americans won. The race was reported in the Soviet Communist newspaper Pravda as: "The Russian car came in second. The US car finished next to last."

Kleinert R, Lange C, Steup A, et al. Single dose efficacy of tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled trial. Anesthesia and Analgesia 107:2048-2055, December 2008.

Wednesday, November 25, 2009

Yet More on Concealing Negative Antidepressant Data--from Germany

If any more evidence were needed that concealing negative data about (at least) antidepressants is a standard business plan among pharmaceutical companies, we can turn to:

The German Institute for Quality and Efficiency in Health Care set out to decide whether three newer antidepressants, reboxetine (Edronax), bupropion XL (an extended release form of Wellbutrin), and mirtazapine (Remeron) actually work and show any advantages over other antidepressants. I'll let them tell the story:

"In its preliminary report published at the beginning of June 2009, the only results IQWiG could present without reservation were those for bupropion XL. It was forced to add a caveat to the results for mirtazapine, because the fact could not be ignored that study data not provided by Essex Pharma might seriously bias the result. In the case of reboxetine, IQWiG abandoned its analysis of the study data that was publicly available at that time, because it was evident that the manufacturer, Pfizer, was concealing almost two thirds of all data collected in trials to date. An analysis of the available data would have produced a biased picture. Despite several requests, Pfizer had steadfastly refused to provide IQWiG with a list of all published and unpublished data.
"However, after the preliminary report was published, Pfizer and Essex Pharma decided to make the unpublished data and information on trials accessible. Only then was it possible to assess all three drugs based on complete data.
"The analysis of the complete data reveals that IQWiG made the right decision in abandoning its assessment of reboxetine based only on published data. The summary of results from published and non-published trials does not provide proof of benefit of reboxetine, whereas the data from the published trials appear to suggest a benefit."

They went on to report that reboxetine, in addition to showing no benefit compared to placebo, did demonstrate risks of harm compared to either placebo or fluoxetine (Prozac). They proceeded to report some benefits from mirtazapine and more substantial benefits from bupropion XL.

The organization concluded: "This case re-emphasizes the need for a mandatory regulation, which would require all clinical trials to be registered at the start and to have their results published after study completion."

I'm indebted to Jörg Schaaber (Editor, Pharma-Brief, BUKO Pharma-Kampagne, Bielefeld, Germany) for the e-mail notification of this statement (via the Healthy Skepticism members' listserv).

Follow the Money: Who's Screaming Loudest about Mammogram Guidelines?

Thanks again to Marilyn Mann's tip, I am pleased to recommend a post by our PharmedOut friends, Adriane Fugh-Berman and Alice Bell:

This well-crafted post starts out by analyzing the recent mammogram recommendations from the US Preventive Services Task Force, making a number of key points:
  • The USPSTF is a very prestigious group, working in a generally highly evidence-based manner, and squeaky-clean with regard to conflict of interest
  • The recommendation that women consider waiting till 50 to start mammograms, and have them every 2 years rather than annually, is about as noncontroversial as you can get, and matches the WHO recommendations and guidelines in European nations that have excellent breast cancer statistics
  • There was clearly no cost-cutting agenda involved in the USPSTF deliberations, and there are physical and psychological harms due to excess mammograms that are quite independent of cost
How can one then explain the strident screams of outrage that have filled the media, even going so far as to invoke the "death panels"? Fugh-Berman and Bell's answer-- follow the money. They list the various medical organizations that have put out press releases blasting the new recommendations, showing that they have two things in common. First, the language is amazingly similar, almost as if they were reading from the same script. Second, all have received generous contributions from those firms that make big bucks off mammograms.

Their final conclusion: "When critics with conflicts of interest are banned from the argument, the controversy vanishes."

Tuesday, November 24, 2009

Inside the Belly of the Medical Communications Beast

Here is another paper I should have been all over earlier this year--again apologies for my tardiness.

Sergio Sismondo is a philosopher and science-and-technology-studies (STS) guy at Queen's University, Canada. The paper here reviewed is primarily a report of his experience in attending the annual meeting (apparently in 2007) of the International Society of Medical Planning Professionals, one of two large organizations representing medical communications firms. These are the firms that sell their services to pharmceutical and other companies as being able efficiently to "manage" the publication and placement of scientific research papers for maximal marketing impact. When scientific publications are ghostwritten, these guys are the "ghost managers" as Sismondo puts it.

The report is hard to condense, so a few impressions and snapshots. It seemed clear from all the proceedings that ghostwriting was a no-no. Among the folks who do this sort of work, there appeared to be a level of genuine desire to believe that they were upholding the integrity of the scientific process (and there were regular references to the "marketers" with whom they had to work, implying how hard it was to deal with those neanderthals who only cared about money and sales and did not understand science and its requirements). Some speakers attempted to shift all blame to the academic physicians who leant their names to articles they did not write. The reasoning seemed to be--if these dudes were not so lazy (and in some cases, frankly dishonest), then they'd respond on time to our requests that they give us input early in the course of writing the article; then they could legitimately claim authorship and then there need not be any suggestion of ghostwriting; but as it is they force us into a position where the final article ends up ghostwritten. Other speakers responded, however, that the firms create these problems themselves, by not sending a draft to an "author" to review until it has been refined and perfected to get the company's preferred message out, and then with such a tight turn-around deadline that substantive input is impossible.

Perhaps most intriguing were several presentations at the meeting given by medical journal editors. The message they managed to convey was: 1) we are shocked, shocked that you people would ever turn to underhanded things such as ghostwiting; and 2) we really want you to send us your papers to publish, and oh, by the way, look at the impact factor numbers showing that my journal is the best one in which to place your articles. Sismondo captures very well the inherent financial conflicts of interest facing these editors, who benefit in so many ways from publishing randomized clinical trials favorable to the large drug companies, who will then rush to place a lot of ads in that journal and will buy 10s or 100s of thousands of dollars' worth of reprints for their sales reps to distribute. (Editors further will admit candidly that with all the dreck they have to read that is spewed forth by academic physicians who have no writing skills whatsoever, it's often a great relief to turn to an article written by a commercial medical writer who actually knows how to put sentences together.)

Sismondo summarizes the current state of affairs as an STS scholar: "In the ghost management of medical research by pharmaceutical companies, we have a novel model of science. This is corporate science, done by many hidden workers, performed for marketing purposes, and drawing its authority from traditional academic science. The high commercial stakes mean that all the parties connected with this new science can find reasons or be induced to participate, support, and steadily normalize it."

Sismondo adds that there was much talk at the meeting of ethics, but it's not the sort of ethics I learned about in philosophy grad school, but rather a corporate-compliance model of ethics: just tell us what the rules are and then leave us alone to get about our business. The possibility that "ethics" means that this business should not be conducted at all was not, apparently, an acceptable answer.

Sismondo S. Ghosts in the machine: publication planning in the medical sciences. Social Studies of Science 39:171-198, 2009.

Kids, Antidepressants, and Suicide Risk: A Review of Commercial Bias

Here's a somewhat old paper that I should have posted about some time ago-- thanks to "Primary Care Medical Abstracts," aka Rick Bukata and Jerry Hoffman, for their audio review that brought it to my attention.

Jon Jureidini, Australian psychiatrist and chair of Healthy Skepticism, and Leemon McHenry wrote an editorial reviewing the debate over prescribing serotonin-reuptake-inhibiting (SSRI) antidepressants (Prozac and its cousins) in children and adolescents. Basically they were asking--how did it come to be, when the data now show that these drugs very likely produce virtually no benefit in those age groups and run a small but definite risk of producing suicidal behavior, that the experts in the field touted them enthusiastically? They sort through the various stages of the controversy, citing specific papers that used poor methodology or that were selectively reported. These papers are of two types--first, the papers that claimed drug efficacy in the first place; and second, studies published after the issuance of black box warnings on the use of these drugs in kids, claiming that the suicide rate among adolescents immediately rose as a result of the decreased numbers of prescriptions written for SSRIs. They aim a good deal of their criticism at the "key opinion leaders" in academic psychiatry who are financially beholden to the drug industry and who used their position and reputations to defend the widespread use of these drugs; and to a lesser extent, medical journal editors who should have known that a couple of key studies were so severely flawed as to be not worthy of print. Anyone trying to make sense of this particular controversy will find this article a good compendium of who knew what when.

The authors acknowledge their own conflict of interest in that both were associated with a plaintiff's law firm that brought litigation against the manufacturers. As I have noted several times in the past, it is unfortunate that often, the only physicians in a position to know what actually has happened when data are withheld or selectively reported are those who have had access to internal company documents released only as a result of legal discovery.

Jureidini JN, McHenry LB. Key opinion leaders and paediatric antidepressant overprescribing [editorial]. Psychotherapy and Psychosomatics 78:197-201, 2009.

Sunday, November 22, 2009

More from "Evidence in Medicine"--Loss of Trust Matters

My most recent post cited for the first time the "Evidence in Medicine" blog managed by David Rind. I am again indebted to Marilyn Mann for pointing out an eloquent post on the same blog:

Dr. Rind details here how he started out as a Pharma supporter, due largely to their success in developing breakthrough AIDS therapies, and has gradually become jaded with the industry's behavior. His most important point, however, is that he expresses better than many the consequences of the loss of trust when the industry engages in the now-routine behavior of suppressing data that could hamper the successful marketing of their drugs. He highlights what happens to all of us in medicine when we read of an impressive new drug for a serious disease, and instead of thinking, "Wow--what a great advance this will be for the treatment of my patients," we feel forced to think, "OK, now just what is the drug company trying to pull on me this time?"

A while ago, my esteemed colleague Jerry Hoffman and I wrote a minor parable for an emergency medicine journal on "the boy who cried unicorn," a reverse version of the boy who cried wolf. Our point was that if you keep putting a false horn on a horse and trying to convince the public to pay big bucks to see the rare unicorn, eventually they will not believe you even if you should be so lucky as to capture a real unicorn. Which in the pharmaceutical field would be very sad for everyone.

Hoffman JR, Brody H. The boy who cried unicorn: a parable. Annals of Emergency Medicine 46:93, 2005.

Wednesday, November 18, 2009

No Fair Peeking? More Questions about Early Stopping of Trials

In the previous post I mentioned the recent findings about ezetimibe, which happened to be part of the study called ARBITER 6. As one evidence-based blogger, Dr. David Rind has noted--
--the results as published could be consistent with three different possibilities:
  1. Ezetimibe adds nothing to heart disease prevention; niacin is helpful
  2. Niacin is slightly helpful or neutral and ezetimibe actually worsens arterial plaque
  3. All the results of the study are due to chance alone
Option #3 becomes meaningful when we note that the actual hard outcomes in the study were 2 bad events in the niacin arm and 9 bad events in the ezetimibe arm. That is, move just a couple of bad events to a different column and the whole outcome changes.

If the study had been continued longer and more hard outcomes accumulated, we'd know a good deal more about which option made the most sense. (And, of course, knowing which means a lot in terms of what treatments docs should recommend to patients.) So it was therefore very interesting that the study was stopped early. The authors state that this was due to a predetermined efficacy endpoint having been reached:

In theory, a data safety and monitoring board is supposed to be completely independent of the investigators and the commercial sponsor of a study. In actuality, in the past (as I have noted in other posts a while back), some decisions of the "independent" boards have been eerily like the decisions that a commercial sponsor would have made had the goal been to maximize the marketing advantage of the study outcomes. In this case a quick stoppage of the study may have favored the extended-release niacin product being promoted by sponsor Abbott Labs. And a stoppage due to efficacy is stranger than stoppage due to safety concerns, especially when the main outcome measure--thickening of the wall of an artery--is a surrogate marker rather than an actual disease outcome, as Dr. Rind notes.

I remain ignorant of the exact means by which a data monitoring board might be secretly influenced by commercial marketing pressures. But if a further hint is needed that somebody just may be sneaking a peek where they are not supposed to, ARBITER 6 may provide the hint.

(Hat tip to Marilyn Mann for Dr. Rind's blog.)

Monday, November 16, 2009

More Bad News on Ezetimibe--So Why Do We Still Take It?

In the past I did several posts on the ENHANCE trial (like, that showed that ezetimibe (Zetia, Vytorin) was a flop at reducing cholesterol containing plaque within arteries.

The news this week is the New England Journal study--
--in which ironically ezetimibe (Zetia) was stabbed in the back by a competing drug company, Abbott, promoting its own drug, extended-release niacin. A head-to-head trial indicated not only that niacin was better at reducing arterial plaque, but that ezetimibe actually caused plaque to increase at the same time as it was making your cholesterol lab values look better (the same as in the ENHANCE study).

The popular media is full of dire warnings from docs saying, "Just because this trial ended up badly, patients should never stop taking the medicines their physicians prescribed for them." This is despite the fact that no harm has ever been shown to come from abruptly stopping a statin or ezetimibe (which are, after all, designed to prevent fututre events and not to treat an existing disease) that I am aware of; and also despite the overriding fact that ezetimibe was approved for sale in the US despite a complete lack of evidence that it prevented any cardiac events, and based solely on the fact that it lowered cholesterol (LDL) levels by a different mechanism than the statins.

So the various lists are humming with people asking--when ezetimibe was never shown to be useful in the first place, and now has been shown in at least two studies perhaps even to be harmful as well as useless, why are people still taking it and prescribing it?

My own vote for this is the Tyranny of the Numbers.

Over the past couple of decades, Americans (physicians and the public alike) have fallen in love with the idea that you can do a blood test and get a number and it tells you how healthy you are--your cholesterol level, or now the refined version, your LDL. I served on two search committees during my previous academic job for Dean of the medical school, and we asked candidates to tell us how their general health was, and they replied, in a number of cases, without us having asked for that number, by telling us what their cholesterol levels were. As if they could reduce their entire health status to a single number. And these people wanted to be Dean of a medical school for Chrissake.

If you are totally in love with the idea that you can measure a magic number and it tells you that you are healthy, then you are equally in love with any medicine that will make that number better--regardless of what that medicine actually does inside your body. Hence Zetia and Vytorin.

I mention that hunch, in the context of this blog, simply to make the point that drug companies are smart when they market. They know that as powerful a juggernaut as their marketing machine is, they generally cannot make the proverbial silk purse out of the sow's ear (which is what we used to try to do before we decided to put lipstick on the pig). Cliches aside, you cannot make people take a drug when your message arrives completely out of left field and people have no conceptual hook on which to hang it. But if you can tie your message to something people already believe in and cherish, then you can put lipstick on the ezetimibe pig and everyone will invite it to the prom. Almost all effective drug company marketing consists of this clever hitching of the drug company message with some strain of U.S. popular culture that pre-existed the message (even if in an earlier life, drug company marketing may have helped to birth that popular culture phenomenon).

Saturday, November 14, 2009

More on Suppression of Unfavorable Trial Results--and a Warning Note

If I had not gotten off onto the COI tangent in recent posts, the big news of the week would probably have been the publication in the New England Journal of the paper by Vedula et al. on selective outcome reporting for gabapentin.

The quick once-over is that in order to reveal how research sponsored by pharmaceutical companies sometimes undergoes selective publication or suppression of data, to favor marketing the company's drug, you need both the publication itself (the "after") and some snapshot of the actual research data in its more-closely-raw state (the "before"). (Or, to show that the data was entirely suppressed, you need the "before" that is not followed by any "after," despite enough time having elapsed to allow for publication.) One way to get the "before" is to get the trials submitted to the FDA as part of successful new drug applications. (See paper by Rising et al. mentioned below.) Another way is to get hold of confidential in-house company documents that are released as part of the discovery process in a lawsuit.

The latter method was used in this instance. Pfizer, after acquiring Parke-Davis, was stuck with lawsuits against the latter company around its marketing of gabapentin (Neurontin), especially its off-label uses for which legally the company was not supposed to market at all. The major of-label diagnoses for which gabapentin was commonly recommended include various pain syndromes and bipolar disorder; its major labelled use is as an anti-epilepsy drug. Vedula and colleagues (two of whom worked with plaintiff's lawyers in the relevant suits) obtained reports of company sponsored trials investigating the off-label uses and compared those internal reports with published results for those trials that were eventually published.

What they discovered will be no news to anyone here--more evidence of the routine manipulation and suppression of data to make the favored drug look better. The authors particularly looked at the primary outcomes reported in the eventual publication vs. in the original trial results. In no less than 2/3 of the published trials, there had been a change in the primary outcomes. Secondary outcomes that were statistically significant were substituted for primary outcomes that were not; or else new primary outcomes appeared out of nowhere in the process of publication. (Without going into a lot of detail, this basically is not kosher and increases greatly the likelihood that you'll report as a true scientific outcome something that actually occurred solely by chance.) The trials that were not published were primarily those that showed gabapentin in an unfavorable light.

Lest anyone think that this was a fluke due to the company's goal of off-label marketing, Vedula et al. cite the earlier paper by Rising et al., which used FDA documents to cover a much wider class of drugs, and showed very similar results.

Now for the warning note. Vedula et al. very appropriately balance their claims of undue commercial bias by admitting the presence of apparently non-commercial bias. Specifically, they cite the paper by Chan et al. looking at 48 trials funded by the Canadian Institutes of Health Research, and showed that in 40 percent of those trials there were differences between primary outcomes as reported in the actual trial and in the final publication. The bottom line seems to be that trial registries are urgently needed for both commercial and non-commercial research, even though the quantitative problems in commercial research appear to be more substantial.

Vedula SS, Bero L, Scherer RW, Dickersin K. Outcome reporting in industry-sponsored trials of gabapentin for off-label use. New England Journal of Medicine 361:1963-71, Nov. 12, 2009.

Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation. PLoS Medicine 5(11):e217, 2008;

Chan A-W, Krleza-Jeric K, Schmid I, Altman DG. Outome reporting bias in randomized trials funded by the Canadian Institutes of Health Research. CMAJ 171: 735-40, 2004;

COI: Further Response from Stell

Folks, I trust this will be the last post on this particular exchange; any further discussion will be relegated to comments to posts. However, I think the topic is well worth the headlines because the definition of "conflict of interest" is central to our discussion--if we do not know what COI is, then much of the rest of our ethical concerns fall down. (Hence the shrewdness of a counterstrategy that attacks the definition directly.)

Lance Stell has kindly replied to my most recent post (one down) as follows:’s how I summarize your [Brody's] response.

· Langbein is sensible, but is not obviously relevant to the question at hand –
o Comment: How could Langbein not be obviously and directly relevant where the underlying ethical issue is fiduciary trustworthiness?.
· Langbein really provides more support for your (prohibitionist) view than my view (a management/disclosure view).
o Comment: Huh?
o With regard to overlapping relationships, Langbein makes “management/disclosure” the default. He is not a prohibitionist.
o Langbein does allow that some relationships are so toxic that prohibition is the right prescription. But even in proven toxic circumstances, he argues for a “reasonableness, best-interest” defense.
o You probably assume that your book provides ample empirical proof of severe toxicity.
o But no. Influence, even when established, is not thereby “undue-influence,” let alone toxic influence.
o There is ample evidence that doctors chronically fail to intensify therapy as they should (esp. in DM and HTN).
o Doctors’ clinical inertia is a chronic problem. Good quality CME may offset it somewhat.
o What may be said at CME events is tightly scripted, especially where drugs are concerned.
o Doctors have been criminally indicted for off-label use promotion. Free-speech anyone?
o At industry-sponsored CME, the corporation’s legal department screens the Power Points for staying well-within the FDA’s PI.
o The issue w/ CME is educational quality, not provenance.
o IMHO, Pharmascolds tend to have a provenance-fixation, rather than a quality-fixation.
o Huddle and Stossel have completely shredded the pharmascold COI research as having somehow proven “toxicity-with-patient-harm-resulting.”
o Even Wazana, a lead pharmascold, candidly admits that the COI research that she has reviewed hasn’t even examined patient outcome.
· As a card-carrying pharmascold you suggest (and by your book title imply) that doctors who consult for industry or attend sponsored CME should bear a “black box” warning. “Patients beware, your doctor maybe have acquired drug-company dependency.”
· This is an ad hominem (circumstantial), isn’t it?
· Finally, your working diagnosis for me: I naively “inhaled” at ACRE’s founding in July and am now either early-onset addicted or at-risk for – drug-company dependency myself.
o Comment: I was invited to speak at the ACRE meeting. No one paid my way. I attended on my own dime.

OK, that's Lance. Just a few comments in reply.

Prof. Stell appears to be astounded, first, that I sugggested that Langbein may not even be relevant to the Pharma issues; and second, he is even more astounded that I suggest that if Langbein is relevant, he actually defends the pharmascold view more than the views of pharmapologists like ACRE (which whom Stell has now thrown in his lot completely I gather).

The reason why Langbein is not (very) relevant is simple. His article is about trust law and the sole-interest rule. The criticism he lodges against that rule is quite dependent upon the detailed history of trusts and trust law that he provides in the article. So yes, it is about a fiduciary relationship, but one that has very different features (and a completely different set of empirical facts) from the impact of Pharma on the physician-patient fiduciary relationship.

The reason why despite that, Langbein offers more comfort to pharmascolds is more complex and I tried to give the detailed case in my previous post. But by way of a quick summation, the case is basically this. Stell and his ACRE colleagues realize that the only way to ward off the attack of the pharmascolds is to redefine 'conflict of interest' in such a way that it either disappears as a factor, or else that it becomes so widespread and omnipresent that one cannot distinguish financial COI with drug companies from a host of other COI's that we find acceptable in everyday life (which is just another way of making it disappear as an ethically relevant feature of the landscape). By contrast, Langbein offers no redefinition of COI and sees no need to do so. The pharmapologists see no ethical problem where the pharmascolds see a ton of them. Langbein sees exactly the same ethical problems as do his opponents who favor retaining the sole interest rule in trust law; he simply proposes a different solution.

Now, here is where we pharmascolds may have been sloppy in our arguments so as to have misled folks like Stell to think he has scored points against us. Stell seems puzzled that I would defend Langbein as reasonable, since my position against the pharmapologists is that most COIs between medicine and Pharma should be avoided, not accepted and "managed"; whereas Langbein obviously calls for managing COI in the area of trust law. (As a sidebar let me say that a "management strategy" makes more sense in trust law than in medicine/Pharma because the trustee is more directly under judicial control and review.) However, the argument I make in HOOKED has two parts: 1) a definition of COI that explains why it is a serious ethical problem that implicates patient trust; and 2) a further argument that most COI in medicine should be divested and not merely managed. If I were trying to claim that #2 followed directly from my definition, then indeed I would be open to all the criticisms that Stell throws in my direction.

It is important that we not expect the definition of COI to do more work for us than it can. Let's go back to Erde's fundamental analysis as I review in HOOKED. Erde insists that a statement that a COI exists is not a statement that a person has necessarily done anything ethically wrong. The person has, rather, placed herself in a position where she is at risk of doing things that are ethically wrong. The actual wrongdoing is a rebuttable presumption (which seems to be exactly what Langbein is saying).

Now suppose that in addition to the fact that a COI is present, we have some additional facts. First, significant patient harms have actually occurred as a result of those sorts of COIs in the recent past. (ACRE and Stell apparently deny that this is true in the Pharma case, and that is what would lead me to ask what he had been inhaling at their meeting--I made no suggestion whatever as to financial ties.) Second, the protections that have been offered to "manage" these COIs (such as disclosure) have been ignored or widely abused. Third, the COI is not a part of any arrangement that is necessary for medical practice or research to be properly conducted. Now, if all these things are true, it becomes more reasonable to blame the individual for entering into the arrangements that constitute the COI (such as signing up for a company speaker's bureau). But notice that the blame arises from the extra facts. It does not arise from the mere definition of COI. The charge of wrongdoing implicit in the label 'COI' remains a rebuttable presumption, by definition.

Friday, November 13, 2009

COI: My Reply to Stell

In the last post I turned the microphone over to my esteemed colleague, philosopher and bioethicist Lance Stell. He apparently accepted the definition of 'conflict of interest' attributed to him in the editorial by Michael Weber that was the subject of the post immediately preceding. He then proceeded to offer a further defense of that definition of COI, and cited as his inspiration for that definition the work of a Yale law professor, John Langbein.

I have now spent a pleasant couple of hours reading the 63-page article by Langbein that Prof. Stell refers us to. My conclusion is that it makes excellent sense, is grounded in what appears to be a thoughtful historical analysis, and I have no problem at all saying that he makes a good case for the conclusions that he argues for. (Whether he is actually right or not hinges on matters of trust law about which I am wholly ignorant, so I must withhold judgment. All I can address is the internal logic of his arguments.)

It also seems clear to me that Prof. Langbein's article has nothing at all to do with the debate over physicians and COI in relation to Pharma--or, if it does, that it supports conclusions opposite to those drawn by Stell and ACRE.

What Prof. Langbein sets out to show is that a principle of the law of trusts, the sole interest principle, is outmoded and should be replaced. According to this principle, if you are a trustee, you are assumed to be disloyal to the person you are the fiduciary for, if you enter into any deals that benefit you in any way--even if the result for the trust is a net benefit from the deal.

Prof. L. notes that the law has already been modified to grant him a good deal of what he wants--because the law now recognizes a bunch of exceptions to the sole-interest principle. That is, the law recognizes now that there are many ways in which it might be in the mutual interests of both trustee and fiduciary to carry out certain business arrangements. All Prof. L asks for is that these exceptions be made the new default principle.

Thus far it is not at all clear why Prof. Stell should imagine that this article is at all informative about COI in medicine/Pharma. The key line he quotes is, "The very term 'conflict' is an epithet that prejudices our understanding..." So I read Prof. L's article with the question in mind--does what he say here undermine or support the view of COI that I , as a card-carrying "pharmascold," propose is best? My conclusion is that Prof. L. says a lot more in support of my preferred view of COI.

Prof. L. wishes to allow transactions in which a COI exists but in which the interests of all parties are nevertheless best served by allowing what the sole-interest rule would prohibit. This is completely in keeping with most COI policies in academic medical centers. An example commonly discussed is the physician who owns a business interest in some new discovery. The ordinary rules would preclude that doc from running a research trial to test that discovery. But the discovery may be such that the only person on earth with sufficient knowledge of the new discovery, to be able competently to carry out the necessary research, is the doc who discovered it in the first place. The policies then commonly state that the doc may serve as the principal investigator for the study, but that he must accept additional oversight to be sure that he is not abusing his privilege as PI. So far nothing here to disagree with Prof. L's take on the matter. Prof. L at several places in his article calls for further regulation to prevent possible abuses.

One point that Prof. L. makes, that would at first glance seem to recommend his views to Prof. Stell and to ACRE, is the ubiquity of COI. You cannot get rid of COI because it's everywhere you look, he says. But then see where he takes this point. First, he distinguishes unavoidable and avoidable COI and agrees that it may generally be sound policy to prohibit the avoidable COI even if you end up having to tolerate the unavoidable. We pharmascolds, of course, argue that most of the COI we object to is avoidable. Docs can buy their own dinners and pay for their own CME. Academic docs who want to promote new discoveries can communicate freely with industry, but need not become paid consultants and speakers on behalf of industry--or, if they do want to do this, they can work part-time as salaried industry employees, and only part-time at the academic medical center. Famous academic "thought leaders" can actually write their own articles--or, if they want hired ghostwriters to do it for them, admit that and make the real writer the first author.

Further, while demanding changes in the sole-interest principle, Prof. L. nevertheless acknowledges the core reasons why the principle exists. For example (p. 953), he criticizes the principle, "What the sole interest rule does in such a case is to identify some conceivable but conjectural evil and then conclusively presume that this farfetched plot actually transpired, by refusing to let the putative evildoer prove that no such thing happened." Sounds pretty uncompromising. But he follows quickly with, "I do not mean to say that the trust tradition is wrong in being alert to the possibility of abuse [in the sorts of cases being referred to]." Now, this is precisely where we pharmascolds and ACRE/Stell seem to part company. Because they think that COI is sometimes applied in too sweeping a fashion, or because they think COI is ubiquitous and unavoidable, they do conclude that it is all a lot of hogwash, and that Pharma money and gifts and inducements create no ethical problem of any sort whatsoever, except in the fevered imagination of people like me. But if they conclude that, I would say, they cannot turn to Langbein for support.

Another point at which Prof. L. seems to offer much more support for my own position than for Stell and ACRE is where we call upon heightened standards of professionalism in medicine to get docs to refuse to accept Pharma freebies and bribes/handouts. Prof. L. includes in his historic survey (947-48) that one of the changes that has occurred since the sole interest rule made sense, is that the business of being a trustee has become much more professionalized. He mentions as his key example enhanced recordkeeping, driven by the "process values" that charaterize "good trust administration." With these improved records, if the trustee actually cheated the trust, you an always go back into the records and find out when and where this happened; and knowing this provides a strong incentive to the trustee not to abuse his power. Gosh--sounds to me as if Prof. L. is invoking professional standards as a defense against abuse and misconduct.

Final matter--I take Prof. L. to be making a claim that could be characterized as an account of successive pendulum swings. There was a time in history, he says, when the sole interest rule made good sense. Then a bunch of things changed, but the rule remained petrified. Nonetheless the pendulum has swung back toward the middle because more and more exceptions to the rule have been recognized. Prof. L. now calls for the final pendulum correction by replacing the rule with a more up-to-date principle.

Again we see why this analogy is superficially attractive to ACRE adherents. But let's ask--over the past several decades, which way has the Pharma pendulum actually swung? ACRE claims that at least in the last few years, the pendulum has swung wildly in the direction of discouraging financial exchanges between docs and Pharma, even when these exchanges might make patients better off (as they believe nearly always occurs). We pharmascolds on the other hand believe that the past 30-40 years have seen a huge pendulum swing in the direction of normalizing and accepting all sorts of blatant abuses and unprofessional behavior on the part of docs, and the reforms of the last few years have only just begun to edge the pendulum a few notches back toward the center-- though we still have an incredibly long way to go. I leave it to the reader to fill in your preferred account of which "pendulum" narrative seems more plausible to you.

So for all these reasons I believe that a fair-minded reading of Prof. Langbein's paper, far from undermining my own preferred definition of COI, would actually support it. As to what Prof. Stell said in the post that I reprinted from his e-mail to me, the only point to which I would call attention is his remark, "Some commentators quote GB Shaw as holy scripture [presumably when he said that it makes no policy sense to pay a surgeon or cutting off your leg unless you want surgeons to cut off a lot of legs]. And if so, buy into his socialist biases, whether self-consciously or not." C'mon, Lance--you cannot mean that in order to decide that fee-for-service payments to docs constitute a form of COI that incentivizes overtreatment, you have to be a socialist? Whatever those ACRE people were smoking at their July meeting, you should never have inhaled.

Langbein JH. Questioning the trust law duty of loyalty: sole interest or best interest? Yale Law Journal 114:929-990, 2005.

COI: Reply from Lance Stell

Since I posted the commentary just downhill from this post, I received a quick response from my colleague Lance Stell. I am pleased to quote here the meat of his reply, toward the goal of promoting scholarly inquiry and discussion.


You acknowledge drawing inspiration for thinking analytically about COI from Erde. I draw mine from John Langbein, a trust law scholar.

Langbein writes, “The very term “conflict” is an epithet that prejudices our understanding that some overlaps of interest are either harmless or positively value enhancing for all affected interests.” [ “Questioning the Trust Law Duty of Loyalty: Sole Interest or Best Interest?” 114 Yale L J 929 (2005)].

If you’re not familiar with this article or Langbein, I highly recommend both.

In my view, Langbein is correct. COI, as used in pharmascold-commentary on the physicians’ relationships with industry, is an epithet.

How so? “Harmless” or “value-enhancing conflicts”, if not oxymoronic for pharmascolds (Tom Stossel’s term), languish as empty ethical categories. If populated at all, it’s token “tip of the hat.”

Traditionally, physicians’ relationships with a patient have involved that of a diagnostician, a therapist and a source of billing. The physician is permitted to offer treatment for conditions he diagnoses and to bill or somehow be reimbursed for doing these. This manifests acceptance of Plato’s opportunity-cost axiom – “no one takes on the troubles of strangers, to straighten them out, but everyone expects pay for that.”

The relationships of diagnostician, therapist and biller for services overlap, to use Langbein’s term. The associated incentives involved are very complex. Some incentives incline to advantage taking (medicalization, sometimes to the point of quackery, over-utilization in FFS or under-utilization in capitated settings, over-billing/up-coding, and the encouragement of valetudinarianism with a resulting loss of patient autonomy).

Reputational incentives and disciplinary incentives (because of physicians’ relationships w/ colleagues, licensing boards, pharmacy benefits managers, credentials committees, the plaintiff’s bar, third-party insurers, and the general public) work in off-setting directions.

On the whole, we all seem quite confident that allowing physicians to offer treatment for what they diagnose encourages dutifulness (w/ allowances for referral, but w/ scorn for fee-splitting, a practice common in Japan). Yet Westerners are vexed over the third relationship, that of reimbursement. Some commentators quote GB Shaw as holy scripture. And if so, buy his socialist biases, whether self-consciously or not. GB Shaw is not lionized among intellectuals in Japan, where specialists pay up to $2500 for a referral.

More reason to suppose that COI is an epithet.
To say of a professional, “Over the past year, Dr. S has substantially increased her conflicts,” implies presumptively (& especially for pharmascolds) that she now has a professionalism-based reason to “eliminate, reduce, minimize and/or to disclose” all of them.

There is additionally the blind spot in the jihad against physicians’ relationships with industry that financial relationships are more ethically toxic than non-financial sources of bias. Levitsky is one of the few commentators to acknowledge that non-financial relationships may be more toxic ethically than financial ones.

In my view, the COI-label is not only an “epithet” (Langbein’s characterization) it has all the properties characteristic of a “framing bias” (a point I made in my OPC supporting Tom Huddle’s article in AJOB). I’ve agreed to write an article further elaborating this claim.

Best regards, Lance

Lance K Stell, PhD, FACFE
Thatcher Professor of Philosophy
Director, Medical Humanities Program
Davidson College
PO Box 7135
Davidson, NC 28036
Clinical Professor of Medicine
UNC-Chapel Hill School of Medicine
Medical Ethicist
Department of Internal Medicine
Carolinas Medical Center
PO Box 32861
Charlotte, NC 28232

Thursday, November 12, 2009

COI: Define It Narrowly Enough and It Goes Away

Thanks to a couple of friends for alerting me to Dr. Michael A. Weber's editorial in the Journal of Clinical Hypertension, entitled, "Academic Physicians Confront a Hostile World: The Creation of ACRE." You can get a sense from the "poor us" tone of the title what this defense of the Association of Clinical Researchers and Educators is going to be like. I could go on for a while about the "hostile world" that expects that academic physicians might actually manage to live on their salaries, that are generally several times greater than those of any other academics, without also stuffing their pockets with industry largesse. But of greater interest is the discussion of the definition of conflict of interest (COI).

In a section labeled "Conflict of Interest: A Disturbing Misnomer," Dr. Weber quotes with approval a speaker at the inaugural ACRE meeting, Prof. Lance Stell of Davidson College, whom he described as a "nationally recognized medical ethicist." I consider Lance a good friend of many years standing and a fully legitimate philosopher-ethicist, but the fulsome description leaves out that on this particular issue, Lance's stance is probably quite atypical of bioethicists (though no one has done a survey so I could never prove that).

The reason Dr. Weber likes Lance Stell's definition so much, and no doubt why Lance was the only bioethicist I am aware of that was invited to speak at the ACRE conference, is that he is said to define COI as what "occurs when practitioners accept personal return for actions that could violate their professional obligations. In essence, to accuse a physician of conflict of interest would require empirical proof that, in return for a reward, an action was taken that resulted in diminished care or even harm to patients." Given that starting point, Dr. Weber then says very reasonably, "Clearly such occurrences are extraordinarily rare..."

This definition contrasts quite markedly with the definition of COI that I offer in HOOKED, which in turn is based on a definition constructed by philosopher Edmund Erde. By the definition I favor, a person may be involved in a COI if she becomes involved in certain social arrangements, which would cause a reasonable observer to believe that a person of normal human psychology would (under those arrangements) be tempted to forsake her professional obligations. Erde, in constructing his definition, explains that he did so with the idea that the core concept that COI needed to be grounded in was trust in a social role. I believe that judgment to be exactly correct-- it is precisely the concerns we have about loss of public trust in physicians and in medicine as a whole that motivates our present concerns about COI.

It should be no great surprise that we could make COI go away if we engaged in the right sort of definitional gerrymandering. The question is whether that sort of definition seems genuinely to enlighten us about the core ideas and behaviors, or whether it rather serves to obfuscate the issues.

I am going to stick my neck out here as I am not schooled in the laws regarding bribery. But my current state of understanding is that you could arrest a public official on a charge of bribery if, say, he was observed to have been offered money in exchange for his vote on some pending legislation, and on accepting the money he indicated his willingness to vote the way that the payer wished him to.

Now, imagine that we were to apply the logic Lance Stell uses to define COI to the bribery case. The first thing we would note is that we cannot arrest the corrupt politician just because he takes the bribe and agrees to change his vote. We have to wait until the vote occurs and see that he actually does vote the way the bribe required. Nor are we done yet. We also have to see the outcome of the vote. Let's imagine that despite the politician voting "no," as the person paying the bribe wished, the legislation passes anyway. Then there was no harm, associated with the bribe; and so by the Stell approach, there would have been no crime of bribery. I would not be surprised under those circumstances to be told that the cases in which public officials are bribed are vanishingly rare.

I suggest that the bottom line is:
  • What we are concerned about in the COI issue is public trust in medicine.
  • Public trust can be lost just as much by the appearance or suggestion of compromising behavior as by the behavior itself.
  • Therefore things that create appearances or suggestions that would reasonably cause public trust to be lost ought to be included in the definition of COI.
  • This is especially true when the social arrangements that give rise to the suggestions or appearances are not essential to the conduct of medical practice or medical research, and consist of extra perks for the academic physician. (I gather that the ACRE folks argue that taking money from industry is essential to medical research, beause absent the good ol' entrepreneurial spirit and profit motive, many fewer discoveries will be made. That debate will have to occur on a different occasion.)

Incidentally, you might wonder why a hypertension journal seems to be going out of its way to provide a platform for ACRE and its preaching. You can get a sense of why this is so by reading more about where some of the ACRE leaders get their money, in Danny Carlat's recent blog on the topic:

Weber MA. Academic physicians confront a hostile world: the creation of ACRE. Journal of Clinical Hypertension 11:533-36, 2009.

Erde EL. Conflicts of interest in medicine: a philosophical and ethical morphology. In: Speece RG, Shimm DS, Buchanan AE, eds. Conflicts of interest in clinical practice and research. New York: Oxford University Press, 1996:12-41

Tuesday, November 10, 2009

Retraction: Nemeroff and Ghostwriting

In a previous blog post:
--I did too little factchecking and accordingly made an incorrect assertion regarding Dr. Charles Nemeroff and ghostwriting.

The facts on which I was relying, and which do not support what I said at first, can be found in two posts on Danny Carlat's psychiatry blog:

Here's a recap. Dr. Nemeroff approached two of his academic psychiatry colleagues to participate in a discussion at a psychiatry meeting in Hawaii, to be videotaped by Bristol Myers Squibb, regarding the company's antidepressant patch, EMSAM. An article based on a transcript of that video was then published in the journal CNS Spectrums.

Critics noted apparent errors in that article, leading one of Dr. Nemeroff's co-participants (and listed co-authors of the article), Dr. C. Lindsay DeVane, to protest to Dr. Carlat that the article as a "piece of commercial crap" that did not accurately reflect his views. Dr. DeVane implied to Dr. Carlat that the first draft of the article had been written by a ghostwriter hired by the drug company, and contained numerous inaccuracies; Dr. DeVane denied having seen the final draft before publication. The former editor of CNS Spectrums, James M. La Rossa, Jr., then wrote a comment to Dr. Carlot's post, complaining about current company-sponsored practices in the publishing world, and adding, "I am willing to bet dollars to doughnuts that Nemeroff never saw proofs of the article either."

Dr. Carlat said in his later post that somebody must have gotten to Dr. DeVane, as he later retracted his comments and claimed that the CNS Spectrumsarticle was accurate, not ghostwritten, and that all three co-authors were "heavily involved in multiple edits." There were, as Dr. Carlat said, several reasons to regard Dr. DeVane's later retraction as disingenuous, especially because as he noted the first time out, his published research had stressed the lack of drug-drug interactions as a problem with antidepressants, whereas the CNS Spectrumsarticle seemed especially to claim that EMSAM was a superior product because it avoided drug-drug interactions.

Bottom line: others alleged (though one later retracted) that Dr. Nemeroff was involved with a ghostwritten article, but Dr. Nemeroff himself never admitted to this, in the specific instance that I was referring to.

I stand by my initial observation however in that anyone who claims to have written 450 articles, who keeps up the sort of travel and speaking schedule that Dr. Nemeroff apparently does, and who is well known to be extremely cozy with numerous pharmaceutical companies, has to be under suspicion of at least some of those articles being ghostwritten for him. Which is part of the reason why ghostwriting as a practice is such a basic threat to the integrity of medical science.

Monday, November 9, 2009

"Health Care Renewal" on AAFP's Tone-Deaf Reaction to Coke Controversy

I appreciate our fellow blogger Roy Poses over at Health Care Renewal adding some further insights to the American Academy of Family Physicians (AAFP)/Coca-Cola controversy:

Dr. Poses wonders, as I have, why the leadership of AAFP seems so tone-deaf to the outcry that points out how bad the organization has made itself look by signing the deal with Coke to support public "education" about obesity. Dr. Poses, however, was far more energetic in doing some research, and his results are as follows:

"Nonetheless, one would think that the latest round of criticism would make the top leaders of this august professional society less comfortable about the organization's financial relationships with pharmaceutical, biotechnology, and now beverage corporations. I fear, though, that they may live too much in the sort of bubble that now protects top executives of most large health care organizations to really question their corporate ties. After all, according to the most recent (2007, covering 6/2007-5/2008) US Internal Revenue Service form 990 filed by the AAFP (via Guidestar), its leaders get sufficient compensation to put them into such a bubble. For example, Dr [Douglas] Hensley [AAFP CEO] received $441,027 regular compensation and $108,930 in benefits and deferred compensation, compared with a median compensation for family physicians in 2008 reported as $159,000 ..."

I guess that when your ears are stuffed with that many dollar bills, tone-deafness is the logical result.

Saturday, November 7, 2009

U. Miami: Send Us Your Professionally Challenged

When the poster child for everything this blog inveighs against, Dr. Charles Nemeroff, was finally stripped of his chairmanship of psychiatry at Emory after many years of blatant conflicts of interest, I had finally hoped I could continue these discussions without again having to mention his name. But I had reservations. The uncharacteristic meekness with which Dr. Nemeroff appeared to accept his chastisement and demotions somehow seemed to hint that there were more episodes of this soap opera yet to come.

We now read that Dr. Nemeroff has been hired by the University of Miami as its new chair of psychiatry:

At first blush this would appear to indicate that Miami has put up a neon sign, "Want to Get Rid of Your Problem Faculty Who Appear to be Ethically and Professionally Challenged? Send Them Here! Group Rates Negotiable."

Miami's response? "Pascal Goldschmidt, dean of UM medical school, called Nemeroff ``an exceptional psychiatrist and an exceptional scientist who has one issue in which he recognizes he made a mistake,'' in not telling Emory how much he was getting from drug makers."

To anyone who has followed Dr. Nemeroff's career, this is sort of like saying that Jack the Ripper was a dedicated feminist, only he had one issue. The specific question of whether he honestly reported to Emory how much outside income he had made is just the tip of the iceberg. To reduce the question of his professionalism to that single matter indicates either denial or willful ignorance of the record.

"In Miami, Goldschmidt said Nemeroff was multidimensional -- strong in basic research, treatment of patients and building programs such as suicide prevention.
His biography lists stints as president of the American College of Neuropsychopharmacology and the American College of Psychiatrists. He has published more than 750 research reports and reviews.
``I know I'm going to take a little smack in the face for this hire,'' Goldschmidt said. ``But you don't do anything important without taking some risks. It's very important that the people of Miami have access to a phenomenal psychiatrist like this.''

How does a person of Nemeroff's age and rank get to have written 750 publications--especially with how busy he obviously was with administration, fundraising, and schmoozing with corporate bigwigs? (Academics 10 years older than Nemeroff would ordinarily be considered superstars if they had 200 articles to their credit.) Given that Nemeroff admitted on at least one occasion that he put his name to a ghostwritten paper, and given what we know about the frequency of ghostwriting in psychopharmacology specifically, one has to question just what percentage of his actual output is honestly attributable to him.

And what exactly does the Dean mean by calling Nemeroff "exceptional...phenomenal"? This is a person who has probably done more than any single individual to reduce academic psychiatry to a crassly commercial enterprise. In the process, he has always kept a stream of corporate cash flowing into whatever institution currently harbors him. That appeared to many skeptics to be the reason why Emory took as long as they did to seriously get on his case. That would appear also to be the main attraction for Miami.

I will once again protest, despite apparently mounting evidence, that I have no personal vendetta against Dr. Nemeroff. I have never met the man. He may be, for all I know, a charming fellow, though one would imagine that whatever behavior earned him the nickname among his fellow academic psychiatrists of "boss of bosses" would argue against too benign a portrayal. I am beating this dead horse, that refuses to stay dead and keeps rearing up, for one simple reason. Grossly unprofessional behavior that is nevertheless highly profitable for both individuals and their institutions will never stop unless engaging in it brings down consequences upon one's head. If the reward for being Charles Nemeroff is to be offered a chair at one medical school when one has been kicked out of one's chair in disgrace at another, then the consequences appear to be pointed in exactly the wrong direction.