Tuesday, June 30, 2009
Two bills, from Vermont and New Hampshire, that would restrict medical information companies from using physicians' prescription data and selling the data to drug companies to assist with marketing (as when the drug rep goes into the doc's office knowing exactly how many prescriptions the doc has written for the company's drug and all competitor drugs), have been essentially on hold as the court system decided what to do about them. The U.S. Supreme Court has now refused to review the New Hampshire law; and a New York federal court has refused to issue an injunction against the Vermont law, which goes into effect tomorrow.
The laws basically hold that physicians' prescription data are confidential and you cannot sell them without the physicians' permission. The rulings are a defeat for the pharmaceutical industry which relies heavily on these data sources--not to mention the commercial outfits that sell the data for megabucks. Prescription Project offers a fact sheet on the data mining issue at: http://www.prescriptionproject.org/solutions/rrf?id=0001.
Carlat, Bremner and colleagues have for some time been deeply suspicious of the process being used by the American Psychiatric Association (APA) in coming up with the current revision of its Diagnostic and Statistical Manual (DSM-V). DSM is huge--it essentially controls psychiatric diagnosis, which in turn controls insurance payments for psychiatric care. The charge from some quarters is that the process has been unduly secretive and that voices critical of some of the measures being considered are excluded.
This is the sort of in-house tiff that non-psychiatrists could be forgiven for yawning at, and who's to say who's right in this sort of back-and-forth, right? Well, Dr. Carlat tells us that the tiff has now degenerated into a brawl, and that the implications are huge for the role of the pharmaceutical industry in mental health.
The trigger for this latest round of pleasantry is an editorial in press at the Psychiatric Times by Dr. Allen Frances: http://www.beforeyoutakethatpill.com/2009/6/Frances_DSM-5.pdf. Dr. Frances was the head of the APA task force that produced the last revision of the manual, which you'll be astounded to learn is called DSM-IV. (Actually there is also a DSM-IV-R but let's not go there.) He offers a thoughtful, well-reasoned and well-documented critique of DSM-V to date. His main criticism is that the DSM-V people have been not at all shy in proclaiming that their edition will revolutionize psychiatric diagnosis, preparing the world for a sea change between the fourth and fifth editions. Dr. Frances asks: And this sea change in diagnosis will be based on exactly what new scientific discoveries? Exactly what have we learned about the nature, causes, and treatment of psychiatric disorders in the last decade that merits turning the old diagnostic categories on their heads? Well, actually, hardly anything at all.
I happen to agree with Dr. Frances that psychiatry has been afflicted with this dearth of new knowledge, which in part explains why recent generations of psychiatric drugs end up looking much worse than they were touted to be when first introduced, as we have documented ad nauseam in this blog. But of special concern to us is how Dr. Frances characterizes the unintended consequences of the announced directions DSM-V is taking. Here are some key passages from his editorial. First, he mentions that even careful preliminary field studies often underestimate how small changes in diagnostic criteria can have a huge impact on the numbers of cases diagnosed: "Thus are false 'epidemics' created.... This issue becomes especially poignant when one considers the great and skillful pressure that is likely to be applied by the pharmaceutical industry after the publication of DSM-5. It has to be assumed that they will attempt to identify every change that could conceivably lead to a marketing advantage--often in ways that will not have occurred to the DSM-5 Task Force. In order to promote drug sales, the companies may well sponsor expensive 'education' campaigns focusing on the diagnostic changes that most enhance the rate of diagnosis for those disorders that will lead to the increased writing of prescriptions."
Dr. Frances goes on: "Undoubtedly, the most reckless suggestion for DSM-V is that it include many new categories to capture the milder subthreshold versions of the existing more severe official disorders. The beneficial intended purpose is to reduce the frequency of false negative missed cases, thus improving early case finding and promoting preventive treatments. Unfortunately, however, the DSM-V Task Force has failed to adequately consider the potentially disastrous unintended consequence that DSM-V may flood the world with new false positives. ... The result would be a wholesale imperial medicalization of normality that will trivialize mental disorder and lead to a deluge of unneeded medication treatments--a bonanza for the pharmaceutical industry but at a huge cost to the new false positive 'patients' caught in the excessively wide DSM-V net."
Well, Dr. Frances' criticisms of the Task Force did not sit well in the halls of the APA, and so before the editorial was even published, an APA rebuttal was sent out over the signature of the President, the chair of the Task Force, and other worthies (http://www.scribd.com/doc/16953085/PsychTimesFrancesResponse-062909-FINAL). The rebuttal basically denies the truth of most of what Dr. Frances says, especially about the secretive and closed nature of the DSM-V process. (More on that a bit later.) But what seems quite rich, and prompted Dr. Carlat's "brawl" description, was the way that the APA leaders tore into Dr. Frances's reputation. Dr. Frances, as the above quotes indicate, leaned over backwards to avoid impugning the motives of the Task Force; he spoke over and over of "unintended" consequences, and did not accuse anyone in the Task Force of actually having conflicts of interest with the pharmaceutical industry. In reply, the APA leaders directly accused Dr. Frances of writing his editorial due to his own financial conflict--they claimed that he was about to lose income as the author of a guidebook to the old DSM-IV, and so that was what prompted both the content and the timing of his criticisms.
As Carlat points out, this is such obvious balderdash that it is astounding that anyone in organized medicine could imagine for one minute that this charge would win them any debating points. Like, it was only one day a week ago or so that Dr. Frances woke up and suddenly said, "Omigosh, I'm about to lose all my royalty income because once they publish DSM-V, no one will want to buy my guide to DSM-IV any more"? Like the psychiatric community has not known for years that DSM-V was coming? Plus book authors like me well know how close royalty income on even highly successful books approaches the sums that paid consultants to the drug industry routinely take home.
And just who is making this accusation of financial conflicts of interest against Dr. Frances? Lead author is the APA President, Dr. Alan F. Schatzberg. Does that name ring a bell? How about our previous posting, http://brodyhooked.blogspot.com/2008/08/how-conflicts-of-interest-poison.html? And it's this pot that is calling the kettle black?
I promised one additional comment about the secrecy issue. It turns out that one way that the DSM-V Task Force has imposed secrecy, according to the critics, is by getting members to sign nondisclosure statements. The APA rejoinder is that, "'Confidentiality Agreements' Frances and his colleagues cite as evidence of secrecy around DSM-V Task Force are in reality legal documents designed to protect intellectual property. Attorneys for the APA worked with the DSM-V Task Force and Work Groups to develop these agreements to protect the work product of these volunteers." Dr. Frances reports that at no time during the creation of DSM-IV was it found necessary to resort to such "confidentiality agreements."
My question is a simple one. When I read a statement like the above passage from the APA leaders, I would not be at all surprised if I were reading a document produced by private industry, worried about protecting its property and its profits above all else. I would, however, be a bit surprised to see the same language emanating from a professional society whose purported aim is public health and service. Am I the only one who thinks the line between these two types of enterprises has become way too blurred?
Monday, June 29, 2009
Here's the short version:
- Advanced Medical Optics, later acquired by Abbott, made a contact lens solution.
- The solution was pulled in 2007 after a CDC investigation linked it to cases of a rare, serious eye infection, Acanthamoeba keratitis, resulting in at least 70 claimed cases of blindness or permanent vision damage.
- The company had at least 9 complaints, that it failed to report to the FDA, during the year prior to the solution's removal from the market. When FDA inspectors showed up at the plant to investigate the product recall in June, 2007, they then discovered the complaint letters.
Here is the kicker. When asked why they had not sent reports of the complaints to the FDA as required by law, the company replied that as they had never claimed that the eye solution protected users against Acanthamoeba infection, they were under no legal obligation to report these complaints.
To which I offer two responses.
I'm not a lawyer but I play one on TV. (Actually I don't.) If I did, my lawyer-character would offer the opinion that U.S. law requires that drugs be both safe and effective. The law requiring that they be safe actually dates back to the original FDA act of 1906, while the requirement that they be effective only goes back to the 1962 amendments passed post-thalidomide. What you claim on the drug's label has a lot to do with the question of whether a drug is effective (for the indication claimed). It has nothing to do with whether a drug is safe. By contrast, a company's legal duty to report complaints of adverse reactions to the FDA is part of the FDA's duty to monitor a drug's safety. So to compare labeling with a duty to report adverse reactions is to compare apples and oranges.
My next response is more important. The Korean branch of a major drug company recent got a sort of skunk cabbage award within the business community when its CEO replied to a group of AIDS activists complaining about the high cost that made one of its HIV drugs unaffordable, that the drug company was not is business to save lives but to make money. This is something that most companies believe, and act like, but not something that most companies say. With Advanced Medical Optics, we now have another example of a firm that is so twisted in its thinking and behavior that it will say flat out that it has no business whatever assuring that people who put its solution into their eyes do not go blind as a result--so long as the money rolls in. Those who still believe that our salvation lies in the unfettered free market please raise your hands.
Thursday, June 25, 2009
The Columbia Journalism Review, as part of its health reform coverage, offers an interview by Trudy Lieberman with former and now recovered health insurance executive Wendell Potter:
I can give you the flavor of the interview if I repeat Potter's statement about how he came to decide it was time to abandon his industry post:
"A couple of years ago I was in Tennessee and saw an ad for a health expedition in the nearby town of Wise, Virginia. Out of curiosity I went and was overwhelmed by what I saw. Hundreds of people were standing in line to get free medical care in animal stalls. Some had camped out the night before in the rain. It was like being in a different country. It moved me to tears. Shortly afterward I was flying in a corporate jet and realized someone’s insurance premiums were paying for me to fly that way. I knew it wasn’t long before I had to leave the industry. It was like my road to Damascus."
If that is not a powerful statement about the state of American health vcare--a scene that Michael Moore would have given a lot to include in Sicko--I'd like to know what is.
Potter is not a great fan of the insurance industry. He recounts the strategies that the industry used in 1993-4 to kill Clinton health reform, and how they are positioning themselves in 2009 once again to kill any reform that does not send huge profits in their direction. Highlights:
- These companies are for-profit firms and are slaves of Wall Street. Anything that would actually enhance health care for the U.S public is of no interest to their shareholders. Anything that would increase profits is--even if it means denying care to the sick. That's the top, bottom, and middle line.
- Insurers will out out a PR blitz as to how socially conscious and pro-reform they are. They will then set up a shadow campaign, run by middlemen posing mostly as grassroots organizations that have no ties to the industry, designed to kill any real reform. What they say publicly and what they are trying to do behind the scenes will be two different things.
- We saw the insurers recently in their true colors when they went before Congress and refused to rule out cancelling a person's policy if the individual develops serious and costly illnesses. If they can go over that policy with a fine tooth comb and find a single thing that person failed to fill out correctly when she applied for insurance, then the policy will be cancelled and that person will be without coverage henceforth (since any new policy would be prohibitively costly). It makes no difference if the single thing that was accidentally left out is irrelevant to the later illness; any excuse to cut costs will be ruthlessly taken advantage of.
- When a bill is finally under consideration in Congressional committees, then we can expect the insurance lobby to go even deeper underground, and even the "grassroots" PR will not reveal the true negotiations that are going on behind closed doors. The industry has lobbying muscle on both sides of the aisle, enough, they hope, to insure that any bill unfriendly to insurance interests will die a quiet death out of public sight.
I wish everyone in the US would read Lieberman's interview with Potter, in my role as a member of Physicians for a National Health Program. There is really only one conclusion a smart reader can come to after reading that interview--these people cannot be trusted. Any attempt at health reform that allows these folks at the table is a sham. The single payer advocates, who say that we must get rid of private insurance and basically start over, are right, however politically inconvenient their message may be. The politicians who have said that single-payer is off the table, period, from the start are in fact doing the bidding of the health insurance industry, and are would-be reformers in name only.
Tuesday, June 23, 2009
Short version: a pair of stars has signed on to do a move based on the book Hard Sell by Jamie Reedy, former Pfizer drug rep, describing his experiences marketing Viagra.
When I was writing HOOKED, I did cite Reedy's book, in large part because it offered a very rare look behind the scenes at the drug rep's workaday world. I tried, however, to rely on it as little as possible because Reedy made it clear from the get-go that he was an atypical drug rep. I assume that the average drug rep is a hard-working individual who wants to succeed at her chosen career--however unfortunate, in my view, the impact of that career is on the medical profession (which should stand up for its own ethical values, and not blame the drug reps it if has trouble doing so). Reedy, by contrast, made his goals quite clear in the early pages of his book--he wanted to get as much money from his employer in exchange for doing the least possible amount of work.
Maybe Reedy was creating a literary persona to make his story more fun to ready, but bottom line was that he seemed to be such an all-around sleazeball that I could not be sure whether to believe anything he wrote--hence my decision to quote only those few aspects of his book that seemed to rely only on solid facts.
From Pfizer's standpoint, the bad news is that they are making a movie based on this guy's book (the guy whom Pfizer fired as soon as they found out about the book). The good news is that from the fluff piece about the movie, the film will have virtually nothing at all to do with the book. I personally recommend not seeing it, even though the photo provided of the prospective female lead is quite fetching.
One question was: Given that drug firms in the US spend around $4B annually on direct-to-consumer ads, where does Rep. Rangel get the idea that he can come up with $37B in tax savings, to help finance health reform, by ending this deduction? My own guess was that these are 10 year projections, the usual coin of the realm in discussing health reform, and that assumes that the industry gets to deduct nearly the entire cost of ads. Thomaselli's take:
"There seems to be some issue as to where the $37 billion tax figure comes from, considering the pharmaceutical industry spent $4.7 billion on DTC advertising last year. It is likely Mr. Rangel is referring to total sales costs, costs for sales representatives, free samples and more."
The next question--exactly where did this tax deduction come from in the first place? Us pharmaskeptics were prepared to learn that somehow Congress had been lobbied into passing a special tax exemption for the drug industry only--though I had to admit being ignorant, myself, of any such action. Thomaselli fills us in:
"Dick O'Brien, exec-VP-director of government regulations for the 4A's, said advertising for any product is fully tax deductible as a necessary business expense. Mr. Rangel's proposal would eliminate the tax deduction for one product category, prescription medications, in effect making it more difficult and more expensive to advertise than another category."
So if that account is true, then it appears that Rep. Rangel is not proposing to repeal a special tax deduction enjoyed by the drug industry alone, but rather to exclude the drug industry from a general business deduction now enjoyed by all manufacturers. If so then the road toward enacting this plan would seem to be much steeper, especially given the fact that the media, who enjoy the advertising fees paid by the drug companies for those ads, are now squawking loudly about this proposed taxation.
Thursday, June 18, 2009
Why are you making such a big deal about industry sponsorship of research? It must be fairly easy to read a medical journal article, assess the methods employed, and decide that a study is of good or poor quality--that one can or cannot trust the findings. Isn't that the key variable--that one can or cannot trust the findings--rather than whether or not the study was sponsored by a drug company?
For this reason I feel justified in placing on record a case study, showing just how far one often needs to "drill down" to discover the evidence of bias in a commercially sponsored research publication. For this example I must thank my friends Rick Bukata and Jerry Hoffman and their excellent audio service, "Primary Care Medical Abstracts."
For their May, 2009 issue, Rick and Jerry discussed a paper by Ho et al. in Lancet (a top tier journal, which would lead some to imagine immediately that no possible skullduggery could have made it past the distinguished editors of this journal). The basic idea here is that Merck (who funded the study and whose role is clearly labeled in the paper) has an investigational drug for migraine headache that is in a new class, calcitonin gene-regulated peptide receptor antagonists. Merck obviously hopes that this new medicine, when approved, will quickly become the preferred therapy for migraine in place of the older standbys, the triptan drugs, which are currently going off patent and becoming cheaper.
The study was set up to compare two doses of the new drug, called telcagepant (we assume Merck will think of a melodious brand name instead of this nearly-unpronounceable generic name), the older standard drug, zolmitriptan at maximum recommended dose, and placebo. They looked at a variety of migraine symptoms at both 2 and 24 hours after the initial drug dose.
How did the drugs compare? Here's how the authors of the paper reported their outcomes in the abstract (the only part of the paper that many busy clinicians ever read): "Telcagepant 300 mg is effective as an acute treatment for migraine with efficacy comparable to that of zolmitriptan 5 mg, but with fewer associated adverse effects." In other words the new drug is clearly better than the old drug.
The abstract prepared by the Primary Care Medical Abstracts team expressed the same data but with a more cautious spin: "In this study, a 300mg dose of...telcagepant was not more effective that zolmitriptan for the treatment of acute migraine."
But to get the full story we needed to wait till Jerry Hoffman had his say on the audio disk. Jerry pointed out a feature of the study design that was not mentioned in the abstract at all, and that was only discussed in the methods section and in Figure 1. The study design called for the option for any subject to receive a second dose of medication at 2 hours past the initial dose, if needed. This feature makes sense because migraine headaches often rebound within the first 24 hours or are not completely relieved by the first medication dose, or both. If the subject was assigned to the placebo group or the zolmitriptan group, the second dose would be placebo. If the subject was assigned to either of the telcagepant groups, the second dose was randomized, half the subjects getting a second dose of telcagepant, the other half getting placebo.
Now, stop and think. Can you imagine any legitimate scientific question that would be answered by having the study design as described? I cannot imagine one. I have to conclude that this study design must have been selected purely for its marketing impact, and not as a way of doing science.
So you can see that the playing field was not level--as Jerry pointed out. A single dose of zolmitriptan was being compared to the possibility of repeated doses of telcagepant. (In actual fact, about half of all the subjects required a second dose, so a total of a quarter of the telcagepant subjects got a second dose of an "active" drug instead of placebo.)
This understanding of the true study design puts quite a different spin on the reported outcomes. What if half the zolmitriptan subjects, who needed a second dose, had been given a second dose of zolmitriptan? Would telcagepant still have been "as effective as" zolmitriptan--or would the older standby drug, and the soon to be the probably much cheaper drug, have proven superior?
You can pretty much answer this question for yourself by studying the finer details of Table 3. Efficacy for each study endpoint was expressed as a percentage of subjects who achieved the target outcome. In almost every single category, at 2 hours, the percentages reaching target were higher for zolmitriptan than for either dose of telcagepant, with the single exception for phonophobia (being bothered by loud noises). In photophobia (being bothered by bright light), the higher dose of telcagepant was slightly better than zolmitriptan (51% vs. 50%). For example, a secondary endpoint, "total migraine freedom [at] 2 hr" was achieved by 22.9 % of the higher-dose telcagepant group, and by 27.2% of the zolmitriptan group. The only endpoints for which there was any superiority for telcagepant were those endpoints that looked at sustained effects over 24 hours--where, as we saw, the playing field was not level and a quarter of the subjects in the telcagepant groups got an extra medicine dose. Even there, the differences were nothing to write home about--for "2-24 h sustained pain freedom," 20.2% of the higher dose telcagepant group, vs. 18.2% in the zolmitriptan group.
Exactly how did the methods section of the paper explain the strange methods, by which one active medication group got a second dose that was denied to the other? Here's what Ho et al say: "The efficacy of the optional second dose is not discussed here since the sample sizes were limited. A prespecified meta-analysis across all of the telcagepant phase III studies is planned to address the therapeutic effect of the second dose." Pardon my cynicism but I interpret this statement as: "We won't report the role of the second dose in skewing the study findings now, because then the reader might actually put two and two together. Instead we'll report them (if we ever get around to it at all) separately at a later time, when we hope you'll have forgotten about the issue, and when we can put a favorable spin on whatever we find one way or another." As I have demonstrated, even without an explicit report from the authors, the raw data in the tables, which the average reader would never bother to look at, hint very strongly that the optional dose at 2 hours skewed the results in favor of telcagepant--and without that skew, the expensive new drug would in all probability not have performed as well as the older and cheaper drug.
I know I put you to sleep a long time ago. My take home message is very simple--this is often how carefully you have to read a published article in a medical journal to be sure you have detected any bias that apparently was introduced by commercial sponsorship. And that, in turn, is why commercial bias and conflict of interest is such a plague on scientific medicine.
Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomized, placebo-controlled, parallel-treatment trial. Lancet 372:2115, Dec 20/27, 2008.
The AMA's Council on Ethical and Judicial Affairs (CEJA) came out with a report on the funding of CME programs by industry that seems to have attempted to Solomonic task of cutting the baby in half to satisfy the warring factions. The AAFP president spoke in favor of the CEJA report, but ultimately the AMA's House of Delegates returned the report to CEJA for some fine-tuning before it could be adopted.
The Solomon business consisted of developing two categories: "ethically preferable" and "ethically permissible." In a nutshell, "ethically preferable" corresponds to what in HOOKED I called the divestment strategy, of getting financial conflicts of interest out of CME, period. That strategy also happens to match what the recent IOM report called for in CME funding. "Ethically permissible" corresponds to an optimal management strategy, allowing some conflicts of interest and attempting to create strict rules and firewalls to control them.
Critics of the report immediately pointed out that CEJA had never previously issued a report with these two categories before. The thrust of the testimony against the report appeared to focus on the heavy dependence that CME programs now have on industry funding. In reply, Richard Frankenstein, a pulmonologist and past president of the California Medical Association, said that physicians should get into the habit of paying for their own CME themselves, and realizing that industry would not fund CME unless they saw a direct dollars-and-cents benefit on their balance sheet. As best as one could intuit from reading this report, the delegates did not cheer wildly at that speech.
The article, adopting the reticent tone of most in-house medical journalism, steered clear of the critical question, "In sending the report back to CEJA for refinement s0-called, what changes did the majority of the delegates wish to see, really?" The final paragraph of the story gives the broadest hint--the delegates did not like the terms "ethically preferable" vs. "ethically permissible" because they suggest that one set of practices is ethically less good than the other. (Well, duh.) The delegates wanted to see a report that did not use those categories.
If CEJA cannot cut the baby in half and get off the hook that way, then what do the delegates want of them? Apparently it is not that they would state flatly that industry support of CME is unethical. So the only alternative would be to give the full ethical seal of approval to the status quo--where conflicts of interest are "strictly managed" and we continue to pay for more than half of all CME with industry money.
We bioethics folk have seen this move before. Every time CEJA acts responsibly and professionally (as they most generally do, having decent members and an excellent staff), and tries to call the medical profession to a higher ethical standard than commonly exists in the community, the House of Delegates is likely to take umbrage--"what! me unethical?" -- and force them to back off. Short version: don't expect real ethical insight about controversial aspects of CME any time soon from the AMA.
My own personal plea to CEJA would be not to "fine tune" the report and to let it die. If the House of Delegates in its infinite wisdom does not want ethics, fine--let them not have it. But don't pander to the bottom feeders by watering down the report even more.
Wednesday, June 17, 2009
The article provides no real background on the deduction, or the reasoning behind it, but makes clear that we are not talking about a brand-new tax but the repeal of an existing tax deduction. (I admit that I am not aware myself of most of the backstory here.)
Until such time as I am enlightened by those in the know, I will presume that we have here yet another case of the drug industry talking out of both sides of its mouth when it goes into propaganda mode. The industry takes every possible opportunity to wrap itself in the mantle of the so-called "free market." The industry also takes every tax deduction that it can get friendly legislators to grant it. A good source on the many tax deductions enjoyed by the industry is Marcia Angell's The Truth about the Drug Companies.
Tuesday, June 16, 2009
Background: The med students at AMSA get major credit for being the first medical organization to come out with a serious "Pharm free" campaign, at a time when most players on the academic medicine scene were still puttering on about the need to "manage" the "inevitable" conflicts of interest. It was a piece of political genius on their part to realize that there was no better way to get publicity for your cause, and to get the attention of the dean of a med school, than to assign that school an "F" grade on a "report card." A problem, however, was that the first report card was an impressionistic exercise and could easily be dismissed as full of observer bias. Now, enter the Pew Prescription Project. AMSA and Pew teamed up to create a sound methodology for the scorecard and provide a set of reasonably objective criteria.
The Prescription Project now notes with pride that the number of A and B schools has increased and that fully 30 percent of med students nationally are now receiving their education at A or B schools. My own state of Texas seems to get the "most improved" award, due to a couple of factors. There has been tremendous student grass roots effort, at my own school (UTMB) the work of the Pharmaceutical Awareness Group. Also, the UT System decided centrally a little more than a year ago that it was too embarrassing for all their schools to get Fs, and so pressure built on all medical campuses of UT to adopt a policy patterned after the strict policy at Stanford. (You'll see from the scorecard that the 4 Texas med schools that are part of the UT system have an A, two Bs and an I grade; the 4 that are not part of UT rank with a B, D, F, and I respectively.)
Overall she noted the pattern, that the AMA seems to be in bed with Big Pharma and the Republicans in opposing key aspects of the Democratic health reform proposals. The AMA indeed seems less interested in defending either health or medicine, and rather more committed to extolling the presumed virtues of the "free market." However, if you read the detailed AMA statement (to which she provides convenient links in her article) in response to the Senate Finance Committee, you'd see that in one key area, the AMA parts company with the drug lobby. Even the right-leaning ideologues who make up the leadership ranks of the AMA could not stomach the industry's position opposing comparative effectiveness (CE) research. Being, in the final analysis, physicians, they could not oppose a system that would perform scientific studies and inform them of what works and what doesn't.
Meanwhile, the Kaiser Daily Health Policy Report tells us today that the Republicans are pushing back harder against the Democratic bills, and that a ban on CE research is a key feature of the response bill that they are now offering:
This suggests both that the pharmaceutical industry has basically bought off the GOP lock, stock, and barrel and harnessed the elephant to its opposition of CE. The fearmongers are now working overtime to convince us that CE is a sneaky way for the government to take over medical care and "come between you and your doctor." It seems quite intriguing that CE research has zoomed to the top of the charts, right alongside a public insurance option, as the hot potato of partisan bickering over health reform--another sign of how successful Big Pharma's lobbying machine is in imposing the industry's preferred agenda on the entire political process.
Monday, June 15, 2009
Both in HOOKED and on this blog I have documented previous accusations of ghostwriting, so I'll try to comment here mostly on what is new. Of most interest perhaps is a guide called "Medical Press: Pre-Launch Feature Outline" (unfortunately, undated) which was an internal how-to primer on preparing ghostwritten articles. It covered both what the article should say to boost Zyprexa sales and how to find a compliant putative author to put his or her name on the final published paper. As the Bloomberg reporters recount, "The guide also offered tips on how to find authors by identifying a 'key opinion leader' and providing them either an outline of the article or a finished copy. Authors could include a study investigator, an advisory board member or 'Lilly-friendly' doctor, according to the documents."
The main importance of this passage is the frank admission that the puitative author might be sent a finished copy of the article. Up until now, the company and the putative author, when confronted, have routinely defended themselves by insisting that all that was provided by the company was a rough draft and that the author listed in the journal then made extensive changes in it. Even if that were true, it is still a violation of standard authorship ethics guidelines not to list to "ghost" author who actually wrote the first rough draft. But it is also more in keeping with the assertions of insider-whistleblowers like psychiatrist David Healy that in fact, few if any modifications to the draft are routinely made.
Sadly this "guide" does not state the going price paid to the putative author whose name appears on the published article. I have only been able to document payments of as high as $1000. Colleagues in the know tell me that figure is woefully low, but I still cannot find written documentation of anything higher. It's well documented that the "ghost" writer might be paid $20,000 for an article that is successfully placed in a top-tier journal.
Another insight is provided by a passage that recounts an exchange over a paper putatively authored by Dr. John Buse of UNC-Chapel Hill, a former president of the American Diabetes Association. The paper, actually authored by Lilly staffer Patrizia Cavazzoni, took issue with another paper that stated that there was a substantial risk of Zyprexa causing diabetes--the side effect (along with weight gain) that is today prompting the spate of lawsuits against manufacturers. The skeptical paper defending Zyprexa was submitted to the Journal of Clinical Epidemiology. When the paper was not promptly published, Lilly folks became concerned and in November, 2002, Lilly's senior scientific communications coordinator, Suraja Roychowdhury, wrote the journal. The editor, Andre Knotterus (here quoting the Bloomberg article) "replied in an e-mail that it was 'a bit strange to be contacted by the Lilly product team. Dr. Buse and coauthors can contact us directly next time.'"
Okay, let's get this straight. When journal editors are criticized on the issue of ghostwriting, they routinely reply that they are not private detectives, and that if Dr. Bigname sends them a paper and swears up and down that he actually wrote it himself, how is the poor little bitty journal to know different? So here, apparently, we have a paper submitted to a journal editor, and then a production team from a drug company calls the editor to complain that the article was not published as fast as their business plan called for. Instead of wondering, "Hmm, I wonder if this could have been a ghostwritten article, which good journal ethics requires that I refuse to print?" the editor instead says, "Next time, by the way, have the fake author send me the message instead." There is here at least the appearance of full journal complicity in the ghostwriting arrangement.
For the record, Dr. Buse denied to Bloomberg that he had ever put his name on an article that he did not write. He then proceeded to tell the reporters 1) that he had no recollection of who said what to whom regarding that particular paper on diabetes; 2) that his experience showed how biased an academic physician can become who works regularly for the drug companies; and 3) that in his opinion ghostwriting used to be very common but is becoming much more rare. I must say that for somebody who has never personally been involved in ghostwriting Dr. Buse seems to know a lot.
Finally the article makes the point that several of us critics of Pharma have stressed--we know of no case where an academic physician has been fired or has received any serious sanctions after being caught putting his name to a ghostwritten paper. Given that everyone agrees that ghostwriting is a clear and egregious violation of scientific publication standards, the current track record of academic medicine in policing itself is abysmal.
Contacted by the Bloomberg reporters, Lilly protested that its legal opponents in the current wave of lawsuits are cherry-picking damaging documents, quoting them out of context, and creating an erroneously negative picture of Lilly's corporate practices. There is of course the danger of this occurring whenever tens of thousands of pages of documents are released and reporters have to paw through the pile for the juiciest bits. That's why it is so important to know the background--what has been demonstrated in previous accounts of whistleblowing that are not dependent on this same stack of documents. As HOOKED and this blog will demonstrate, the facts contained in the Bloomberg News account are believable because reasonably consistent with what we have known previously about ghostwriting practices.
A tip of the hat to Roy Poses' Health Care Renewal blog for heads-up on the Bloomberg News article.
NOTE ADDED 6/15/09: The paper by Buse that I referred to above, on further inspection, turns out to fall very questionably under the "ghostwritten" category. John B. Buse is listed as the first author, but the Lilly staffer, Patrizia Cavazzoni, is clearly listed as the second author. The paper as a whole is also clearly labeled as funded by Lilly. If indeed the paper was primarily written in-house by Lilly staff, then the most serious ethical infringement was the listing of Buse as a first author.
Buse JB, Cavazzoni P, Hornbuckle K, et al. A retrospective cohort study of diabetes mellitus and antipsychotic treatment in the United States. J Clin Epidemiol 56:164-70, 2003.
Monday, June 8, 2009
Glen Spielmans, a psychologist at Metropolitan State University, St. Paul, is author of a paper currently posted ahead of publication on the Social Science & Medicine journal website (subscription required). He replies on internal company papers released through legal action to document the marketing scheme pursued by Eli Lilly in trying to get physicians, especially in primary care, to prescribe Zyprexa (olanzapine) liberally and far in excess of the labelled indications. As he points out, these off-label marketing schemes eventually netted Lilly a $1.4B fine, the largest corporate criminal fine in US history.
Lilly had high hopes for Zyprexa, at one point anticipating that annual sales could reach $10B. There were only two problems with their miracle drug. First, it did not work very well for many of the off-label uses for which it was tested, such as behavioral problems in dementia and mood disorders. For that matter, the original claims that Zyprexa, as a "second generation" antipsychotic, really worked any better than the old first generation drugs for any of the labeled indications (psychosis), were never well documented and recently have been largely debunked. Second, the claims of a wonderful safety record were undermined when it was finally revealed that the drug causes serious metabolic disruptions and weight gain in many patients, sufficient to cause the onset of diabetes in some.
Lilly targeted much of its off-label marketing at primary docs, knowing that they saw a large number of patients who are basically unfulfilled and unhappy, but who may not have a diagnosable mental disorder according to strict psychiatric criteria. The company prepared a number of patient vignettes its speakers and reps could present to docs. Each vignette was of a patient who had some mental symptoms, but was clearly not psychotic. Each was designed to suggest to the doc that a lot of patients who came though the door must have undiagnosed, serious mental disorders, for which she could both safely and effectively prescribe Zyprexa.
For example, consider "Donna," a mid-30s single mom, who on one visit complains of feeling anxious, irritable, sleeping more than usual, and having trouble concentrating. It's pointed out to the doc that several appointments earlier, "Donna" had been elated and talkative and reported little need for sleep. Though the severity of symptoms depicted in "Donna's" case falls far short of the official criteria for diagnosing bipolar disorder, the point of the vignette was to convince the doc that "Donna" had a significant, complicated mood disorder that could be successfull treated in the primary care setting with Zyprexa--with no need to refer to a psychiatrist for a formal diagnosis, presumably.
Without boring you with a lot more detail, I would suggest that there is only one possible conclusion a person could come to on reading the evidence that Spielmans has compiled from the legal record. None of this had anything vaguely to do with science or education. It most certainly has nothing at all to do with improving patient care. All of it had to do with selling a drug.
Why is any of this even worth mentioning, since by now we have heard this same sorry story so many times? A couple of weeks ago, Kris Hundley, reporter for the St. Petersburg Times, briefed us on a batch of internal company memos recently released in an Orlando court (http://www.tampabay.com/news/business/article1002805.ece). This time the company was AstraZeneca and the drug was Seroquel, another newer antipsychotic which also causes weight gain and diabetes. The AstraZeneca documents show a similar pattern of pushing off-label use and hiding unpleasant findings about side effects or lack of effectiveness from docs. But the most notable passage in Hundley's article was:
AstraZeneca marketers were jealous of what they saw as competitor Lilly's ability to cast questionable study results in a positive light. "They (Lilly) are able to spin the same data in many different ways through an effective publications team," according to a 2003 memo. "Negative data usually remains well hidden."
Way to go, Lilly--AstraZeneca admits that you were the leaders in the race to the bottom.
Spielmans GI. The promotion of olanzapine in primary care: an examination of internal industry documents. Social Science & Medicine 2009 (e-pub ahead of print; doi:10.1016/j.socscimed.2009.05.001).
Hundley K. Memos: results hidden to peddle antipsychotic. St. Petersburg (FL) Times, May 20, 2009.
According to this recent blog from Canada--
--the scandal is growing due to revelations that it wasn't just one fake journal. Apparently Merck had been working with the publisher Elsevier to put out an entire medical library of journals, in all relevant specialties, each one the "Australasian Journal of Such-and-Such." It seems now that Merck paid Elsevier to produce 9 of these fakes and planned an additional 13.
Non-medical people might be a bit puzzled by what is going on here so let me add some background.
In the 1940s and 1950s, direct mail was one of the major ways that drug firms advertised to doctors. Some of the direct mail ads took the form of newsletters or mini-magazines. These were clearly labeled by the name of the drug firm and everyone knew it was advertising.
Doctors eventually got sick of their mailboxes being flooded daily with this deluge of ads and so direct mail lost popularity. Drug print advertising then shifted to two venues. First, Drug companies bought ad space in "respectable" peer-reviewed journals such as JAMA and The New England Journal. These ads were clearly marked as ads and were kept separate from the editorial content of the journal. Second, many "throwaway" journals were published. These were sent free to physicians, and their contents were not subject to the scientific peer review process used by the "respectable" journals. They had both ads and articles, but the articles often extolled various drugs and were not expected to be written with the rigor or without bias in the way that would characterize a peer-reviewed journal. Everyone knew that these journals relied for their entire existence on drug company ads and so were essentially the creatures of the drug industry. The "respectable" journals were indexed in the Index Medicus of the National Library of Medicine (later Medline and now, Pubmed); the "throwaway" journals were not.
Now, enter Merck and Elsevier. As detailed in my previous post, what seems different about this more recent bit of skullduggery was the company's attempt, with the publisher's full acquiescence apparently, to produce a journal that would look to the casual reader just like a "respectable" peer reviewed journal, creating the impression that all its articles had received the careful scientific review that characterizes such journals. Yet in reality the journal content was solely the in-house product of the drug company--in short, a throwaway journal in peer-reviewed, indexed clothing.
Merck looks a bit silly here for trying to advertise while pretending that it was not advertising. But the real bouquet of skunk cabbage has to go to Elsevier. Here is a major publisher that preens itself because it puts out so many highly respectable, peer-reviewed, indexed journals, willing to compromise the integrity of its own products by producing a set of cheap imitation journals, just to make a quick buck (or millions of them, more likely). Elsevier has not yet revealed what Merck paid it to do this dirty work, which is in keeping with what I wrote about in HOOKED-- the big journal publishers are very tight with their financial data and figure what they do is none of your business.
Sunday, June 7, 2009
I responded to him at some length and being a lazy sort of individual, reasoned that maybe I could make the response double as a blog posting. I think the general tone of his comments can be discerned from my responses to them and a couple of key quotes contained below, so I'll not reprint any of his original remarks.
It seems clear from the list of recommendations at the end of your manuscript on COI that we agree on a good deal. I also agree with you and always say this when asked to speak on COI, that the device and pharmaceutical industries require different approaches when it comes to the presence of sales reps in the hospital. Devices, for their proper use, need a hands-on demonstration and the ability for hands-on adjustment and modification, that is not true for a pill or capsule. Therefore the trained engineer/device sales rep must assume in role in the hospital, including presence in patient care areas, that would be quite unnecessary and in my view highly improper for a drug rep.
The sentence that struck me as being most in agreement with my own views was, “Second, industry gifts that have no reasonable bearing on innovation, education or the practical elements of commercialization should disappear.”
Where then do we disagree? It would seem that our disagreement resides mostly in the way we define and assess COI. You say correctly that the mere presence of COI should not be presumed to equate to actual misconduct. I interpret this position to be the same as arguing that if we discover that a judge who is deciding a lawsuit between Company A and Company B owns $50,000 worth of stock in Company B, we should not accuse that judge of misconduct. Rather, we need concrete evidence that he ruled differently in the case than he would have, had he owned no stock. It is always possible that a judge of integrity, who owns that much stock, would simply put that consideration out of his mind and rule exactly the same as he would have if he had no financial stake. Absent concrete evidence of misconduct, we should not impugn the judge’s integrity by making any accusations.
Of course, this is not how we actually behave. We expect that a judge who owns stock in one company would recuse himself from the case. Failure to recuse would be seen as a clear instance of judicial misconduct. Why? As I attempt to explain in the chapter in my book, Hooked, on ethical fundamentals, I follow Ed Erde in seeing COI as essentially bound up with the idea of trust in a social role. A person who has a COI is a person who has allowed himself to be placed in a situation where thoughtful observers would worry that he’d be tempted to neglect the interests that he is duty-bound to protect, in favor of some personal interest of his own. This situation renders him less trustworthy in the eyes of those observers. A profession that depends greatly on public trust to be able to carry out its function—such as the judiciary, or medicine—has to be very worried about COI due to the potential for loss of trust.
The serious dangers of loss of public trust in medicine were especially brought home to me recently in discussions with a colleague here in pediatrics who is an expert on childhood immunization, and who is very worried about the potential for major outbreaks of infectious disease due to the large number of unimmunized children in some communities. This is directly attributable to the rise of celebrity “experts” and associated websites, proclaiming the dangers of vaccines for kids and the lack of any need to have one’s children immunized. These celebrities proclaim that you should trust what they say and not trust what your kid’s doctor says. Enough people today believe them so that we have a genuine danger to the public health. So I think we have reason to view trust in medicine as a precious public commodity, and dangers to that trust are matters of serious import.
Now, how do we proceed when we realize that two things are true?
1. Physicians and industry, working together, are needed for future innovations in health care that will greatly benefit future patients.
2. COI is a serious matter and we must do whatever we can to reduce or eliminate it.
What I see industry mostly trying to do today is to stress truth #1 and to try to fudge truth #2. The truly responsible course of action by contrast would be to accept truth #2 and then ask, how would financial arrangements be altered between physicians and industry so as to maintain as much as possible of the essential features of truth #1. At least some of your recommendations strike me as positive moves in that latter direction. That is, physicians should be paid exactly what it costs to perform whatever actions actually produce the innovation, and should not have any financial entanglements with the company beyond that. Physicians should take the attitude that engaging with industry is an opportunity to serve the public health and not an opportunity to strike it rich. That may sound incredibly idealistic, but I agree with the IOM that the stakes are too high if we fail to act. What is scary about Sen. Grassley is not that he is exposing greedy, irresponsible docs. It is that doing so on his part is like shooting fish in a barrel—he has such a wide choice of easy targets that he hardly knows whom to expose first.
A small point—I think an economics purist (of which I am certainly not one) would object to anyone who extols both the free market and the patent system. A patent is a state-granted monopoly and hence by definition an interference with the free market—a justified interference if it results in the social good of increased invention and innovation. Bu it ain’t the free market.
I later had some responses from this correspondent, and have myself responded back. I will send him a copy of this post to see if he wishes to have his comments made public, either with name identified or anonymously.
Monday, June 1, 2009
GoozNews offers a comprehensive summary of a new policy thrust at the FDA, under the new leadership team, that promises stricter policing of direct-to-consumer advertising, both television and online. We can expect much better efforts to assure that the negative aspects of drugs are highlighted alongside the positives. (No more reading a list of 900 side effects during the last 1.2 seconds of the ad.) And the industry appears to be paying attention.