Sunday, September 27, 2009

The More Things Change...

It's been a good while since I posted anything about exhorbitant gifts to docs or the incredible sums spent by drug firms on marketing, and you might have gotten the impression that things have changed. At least in Australia, apparently not.

The original source for this is, though you need a subscription to access, apparently. And this is a chance to say thanks to the Healthy Skepticism list serv for tipping me off to this news item.

Anyway, somebody apparently wondered what was the top Pharma event of the year so far Down Under, and the answer turns out to be--Wyeth's million-dollar weekend, dedicated to convincing docs to prescribe their new antidepressant, Pristiq (desvenlafaxine). The sum was reported to the oversight body, Medicines Australia, as tops on the list of all such events sponsored in that country between January and June 2009, with everything on the list sporting a total price tag of about $31M.

Now, you might wonder what it is about Pristiq that would make Wyeth want to spend $1M to promote it, and the answer seems pretty clear. Wyeth's old antidepressant is Effexor (venlafaxine). Effexor is going off patent and becoming available generically. If you remember your old organic chemistry class, you'll note that desvenlafaxine is probably the active stereoisomer of venlafaxine. In other words, all they did was tweak a tiny portion of the Effexor molecule and out came Pristiq--just as Prilosec became Nexium. The old evergreening trick once more, and a classic "me too" drug that has no advantage over older, and now cheaper drugs.

UK Ahead of US in Disciplining Ghostwriting?

From Roy Poses' Health Care Renewal blog:

This post briefly reviews the case of Dr. Aubrey Blumsohn of Sheffield University, England, who was dismissed by his university some years ago after he went public with a dispute with a drug company (Procter & Gamble) sponsoring his bone research, demanding that he have the right to review all the relevant data. At the time his senior colleague at Sheffield, Dr. Richard Eastell, urged him to drop the matter and avoid offending such an important sponsor of University research.

Flash forward to today, and to reports in The Guardian that Dr. Eastell has been called before the UK's General Medical Council under charges of putting his name on ghostwritten papers. The specific allegation is--you guessed it--that he allowed his name to be put on papers for which he was unable to see all the relevant data.

Now, it would be nice to be able to report that justice was being done to Dr. Blumsohn, though it is a tad late for that. Still, I wanted to get a post up pronto on this topic because of a regular refrain in my previous posts on ghostwriting--when is a university ever going to take action against a star academic who's proven to have been involved in ghostwriting? OK, in this case it's the UK General Medical Council (sort of the equivalent of a state licensing board in the US) and not the University, but it does appear the Brits are out ahead of us in trying to do something about ghostwriting and the problem it poses for the integrity of the medical research literature.

Wednesday, September 23, 2009

Unhealthy Skepticism about Flu Immunizations

Healthy Skepticism is a website that I have been proud to be a member of and that assisted me greatly in all of my research. I am a member of HS and also of a listserv that includes HS members and generally find it highly informative. So it pains me to have to dissociate myself from a recent thread on that listserv and website that I believe to be quite wrong. I am taking this public stance because I think the issue holds lessons for us Pharmascolds, in terms of how we can go too far in our opposition to the bad practices of the pharmaceutical industry.

My concern is with a piece posted on the HS site, "In the Face of Swine Flu, Common Sense and Science":

The author is a Spanish GP who also holds a couple of academic posts. As a family physician I have been on the receiving end of attacks due to having dared to speak out on medical issues, when the relevant subspecialists thought that only they were entitled to express opinions. So I might have been expected to immediately identify with the author.

The basic thrust of the piece is that swine flu is an example of "disease mongering"; that the vaccine is unnecessary because the disease is very mild; the vaccine has been rushed into production and so cannot be known to be safe; and anyway, the seasonal flu vaccine has been overpromoted and is not really scientifically shown to be of benefit.

Let me separate my reactions into two parts--seasonal flu and swine flu.

I have followed the literature for many years on the health benefits of seasonal flu vaccines. (I personally always get my flu shot each fall, even though I am not now doing direct patient care.) I have been impressed with the nearly uniform showing in all studies that flu vaccines are highly beneficial and highly cost-effective. Indeed it is one of the most cost-effective preventive interventions available to us. So trying to cast doubt on the wisdom of a swine flu vaccine by attacking the benefits of the regular seasonal vaccine seems completely wrong-headed.

As to the swine flu, we charge the public health authorities with preparing a vaccine each year that will protect us from the dominant strain of flu that is going to appear in the fall. This year, the appearance of a novel strain of H1N1 flu (swine) created great concern because most Americans under age 60 have never been exposed to a similar flu virus, so natural immunity was thought to be very low. And indeed, at this time in the U.S., there are near-epidemic levels of flu, very unusual for this early in the fall, and more than 90 percent of it is H1N1 (though when they started making the vaccine, no one could have known this would necessarily happen). Every year the task of making the flu vaccine with the correct strains of antigen is a crap shoot and any year you could guess wrong. The swine flu is being manufactured using the same techniques as used for the seasonal flu, which has an excellent safety track record ever since 1976, the year of the last swine flu scare.

In short I see no reason whatever to interpret anything related to swine flu vaccination as a public health response, as somehow related to disease mongering by the pharmaceutical industry or its allies or shills.

Now, where the author of the HS piece questions the use of antivirals, I think he is on firmer ground. Antivirals for flu have in the past been significantly overpromoted.

The HS piece ends with this language:

"Note: The only purpose of the author is to transmit the best knowledge about the problem at present, and for that he has reviewed the world literature. This text is an informative one, not for clinical use. Sadly, the information you can obtain from others sources (public organizations, scientific societies, media) is very different; they will know why."

This appears to be a gratuitous ad hominem attack on anyone who disagrees with this author's conclusions, and seems utterly uncalled for.

I may add that I checked into a couple of the authors' citations, and was impressed that the conclusions reached by those articles did not square with the conclusions offered in the HS piece.

So why do I make a big deal of my personal disagreement with this particular piece of writing (one that HS was apparently proud enough of, to have translated into several languages for dissemination)? Again, I need to beware attributing motives to others. But we have to be very cautious that our distrust of the drug industry and its many devious and dishonest practices, and of our physician colleagues who eagerly do the industry's bidding, not spill over into areas where it does not belong. When we decide that any product manufactured by the drug industry is therefore unsafe or unneeded; or that any effort to raise public concern about a disease is therefore commercialized disease-mongering, then I think we have clearly crossed over that line.

Sunday, September 20, 2009

Nature on Grassley and Sunshine; How High Up the Food Chain?

A news article and an editorial in the British journal Nature offer a number of comment-worthy points. The editorial is open access:

The editorial speaks in praise of the Grassley-Kohl Physician Payment Sunshine Act and notes that it now stands a good chance of passing as part of any health reform bill that moves through Congress this year. (It was incorporated into the Baucus markup for the Senate Finance Committee last week.)

The news analysis by Meredith Wadman is primarily a profile of Paul Thacker, Grassley's principal staff investigator who's behind many of the most significant coups that the Iowa Republican has pulled off in the last few years, expopsing major academic physicians for serious underreporting of funding received from industry either to the NIH, to their home universities, or both.

The article spends a fair amount of time discussing the downfall of Emory University former Chair of Psychiatry, Charles Nemeroff, whose many escapades we have followed closely in this blog. Dr. Nemeroff apparently gave Wadman his first statement to the press after being disciplined by Emory: "I made mistakes in the area of conflict of interest for which I am sorry and remorseful. However, the mistakes I made were honest mistakes... in my view at the time, in keeping with my understanding of the current Emory policies.... I also plan to use my recent experience to help others avoid problems with conflict of interest from the lessons I have so painfully learned."

There are a couple of undercurrents in the Wadman article and also in the editorial that require some critical comment. Wadman quotes Joseph Cubells, a neurogeneticist at Emory, in defense of Nemeroff. Cubells objects that the case against Nemeroff is hardly as black and white as the media have made it out; and he also praises Nemeroff for "intellectual honesty," especially for including a psychotherapy-only comparison group in a major NIH study of depression that was temporarily halted because of the COI issues.

I concur with Cubells that comparing antidepressants to psychotherapy only is generally not a move designed to win friends among the drug industry, as long as the trial sets up a truly level playing field. However, his portrayal of Nemeroff as basically an honest guy who got tangled up in a complex set of morally confusing circumstances is not the impression that I get from some of my psychiatrist colleagues, who are quick to point to Nemeroff's national reputation within their field. The fact that he was commonly referred to by the nickname "boss of bosses" suggests that traits besides intellectual honesty were prominent in his character. If today he is truly repentent I give the man full credit.

The other important undercurrent in both the Wadman article and the editorial is the reminder that people like Nemeroff were (at least till recently) avidly recruited by academia because they promised to do just what their own bosses wanted--drive the gravy train of lucrative industry-funded research contracts straight through the university's front gate. If Emory treated their problem child with kid gloves for many years, it was clearly due to the ease with which he could have picked up his whole operation and moved to another university that would have been all too glad to welcome him and his Pharma bucks. As Wadman notes, at times, research grants from NIH and its daughter, the National Institute of Mental Health, specified that recipients should link up with industry to be sure that new discoveries were quickly brought to market to help patients faster.

That comment does, to my mind, offer something of a defense for at least a number of the academic docs now being pilloried for their COIs. The basic question is always the same--when there is bad behavior within an organization, how high up the food chain do you assign responsibility? Were the faculty who took all the industry cash the bad guys, or are they in effect taking the fall for their higher-up administrators who encouraged and abetted them?

Let's be blunt. Today, academic medical centers have got religion and are falling over each other to implement tough new COI policies. All of these COI policies are aimed at individual faculty. Supposedly if the faculty member brings in mucho Pharma research grants, he's golden. But if that same faculty member starts to line his own pockets with speaker's fees, consulting fees, and stock options, that spells trouble.

Now let's turn this around from the Big Pharma perspective. Two "key opinion leaders" from academic medical centers approach you for research funding. One of them says, "By the way, just so there's no confusion later on, I am very happy to perform legitimate scientific research for your firm. But I have strong views on individual COI and would prefer not to take any money for any other activities, such as your speakers' bureau and for consulting." The other doc is clearly ready to jump into bed with them for as high stakes as he can play.

With whom will the company rather do business with-- Goody Two Shoes? Or the doc who's made it clear that he's for sale? So who's most likely to land the really big research grant? And later on, who's more likely to be hobnobbing with the upper echelons of the drug firm, to be sure that he gets first dibs on the next big grant, and the next?

In short, by asking their top faculty to be squeaky clean on individual COI, but to be sure to keep the big Pharma money flowing onto campus, academic medical centers are sending their faculty a decidedly mixed message.

All of which is why, as I wrote in HOOKED, the really important COI policies are for institutional and not individual COI.

Wadman M. The senator's sleuth. Nature 461:330-34, 12 Sept. 2009.

Friday, September 18, 2009

Enter the Ghostbusters

While I have been out to lunch recently (actually, out of town for part of the time) and not blogging, the Pharma/medicine news has kept rolling in. Fortunately my fellow bloggers have been on the job. One big story is a paper written by some of the editorial staff of JAMA, as yet not peer reviewed or published in a journal, but presented at a conference, and covered by the New York Times:

The study, by Joseph Wislar and colleagues, asked authors listed for 630 articles in 6 top medical journals to respond to an anonymous on line questionnaire. The results suggested that 7.8 percent of these articles had been ghostwritten. The New England Journal actually topped out the other journals at 10.9 percent, leading its editors to throw the most skeptical barbs at their rival journal's study. However, most believe that the problem in any study such as this is underreporting rather than over-, hence suggesting that the true rate is probably even higher.

In response to my earlier question about whether journal editors are taking this seriously enough and doing all they can to police themselves, the second Times article highlighted a nice editorial in Blood. (That's not a Halloween publication but rather the official journal of the American Society of Hematology.) There, editors Cynthia E. Dunbar and Martin S. Tallman reported back in January that one reviewer became suspicious of an unsolicited review manuscript submitted by "a prominent clinical investigator." The academic acknowledged the assistance of another peron, without specifying what role that other person played. The reviewer happened to know that the other person worked for a pharmaceutical company, whose product was prominently featured in the review article. (The pharmaceutical connection was also not disclosed.) Following more investigation, the editors decided this was actually a ghostwritten article and rejected it. The editors added, "Once we began to systematically seek clarification of the degree to which a pharmaceutical company had been involved in any aspect of writing, editing, or researching review articles, within 2 weeks we had rejected 2 additional unsolicited manuscripts. "

This bit of anecdotal testimony perhaps helps answer the question--just how common is ghostwriting--and tends to confirm previous reports that it is all too common. The poohbahs for the drug industry interviewed by the Times naturally insisted that the industry was doing all it could to implement new guidelines (expected in October) to bring industry practices in line with the international medical journal editors' proposed rules. To which the obvious reply is--why so late? Given that these rules were promulgated years ago, and the ghostwriting issue has also received publicity for many years, why is the industry only now taking action? For that they expect a pat on the back? (The industry also objected strenuously to proposals that any academic author caught signing a ghostwritten article be banned from further publishing in that journal for some period--it would "chill" research, they feared.)

The Blood editors also very kindly summarized for us an incident I wrote about in HOOKED which reminds us as to why all this is important:

"If our appeal to better instincts is insufficient, read the New York Times account of the Annals of Internal Medicine paper on a Vioxx clinical trial that failed to include the deaths of several patients. The paper's first author admitted that "Merck designed the trial, paid for the trial, ran the trial ... Merck came to me after the study was completed and said, ‘We want your help to work on the paper.’ The initial paper was written at Merck and then it was sent to me for editing." Documents made public in court indicated that Merck's marketing department initiated and managed this trial solely as a mechanism for exposing a wide swath of primary care physicians to the drug, instead of pursuing real research questions." [citations omitted]

Dunbar CE, Tallman MS. "Ghostbusting" at Blood. Blood 113:502-3, 2009.

Wednesday, September 9, 2009

Who's Insulting Whom?

Our friend Danny Carlat has devoted his recent blog posting: the mailing he received from Schering-Plough regarding their new psychiatric medication. Seems they did not quite get it when Dr. Carlat famously came out of the closet in the national media spotlight as a former paid drug company speaker who had seen the light and vowed to sin no more. They offered him lucrative deals if he'd agree to join the speakers' bureau for the new drug, with a chance to earn up to $170,000 annually. (If you want to see the hourly rates check the blog posting.)

As you can see by the URL above, Dr. Carlat initially had the bad manners to refer to his colleagues who did sign up for the speakers' bureau as "drug whores." That led to a couple of interesting comments on his blog. One commentator objected to the derogatory word "whores" as a form of discrimination against female sex workers who, virtually universally, would be very happy not to be paid sex workers, if only they had a realistic option. Dr. Carlat agreed and so his post is now titled, "Schering-Plough to SAPHRIS Hired Guns: Come and Get It!"

That put me in mind of one of my favorite newspaper letters to the editor. Many years ago, during the infamous OJ trial, a common remark made in the media was that the antics of the defense attorneys were "turning the courtroom into a circus." That led to a letter from a circus ringmaster, who explained in some detail exactly how carefully planned and structured were all the events that went on in all three rings of his circus at any given time. He expressed his sense of insult that anyone would compare his very neatly orchestrated circus with the godawful mess that was the courtroom in question.

So now we have it, my fellow physicians. Female sex workers don't have any real choice as to how to earn a buck. We physicians do. So we ought not call the physicians who become paid speakers for the drug industry "whores," lest we insult the sex workers by the comparison.

Sunday, September 6, 2009

Registering Clinical Trials--Less than Meets the Eye?

The current JAMA features an article (subscription needed to access) by an international team of authors headed by Dr. Sylvain Mathieu of Paris. The authors decided to study what has happened as a result of the requirements from leading medical journals (initiated in 2005) that all clinical trials should be properly registered--in theory allowing anyone to compare the final, published results of the trial with the original design.

They found 323 trials that were published in 2008 in high-impact medical journals, either general or in one of 3 specialties (cardiology, rheumatology, gastroenterology). They discovered that only 45% of these were adequately registered. Others were not registered until the trial had been completed (14%), and with no or an unclear description of the primary outcome (12%). More than a quarter were not registered at all.

In about half the cases, there were insufficient data to determine what sort of bias would have been introduced by a change in the primary outcome from that originally identified in the study methods to the one featured in the published report. In the other half, in 19 of 23 studies, an outcome for which the results were statistically insignificant was replaced by an outcome whose results were significant.

Naturally a person like me would wonder--and what association did commercial sponsorship have with whether the authors ended up playing fast and loose with the study design? About 56% of the trials in this review were commercially sponsored (and sponsorship was not reported in another 9%). That would seemingly have allowed some comparisons to be made. But these authors reported no data based on associations with commercial sponsorship.

The most worrisome finding was that the authors found evidence of selective outcome reporting in 28% of studies that were properly registered. This suggests that neither the editors nor the reviewers took the time and trouble to use data available in open trial registries to see whether the outcomes reported in the final publication were indeed the outcomes listed in the pre-trial study design. In short, in these instances, the whole reason for trial registration was subverted by the failure of journals to take advantage of the data.

So let's leave aside the question that we wish had been answered, but was not--whether commercially sponsored studies were more likely to be registered incorrectly or incompletely, or to have partial or biased reporting of endpoints. We have long asked--why do articles get published in major medical journals that are ghostwritten or that suppress key data in the interests of marketing drugs? The usual reply from the journal editors is that they are not detectives. If the authors flat-out lie to them about who wrote the article, or what the endpoints were, how is the journal going to smell a rat? In a previous post ( I noted the criticism that even if journal editors lack the detective facilities to identify ghostwritten articles, that hardly explains why no article has as yet been officially retracted by a journal once ghostwriting was proven by another route. Now, in light of the Mathieu study, journal editors need to explain why they cannot be bothered to cross-check trial reports against registered data that are available in plain sight.

It appears that it's not simply the case that journal editors make rotten detectives. Journal editors don't seem to run a very tight ship even when other people do the detective work for them and hand them the results neatly giftwrapped.

Clinical trial registries were supposed to solve this problem. Do we have here yet another example of Epstein's Law--"If you think the problem is bad now, just wait till you've solved it"?

Mathieu S, Boutron I, Moher D, Altman DG, Ravaud P. Comparison of registered and published primary outcomes in randomized controlled trials. JAMA 302:977-84, Sept. 2, 2009.

Saturday, September 5, 2009

COI vs. Investigator Bias: Clarifying the Issues

A recent paper (subscription required to access) coming out of the departments of epidemiology and statistics at UCLA offers a new take on conflicts of interest in pharmaceutical research, plus some valuable conceptual clarification.

To lay a bit of groundwork, most approaches to conflicts of interest in medical research, and whether they should be either disclosed or avoided, starts from one of two positions. The position I favor begins with the ethical values of professionalism and scientific integrity and looks askance at competing interests that might distract physicians or investigators from their primary duties to serve the patient, the public health, and scientific truth. In reply, defenders of close industry ties have appealed to the values to collaboration in the service of scientific innovation. The latter group has championed the notion of "intellectual conflict of interest" as a way of arguing that many things besides taking money from commercial outfits can bias the scientific investigator, and since in fact COI is all over the place, and essentialy unavoidable, stop obsessing about it and let the cash flow.

To this mishmash Sander Greenland brings a refreshingly empirical perspective which is value-free to the extent that anything in medical science can be value-free (another discussion I won't attempt here). Basically, Greenland asks about the broad category of investigator bias, which he defines as "the biasing of study results towards results expected or desired by the investigator." He approaches the problem as if he were the evaluator of a research study--such as would be the case if he were a physician reading a medical journal and wondering whether or not to apply the results of that study to his own practice. He describes his role as placing bets on the probability that the results of any study would approximate the scientific "truth" (again, whatever that is). He then asks the core question: If I am that evaluator placing bets on the truth of study results, would I be assisted by the disclosure of one particular sort of investigator bias, that which results from financial ties to the sponsor?

Greenland notes that both Type 1 and Type 2 errors are possible in placing bets. If he pays too little attention to commercial bias, he may accept study results that are untrue and misleading for care of patients. But if he goes overboard in attaching too much weight to COI, then he might reject true findings, which would have a similarly bad impact on patient care.

Greenland then proceeds to jump through a bunch of mathematical and statistical hoops where the likes of me cannot follow. Where he ends up after those gymnastics seems to be this. First, he agrees with folks like me that commercial COI-related bias is not something we just dreamed up because we hate the drug industry; it is real and substantial. If he didn't take it into account he couldn't place his "bets" rationally. Second, Greenland agrees with those urging disclosure of COI as a minimum requirement. As a rational bettor, he would be significantly aided in making his bets by having that information available.

Put slightly differently, Greenland disagrees with some earlier commentators who have criticized mandatory disclosure of financial COI, because it unfairly taints the way we read a new research study, where we should focus exclusively on the actual study methods to decide whether or not the results are trustworthy. And he does so without making any value judgments whatever about the personal intentions of any actors, or the goodness or badness of taking any form of money from industry. So far as he is concerned, everyone engaged in these practices might have the noblest intentions and the purest motives, and it would make no whit of difference for his calculations and results.

So to sum up, one thing the Greenland paper seems to offer us is an empirical approach to defending the propriety and indeed the necessity of full disclosure of financial COI in medical research publication. The second, I suggest, is a valuable conceptual clarification. Greenland seems to be suggesting that the proper umbrella concept is this thing called "investigator bias." Under that large category, bias resulting from financial COI forms a subcategory. As I have said in previous posts, buit without the fine-tuning of this language, those who try to introduce the concept of "intellectual conflict of interest" err in equating the specific problems associated with financial COI with the much more general problem of research bias overall. If we see that the general category is investigator bias, and the subcategory is financial COI, we have no need to introduce a new (and I would argue, spurious) concept such as "intellectual COI."

Thanks to Roy Poses at Health Care Renewal blog for calling this valuable paper to my attention.

Greenland S. Accounting for uncertainty about investigator bias: disclosure is informative. J Epidemiol Community Health 63:593-98, 2009.

Wednesday, September 2, 2009

Another Clue on Ghostwriting Frequency

Danny Carlat's psychiatry blog (, Sept. 1) recently pointed us to a New York Times article on industry CME practices:

In turn, Dr. Carlat provided the link to the document that had been circulating in U.S. Senate committee on which the Times article had been based--the secret Forest Labs Lexapro marketing strategy report for FY04:

Now, I have not had time to study all the 88 pages of this document, and if I do, I may have more to report on CME and other issues (remember, I do have a day job). But in giving it a quick skim, I was struck by one passage that might be pertinent to the debate over ghostwriting that we've been attending to in recent posts. The questions we want to ask include: is the incidence of ghostwriting going down recently as new rules and regs come into play? Is the incidence of ghostwriting really as high as some claim (David Healy, the Welsh psychiatrist, saying that just about every paper on psychopharmacotherapy is ghostwritten until proven otherwise)?

Here is a brief snippet from the Lexapro marketing plan (p. 24 of the PDF on-line file; pages in the original are not numbered):

"Bylined Articles. Bylined articles will allow us to fold Lexapro messages into articles on depression, anxiety and co-morbidity developed by (or ghostwritten for) thought leaders. We will identify a Lexapro thoughtleader to place 2-3 bylined articles in trade journals, consumer publications and on the Internet. ... Budget: $100,000"

The way I read this passage is that on the one hand, the list of publications does not include medical professional/scientific journals, and so one could defend the company by saying they have a different policy for those publications. On the other hand, the suggestion I am forced to from this passage is that the ghostwriting of articles, and giving them to thought leaders to sign their name to, is a completely everyday, unremarkable, ho-hum practice within the company, not worth a second glance. Which in turn seems to suggest that as recently as 2004 we could have expected ghostwriting to be a major part of the marketing campaign for any drug from this company.

Incidentally, just a quick reminder about what drug we are talking about. Forest's older drug, Celexa, was about to go off patent. Lexapro is the active stereoisomer of Celexa--meaning that chemically it is virtually identical. It is the "me too" drug par excellance. The big marketing push for Lexapro was primarily aimed at getting those who wrote for Celexa prescriptions in the past to switch their brand loyalty to the new, and much more expensive drug rather than start writing prescriptions for cheaper, but equally effective generics. In other words, a massive rip-off.

Pfizer Assessed Record Fine--Why We Need a Reminder of Our Mission

The AP has released the details of the record $2.3B fine assessed against Pfizer for off-label marketing of Bextra and other drugs:

Readers of this blog, all half dozen of you, might be wondering what my reaction to this news is. A few more recent readers of the blog might imagine that I'd be chortling about the evil drug industry finally getting their just desserts.

So it may be time to stop, take a deep breath, and remind ourselves of why we are here. As the old saying goes, we have been up to our ass in alligators for a good while now--anyone recall which swamp we came to drain?

One major point to be followed by a minor point.

Major point: My purpose in writing HOOKED and later in starting this blog has never been to vilify the pharmaceutical industry. I take for granted that we live in a capitalist society and that in such a society it is a good thing to make a profit by selling products or services that people want. Moreover, the drug companies could have chosen to be Philip Morris, or run gambling casinos. Instead they have chosen to try to make a profit by selling substances that can contribute, sometimes in very significant ways, to improving human health. They have also undertaken some degree of risk by not only selling old substances but trying to discover new, helpful and safe substances. All that is behavior ideally to be rewarded and honored.

Like most institutions that intend to do good, the drug companies also occasionally do wrong. When they do so, we should make note of it and there should be appropriate consequences. The new $2.3 hit on Pfizer is presumably such an instance of serious wrongdoing that we hope is being appropriately punished. (You might argue that for the major players in the U.S. drug industry, even $2.3B is peanuts, but that is another discussion.) But that is a very different matter from saying that an entire industry, and the people who work for it, are all evil.

This blog exists for an entirely different reason--to hold an ethical mirror up before the medical profession and to ask what our relationship is and should be with the pharmaceutical industry. When we became doctors, we did not get up and swear an oath to maximize sales and profits. We got up and took an oath to put the patient's interests, and by implication the public's health, ahead of our own. To what extent, then, can professionals be true to that oath and still engage in activities that suggest a very close tie with the interests of the pharmaceutical industry?

After doing the 6-7 years of research that went into HOOKED, I concluded that physicians lining their stomachs and pockets with the largesse frequently provided by the industry was behavior ultimately inconsistent with that professional obligation. I concluded that this did not mean, "medicine = good, pharmaceutical industry = bad." Rather it meant: "Medicine and pharmaceutical industry = different interests." There may be a significant conflict of interest between what is good for drug company sales and what is good for the public health. This conflict is not ubiquitous; but it occurs often enough so that it is an important feature of the ethical landscape. That led me to conclude that how physicians relate to the industry should be reformed in major ways--some of which, since HOOKED was published 2-1/2 years ago, have actually come to pass.

In passing I will note that this is one of the biggest bones I have to pick with the ACRE crowd as discussed in a number of previous posts. My ability to say that I am not accusing the drug industry of being evil, just pointing out that the professional ethics of medicine requires that we not identify our interests with theirs, depends totally on the ethical meaningfulness of the idea of conflict of interest. ACRE has been doing its level best to trash that idea--to say that if you see COI at the medicine-Pharma interface, you are either prejudiced, or logically muddled, or envious. If I did not have the concept of COI to employ as an ethical tool, then I would be forced into the silly position of arguing, "medicine = good, pharmaceutical industry = bad." Myself, I would rather have COI.

So when I read about the $2.3B Pfizer fine, my question is--where and how were the docs involved? What role did we play? It would be wrong if Pfizer ended up with egg on its face and the docs who all made this possible--the hired shills/speakers, the "key opinion leaders," the researchers all too happy to spin or doctor the research data, the docs who put their names on ghostwritten articles if there were any-- walked away smelling like roses.

OK, are we clear now on what the basic issues are?

Minor point--at the risk of appearing to contradict what I have just said at length, I will focus on one sentence out of the AP article. I mention it lest you think I was being overly critical of the industry in a recent post (yesterday to be precise) when I wrote the following:

Even as far back as 1984, before the really cutthroat era of marketing competition we have seen since then, we did not have an industry that aimed to keep well within the bounds of law and ethics, and where only a few bad apples transgressed. Instead we had an industry, and apparently still do today, where skating as close to the edge of the ethical and legal thin ice as possible is the day-to-day business plan. When a skater falls through the ice we cannot dismiss it as an unfortunate aberration. We must see that this is a predictable outcome of deliberately chosen corporate strategy.

We now read from the AP that part of the reason the Pfizer settlement was so high compared to previous legal penalties was that Pfizer was viewed as a repeat offender:

"Mike Loucks, the U.S. attorney in Massachusetts ... said that even as Pfizer was negotiating deals on past misconduct, they were continuing to violate the very same laws with other drugs."

I rest my case.

Tuesday, September 1, 2009

Hooked: One of 10 Top Healthcare Investigative Blogs?

Ordinarily I ignore the occasional awards that come our way out of the blogosphere as most of them seem to be advertising come-ons. But this award seems thoughtful and considered:

I post it here not mainly to take credit but in case you wanted to check out which other blogs got the award too.

Some Great Ghostwriting Quotes

Thanks to Margaret Soltan's academic blog:

...we have some great quotes related to ghostwriting. First, reportedly said by Mina Dulcan, the editor of the Journal of the American Academy of Child and Adolescent Psychiatry, two years ago to the BBC, after being told that a paper she had published was both ghostwritten and contrary to the known data: “I don’t have any regrets about publishing at all. It generated all sorts of useful discussion which is the purpose of a scholarly journal.”

Gloria Bachmann, a professor of obstetrics and gynecology at the Robert Wood Johnson Medical School in New Jersey, defended appending her name to a ghostwritten article to the New York Times: "This is my work, this is what I believe, this is reflective of my view.”

That in turn led to a comment on the blog: "I would like to go on record for the first time and declare that I am the author of Moby-Dick. It is what I believe. It is reflective of my view."

Fairness in Enforcing COI Regs by Journals, and Many Other Things Also

Warning: Long post; may be sleep-inducing. Read at bedtime if insomniac.

Laurence J. Hirsch, MD used to manage the Medical Communications Department for clinical research publications at Merck (2001-2006). He now works for a device company. This post concerns a paper he just published in the Mayo Clinic Proceedings:

To give some more background, I have previously blogged about Association of Clinical Researchers and Educators (ACRE), for instance, The paper by Hirsch was presented at ACRE's inaugural meeting in July, so you can see it reached print in nearly record time given the glacial pace at which most medical journals operate.

The general gist of Dr. Hirsch's paper is that if medical journal editors are going to demand certain measures in response to financial conflicts of interest (COI) from people associated with the drug industry, they should demand equal obedience from those with other, non-pharmaceutical COIs. The specific grievance he seems to have in mind is the paper by Ross et al. on ghostwriting--which by the merest chance deals with events at Merck that were presumably under Dr. Hirsch's direct supervision when he worked there.

The Ross paper disclosed the fact that the information on ghostwriting related to Vioxx was obtained from the discovery process in lawsuits against Merck for heart disease deaths blamed by victims on taking Vioxx. A couple of co-authors admitted to receiving money from plaintiffs' attorneys for their work on these lawsuits.

Dr. Hirsch states that by the standards commonly applied to pharmaceutical COI, this is very inadequate disclosure. One co-author, David Egilman, has, according to Dr. Hirsch, earned $20-25M in his 20-year career of offering expert testimony on behalf of plaintiffs' attorneys. He allegedly reported that he had testified on matters as diverse as asbestosis, suicide risk with SSRIs, and silicone breast implants. This range of testimony certainly raises the possibility that Dr. Egilman would be considered what is contemptuously referred to in medical circles as a "hired gun."

I said: raises the possibility. The other possibility is that Dr. Egilman does in fact possess a wide enough range of expertise to legitimately be considered an expert witness on diverse drugs and risk factors. When we find out that he holds an MPH degree as well as an MD, and works on health policy, environmental health, and occupational health issues at Brown University, we can see that he might in fact qualify. That being admitted, I still think that $25M is a lot of bread.

Another co-author, Krumholz, had received reportedly some $300,000 for consulting with plaintiffs' attorneys on matters specifically related to Merck and Vioxx.

Now, so far, Dr. Hirsch is in my view on solid ground. I think it matters whether a person who consults with a drug company made $100 or $1M. The higher the number, the more likely it is given human psychology that the person will come to identify the company's (or the attorneys') interests with his own. If I have made $25M in my lifetime claiming that large corporations are evil, then I will certainly have a hard time dispassionately weighing new evidence that might show that they are not that bad after all. Sauce for the goose, sauce for the gander--if such disclosure is expected for Pharma hangers-on, same should be true of financial COI from other sources, including tort lawsuits.

You might notice that Dr. Hirsch's paper runs some 11 pages. You might wonder--the point I conceded above to be a solid point could be expressed very well in 2 pages. So what else does Dr. Hirsch have to say to illuminate the thorny issue of COI?

The fact is that the remainder of the paper, so far as I can discern, is a diffuse mishmash of non sequiturs and vague fingerpointing. I'd bore you to death with a complete rundown so just a couple of examples.

Early on Dr. Hirsch offers what appears to be the mantra of ACRE: the pharmaceutical industry has recently lost respect among the U.S. public due to "[a] small number of highly publicized incidents." In other words, COI is no big deal really; if you could just have weeded out a handful of bad apples, the rest of the industry has a spotless reputation, and academic docs could stuff their pockets with Pharma largesse guilt-free.

Two replies to the ACRE mantra--first, if true, it would undermine the one other part of Dr. Hirsch's article that makes some logical sense, the recommendations at the end where he proposes some Pharma business reforms. His proposed reforms would be completely unnecessary if the trouble was limited to a few bad actors.

Second, as I have detailed at length in HOOKED and later on this blog, the "few bad apples" defense simply rings false when compared with the facts. Rather than repeat all of HOOKED here, I will simply remind readers of one source that I cited--John Braithwaite, an Australian sociologist, who published a book, Corporate Crime in the Pharmaceutical Industry, way back in 1984, well before Vioxx and similar recent scandals. Consider the title of his book, which was a scholarly tome not intended for the mass paperback market. Not corporate unethical behavior or corporate misdeeds but crime. One of the revelations Braithwaite offered was that he had interviewed several corporate VPs at various firms who informally bore the title, "vice president in charge of going to jail." The "post" existed because the company had deliberately configured lines of authority and responsibility in such a way that the buck stopped with that VP, in the event the ongoing criminal activities of the firm should ever come to light and be investigated; and this VP received a compensation package that accommodated the extra personal liability he was placed under as a result. (Footnote: This "post" later disappeared as a result of major court rulings that held that it would be the CEO, not some underling, who would go to jail in such circumstances.)

I tell that anecdote from Braithwaite to make a simple point. Even as far back as 1984, before the really cutthroat era of marketing competition we have seen since then, we did not have an industry that aimed to keep well within the bounds of law and ethics, and where only a few bad apples transgressed. Instead we had an industry, and apparently still do today, where skating as close to the edge of the ethical and legal thin ice as possible is the day-to-day business plan. When a skater falls through the ice we cannot dismiss it as an unfortunate aberration. We must see that this is a predictable outcome of deliberately chosen corporate strategy. (Hirsch insists in a couple of places that the rules on ghostwriting have substantially changed for the better in the last few years, and that we are now seeing scandals left over from 1995 and 2000, which are really old news and no longer pertinent. Maybe so. But how would we know, when the industry continues to handle its internal affairs in such a secretive way, that evidence of bad behavior, if there is any, only pops up when the firm is sued for damages and courts force the discovery of internal memos?)

Just to give one more example of a non sequitur, Hirsch mentions at one point that of about 20 Vioxx lawsuits against Merck, so far, plaintiffs have won only 3. Hirsch asks how this could have been the case if "Merck's conduct was anywhere near as egregious as depicted by ...authors". What does it take to win a tort lawsuit against Merk over Vioxx? One has to show that one's heart attack or stroke was caused specifically by Vioxx and could not have sprung from other causes. Anyone who has passed the most basic course in biostatistics knows that we can have highly certain knowledge that a drug (let's say) increases the risk of dying from a heart attack by 2, 3, or 10-fold, and yet never be able to say in any individual case that a drug was the cause of that patient's heart attack. Indeed if we are to be astounded at all, it is that even 3 plaintiffs won.

So anyway, if you are still awake, we have to explain why a journal such as the Mayo Clinic Proceedings published an 11-page paper that makes a couple of valid points that could have filled a long letter to the editor, and where the remainder is illogic and innuendo for the most part. This is especially odd when we learn from the editor of the Proceedings, Dr. William L. Lanier, that the journal has not solicited any papers specifically on the topic of COI, but has only published such papers when they have passed "the journal's stringent peer-review standards." I suggest that you read Dr. Lanier's editorial that accompanies Dr. Hirsch's paper:

In my humble opinion, you'll see where the journal's "stringent" standards come from. Dr. Lanier's editorial is 6 pages, relatively long for a typical medical journal editorial. It contains much of the same sort of rambling innuendo with a minimum of logical argument as does Dr. Hirsch's original paper, so that at several places I had to scratch my head to determine just what point Dr. Lanier was trying to make.

This post is already way too long, but as my charge against Dr. Lanier's editorial skills is serious, I feel obliged to offer at least one back-up point. Lanier says: "One wonders what the ghosts of Mayo Clinic greats Drs Edward Kendall and Philip Hench [winners of the 1950 Nobel Prize] would think of the current situation in which industrial affiliation in virtually any form places an investigator and his or her published material under suspicion. Working in concert with Merck & Co during World War II, Kendall and Hench's research eventually led to the discovery and clinical introductioon of cortisone."

Yes, indeed, one wonders; and so I for one would like to consult the historical record. Did Kendall and Hench put their names on articles actually written by hired PR staff at Merck? Did they conspire with Merck to suppress the publication of data that might later hurt cortisone sales? If they did none of those things then I would hope we'd say that collaborating with industry meant something different in the 1940s than it does today. If they did some of those things, I'd hope we'd put an asterisk next to our admiration for them (as I suggested in HOOKED we must do with Soma Weiss, another research great of that era).

But, geez Louise, guys, let's face up to the basic point we keep coming back to--if the drugs being discovered and aggressively marketed by Big Pharma today were cortisones rather than Vioxxes, we wouldn't be having this conversation at all.

Addendum 9/2/09: In the post above I tried to give Dr. Hirsch the benefit of the doubt by assuming that when he claimed that Drs. Krumholz and Egilman had received major sums from tort lawyers, at least he had his facts right. I was careful however to hedge my language as I had not had the opportunity to do any independent fact checking.

I have now been contacted by Dr. Krumholz who told me: "just FYI – the claim that I made over $300,000 is not accurate – and was never checked with me – and is not supported by the reference." I was also contacted by another party that wishes anonymity, but who offered some detailed background that suggested that the claims made about Dr. Egilman were also inaccurate.

Now, as I said in the post, I grant the basic conceptual point that Dr. Hirsch made, which is that a COI involving taking money from drug companies should be handled the same as a COI involving taking money from tort lawyers. But that assumes that Dr. Hirsch has his facts straight. If he does not, and he has simply maligned Drs. Krumholz and Egilman without just cause, then of course the sins of which he is guilty go well beyond writing a rambling article. If that should turn out to be the case--again I stress that I have done no independent fact checking--then I add my own apologies for being a vehicle of spreading the misinformation.