Should Drug Companies Censor Medical Journals?

I have previously addressed the debate over the safety of the diabetes drug Avandia (rosiglitazone) between Steve Nissen, head of cardiology at the Cleveland Clinic, and GlaxoSmithKline, the drug's manufacturer:
http://brodyhooked.blogspot.com/2010/04/more-on-avandia-saga.html
http://brodyhooked.blogspot.com/2010/02/secret-avandia-tapes-comedy-or-smoking.html
http://brodyhooked.blogspot.com/2010/02/avandia-story-failures-of-regulation.html

So a further round of fisticuffs between these worthy opponents in the European Heart Journal (subscription required) might seem like old news--were it not for the bit of interest GSK added by calling on the journal to censor Dr. Nissen's previous editorial.

Dr. Nissen had written his editorial, "The Rise and Fall of Rosiglitazone," giving his take on the whole matter. The journal had published the editorial on line but it had not yet appeared in the print edition. GSK, in the person of Moncef Slaoui, Chair of Research & Development, wrote a long letter to the editor of the journal disputing Nissen's account point by point, and including the statement: "We strongly disagree with several key points...most importantly those which imply misconduct on the part of GSK... On this basis GSK believes that it is necessary for the journal to withdraw this editorial from the website and refrain from publishing it in hard copy, until the journal has investigated these inaccuracies and unsubstantiated allegations."

Nissen responded with his own point by point refutation of GSK's point by point refutation. He introduced his letter: "Pharmaceutical companies have abundant resources for delivering their messages to physicians and the public. Physician-scientists essentially have only medical journals through which we communicate... If we allow a pharmaceutical company to control what we are allowed to publish, scientific discussion and debate would suffer irreparable harm. This demand from GSK constitutes an unacceptable attempt to interfere with the editorial decisions of a major medical journal."

The EHJ editors chimed in, "Scientists know what a good argument is and will consider its merits and evidence...However, we cannot suppress concerns, data or divergent opinions--we must consider them and argue with data, numbers and plausibility. Only through such a discourse can progress evolve."

As a side matter, one of the Nissen accusations at which GSK took the greatest umbrage was that they "stole" a copy of the manuscript of Nissen's meta-analysis while it was still under review with the New England Journal. To defend their counterclaim that they were essentially innocent bystanders who received a faxed copy of the manuscript that they had never requested, they cited an earlier publication that I did not realize existed, in which the leak of the manuscript was reported as a news item in Nature by Brian Vastag about 7 months after the event occurred. Vastag offered an interview with the leaker, Dr. Steven Haffner of the University of Texas-San Antonio. At that time, and apparently later as well, the New England Journal declined to say anything about what had been done with Haffner, though they added that routinely such an offense would lead to a future ban from reviewing and from contributing editorials and review articles. Vastag quoted Haffner about his decision to fax the copy of the manuscript to a former resarch collaborator who worked for GSK, "Why I sent it is a mystery...I really don't understand it. I wasn't feeling well. It was a bad judgment." He went on to say--this is apparently the part that GSK liked and why they cited Vastag's article in their reply to Nissen--that his collaborator at GSK had not requested the manuscript (how could he if the manuscript was presumably under confidential editorial review at the time) and was "probably a bystander." No further comment.

Nissen SE. The rise and fall of rosiglitazone [editorial]. European Heart Journal 31:773-776, 2010.

Slaoui M. The rise and fall of rosiglitazone: reply [letter to editor]. European Heart Journal (advance access e-published April 23, 2010).

Nissen SE. The painful truth [letter to editor]. European Heart Journal (advance access e-published April 23, 2010).

Luscher TF, Landmesser U, Ruschitzka F. Standing firm: the European Heart Journal, scientific controversies and the industry [editorial]. European Heart Journal doi:10.1093/eurheartj/ehq127 (advance access e-published April 23, 2010).

Vastag B. Reviewer leaked Avandia study to drug firm. Nature 451:509, 2008.

What Do Patients Think of Docs' Financial Ties?

Adam Licurse, leading a team primarily from Yale, has contributed to our understanding of patient attitudes toward physicians having financial ties to industry (subscription required). Licurse et al. attempted a systematic review of the available literature on this subject. They identified 20 studies, most of decent or better quality, that addressed their questions. Let me quote their key conclusion: "When asked about the importance of disclosing certain [financial ties], patients and research participants largely want to know about physician and researcher [financial ties]. In clinical care, many patients believed that industry gifts of a personal nature to physicians are unacceptable, whereas fewer found professional gifts to be unacceptable. Patients are concerned that these gifts affect the cost and quality of care and that these gifts influence clinical judgment." The situation seemed less clear in research; most studies wanted to know whether people would be less likely to participate as subjects in research if they knew that the investigator had financial ties, but several studies seemed to indicate that this would not be a very big factor.


People coming at the subject from my own bias would tend to wish that the research would show massive distrust of physicians if patients found out about financial ties. The research that is available hardly shows that univocal or extreme an answer. However, neither does it support a claim one now hears from our friends the pharmapologists-- that there are simply no compelling data that the issue of financial ties and disclosure has anything to do with public trust in medicine at all. For example, here is Dr. Thomas Huddle, replying to his critics in a January article that I blogged about previously (http://brodyhooked.blogspot.com/2010/02/what-would-it-take-to-prove-harm-from.html): "Surveys have repeatedly shown that large majorities of patients do not regard the promotional items and food involved in typical detailing to be ethically problematic."

Dr. Huddle is strictly correct, but his assessment tells only a piece of the story. Plus he cites only three sources for his claim, all published before 2000. The Licurse review includes several surveys conducted within the last decade. One of them, by Jastifer and Roberts, notes in passing that more recent reviews appear to show patients as more critical of financial ties than surveys done in the 1990s (as would be very reasonable given recent publicity, and findings in some early studies that few patients were even aware of the nature of these ties).


Here is how I would summarize the Licurse et al. review: There is sufficient evidence to believe that a significant number of patients are concerned about financial ties between physicians and industry, in ways that implicate public trust in medicine.


Licurse A, Barber E, Joffe S, Gross C. The impact of disclosing financial ties in research and clinical care. Archives of Internal Medicine 170:675-82, April 26, 2010.


Jastifer J, Roberts S. Patients' awareness of and attitudes toward gifts from pharmaceutical companies to physicians. International Journal of Health Services 39:405-14, 2009.

Federal Settlements: The ACRE Perspective

A brief footnote to the previous post on AstraZeneca and Seroquel:

As I reported a little while back, I had the pleasure recently of listening to a major presentation (at Davidson College, NC) by our colleague at Harvard and ACRE, Dr. Thomas P. Stossel: http://brodyhooked.blogspot.com/2010/04/encounters-with-dr-tom-stossel.html

Dr. Stossel did such a nice job of summarizing the world view of the ACRE folks that I will take this opportunity to comment on one point that's relevant to the recent AstraZeneca case.

Dr. S. was fully aware that when he tries to present his rosy view of the great advances in human well-being produced by recent Pharma and biotech breakthroughs, his critics will trot out "anecdotal" evidence of industry wrongdoing. One such anecdote is the settlement agreed to by a major drug firm when charged by the Feds with criminal conduct. As I recall, Dr. S. even provided his own list on a slide of some two dozen of these recent settlements.

He then gave the Pharma spin on that list. First of all, he said, if you think about all the wonderful new drugs and all the lives that they have saved, etc. this list looks pretty puny.

Second, we have to realize that in these cases, the drug companies are basically powerless and the Feds hold all the cards. The penalty the Feds can exact is capital punishment--a drug company found guilty of a crime automatically loses all ability to do business with Federal programs such as Medicare, Medicaid, VA, etc. for a certain number of years. That would be the death knell for any drug firm. So companies accused of crimes by the Feds cannot take the risk of defending themselves in court; they have no choice but to settle. Therefore (implies Dr. S.) most of these charges are completely false and baseless, and the companies settle solely because they are forced into it. (And of course, in most cases, the company denies wrongdoing as part of the settlement.)

OK, so that is the ACRE take on the matter. My replies:

• It is reassuring to know that the Feds do not find evidence of criminal wrongdoing in the marketing of every single drug that has recently come on the market. What I think the list proves, however long or short it is, is exactly the point that I have stressed ad nauseum in this blog--that we see here a recurring business strategy across the entire industry and not the actions of an occasional rogue firm.
• If you look at what it takes to put together one of these legal actions against a drug company--usually an inside whistle blower plus some 5-6 years of legal investigation--it is not surprising that a relatively small number have been brought. We can argue over whether these are all unjust accusations against firms of stellar virtue, or merely the tip of the criminal iceberg.
• The "capital punishment" works both ways. The Feds (specifically, the White House and DHHS, given that the executive branch and DOJ are the ones bringing the suit) know what would be the consequence of actually putting AstraZeneca, Pfizer, Merck et al out of business. First, all their thousands of employees are thrown out of work in the middle of a major recession. Second, millions of patients who rely on brand-name drugs that have no generic equivalent suddenly are deprived of those drugs without warning. If you imagine the political pressure generated by both of those aggrieved lobbies, you can see why the Feds simply would never lower the boom completely on a drug company guilty of even the most egregious behavior. (We have to add that the actual criminal behavior was no doubt engaged in by a tiny handful of company employees, with the vast majority of the workforce being blameless.)
• The end result is that the Feds go well out of their way to never shut down a big drug firm--and resort to subterfuges such as in the Pfizer case, where they "shut down" two drug firms that had actually shut down years previously and no longer existed except as paper targets (http://brodyhooked.blogspot.com/2010/04/cnn-pfizer-too-big-to-prosecute-shadow.html).
• So the real power remains in the hand of the drug firm that's "too big to shut down," analogous to the Wall St. bank that's "too big to fail."

As I have argued in the past this seems to support the role of criminal prosecutions (perhaps for misdemeanors) of high officials of the drug company rather than "capital punishment" for the whole firm. (See post linked above.) But at any rate, the ACRE view of how this all goes down seems to me about 180 degrees off kilter.

The Cost of Doing Business: Same Song, 83rd Verse

And today, the drug company settling with the Federal government on criminal charges against off label marketing is:
AstraZeneca
The drug involved is: Seroquel (quetiapine)
The amount of the settlement is: $520M
The settlement equals what percentage of one year's sales of the drug?: 10.6%
Did the company admit wrongdoing? Yes/No: Of course not
Link to detailed news coverage: http://www.nytimes.com/2010/04/28/business/28drug.html?emc=tnt&tntemail0=y

As you can see, it saves time if I just make it a fill-in-the-blank form.

First, general background: Seroquel is one of the supposedly new-generation antipsychotics that was initially touted as both more effective and safer than the older antipsychotics of the thorazine-haloperidol era. More recent research has disputed the claims of both greater efficacy and greater safety, and calls into question the entire concept of "generations" of these drugs--see for instance http://brodyhooked.blogspot.com/2009/01/are-second-generation-antipsychotic.html. We are sadly not surprised to learn that at every step of the way, the drug companies sponsoring the research, and their physician lackeys, have worked their tails off to distort the research record and to make these sows' ears look like silk purses. In the process they have especially pushed the drugs (due to their supposed safety profile) for use in the elderly, despite the fact that the drugs can cause serious weight gain and tip susceptible patients over into frank diabetes. Because psychiatrists see too few patients to create a really blockbuster market, and expert psychiatrists might actually know something about the downside of these drugs, much of the marketing focus has been on my colleagues in primary care--again relying on the supposed safety profile of the drugs to encourage non-psychiatrists to feel comnfortable prescribing them.

The Feds charge that AZ paid kickbacks to docs as part of a scheme to market the drug for unapproved uses, especially in kids and the elderly. The specific Fed claims include:

• AZ inapproprately influenced the content of CME courses they funded
• AZ hired docs to give talks and do research on unapproved uses
• AZ recruited medical "opinion leaders" to be the fake authors of ghostwritten articles touting Seroquel for unapproved uses, and AZ then used those articles for marketing
• AZ paid docs to come to fancy resorts to "advise" AZ on how best to market Seroquel for unapproved uses

All of this is in violation of Federal anti-kickback statutes.

Based on some of the buzz on the Healthy Skepticism listserv, it appears that this story will not go away quickly. The Feds appear ready to out the academic and other physicians who took those kickbacks.

Being held to public ridicule for taking drug company money to shill for them, illegally, may produce a small incentive among academic physicians at least to watch out for these sorts of entanglements with Pharma in the future. As we have seen many times before, the amount of the settlement, by itself, is hardly a factor, since the company gets about 9 times that much in revenues for every year the drug remains on the market. You can add to that the $656M that AZ has reportedly spent so far to defend itself against about 25,000 civil lawsuits over Seroquel. (If the Vioxx/Merck example is any indication, AZ stands ready to win the vast majority of those suits, given the near-impossibility of proving in a court of law that any individual patient developed diabetes or any other complication solely due to Seroquel and not due to any other co-existing conditions.)

As we have said before, so long as the "cost of doing business" is so reasonable, we can expect drug companies to push the legal envelope regularly, and like Pfizer, swear never to do such dastardly deeds again at the same time as they are planning the next set of dastardly deeds with a newer drug (see http://brodyhooked.blogspot.com/2010/04/cnn-pfizer-too-big-to-prosecute-shadow.html).

How Good Are Generic Drugs?

Thanks to Merrill Goozner for his report and insights:
http://www.thefiscaltimes.com/Issues/Health-Care/2010/04/22/Generic-Drugs-on-the-Hot-Seat.aspx

First, some of my own background: There are several issues that concern us on this blog that all in some way implicate the safety and efficacy of generic drugs as equivalent to brand-name drugs. Specifically, if it were to turn out that we could not rely on generics as reasonably equivalent to the brand-name in a therapeutic sense, then a number of the pieces of advice that we'd like to give to the physician, on how to save money for patients, how to keep well informed about drugs, etc. would no longer be valid and we'd have to start over from scratch. That is why it was a truly big deal when, back in 1989, a Congressional inquiry revealed a payola scandal within the FDA's generics division that allowed non-equivalent drugs to slip through the net (as I briefly described in HOOKED). What I have written since then all assumes that the problem at the FDA was fixed. The issue is especially timely today as many widely-prescribed brand-name drugs either have just gone generic in the past couple of years or are poised soon to do so.

Now, over to Gooz--his article briefly reviews recent charges, taken up by some popular magazines and by psychiatrists in particular, about patients who switched to a generic drug and had an immediate worsening of their symptoms. This led the FDA to convene an advisory committee to review the standards it uses for determining bioequivalence. The short answer is that the FDA internal investigation showed that even if they had adopted a stricter standard, the specific drugs that have recently been questioned all fell within those tighter limits--so there was no scientific reason to change the standards.

Gooz's analysis is extremely helpful because he distinguishes two FDA functions--generic drug approval and on-site inspection of drug manufacturing facilities. Megabrand Generic Drugs Inc. might submit their formulation for a generic version of (say) Zoloft to the FDA. There is, at present, no evidence at all that there's anything wrong with the process the FDA uses to approve that chemical formulation. But then somebody actually has to run a big machine in a big factory and make millions of those generic pills or capsules. And that is where the available evidence would suggest that things could get dicey--especially if the factory is in China or some other country prone to either official corruption or sloppy standards or both. The FDA, it is now widely admitted, has way too few inspectors to keep an eye on all the outsourced drug factories that supply their wares to the US market, as we found out with tainted Chinese heparin recently. So we should fix that and not worry about the official generic approval standards.

Now, my own advice as a no-longer-practicing family doc. What should the physician do when the patient says that after switching over to a generic brand, he has a new side effect, or the drug stopped working? As I understand the matter, two different brands of the drug may be chemically different, having, for instance, a different type of chemical filler. So I have no trouble believing that no matter what FDA standard the generic drug passed, this individual patient just might have a chemical idiosyncrasy so that his body absorbs some substances differently, etc. (Or he might not--the difference truly might be imaginary, or a negative placebo effect--but the research needed to find out for sure is way beyond the time and abilities of most practitioners.) In such cases I always wrote the prescription so as to return to the brand name drug. I never told the patient I did not believe him, or that what he said could not be true because generic drugs are equivalent. And if the insurer did not want to pay the higher price, I always went to bat for the patient (and made sure the reported difference was documented in my chart note to back up the patient's story). But at the same time, I felt obliged to tell the patient not to assume that this meant that other generic drugs were no good. I explained that the same thing could have happened, had he initially been on a generic drug and had been switched to the brand name version. The problem in his case, I proposed, was switching to a different chemical formulation, not to a (generally) worse chemical formulation. The number of patients who ended up needing this special treatment was a miniscule percentage of my practice, so I never thought of it as breaking the bank, but rather as personalized medical care.

Council of Medical Specialty Societies Code: Strong Enough?

The Council of Medical Specialty Societies, of which 32 medical specialty professional organizations are members, has announced a new "Code for Interactions with Companies." Their press release is at http://www.cmss.org/DefaultTwoColumn.aspx?id=110, and the full Code is accessible at http://www.cmss.org/uploadedFiles/Site/CMSS_Policies/CMSS%20Code%20for%20Interactions%20with%20Companies%204-19-10.pdf.

The news release suggests that this is a well-intentioned attempt to address conflicts of interest in medical specialty societies, with a special focus on their role in writing clinical practice guidelines. The Preamble states: "Members and patients count on Societies to be authoritative, independent voices in the world of science and medicine. Public confidence in our objectivity is critical... We know the public relies on is to minimize actual and perceived conflicts of interest. ... [E]very society must be sure its interactions with Companies meet high ethical standards."

I read through the complete Code to try to form an opinion as to how much teeth the Code actually possesses. Based on the most recent flap regarding my own medical specialty society to come to my attention--the AAFP-Coca-Cola deal-- I paid special attention to whether that deal would have been prohibited by this Code. (AAFP is one of the members of CMSS). (For the most recent post here on AAFP, see http://brodyhooked.blogspot.com/2009/12/aafp-coca-cola-deal-letter-to-member.html.) As everyone with whom I have consulted, except for the AAFP leadership, seems to believe that the Coke deal was a clear no-no and a serious conflict of interest, I figured it was a reasonable test case.

As best as I can read the Code, AAFP would have a green light on Coca-Cola. There seems no doubt that the general spirit of this Code runs contrary to the AAFP-Coke deal. But at each critical juncture, the Code seems to leave enough wiggle room for the deal to be justified. For example, so long as AAFP claims to have done all the following:

• decide that writing educational materials for consumers on healthy eating is part of its mission
• decide to include guidance on beverages and soft drinks, independent of the Coke deal
• reveal funding from Coca-Cola
• assure everyone that the content of the materials will not be determined or dictated by Coca-Cola
• Have an internal set of conflict-of-interest policies which it follows in dealing with Coca-Cola

--then the deal is supposedly kosher. The only "violation" I can see is AAFP's failure to reveal the exact amount of the funding that it received. ("Strong six figures" is how the AAFP Prez was quoted in the press.)

A good deal of space is devoted (appropriately) to CME programs. Here I would criticize the Code for being too quick to rely on having funding from multiple firms to make sure everything is above-board. As we have discussed numerous times, getting funding from many drug companies does not eliminate bias in CME; rather, it tends to assure that all the presentations at the CME program will be about drug therapy, with nothing said about exercise, diet, etc. The Code does call for presenters at CME "to give a balanced view of therapeutic options."

We next come to the critical section on practice guidelines-- critical because it has been generally held by guideline critics that of all practice guidelines, those published by medical specialty societies are most likely to be riddled with commercial biases and conflicts. Here I was hoping for a strong statement that guideline panels would be made up of individuals without conflicts of interest, period. The Code instead insists on disclosing conflicts and requires then only that a majority of panelists are free from conflicts of interest relevant to the subject matter of the guidelines. There also seems to be a major loophole in that commercial firms cannot fund guideline development; but they can give funds to a society for later distribution and "repurposing" (whatever that is). To me this suggests a likely route for a sweetheart deal. A firm might let it be known that if a society comes up with a practice guideline that strongly endorses a treatment strategy using a drug that the firm sells, it will later on be willing to pay millions of bucks for "further distribution" of those guidelines. The society might well decide it's worth it to front its own funds to write the guideline, knowing that the firm's later largesse will effectively reimburse it for all expenses and then some. Finally the Code states, "Societies will recommend that Guideline development panel members decline offers from affected Companies to speak about the Guidelines on behalf of the Company for a reasonable period after publication" (emphasis added). Why be mealy mouthed about it? Why not just say flat out that if you agree to serve on a guideline panel, you also agree not to also serve on a company speaker's bureau for X number of years--period?

CMSS proposes to post a list on its website of Societies that sign onto this Code (including societies that are not CMSS members). Societies will be encouraged to certify annually to CMSS that they continue to adhere to the Code." Again-- why not demand annual cerification as a condition of being listed?

Great first draft, guys. When you next revise it, stiffen it up a bit. The Code emphasizes that individual Societies are welcome to adopt stricter provisions than what is in this Code--and I hope they do so.

Note added 4/24: Our esteemed colleage Dr. Danny Carlat had a very amusing and rather more cynical take on this Code-- see his post: http://carlatpsychiatry.blogspot.com/2010/04/medical-societies-new-ethics-code.html
In short he depicts the Code as pure PR fluff with no substance at all.

Encounters with Dr. Tom Stossel

I spent some of last week at Davidson College in North Carolina, in the company of Dr. Thomas P. Stossel, driving force behind ACRE (Association of Clinical Researchers and Educators). Both Dr. Stossel and ACRE have come in for considerable criticism on this blog, so I thought a brief report was appropriate. I am first happy to be able to say that Danny Carlat, over at his psychiatry blog, was correct--I found Dr. Stossel to be personally very congenial and affable regardless what one thinks of his opinions on medicine-Pharma issues. I discovered that he and I have equally compelling reasons for psychopathology, having each of us been raised in our tender years as Chicago Cubs fans.

He and I each spoke at the Speas Colloquium, an annual medical ethics program at Davidson (where our host was Lance Stell, philosopher and another ACRE stalwart). I spoke in defense of the meaningfulness and relevance of the notion of conflict of interest. Dr. Stossel gave an overview of the ACRE position that defends financial ties between medicine and Pharma as the engine that drives innovation, and that sees all recent attempts to limit those ties as both unnecessary and harmful. My limited attempt to hold out an olive branch was to note that ACRE contains a lot of expertise on how medicine can collaborate with Pharma around biotech and pharmaceutical research, so that they could be leading the way to develop an ethically sounder relationship between medicine and the pharmaceutical industry--if only they would admit, for starters, that we currently have a problem. Dr. Stossel obviously was having none of that. He continues the trend in his previously published work of minimizing all bad stuff that happens at the med/Pharma interface--the stuff I have to find time weekly or even more often to post here--as disconnected, rare anecdotes, not as any sort of recurring or worrisome pattern.

In most respects I thought that the talk he gave at Davidson was more or less what we would expect, based on his previous publications. The exception was one slide that he presented on professionalism. The primary source he cited was the recent book by David Wootton, Bad Medicine. The point seemed to be that when folks like me who are concerned about undue influence of commercial interests on medical practice cite "professionalism" as our concern, this ought to be questioned if not dismissed--that much more harm than good has been done over the centuries by invoking "professionalism" in medicine, that "professionalism" has often stood in the way of accepting new scientific evidence, and that it is simply wrong to characterize medicine as something over and above a business. (In short, the sorts of arguments that result when one ignores the more recent, ethical sense of 'professionalism' and invokes only the descriptive, sociological sense of the term.)

My comment here would be that it is perhaps indicative of the strength of the arguments raised by the ACRE folks, to see how wide a swath of ethical countryside they have to lay waste to, in order to defend their chosen position. They want to defend docs taking bundles of cash from Pharma; we invoke conflict of interest as an ethical concern with that approach; so they decide they have to throw out conflict of interest. (Not limit or refine the scope of conflict of interest, mind you, but completely dispense with it.) So now we continue to worry about their heels with some quaint ideas of medical professionalism; and they now find it necessary to dispense completely and totally with medical professionalism. It is not merely a matter of throwing out the baby with the bathwater. It appears to be the baby, the rest of the family, the dog, and the hearth, and still they are not done.

Forget Blood Tests, Just Treat with Statins? More (Partial) Evidence

Warning: If you are up to here with my ragging on about statins and cholesterol, skip this post. The reason I am pursuing this is to try to get to the bottom of the influence of Pharma marketing over both medical science and actual physician prescribing behavior, and I think the statin/cholesterol/prevention story is a rich and multifaceted case study.


A study published in January in Annals of Internal Medicine would seem at first glance to be yet another important piece of evidence with regard to the "lipid hypothesis"--whether statins actually work solely or even primarily by their lipid lowering effects, or if they actually work by some other means such as anti-inflammatory. At a closer look, it does indeed add further evidence that the lipid hypothesis is shaky at best, and it makes a good point about practical strategies for managing heart disease risk. But ultimately it fails to be as important as it might be because it compares only options A and B, when the really best options are probably to be found among C, D, and E.

A team headed by Drs. Rodney Hayward of U-Michigan and Harlan Krumholz of Yale (IMHO, meaning the study is both high quality, and not bought off by Pharma) set out with funding from the VA to try to compare two strategies for preventing heart disease with statins. The "treat to target" strategy is what all the guidelines recommend--measure cholesterol levels, start a statin, keep checking the blood levels and adjust the medicine until you have reached a target level of cholesterol (or, specifically, "bad" cholesterol or LDL). (These guidelines, I hasten to add, were mostly written by folks whose pockets are deeply lined with industry cash, as we have previously discussed.) Hayward and colleagues wanted also to test a "tailored treatment" strategy, which consists of two doses of two different statins. On this strategy, you decide what the cardiac-disease risk level of the person is from some population measurement tool such a Framingham. If the person is medium risk you pick a lower dose of a generic statin. If they are at especially high risk you pick a higher dose of a more potent statin. In neither "tailored" case do you bother to measure cholesterol levels, now or later. The "tailored" strategy is, so far as I interpret the literature, more evidence-based than the "treat to target" strategy.


Cutting to the chase, Hayward and colleagues knew that to do this study as a randomized clinical trial would require huge numbers of subjects, about a decade, and many more bucks than they had on hand (being funded by the VA). So they chose instead to do the study as a mathematical modeling exercise. The things that make their model apparently quite robust were, first, that they made a set of assumptions that slanted in favor of the "treat to target" strategy; and second, that they did a whole slew of sensitivity analyses to see if changing any of many different assumptions changed the outcomes.


Their results were a resounding win for the "tailored treatment" strategy. They could not find a set of assumptions that made the "treat-to-target" strategy come out better in terms of patient benefit. (They did not consider cost in their study, probably simply taking it for granted that the strategy that did away with the need to chase cholesterol levels all over the place would be the cheaper strategy, especially when combined with maximum use of generic drugs.)


So two things seem to follow, at first glance, from this study. One: treating with statins based on risk classification, not based on cholesterol levels, is the better way to go. Two: as both treatment strategies resulted in saving lives and quality-adjusted life years over baseline, then statins are indeed good for primary prevention of heart disease, and the only question is how to use them best.


So: is the first glance view accurate? I think not.


Consider what the study, for all its sophistication, did not test. There was no comparison between trying to use statins for primary prevention of heart disease, using either strategy, and the best reported results of diet/exercise/lifestyle interventions. Also, there was no comparison between a single, low dose "tailored treatment" strategy and the authors' two-dose variation. If one is to believe the work of James Wright and John Abramson in particular, there should have been no difference.


So the question, then, is on what basis did Hayward and colleagues decide that primary prevention with statins works? The answer--they assumed it to be so. They admitted up front that as part of their plan to give up as much handicap as they could to the opposing strategy, they made two assumptions-- that reducing LDL cholesterol accounted for 100% of the statins' beneficial effects; and that reduction in LDL cholesterol is a 100% accurate accounting of how much benefit an individual receives from taking a statin. They immediately add that the first assumption is quite controversial and the second is demonstrably untrue.


They chose to make these assumptions because it suited their narrow purpose of demonstrating the superiority of their "tailored treatment" strategy, and for that purpose it was quite an effective way to design their study. For our purposes, however, those same assumptions mean that we cannot use this study to test out the more skeptical--and I think more evidence-based--positions on statin use in primary prevention.

When I ran a draft of this post by EBM-mayvin Jerry Hoffman at UCLA, he kindly added the observation that I needed to mention "number needed to treat" (NNT). The way Jerry put it, suppose that we located the most up-to-date statistics and presented to a bunch of higher-risk men the option to take statins for primary prevention of heart disease, or not, using the so-called "tailored treatment" approach now that we know it's superior. There is no guarantee that these men would choose the statin therapy even under these "superior" treatment conditions--if we told them frankly about how many of them would have to take a statin before one of them had benefit (such as avoiding a heart attack or death). If men knew that as many as several hundred would have to take statins (being exposed to all the risks of adverse reactions) so that one would get a benefit, they could very reasonably say "no thanks." So even the "superior" treatment strategy is potentially undesirable if the NNT statistics from many large clinical trials are valid.


It is nevertheless nice that we have one more argument to use against extensive screening for cholesteol and LDL and increasing statin treatment levels if the targets are not met. Finally, in conclusion, Hayward et al make an excellent point. Why, they ask, did the "treat to target" strategy ultimtely fail? Their conclusion-- it overemphasized one single heart-disease risk factor, LDL, at the expense of not taking into account the total picture of the individual patient's heart disease risk status. That led to some patients being overtreated, some being undertreated, and overall, less net benefit. This is yet another argument that if anything should guide the use of statin therapy, it's the patient's overall risk status and not any single blood test.

Forget the Science; Docs Already Know the Answers

Thanks to a faithful follower, I was clued into the program on Minnesota Public Radio last week:
http://minnesota.publicradio.org/display/web/2010/04/08/midmorning2
The Midmorning program addressed the recent decision of the FDA to allow a relabeling of rosuvistatin (Crestor) based on the JUPITER trial, about which I blogged several times, such as:
http://brodyhooked.blogspot.com/2008/11/by-jupiter-slick-drug-marketing-great.html
Midmorning had two guests familiar to regular readers of this blog: cardiologist Dr. Steve Nissen of Cleveland Clinic, and family physician Dr. John Abramson. Both are usually known as critics of the pharmaceutical industry. In this instance they took mostly opposing views, Nissen defending the JUPITER results while Abransom took a more skeptical view (with which the bulk of the opinions I blogged about would agree; see http://brodyhooked.blogspot.com/2008/11/by-jupiter-part-ii-more-skeptical-view.html).

Two comments on the program. While the listeners heard pro and con views regarding the reliability of JUPITER, they did not hear much about what I consider the major news from that trial, which is to knock a further hole in the lipid hypothesis for heart disease, that claims that statins prevent heart disease primarily by lowering cholesterol and that regular cholesterol testing is a critical part of good preventive medicine.

The second comment is perhaps the more important, and includes the only mention that I heard of the challenge to the lipid hypothesis (though neither Abramson nor Nissen picked upon it). During the call-in part of the program, a family physician from Marshall, MN, "Vince," offered a different perspective which he presented as representative of all of the family docs he knew. He said that all of them, on reaching age 50, if they had the slightest hint of a risk factor for heart disease, immediately put themselves on cheap generic simvastatin. Vince agreed with those who believe that the lipid hypothesis has been largely disproved, and was quite willing to say that 1) statins probably work more due to their anti-inflammatory effects and not due to cholesterol lowering effects; and 2) therefore, checking cholesterol levels with repeated lab tests is pointless. But Vince also said that he and all his colleagues were completely convinced that statins were effective for primary prevention of heart disease, they hardly ever saw any serious side efects with statins, and now with generic prices they were dirt-cheap, so why not take one?

My own point of view is that "Vince" represents a fascinating partial victory of pharmaceutical marketing over science. (Both Nissen and Abramson agreed to disagree with Vince.) He's right, I think, in debunking the lipid hypothesis. But I think his confidence that statins are so wonderful for primary prevention reflects the huge success of Pharma brainwashing (see my last post on JUPITER-related stuff, http://brodyhooked.blogspot.com/2009/07/more-on-statins-new-bmj-meta-analysis.html.) It's one of those many features of today's medicine that future medical historians will look back on and shake their heads over.

More on the Avandia Saga

We've had several recent posts on the Avandia revelations, most of which emanated from the investigation of the staff of the Senate Finance Committee. Their report can be accessed in full at:
http://finance.senate.gov/newsroom/ranking/release/?id=bc56b552-efc5-4706-968d-f7032d5cd2e4
(see links-- the full report is more than 300 pages of which only about 15 is the report itself, and the bulk being the supporting documents)

Another helpful overview and summary is provided by the Australian journalist Ray Moynihan in BMJ (subscription required). Moynihan summarizes the Senate committee report findings, then gives GlaxoSmithKline's rebuttal, which includes charges that more recent studies are showing that Avandia creates no additional risk of heart attack. Moynihan responds by noting that these more recent studies are all being funded by GSK, and he refers to the study we already posted about in BMJ, showing that authors with financial ties to drug companies were three times more likely to be writing favorably about Avandia's risk profile than were financially nonconflicted authors. Moynihan also shrewdly goes to the real root of the matter--it is not that Avandia is such an all-fired-great drug for diabetes that we should be using it until it is definitely proved to be harmful. In fact Avandia has never been shown effectively to prevent any of the serious complications of diabetes, and so there is a real question as to why it ever should have become a widely used drug in the first place--were it not for overmarketing. In such an instance any hint that the drug might be unsafe should be sufficient grounds to yank it from the market.

Moynihan R. Rosiglitazone, marketing, and medical science. BMJ 340:785-789, 10 April 2010.

What's Driving Overuse of Complex Spinal Surgery?

An important paper in the current issue of JAMA:
http://jama.ama-assn.org/cgi/content/full/303/13/1259?home
(at least for now the journal seems to be providing free access to this article)--looks at Medicare billing data for various forms of surgery for spinal stenosis from 2002 to 2007. The chief author, Dr. Richard A. Deyo of Oregon Health and Science University, might well be dubbed "Doctor Back Pain" for his many publications on that topic, many of which demonstrating conclusively that more conservative and cheaper treatments for back pain work as well as more invasive and expensive ones.

The focus of the present article is on the very common condition of spinal stenosis, which basically means a narrowing of a bony canal through which nerve roots come, resulting in pain due to compressed (pinched) nerves. This type of back pain usually does not get better without surgery. The available research data show that the simplest and least invasive surgery, scrounging out the edges of the bony canal to decompress the nerve, works as well as more complex surgeries that involve fusing one or more vertebrae together. (At least, there are no good data today to demonstrate a clear superiority to the more complex surgical techniques.)

Deyo and colleagues showed that from 2002 to 2007, while the overall rate of surgery for spinal stenosis did not increase, the percentage of cases in which the complex procedures were used climbed from 1.3% to 19.9%. The use of more complex surgical approaches was correlated with a higher rate of complications, a greater risk of death, and more than three times greater hospital charges. In short, a type of surgery that has no proof of added benefit went from a tiny blip on the radar to nearly one-fifth of all surgeries of that type, adding to patient risk and greatly padding the total Medicare bill.

What caused this? Deyo and colleagues are reticent, as is appropriate as just staring at sheets of Medicare data cannot answer cause-and-effect questions. But they mention among the possibilities first, the fact that medical device makers have heavily promoted the implants, cement, and other paraphernalia required for the more complex surgeries (the price for which can add up to as much as $50,000 per operation), and second, that surgeons get paid a good deal more for the complex procedures. (This reminds us of George Bernard Shaw's classic statement in The Doctor's Dilemma in 1911, that if you pay a surgeon to cut off your leg, and don't pay him not to cut it off, don't be surprised if the fellow cuts off your leg.)

A bit of further insight is added in an accompanying editorial:
http://jama.ama-assn.org/cgi/content/full/303/13/1309?home
--by Dr. Eugene J. Carragee of Stanford. Dr. Caragee notes that the difference in surgical fees between the simple decopmpression operation and the more complex surgeries may be on a ten-fold scale. He also notes that there are times when it is technically harder to do the simpler than the more complex surgery--to go in and scrounge out the bone without disrupting the stability of the vertebra or the ligaments may be more difficult than simply slapping on an implant or a graft. So today, he suggests, we are actually paying back surgeons less to do the more difficult (but often more desirable) procedure.

The whole story here is complicated but seems to typify how drug or device industry marketing seldom operates in a vacuum. In this case the heavy promotion of expensive devices interacts with a perverse incentive structure to produce outcomes that cost us all a lot of money and that expose patients to unneeded risk.

Finally, one has to note the apparent lack of interest of the average medical specialist in basic epidemiology. In HOOKED I cited psychiatrist David Healy on this matter. As drug companies promoted the newer generation of antidepressant drugs aggressively in the 1990s, the diagnosis of depression became so much more common that eventually the WHO announced that depression was the second largest cause of disability among all diseases. Psychiatrists greeted that news with great joy, as if making depression that common made them that much more important. Healy noted their apparent disinterest in the basic question--just what made that many people so much more depressed all at once? How does one scientifically account for the diagnosis of depression growing by leaps and bounds? Similarly, if Deyo et al. are correct, the back surgery community as apparently been very little interested in or concerned about whatever made the complex (and more remunerative) forms of back surgery so much more necessary in 2007 than they were in 2002.

U. Minnesota--Evading Responsibility for Reprehensible Behavior

My esteemed ethicist colleague at the University of Minnesota, Carl Elliott, deserves credit on many points. He's been an astute commentator on the corrupting influences of corporate cash on medical practice and research. He also has considerable courage--willing to point fingers and name names not only among our own bioethics colleagues who accept industry money, but also at his own institution when it misbehaves (as unfortunately it has tended to do often of late).

I had heard a bit in the past about the Dan Markingson case in Minneapolis, but until Carl recently gave a lecture on the topic (at the National Undergraduate Bioethics Conference a week ago at the University of Puget Sound, Tacoma, WA), I didn't quite grasp all the essential pieces. The public record is nicely summarized in a newspaper article and in Ed Silverman's summary on Pharmalot:
http://www.pharmalot.com/2008/05/whos-delusional-a-university-doc-a-clinical-trial/
http://www.twincities.com/ci_9292549?IADID=Search-www.twincities.com-www.twincities.com&nclick_check=1
Carl himself added a few extra details that will be forthcoming, he tells me, in a new book he's working on. The following account includes all the details I am aware of from these various sources.

Dan Markingson was the only son of Mary Weiss and seemed to be perfectly balanced mentally. She was therefore shocked when she traveled from Minnesota to visit him in California in the summer of 2003 and found him claiming that aliens had damaged his house and that a secretive world order was planning a "storm" in which Dan would be ordered to kill people. With some difficulty she managed to get him back to Minnesota and then (when his delusions became worse and he started to talk about killing Mary as part of the "storm") took him to the local hospital on Nov. 12, 2003. The hospital had no psychiatric beds open and transferred Dan to the University of Minnesota Medical Center, Fairview.

Dan was evaluated at Fairview by a faculty psychiatrist, Dr. Stephen Olson. Dr. Olson petitioned the court to commit Dan involuntarily because he was unable to make decisions about his care and posed a danger to himself or others. Within a week, however, Dr. Olson was telling the court a different story, saying that Dan had improved enough to warrant a new recommendation. The court agreed and dropped the involuntarily commitment order, contingent upon Dan's adhering to his doctor's treatment program. That program, it now turned out, was to participate in a national study of anti-psychotic drugs called CAFE. According to the study, Dan would be randomly assigned to one of three standardly used drugs for psychosis, Seroquel, Zyprexa, or Risperdal (in the end, it was found, he was randomized to Seroquel).

These events take on a different coloration when you look at some of the relevant financial arrangements. The U. Minn. Department of Psychiatry had agreed to participate as one of the 26 sites in the CAFE study, and if they completed their role in the study, stood to earn $327,000, some of which would go personally to Dr. Olson. Specifically, Dan Markingson as a research subject was worth $15,000 to the University. AstraZeneca, sponsor of CAFE, had been on Minnesota's case earlier for insufficient subject enrollment. (The protocol called for newly diagnosed schizophrenics who had never been treated previously with drugs, a difficult-to-identify group.) Until Minnesota launched a special unit in its hospital specifically to screen all patients for potential research enrollment, the company had threatened to eliminate them from CAFE, putting their hoped-for funding in jeopardy.

From Mary Weiss's viewpoint, things were not going well at all. She was flabbergasted when told that her son, who was delusional and far from his normal self, suddenly was sufficiently competent to consent to a research trial. As she visited him over the ensuing weeks, she became convinced that whatever drug he was randomized to was simply not working, and that he needed a different treatment. She wrote numerous letters and protested in person to the Department of Psychiatry, which ignored her input totally. (It is pretty standard for psychiatrists, in my limited experience, to decide that the family members of psychiatric patients are either mentally disturbed themselves, or else are part of the environment that may have caused the psychiatric disorder in the patient, leading them to view the family member more as an enemy than an ally in therapy.) On May 8, 2004, Dan Markingson killed himself by mutilating his own body with a knife, leaving a note behind, "I went through this experience smiling!"

Dr. Olson and his colleagues expressed regret but not surprise that such a severely disturbed patient should have committed suicide, and noted that the research study could not have caused the death, as the three drugs were all in common use and in almost all circumstances, Dr. Olson would have started Dan on one of those three drugs, trial or no trial. In theory the research trial was to Dan's advantage because it assured closer monitoring. From Mary's point of view, Dan had been effectively coerced into the trial, being told that he'd be committed again unless he consented, and was unable at that point in time to make rational decisions about enrollment or nonenrollment. While the trial did not perhaps dictate the initial treatment, it certainly became a factor in keeping Dan on a treatment for many months while (as per Mary) his symptoms actually were worsening, as the University stood to lose their funding if he had been taken off the study drug.

The next to last chapter was that Mary Weiss sued the University and Dr. Olson. The court threw out the suit against the University arguing statutory immunity for a state institution. She collected, she said, $75,000 in a settlement with Dr. Olson which only went to pay her outstanding legal bills.

The last chapter is an especially sad commentary on the University as poor citizen of the community. Having gotten off the hook via statutory immunity, we would have expected the University to declare victory and retire from the field. Instead the U. took the unusual step of countersuing Mary Weiss to collect $57,000, which it claimed were its own legal fees in defending against her suit. Mary had no money to defend herself against the countersuit. She was forced to reach a settlement with Minnesota, one provision of which was to promise not to appeal her original ruling.

What are we to make of this countersuit? In HOOKED I discuss the phemonenon of SLAPP, "strategic lawsuit against public participation." A SLAPP happens when a powerful party with deep pockets but with a very weak legal position sues a citizen who's making noise about the issue in a way that's uncomfortable for the powerful party. The suit may have no real legal merit and is almost sure to lose when and if it comes before a judge. But the weaker party has no financial ability to pursue the lawsuit to its conclusion, and is forced to settle as quickly as possible. This usually is a strategy for sending a chilling message to anyone bold enough to criticize the powerful party--don't do it, says the message, or you may just find yourself entangled in a lawsuit from which it will take all of your money to extricate yourself. In this specific case, the purpose of SLAPP might have been to prevent an appeal that the University feared it would lose, especially if the behavior of Dr. Olson was viewed in light of the financial conflicts of interest.

CNN: Pfizer Too Big to Prosecute; Shadow Company Takes the Hit

A bit of ancient history: As I described in HOOKED, Australian business sociologist John Braithwaite, in the course of doing the research for his 1984 book, Corporate Crime in the Pharmaceutical Industry, was interested to discover that more than one U.S. drug firm had a position in the organizational chart informally called "vice president in charge of going to jail." The lines of authority were arranged so that, if the firm was ever caught doing illegal things, this particular VP would take the hit and thereby protect higher-ups from criminal prosecution; and that VP's compensation package included appropriate recompense for this service. This handy arrangement was later messed up by a U.S. Supreme Court ruling in a case called Park. According to Park, I gather, the court held that if a company did wrong, and somebody had to be blamed, it had to go up to the CEO. So the position of "VP in charge of going to jail" presumably went the way of the dinosaurs and the dodo.

Now fast forward to the present. According to a CNN special report:
http://www.cnn.com/2010/HEALTH/04/02/pfizer.bextra/?hpt=Sbin
--the old VP in charge of going to jail has been replaced with the shell company in charge of being prosecuted for the main firm's misdeeds. This is a much nicer arrangement as there really is no shell company, so no one has to go to jail, or to be paid extra for running the risk.

A number of media sources have been discussing the recent settlement between US Federal prosecutors and Pfizer over the off-label marketing of Bextra. (See my previous post on that topic, http://brodyhooked.blogspot.com/search?q=bextra.) The angle that most of the media have explored is that the actual amount of money paid out by Pfizer in fines and lawsuits, even though it tops $2B, is so far short of the profits the company made from Bextra sales as to be a mere pittance. (CNN calculates that Pfizer has so far paid out the equivalent of three months' worth of profits for a drug that was on the market for several years.) The documented fact that Pfizer was engaged in this illegal off-label marketing of Bextra at the same time as it was pleading guilty to earlier instances of illegal off-label marketing, and promising up, down, and sideways that it had learned its lesson and would never do those terrible things again, shows that for the big companies, these fines are nothing more or less than a cost of doing business and therefore fail to serve as any form of deterrent against future wrongdoing.

CNN chose to shine its spotlight on a somewhat different angle. As I covered in the previous post, the basic Federal problem in prosecuting Pfizer was that it is "too big to jail" in much the same sense that the global banking giants are "too big to fail." The law requires that if Pfizer were to be successfully prosecuted for criminal offenses, it would be immediately banned from doing any business with either Medicare or Medicaid. This would have two consequences. First, a large number of patients who now depend on Pfizer drugs, including some brand name products for which there is no generic substitute, would be unable to get their medicines. Those people and their physicians could be expected to set up an immediate howl that would quickly be heard in the halls of Congress. Second, unable to sell to such huge markets, Pfizer would probably go bust. That would lead to the unemployment of thousands of company employees, most of whom had nothing to do with illegal marketing, in the middle of a severe recession, and the resulting howl would be heard immediately in the halls of Congress.

What to do? The creative Feds have successfully prosecuted a company for Pfizer's misdeeds. That company freely admitted its guilt and as a result is now banned from selling any drugs to Medicare or Medicaid. The company is called Pharmacia & Upjohn Co., Inc. Old-timers might recall that both Upjohn and Pharmacia are former drug firms that were bought out by Pfizer and thereupon ceased to exist as independent firms. Pharmacia & Upjohn Co., Inc. has no assets or employees and manufactures no drugs. It exists only as an on-paper shell company, totally owned by Pfizer. It was actually invented back in 2007 by Pfizer for the same purpose, to take the hit for an earlier prosecution. Since it happened to still be around, on paper, it was the best target to take the hit for this latest offense as well.

As I reviewed in that earlier post, Ann Woolner wrote in Business Week that nothing today prevents the Feds from prosecuting a drug firm and its executives under misdemeanor instead of felony charges. You can throw somebody in jail for certain misdemeanors. If you want to send a message to drug companies that they cannot get away with illegal behavior, while avoiding the serious consequences of a company like Pfizer actually going out of business, the best way to do this (says Woolner) is to charge some of their top executives with misdemeanors and throw them in the slammer for 6 months or whatever the law allows. What we would now have to guard against is these execs setting up shell companies of themselves and telling the Feds to put that shell company into jail instead of them. I guess when you have that kind of bankroll to hire the country's smartest lawyers, anything is possible.

Pharma and the Gumshoes, Revisited

This post might best fit in the You Can't Make This Sort of Stuff Up category, but I'll try at the end to draw a meaningful lesson from it.

Eamon Javers at Politico recently revealed:
http://www.politico.com/news/stories/0310/35212.html
--that Amphastar Pharmaceuticals, Inc. paid more than $100,000 to a private investigation agency, Kroll, to snoop on Janet Woodcock, Director of the FDA's Center for Drug Evaluation and Research, and on Moheb Nasr, director of the FDA's Office of New Drug Quality Assessment. Turns out that Amphastar was suspicious because the FDA seemed to be dragging its feet in approving its generic-drug application for a low-molecular-weight heparin (anti-clotting drug). The company decided that maybe the FDA was favoring its rival company, Momenta Pharmaceuticals, and so set out to see whether Woodcock and Nasr had any ties to Momenta. They were especially suspicious because Woodcock and one of the co-founders of Momenta had appeared together on a program in Thailand in 2007.

In the end nothing suggestive of inappropriate ties or influence surfaced. One has to wonder about just what Amphastar got for its $100K. According to Javers's article, among the facts Kroll unearthed about Woodcock were her birthdate, the state in which her Social Security number had been issued, who her husband was, and the value of their home. Brilliant detective work, that.

Amphastar's general counsel protested "there was no impropriety" in its hiring Kroll and going after Woodcock and Nasr in this way. Sen. Max Baucus denounced the matter as "an outrage" and added, “Pharmaceutical companies should be focusing on getting their drugs approved based on health research and science rather than wasting their resources hiring private investigators to snoop around the lives of FDA regulators and their families.”

Much as I approve of Sen. Baucus's additional sentiments, I find his denunciation of Amphastar somewhat naive. After all, drug companies have observed how easy it is to wave around a wad of cash, and have academic physicians swarming around like flies on garbage, eager to grab their share in exchange for doing whatever the company wants. The companies figure that if it works for them, their competitors must be doing it too. From those observations it's a short jump to conclude that if people as high up on and social-respect ladder as academic physicians act like that, then FDA officials must, too. So this is simply a matter of rational calculation on Amphastar's part--except, perhaps, for the detective firm they hired. (Just kidding, Kroll folks; please don't start going through my trash.)

PS: If anyone wonders what the history is of drug firms hiring private eyes, read HOOKED on the Betty Dong case in which the pharmaceutical company used private investigators to try to discredit an academic investigator who got results the company didn't like. Or for a more colorful read, go to John Le Carre's novel, The Constant Gardener.