Tuesday, June 29, 2010
Applbaum focuses much of his research on company documents revealed as a result of litigation against Eli Lilly over Zyprexa. In the earlier paper he reviewed these documents, supplemented with interviews. In his more recent paper he focuses on one part of the Zyprexa story--the decision by the Japanese health ministry in 2002 to require a warning label and to send a "dear doctor" letter about side effects. Lilly was concerned that the warning letter would exert global influence and so sought to counter its impact aggressively. In what follows I select threads from both articles in order to identify what I take to be Applbaum's key lessons.
Applbaum begins by teaching us marketing neophytes about "channels." Marketing drugs is highly complicated because there's no direct pipeline from the manufacturer to the end-user. Lots of folks control and manipulate the pathway that delivers the drug eventually to the mouth or body of the patient--most notably the physician who has to write the prescription, but also insurance companies, government regulators, managers of hospital formularies, and numerous other players. The key to selling drugs successfully today is first, to be able to control the channel: "Pharmaceutical manufacturers, like other marketing-driven enterprises, have realized that it is less in the product, the brand or even the patent where their fortunes lie, but in the stream, the marketing channel. Once you control the channel, you can insert any product you like into it, no matter how useless or dangerous."
But, if Rule One is control the channel, Rule Two is not to appear obviously to do so. Modern marketing lingo is full of words about "synergy" and so forth. The basic idea is to figure out ways to bend other parties to do what you want them to, by appealing in each case to their own interests, so that you never appear to be using power over them but always with and alongside them. It is in pursuit of this goal that pharmaceutical companies patiently and painstakingly unleash so many different measures at so many different levels, at such a high expense, as part of their strategy to market any given drug. Applbaum summarizes all the elements, for example, that went into marketing the SSRI antidepressants: "combined marketing and R&D divisions created and publicized research to demonstrate the efficacy of the drug; obtained academic 'key opinion leader' (KOL) endorsements for professional audiences (people whose careers and pocketbooks improved simultaneously); aired celebrity spokespeople and advertising to educate the lay public about the disease; lavishly funded antistigma campaigns; promoted among family doctors the use of abridged depression questionnaires and educated, and thus empowered, these dotors (and eventually their non-MD assistants) to look for telltale signs of depression and treat it; enrolled (in some cases, also bankrolled) the support of patient advocacy groups and solicited testimonials from among them; generated certified guidelines formulated and endorsed by psychiatrists in the employ of industry, to be adopted by hospital formularies and public insurance programs; took a lead role in determining the curriculum and scientific programs at continuing medical education programs and professional congresses; designed Web sites with diagnostic self-tests encouraging consumers along the path from self-diagnosis to the request of medication at the doctor's office.... The result was a phenomenal increase in the diagnosis of conditions for which a prescription of an SSRI ensued."
The way the company conducts this complex orchestra "results in the ability to pull all those disparate strings so that it looks like there is a consensus firming up from multiple locations, and hence it is not manipulated, cannot possibly be manipulated. One of the reasons the manipulation is obscure to us is that it seems as if they are not supervising the process at every step, because their hands are off the process so much of the time--And how, anyway, could they control the entire system?"
Turning next to the specific Japanese context, Applbaum claims that Eli Lilly managed to turn aside the threat to Zyprexa sales essentially by " a strategy of creating a shadow science to drown out noncompany-sponsored (and competitors') research reports on the side effects of the drug." The way in which this strategy is most at odds with the drug industry's self-image, and propaganda image presented to the medical profession, of its partnership in the pursuit of hard scientific evidence, is that, "the company treated the medical concerns associated with their drug as a relative and fungible truth--in short, as a brand truth that they had the right and the resources to control. The Zyprexa documents show how Lilly sought to deceive physicians in the United States about the severity of of the side effects, using the physicians' own incomplete knowledge against them." Thus, "An initial estimate is that about three quarters of the 5506 pges of Zyprexa documents are devoted to what Sergio Sismondo (2007) calls the 'ghost management' of science, and much of that to the side effects issue. Research is manipulated into sales fodder. Each claim in the doctor's office should be supported by research, and research is 'ordered,' as though from a shop, accordingly."
One footnote to the Zyprexa story in Japan is that the Japanese apparenly had no idea of how patient advocacy groups could be set up effectively to market drugs, so Lilly arranged for a selected group of patient family advocates to travel to Chicago to attend the annual meeting of the U.S. National Alliance of Mentally Ill (NAMI).
Applbaum notes the importance of understanding "channel marketing" as a way of understanding general issues that extend beyond the drug industry: "The master of synergistic power does not sell the channel outright. Instead, through manipulating partial truths and through capturing majority shares of heart, mind and voice, the disappearing synergist creates the context in which many social actors can move in a single direction even when they have competing interests. It is social process itself that is being pushed down the channel, while corporations collect only tolls." (Applbaum adds in a footnote that it is precisely because so many physician KOLs don't understand this, or don't wish to understand this, that they imagine that they somehow remain independent of the pharmaceutical industry because they consult with several competing companies rather than only with one.)
In HOOKED, I spent some time reviewing the Dichter study of pharmaceutical sales from the 1950s, one of the first documents to lay out the drug rep's strategy of being able to guide and manipulate the physician's prescribing precisely by appearing never to intend or to be able to influence his prescribing--strategies that the writings of Michael Oldani and Shahram Ahari have more recently brought up to date. I find it intriguing that Applbaum has painted a picture of the drug company's action in manipulating the marketing channels that almost exactly mirrors, at the social level, the individual psychological techniques long used by (and taught to) reps.
Applbaum K. Getting to yes: corporate power and the creation of a psychopharmaceutical blockbuster. Culture, Medicine and Psychiatry 33:185-215, 2009.
Applbaum K. Shadow science: Zyprexa, Eli Lilly and the globalization of pharmaceutical damage control. BioSocieties 5:236-255, 2010.
--I included references to the very angry reactions to the ACCME ruling from both NIH and the American Heart Association. Thanks to loyal reader Marilyn Mann, I can now report that the AHA's anger at least seems to have been effective:
In short, first ACCME first said that scientists who are paid full-time by industry cannot give CME talks, for credit, about their company's products. (I mistakenly said at first they could not give any talks at all, which seemed way unreasonable, and then corrected that misimpression.) That led the leadership of AHA to have a hissy fit. That led ACCME to change its mind and restore the CME credits they had been prepared to strip from the AHA's planned fall conference. The reason given was that somehow AHA had persuaded ACCME that their internal controls over speaker bias were sufficiently strict to be sure that no one says anything out of line. Marilyn asked me how to explain this as the ACCME decision making process seemed pretty opaque to her. I said, join the club.
My pals who follow this more closely than I, as well as numerous previous news accounts, consider AHA one of the most-in-bed-with-industry medical organizations, well known for accepting huge sums and for filling their guideline panels with conflicted folks.
The previous meta-analysis (by Brugts et al.) concluded that statins, used in high-risk patients without existing cardiovascular disease, do prevent death and vascular disease, but with a high number needed to treat (NNT). This, I noted, was compatible with previous studies. The newer meta-analysis takes issue and notes that Brugts included in their analysis a number of subjects who actually already had existing vascular disease. The analysis focuses on studies that report patients clean of existing disease (primary prevention), and looks at all-cause mortality as the endpoint of concern. (One of the studies they include is JUPITER, of which more below.)
Ray and colleagues then crunch the numbers (from 11 studies looking at 65,229 subjects for 244,000 person-years) and conclude that there's no statistically significant drop in all-cause mortality from prescribing statins for primary prevention of cardiovascular disease.
If you go back and look at the individual studies, most of them were negative, but the major outlier was JUPITER. I previously addressed JUPITER in several posts:
In the oldest of these posts, I argued that JUPITER may in fact be valid in claiming that if you gave a statin to a group of patients thought to be high-risk for heart disease because of having a positive C-reactive protein test even though they had normal cholesterol levels, you'll see reduced heart attacks and reduced deaths (though again with a high NNT). (Later I had to modify that rosy view as more criticisms of JUPITER came forward.) But the main message I thought had been completely missed by the media is that JUPITER knocked a huge hole in the "lipid hypothesis" of cardiovascular disease-- that statins reduce risks of bad stuff happening by means of reducing "bad" cholesterol. By standard cholesterol guidelines, no one in JUPITER needed to take a statin.
The new article in Archives that further beats up on JUPITER is by another international team, this time led by Dr. Michel de Lorgeril of Grenoble, and including our good friend Dr. John Abramson (of Overdo$ed America fame). A lot of their criticisms are too technical to make very interesting reading, but they note several features about the numbers that raise serious questions of bias. Just to grab one example, they note that in a comparable population, the death rate among people with serious cardiovascular disease is about 40%; but among patients in JUPITER, it can be calculated to be between 5 and 18%. Either these were very unusual patients, or something is fishy. They also note that the JUPITER trial was stopped early, presumably because of a previously selected statistical tripwire. The exact reasons for stopping the trial early were never explained, and close inspection of the data shows that when the trial was stopped, the data in the treatment and placebo groups were converging, suggesting that the statistical difference would have been erased had the trial been continued longer. When trials are stopped early, the effect size reputed to the drug treatment is generally bigger than otherwise. Finally, they claim that while the head of the data safety and monitoring board that decided when to stop the trial was said to have been independent of company sponsorship, the same person has served in that capacity in several commercially-sponsored drug trials.
In short, de Lorgeril at al. claim that evidence of bias due to commercial funding shows through in a number of aspects of the JUPITER trial.
(If you want a brief recap of these facts, plus word of a new report showing that statins might help prevent recurrence in men who have had surgery for prostate cancer, see Melissa Healy's article in the Los Angeles Times: http://www.latimes.com/news/science/la-sci-statins-20100629,0,7388273.story)
Ray KK, Seshasai SRK, Erqou S, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Archives of Internal Medicine 170:1024-1031, June 28, 2010.
de Lorgeril M, Salen P, Abramson J, et al. Cholesterol-lowering, vardiovascular diseases, and the Rosuvastatin-JUPITER controversy. Archives of Internal Medicine 170:1032-1036, June 28, 2010.
Monday, June 28, 2010
Dr. Deborah Korenstein and colleagues from Mt. Sinai in New York set out to do a survey that looked at various specialties and that also compared trainees (both med students and residents) with attending physicians. They also explicitly asked about both the pharmaceutical and the device industries, whereas most previous surveys had focused solely upon the former. As a convenience sample they used departments in Mt. Sinai-affiliated hospitals, tilting the total sample toward a more academic environment. They achieved a 67% response rate.
Overall they found favorable attitudes toward interacting with drug and device companies and taking what they offered. Similar to previous surveys, they found that physicians were more leery of the more expensive gifts, more accepting of gifts that seemed explicitly related to patient care, and convinced that their colleagues were easily swayed by gifts much more than they themselves were.
What might be viewed as new findings included a generally higher level of acceptance among the trainees, despite the authors' hypothesis that the younger generation might have been more swayed by recent anti-Pharma publications and guidelines. Physicians familiar with the strict guidelines limiting Pharma gifts and contacts also expressed more critical attitudes, suggesting that these guidelines do exert some influence. Finally, the major specialty-related difference was a generally higher level of acceptance of gifts among all surgical specialties and a lower level among pediatricians.
It's worth noting that this survey was conducted in 2008, before the inauguration of the voluntary PhRMA code of conduct banning a number of gift items in January 2009. One would be curious as to how numbers derived after that major policy change would compare. Also, given the biased sample which would seem to favor a more academic type of environment, it seems disappointing (from the pharmascold pespective) that attitudes toward acceptance of gifts were so favorable; one would assume these attitudes would have been even more favorable if measured among regular community practitioners.
Korenstein D, Keyhani S, Ross JS. Physician attitudes toward industry: a view across the specialties. Archives of Surgery 145:570-577, June 2010.
Saturday, June 26, 2010
--Dr. Michael Kirsch kindly calls our attention to a recent New York Times report by Natasha Singer and Duff Wilson:http://www.nytimes.com/2010/06/24/business/24meded.html?scp=1&sq=university%20michigan%20continuing%20education&st=cse
--which in turn provides us with important news on the CME front as well as a critical correction to the comments I offered in that earlier post.
The news item is that the University of Michigan announced that as of next January, they will become the first medical school to accept no drug/device industry funding for any school-sponsored CME (continuing medical education) program. In taking this lead, Michigan follows its earlier trend in being one of the first schools to implement a strong "drug reps off campus" policy. (Somehow Stanford hired a better PR agent and so got tons of publicity when they did the same thing more than a year after schools like Michigan and Wisconsin had taken the first steps.)
In HOOKED I wrote that the average medical school, as of a couple of years back, received about 50% of overall CME funding from industry. That sum varied widely; some conferences had virtually no industry funding, which in turn meant that other conferences were funded almost totally by industry. Michigan estimates it will be giving up about $1M of funding annually by its new policy. That shows what most med schools have at stake in the relationship with industry.
Now for the correction. I ran my mouth last post about the different types of talks that industry speakers might give, and offered my concerns that by banning all talks by industry speakers, the recent rules of the ACCME might actually have gone too far. So I am pleased that the Times report corrected my misimpression. The Times reporters state that the rules are indeed designed to respect the distinction that I was worried about. That is, scientists or physicians hired full time by industry can speak all they wish to about any basic science research. What they cannot talk about is a product of their company. I think that's a reasonable dividing line. By the time a research idea or concept has gotten so far down the pipeline that there's an actual product being readied for the market, there ought to be sufficient published literature for a neutral sientist to be found who can assess its pros and cons. There seems little danger that physicians will be deprived of up-to-date but unbiased information merely because a company employee cannot give that talk.
Wednesday, June 16, 2010
At issue is a new ruling from the continuing education (CME) poohbahs, the ACCME, on eliminating any industry scientists from accredited CME programs. The article quotes a number of my esteemed colleagues among the "Pharmascold" camp who are quite pleased with the ruling. It also quotes some standard medical society types who are going ballistic over it, as well as some level-headed folks like George Lundberg, former JAMA editor, who's fully attuned to the dangers of commercial conflicts.
My own view is quite conflicted and might fall under the heading of "hard cases make bad law." I think the problem is generalizing from specific cases to a general prohibition in all cases. I think if we had a set of case examples of industry scientists giving presentations at CME conferences, we could readily classify them into two piles, "ought to be allowed to speak" and "nothing of educational value lost if this dude is kicked out", for example:
- Case 1: A conference panel is looking at the future of pharmacologic management of diabetes. They begin by accepting the premise, that large-scale trials have failed to show patient-oriented benefits from tight control of blood sugar in Type 2 diabetes, so more drugs to lower blood sugar are a bad idea. An industry scientist familiar with the basic biological mechanisms of diabetes lists several aspects of the basic biochemistry of the disease that seem amenable to control by the right sorts of molecules. He makes no comment about any drug now nearing production, but rather sketches out the general principles clinicians need to know to be able to judge the value of potential future drugs.
- Case 2: A drug company is about to market a new drug for angina. A company scientist gives a glowing endorsement of the drug. He reviews a few published studies of the drug and admits that according to those data, the drug has little efficacy but causes some worrisome adverse reactions. He alludes reassuringly to as yet unpublished studies that show that the drug performs much better and has lower risks than the published studies show (but adds, when questioned afterwards, that presently those studies are not available for review outside the company).
I think we could readily agree that the first guy is adding something of real value to the CME and it would be a shame to preclude him from speaking; the next guy is a paid shill and adds nothing from a CME standpoint. If we could write a rule that the first person would be allowed in and the second not, then we'd be where we want to be. Sadly no such general rule that would include all the good cases and exclude all the bad ones is probably feasible.
It would be very nice if we could say, "Look, just write down the general principles and rely on the good judgment of the CME meeting organizers to make the fine-grained, case-by-case judgments." We tried that and the result is the present-day CME mess where commercialization has completely taken over.
So, if throwing out the bath water with an across-the-board rule assures that some babies will be tossed out as well, what do we do? One reaction is to say that so few babies will get the heave-ho that it does not really matter. Supporting this argument is the fact that we must decide what it is that inside company scientists are likely to know about, that neutral outside experts do not. I have a very hard time imagining that this will have a great deal to do with the clinical side of drug development. I would suspect rather that the inside folks will clearly know a lot more about some technicalities of the molecules and the mass production of same, which frankly is the sort of information that puts CME audiences promptly to sleep.
On the other hand I feel badly about a rule that is obviously an exercise in overkill, for baldly political reasons--it feeds into the Pharmapologist accusations that all that we are doing today is an exercise in some "politically correct" hyper-reaction to a basically non-existent problem.
I have always had what I suspect now is an overly simplistic view of the world--that the real problem in the conflict-of-interest realm is not the industry scientist, the guy who has the drug company's name on his business card and on his paycheck, who is known by all and sundry to have been bought and paid for. This person knows to whom she is responsible and can, with perfect integrity, do her job. The problem, I have always assumed, is the presumably "independent" academic physician who claims to be from Harvard or from Stanford or from U. Miami, but who actually takes such a substantial portion of income from industry that he's largely forgotten where public health concerns leave off and industry sales figures pick up. This latter person, who thinks he can walk on both sides of the street without tripping, is the real threat to professional integrity. It's the latter and not the former who should be banned from CME.
Saturday, June 12, 2010
The focus of this effort is Boehringer-Ingelheim's new "female viagra" drug, Flibanserin, which is to be discussed by an FDA advisory committee on June 18. A petition asking that committee not to approve the drug is being circulated and New View will be testifying as a lay group against approval.
I apologize for not being able to follow this particular debate as closely as I would have wished in recent weeks. The major points stressed by New View are:
- Flibanserin was discovered accidentally as part of a search for new antidepressants. It is said to work by modifying several neurotransmitters. So far, drugs that alter neurotransmitter chemistry have been frequently shown to cause severe adverse effects, many of which were not evident in the initial approval trials.
- B-I is taking full advantage of the FDA rules that to be approved, a drug has to be shown to be better than placebo in a few trials, and that is all. The actual amount of improvement shown by subjects in the trials B-I is submitting to the FDA is marginal at best.
- The larger societal issue is the medicalization of female sexual desire and the idea that if a women has low sexual desire, it must be because her brain chemistry is whacked out; it cannot be because she's stressed out of her mind or her boyfriend never bathes or any of the various environmental causes of low sexual desire. According to New View, the marketing campaign that B-I has launched for its new drug pushes all these buttons.
Tuesday, June 8, 2010
Recent events seem to demonstrate that Dr. Carroll was right all along. I was about to post several sources in this past week's debacle at NIMH, but Dr. Carroll has saved me the trouble by masterfully pulling the threads of the story together while also identifying exactly the key issues at stake in this mess-- so save time and just read his post, http://hcrenewal.blogspot.com/2010/06/public-trust-at-nimh.html, which also includes links to most of the critical background documents.
Most of us don't get it that in theory, no professor ever gets a grant from NIH; a university gets the grant. So when the Emory Nemeroff was banned for two years from getting any NIH or NIMH grants due to his blatant nondisclosure of industry funding, that was not really Nemeroff that was being punished, it was Emory; and so technically the Miami Nemeroff is blameless as the proverbial newborn babe and can start taking home NIH grants by the dozen any day. Admittedly that's how the rules were written and so Insel as NIMH director cannot change those rules. And so, again by the letter of the law, Insel did no wrong when he privately advised the Dean at Miami that Nemeroff posed no liability to him whatever as a new hire, in terms of NIH funding potential.
Dr. Carroll then goes on to identify the really most egregious bit of behavior-- the fact that Insel then proceeded to appoint Nemeroff to two NIMH study sections. That was purely a matter of discretion and there was no requirement in any book of rules to make such appointments. The fact that he made them seems to demonstrate beyond a doubt that Insel does not get what's wrong, and that his real priority is to go to bat for his good ol' pal Nemeroff whom it now seems he believes was unfairly punished. In the process, if the integrity of academic psychiatry and of the NIMH goes into the toilet, then so be it, appears to be his motto. Indeed a sorry state for the director of an NIH institute, and an indicator that whatever Insel wrote about in his JAMA article, he has no clue what it means.
Wednesday, June 2, 2010
--adds to our level of concern that trial registries are not having the impact we had sought.
Ewart and friends looked at 158 reports of randomized clinical trials published in high-impact journals in 2008. They were able to analyze 110, including only trials that had been registered. Comparing the trial as described in the registry entry with the final report in the journal, they discovered that 31% of the time, a primary outcome had been changed, and in 70%, a secondary outcome had been changed, without these being mentioned in the publication.
Unlike the earlier paper, Ewart did look at trial sponsorship, but they found no difference related to industry vs. non-commercial sponsorship in whether an outcome had been altered.
Ewart and colleagues suggest that at least some of this problem may result from investigators' lack of familiarity with the registry process, but agree that a serious problem with the interpretation and integrity of trial results arises when changes are made but not explained in the methodology section.
I go back to the same point I made in the previous post--where are the journal editors or reviewers? What is the appropriate division of labor here? Is the reviewer supposed to be the one to check the trial registry, or is the journal editor? Do the instructions to reviewers make clear which is the case? Information is being made readily available now on the internet that is designed to allow us to have greater reassurance that what we read about a clinical trial is kosher--yet people responsible for the journals and their content are ignoring that information. It's ridiculous to say that each journal reader is responsible for going to the web to look up the trial on the registry. If a manuscript is submitted to a medical journal, and something has been altered without explanation from when the trial was first registered, then the editors should demand an explanation or else refuse to publish the paper. What is going to change, and when?