New Cholesterol Controversies: Regaining Perspective

Cholesterol drugs are making some of the big news this week. First, we read that Pfizer is facing a whistle-blower lawsuit regarding purported off-label marketing of Lipitor--trying to persuade physicians to prescribe the drug for lower-risk categories of patients than officially approved (for a wrap up see the WSJ Health blog, http://blogs.wsj.com/health/2007/12/20/a-jug-of-wine-a-loaf-of-bread-and-lipitor/). Then comes the news that Merck and Schering-Plough, already under fire for the delays in releasing the ENHANCE study of Zetia, have been hit by reports that they also have failed to publish other research showing liver damage in patients taking that drug. The risk is admittedly low, but apparently more than had earlier been admitted (see Berenson in today's New York Times).

It can be a bit challenging to keep all this stuff in perspective--what does it really mean for the treatment of high cholesterol? Here's my view.

Recall that Lipitor, along with Zocor and numerous other drugs, are all "statin" drugs, that reduce cholesterol levels by a mechanism that involves the liver. Zetia is a drug in a different family, that reduces cholesterol by other means. Vytorin is a combination pill that includes Zetia plus Zocor.

Who now is prescribed Zetia? As a rule, two major groups. First, people with high cholesterol but who cannot tolerate taking a statin for any of several reasons. Second, people taking a statin in maximum doses, whose cholesterol levels still remain about the guideline "target"
level, may then have Zetia added to the statin in hopes that two drugs will prove better than one in lowering the cholesterol, as indeed they usually are.

So one naturally wonders, as well as what the risks are for these people taking Zetia, just what benefits they might expect.

For Zetia alone, the answer is pretty clear. There is no evidence whatever, in the long term, that taking Zetia reduces your risks of having a heart attack, stroke, or other bad result from cholesterol messing up your arteries. ENHANCE was supposed to provide a glimmer of such evidence by at least saying what effect Zetia had on plaque inside the arteries, but even that has been held back, leading us to fear that the actual trial results were probably unimpressive. And even plaque thickness is a "surrogate endpoint," not a real outcome of interest such as stroke or heart attack.

So, if Zetia alone has no proof of benefit, what about adding Zetia to a statin? That in turn leads to the question--what evidence is there for giving a statin, and adjusting the doses, based on lab measurements of the patient's cholesterol level?

The majority of patients taking a statin for prevention of bad stuff have no known vessel disease, just a risk for developing it later. (This is called "primary prevention.") There are two physicians who have spent a good deal of effort looking at the statin-primary prevention story. They are James Wright of the Therapeutics Initiative project at the University of British Columbia, a well-staffed and well-respected group capable of doing independent analyses of drug trial data; and John Abramson, author of Overdosed America, who gave up medical practice for several years so that he'd have time to do his own number-crunching on the same data. They published their conclusions recently in Lancet, but earlier work on the statin question can be found at the Therapeutics Initiative newsletter:

http://www.ti.ubc.ca/en/TherapeuticsLetters

I believe that their data are persuasive, especially compared to "official" guidelines written by physicians of whom a majority have financial ties to the pharmaceutical industry, as I describe in HOOKED.

Wright and Abramson point out that there is very weak evidence for statins being good for primary prevention. The data are especially weak for two groups--women, and men over aged 65. Since statins overall are very weak for primary prevention if they work at all, there is little reason to get worried about how much they should lower your cholesterol, or what the ideal target level is that your cholesterol should drop to, or any of the other questions that physicians spend a lot of time obsessing about these days if they follow the official guidelines.

Secondary prevention--taking a statin if you already have known vessel disease, such as a previous heart attack--is quite different. The evidence seems very clearcut that statins really help prevent later heart attacks and strokes in that setting. I would go so far as to say that if I had a heart attack, the very first sip of water I took afterwards, I should be swallowing a statin tablet with, and keep on taking one daily as long as I lived.

So you would think, then, that since statins work for secondary prevention, it would make sense in that group to ask what the target cholesterol should be, or what the ideal dose of a statin is, right? Well, Wright's gang looked at those studies and could not find enough evidence to recommend any given target level to achieve, or any specific dose of statin to achieve it with.

The bottom line seems to me to be:

1. Zetia is unproven for anything of real importance.
2. Statins are of very litttle use for primary prevention. If they benefit anyone, they benefit men below age 65 who also have several other risk factors for cardiovascular disease.
3. Statins are excellent for secondary prevention, but we cannot say what dose you should take, let alone what target cholesterol level to aim for, to maximize that benefit--all we can really say is, take a statin.
4. All this business of checking your cholesterol level, and then adjusting the dose of the statin (or adding a drug like Zetia) if you are not reaching the target, is voodoo. It has basically been made up by well-intentioned "experts" but it is not based on firm evidence.

So if all that is true then we can draw the following conclusions about this recent news:

• There are far too many people already, so far as we know, taking statins; so any marketing that tells us that even more people need to be taking statins is probably a bad thing. (On the other hand, if any people with previous heart attacks, strokes, etc. are not taking statins, they should start.)
• Since there is no known benefit to taking Zetia, any added risk from taking it can hardly be justified.

A couple of footnotes. First, I have said nothing here about how statins compare for either primary or secondary prevention, to lifestyle changes such as diet and especially exercise. Dr. Abramson has some choice words on that subject in his book, and they are not friendly to statins. Second, Alex Berenson in his great NYT article today mentions in passing that when the FDA approved Zetia, they relied on studies looking for possible side effects that lasted, at a maximum, 12 weeks. That is for a drug that is designed to be taken for a lifetime, and where other cholesterol-lowering drugs are known to have side effects that may not show up for months or even years after the drug is started. That fact alone is unconscionable; and shows again how the FDA, at least until very recently, was the industry's lapdog. (And even the 12-week-long studies revealed some concerns about liver damage in people taking Zetia, which was then glossed over!)

Berenson A. Data about Zetia risks was not fully revealed. New York Times, Dec. 21, 2007.
Abramson J, Wright JM. Are lipid-lowering guidelines evidence-based? Lancet 2007; 369:168-9.

License Drug Reps? Sorry, Dumb Idea

The Washington Post reports on this week's DC City Council vote (7-6) to require licensure for pharmaceutical reps:

http://www.washingtonpost.com/wp-dyn/content/article/2007/12/11/AR2007121102284.html

Now there are several reasons that I should be in favor of this:

• It seems to be giving PhRMA the fits.
• The sponsor of the legislation, council member David Catania, seems to be a very nice fellow who is getting a solid reputation for his involvement in the pharmaceutical marketing issue nationally.
• It seems to be giving PhRMA the fits.

Sadly, I am obligated on this blog to try to be responsible and not give in to my baser nature, and so I must report that I cannot see any practical justification for this proposal.

The drug rep problem in medicine could be solved overnight. Tomorrow, all physicians could wake up and discover that they possess an interesting ethical organ, known as a spine. (They could also, if they are of the male persuasion, discover that they have a couple of other organs that might be relevant, which I will not go into here.) Utilizing this new-found piece of anatomy, we could decide that from now on we will get our information on drugs only from reliable, non-commercial sources, and that we will make do without the corrupting influence of the cornucopia of gifts from the industry. The industry would immediately lay off all the reps, since if no doctor is willing to see them they are useless.

Problem solved, and no licensure apparatus needed.

Obviously this will not happen overnight, so the licensure thing would be worth thinking about if 1) it might move us incrementally closer to that Promised Land; or 2) it would be of sufficient symbolic value that it would energize and enlighten the masses for the remainder of the work to be done. I admit that I am not sufficiently imaginative to see either of either of those other consequences coming to be. Licensing reps just doesn't have that energizing zing that a really useful symbolic act can have. And it seems unlikely to do anything of substance to make the drug rep problem any more manageable in the short run.

Now, I have been wrong before. I initially was wary of the legislative proposals to outlaw data-mining of prescription information, which has been a big issue among my esteemed colleagues in the National Physician's Alliance (http://npalliance.org/). I now see that those policy measures have in fact been more useful than I imagined they would be, even if only for rallying physicians. So maybe somebody can talk me into switching sides on the DC City Council. But I remain to be convinced. And just because something gets PhRMA's knickers in a knot is not a sufficient reason to favor it, as tempting a criterion as that is.

Much Ado in Springfield, IL

OK, guys, it is a long story, for a town that used to seem like nothing much happened there since they buried Abraham Lincoln in 1865.

The first thing that happened is a drug rep dinner gone sour, which has ended up in threats from some local docs of a libel action against a drug rep whom they accuse of sending out poison pen letters about them. The brouhaha attracted the notice of a local health reporter, Dean Olsen, to whom I'm grateful for most of this information. The newspaper, the State Journal-Register, quite correctly noted that while the flap between the drug rep and the docs was the apparent headline, the real story had to do with the ubiquity of these dinners and the way that the industry woos physicians, and addressed these larger issues in a nice editorial:

http://www.sj-r.com/Opinion/stories/21714.asp

The editorial itself is interesting, but especially interesting is the strong of comments e-mailed in response. (I'm writing this as there are 34 comments posted; by the time you log on there may be more.) Seems like this issue really struck a nerve. On the one hand is an avid free marketer who is upset at any suggestion that drug reps should be restricted or regulated, and is quite blunt about what this is all about (selling, not "education"):

So now the SJR is against sales people? I dont see a problem with the drug reps hosting dinners for the Doctors. If you have ever been to a doctor's office, you will notice that they are very busy. The only time a drug rep has a chance to meet with the doctor in order to sell his drug is usually at on off site event.

Some folks responded as you'd imagine they would, and so this commentator came back with:

So, you guys are saying that it is wrong to take someone to lunch or dinner? Jeez, get with it, that is the way business works. Maybe not in your liberal textbooks taught by bearded professors who enjoy tenure and never have to work for a living but it is reality. Business entertainment is not limited to health care. They all do it. Why? Because it works. I took a client golfing in North Carolina. Why? I got to spend 8 hours with the guy discussing the benefits of my product. And why do you say that the sales people lie? Honestly, I think the customer lies much more often than sales people. Bottom line is in order to sell your product you have to tell people about it. This dinner was a way for the drug rep to bring his expert in and speak with the doctors.

(Note to anyone interested: I do not have a beard.)

Another commentator came to the reps' defense as the bearers of samples:

So the SJR wants freebies stopped. OK - then the paper can explain to patients who cannot afford their medication why free samples are no longer available. For some, the free samples left by drug reps are the only access they have to necessary medications. How many times have you gone to the doctor and left with samples of your medications? Did you enjoy not having to pay for them? Thank a drug rep (and his/her company!). Granted, drug companies are not all wonderful, but they and their reps are not truly evil either. Everyone needs to get their facts straight about how drug reps REALLY do their jobs before slinging insulting and erroneous opinions. It is hard work that often does NOT result in the doctor writing your drug. BTW, no, I am not a rep, just someone who actually cared to be informed before judging others.

Someone else added approvingly:

Thank goodness for the free samples the drug rep give out. Without them and their free samples, we would have a national health care crisis.

Whew! And here I thought we already had a national health crisis. Silly me.

This could go on forever but I will close with a comment from someone who sees it from the restaurant side:

Several years ago I worked for a restaurant that was attempting to build up it's lunch delivery business. Quite by accident I discovered the "drug rep" market and immediately capitalized on it since I was on commission. I also discovered that there were many local doctors who would only see a drug rep if they provided lunch for the entire office staff - no exceptions. The doctors considered it a perk that they were providing free daily lunch for their staff even though it didn't actually come out of their (well-compensated) pockets. Guess who really pays for all these free lunches. You and me, every time we buy medicine. Very few people know about this corrupted system unless they work in this industry. I believe this should be regulated the same way we've restricted the way our elected representatives can be lobbied (which isn't perfect either, but better).

AMSA's Pharm-Free Campaign; Student Activism at UNC

Anthony Fleg, a medical student at UNC-Chapel Hill, is also the leader of the American Medical Student Assn's Pharm-Free Campaign. He kindly alerted me to several developments, including the updated website for their Campaign:

www.pharmfree.org

Anthony and his fellow students have been agitating at their own school to try to limit drug company marketing influence-- see some excellent publicity they gleaned:
http://wunc.org/tsot/archive/sot1205a07.mp3/view
http://triangle.bizjournals.com/triangle/stories/2007/12/03/story2.html?b=1196658000^1557919

The Public Radio story (first link) has a great interview with ethicist Dr. Philip Rosoff at Duke, who pulled no punches in describing the ethical problems raised by Pharma's influence over academic medicine. The newspaper account (second link) is interesting in featuring an interview with Dr. John Buse, one of the medical faculty at UNC. I recently had occasion to reflect on Dr. Buse's case on this blog:

http://brodyhooked.blogspot.com/2007/11/intimidation-of-dr-john-buse-some.html

Not too surprising, Dr. Buse was concerned in his interview about losing the funding the drug companies provide if UNC gets too picky about its ethics.

The Public Radio interview also gave some play to the "report card" that AMSA did of all US medical schools. (They gave their own school, UNC, a "C minus.") Since I have your attention, I will add that we squawked loudly when they gave us an "F" here at University of Texas Medical Branch in Galveston; we thought we deserved at least a C-minus by their official criteria--not that that is much to be proud of. All that goes to say is that the "report card" has turned out to be a very useful publicity device--kudos to the students for thinking of it. AMSA can continue to put the rest of organized medicine to shame for the excellent job they are doing on this issue.

On the Pediatric Treatment of Post-menopausal Women

Some time back, Congress decided to do something to support pediatric research. A recurring problem is that drug companies do not do clinical trials of drugs in children, and so pediatricians have to more or elss guess what doses to use based on adult trials. This occurs because the sales in the pediatric age group might not be great enough to provide an incentive for extending the drug's FDA-approved label to kids. Thinking that the industry needed a carrot, Congress passed a law that allowed a 6-month patent extension on the drug for doing appropriate pediatric research.

Critics of the industry, like Marcia Angell (The Truth about the Drug Companies) charge that Congress miscalculated, and that the value of the 6 months of extra patent protection is now so high that companies are testing drugs that will never realistically be used in kids, just to get the extra patent life.

A recent example of this seems to be the following news release:

http://www.astrazeneca.com/pressrelease/5362.aspx

Arimidex is currently approved by the FDA for use among post-menopausal women in treating breast cancer. AstraZeneca was very happy to announce that it has received an extra 6 months of patent protection due to their conducting pediatric research. Apparently the company decided that maybe conditions in kids that result from excess estrogen, such as breast enlargement in pubertal boys, might be helped by the drug. After doing the research, said the company, they concluded that they would not seek any FDA approval to use the drug in children, after all. (Surprise.)

Out with the Reps, In with the Internet

A while ago, us critics of the medicine-Pharma interactions thought that we might prevail if we could only convince physicians that their cozy interactions with drug reps were not as "back room" as they thought but actually were occurring in a fishbowl--that patients and medical students, for instance, were seeing all this happen and not liking what they saw.

Maybe it worked.

The AP reports that the industry is now intent on scaling back its face-to-face rep action in favor of selling over the Internet:

http://ap.google.com/article/ALeqM5jsqQWRot1GZFb2B489NfPcSwboBAD8TARALG0

There are a number of factors at work--the drug rep arms race that admittedly, to most industry insiders, flooded the market with too many reps; the rising costs of marketing coupled with fears of lower profits as blockbusters go off-patent; and the times, with many of us staying away from the mall so that we can shop on Amazon and eBay.

The article from AP states that docs in many cases refuse to see reps at the office, but are willing to spend 10 minutes talking with a rep by phone as the rep directs the doc to an Internet site with glitzy video presentations about new drugs. The article is silent on the gift angle. Most home computers, last I heard, are not set up to dispense gourmet dinners, or even pens and mugs; so the doc cannot get rewarded as per the old-fashioned rep visit. I believe that e-mail or mail vouchers for various benes have been used in connection with Internet marketing, but this particular story provides no details, and I'd like to hear more from others in the know.

Is this a good or bad development? If, by chance, the gift element has been removed (which I doubt), then maybe things are better. But we still have docs using commercially biased sources of information instead of doing some independent thinking and searching for more reliable data, which cannot be good for patients.

Off-Label: What Are the Issues?

The Prescription Project blog has several links to recent news coverage of the FDA's proposed rules change that would allow companies to market off-label uses of drugs in very limited ways (Dec. 7 posting):

http://prescriptionproject.org/blog/

What I want to do here is to lay out some concerns about the entire "off-label" issue. My worries are that we have been a bit lazy in attacking Pharma's sleazy marketing behavior. Given our natural outrage over the real violations of scientific truth and integrity, we can easily fall into the trap of deciding that anything that places any limits at all on Pharma marketing is a good thing, independent of the actual merits of the proposal. I am afraid that the "off-label" debate has done us the disservice of creating a dichotomy that is not valid--that "on-label"/"off-label" somehow corresponds to good/bad or rational/irrational uses of drugs.

True confession time--in 26 years as a family physician, I probably prescribed a lot of drugs off label. Even truer confession--when I prescribed drugs off label, a good deal of the time, I had no idea that was what I was doing. How could this be?

The basic fact is--how does a practitioner know what is on-label? You have to read the label. How do you do that? The easiest way is to look up the drug in an industry source such as the infamous PDR. There, the label hits you square in the face. Indeed, everything in the PDR is the label and only the label. For that reason we try to teach our med students and residents not to use the PDR as their primary reference source on drugs.

So instead of using the PDR, I look up the treatment for a given disease in a reference that appears to me to be reasonably evidence-based and non-commercial. Now, in so doing, that source might mention which uses of the drug are listed on the label. But my main concern is not that, it is what drug is good for that disease. So I could easily miss noticing the details about the labelling.

All of the above might simply mean that I was a rotten doc. But the following considerations clearly show that "off-label" is hardly synonymous with bad or suspicious prescribing:

1. The great majority of pediatric prescribing is off-label as many very useful drugs have never gotten formal FDA approval for use in kids.
2. When an old generic drug is found to be useful for a new disease--such as hydralazine and isosorbide in combo for heart failure, especially in African-Americans--its use will certainly be off-label, as the generic manufacturers will never pay to do the new clinical trials needed to expand the FDA labeling.
3. Like everything else in Pharma, the decision as to what studies to fund or not by the industry is a marketing decision, not a science decision. The fact that a given indication for the drug was not researched, or that supporting studies were not submitted to the FDA, may have precious little to do with whether that drug is any good or not.
4. And, finally, we all know examples where the FDA labeling process has simply not kept up with what reasonable medical judgment is aware of. The makers of Neurontin were quite legitimately taken to the woodshed for their off-label marketing of the drug for numerous psychiatric disorders, for which it is probably no good. At the same time, the use of Neurontin as adjunctive treatment of chronic neuropathic pain was probably a reasonable choice, even though equally off-label.

Is it a good or bad idea to allow drug companies to market off-label uses? Knowing how the industry can drive a Mack truck through any tiny opening we allow, maybe the best choice is to keep the strictest limits in place. But I cringe when people get sloppy about "off-label" and suggest that the term has some real, medical (as opposed to regulatory and bureaucratic) significance.

More on the True Role of Drug Reps

This post provides no surprises for anyone familiar with these matters, but the quote that follows is so direct and succinct that I could not refrain from putting it out.

Shahram Ahari, former drug rep and now faculty member in Pharmacy at UCSF, has become deservedly prominent among critics of Pharma for publications such as:

http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0040150

Recently (Nov. 8) Mr. Ahari spoke to Capitol Hill staffers regarding the Sunshine Law that would require disclosure of all Pharma payments to physicians nation-wide. He kindly shared his testimony with the National Physicians Alliance. He said, in part,

Part of our job as reps is to cultivate the illusion that doctors can’t be swayed by measly drug reps. And we help the doctors rationalize this by being one of the few friendly faces to enter their office not complaining about their symptoms or paperwork. Doctor, how can you who has 4 years of graduate education plus many years of training be swayed by little old me?

We all know that when physicians protest that they are immune to the marketing wiles of the industry, it's rationalization and not reality. This quote simply drives home what we have long realized, that the rationalization process is very much in the interests of the industry, and they are prime enablers in our own unprofessional behavior. (We docs must still own our own lack of professionalism and our willingness to lap up these convenient rationalizations from suspect sources.)

Drug Industry: Business Is Bad, Part II

My earlier post on this topic--

http://brodyhooked.blogspot.com/2007/11/drug-industry-business-is-bad.html

--was based on an article in The Economist. This time it's the Wall Street Journal that has discovered mostly the same set of facts.

Key quotes:

"Over the next few years, the pharmaceutical business will hit a wall... Generic competition is expected to wipe $67 billion from top companies' annual U.S. sales between 2007 and 2012... that is roughly half of the companies' combined 2007 U.S. sales... 'I think the industry is doomed if we don't change,' says Sidney Taurel, chairman of Eli Lilly... 'The era that created the modern pharmaceutical industry is in fact over,' said Richard Evans,...pharmaceutical consultant... Pfizer is slashing 20% of its sales force, AstraZeneca is cutting 10% of its employees and Johnson & Johnson is shrinking its staff by 4%..."

Some points that seem new to this article: it is suggested that the industry's huge investment in centralized, expensive research based on discovering new molecules and then figuring out what they might be good for, is in part to blame for the dry research pipeline. It may be the case that you simply cannot do science on an assembly line. You need to understand basic biological mechanisms before you can find the next generation of new drugs. Hence, as noted previously, the industry's current love affair with biotech, both buying up biotech firms and creating in-house biotech units.

If you can't lick 'em-- as it seems that the generic manufacturers are getting ready to profit handsomely as popular drugs go off-patent in the next several years, the big companies are ramping up their own generic units to get a bigger piece of the action.

"The dearth of new products has led the industry to invest heavily in marketing and legal tactics that squeeze as much revenue as possible out of existing products." Well, duh-- hence this blog. If the companies were making windfall profits by discovering and selling new drugs that made us all healthier and that cured deadly diseases, there would be no complaints.

Martinez B, Goldstein J. Big Pharma faces grim prognosis--industry fails to find new drugs to replace wonders like Lipitor. Wall Street Journal, December 6, 2007, A1.

"Intellectual Bias": Latest Salvo from Pharma against Reformers?

Okay, I will admit this--I have officially become paranoid. Where others see only individual actions, I now see an orchestrated conspiracy. In a way my paranoia is self-congratulatory. Because those of us who are advocating serious reforms in the medicine-Pharma relationship are finally starting to be heard, we now threaten the industry sufficiently to make us worth powder and shot for a counter-attack.

The first form of counter-attack I became aware of is efforts by industry apologists, like law professor Richard Epstein at Chicago, to re-define "conflict of interest" so that it no longer worries us as an ethical issue. (I'll address that in another venue.)

The second form of counter-attack, I will suggest, shows up in this month's issue of Critical Care Medicine, in the form of a charge of "intellectual bias."

In an exchange of letters to the editor, three NIH scientists, Peter Eichacker, Charles Natanson, and Robert Danner, attack critical care guidelines promulgated by the Surviving Sepsis Campaign. They detail their disagreements with the position those guidelines took in recommending the very expensive drug, Xigris (recombinant human activated protein C) sold by Eli Lilly. (HOOKED details the earlier chapters in the Xigris saga, when Lilly recruited some of my own colleagues in bioethics to inveigh against "unethical rationing" of care in ICU's when many intensivists read the literature and decided that Xigris was simply not worth its high costs.) They point out the many avenues of commercial influence on the SSC, and how other medical groups in Europe and elsewhere are calling for new studies or otherwise rejecting the SSC's advice.

Two members of SSC, Phillip Dellinger and Charles Durbin, then proceed to reply, mainly in the form of accusing the NIH scientists of having no real evidence to back up their claims and yet repeating their attacks on Xigris incessantly despite having no evidence. Here is the key paragraph:

Drs. Eichacker, Natanson, and Danner accuse the SSC of being biased toward industry, yet fail to acknowledge their own intellectual (academic) bias. This form of bias can be defined as presenting personal, entrenched beliefs as scientific truth in an area where no clear-cut consensus exists. We believe this intellectual bias can be more insidious and damaging than the potential bias arising from affiliations with industry.

Now, this is quite a piece of work. The NIH scientists believe that the preponderance of the scientific evidence supports their point of view. The SSC guys believe the same for their own point of view. That makes the NIH people guilty of "intellectual bias" while the SSC remains innocent of that sin.

What is even more breathtaking is that intellectual bias (whatever that turns out to be) is actually much worse than commercial bias. As I have reviewed in HOOKED and on this blog, and as numerous meta-analyses and systematic reviews have shown, commercially sponsored studies are roughly 4 times more likely than neutral studies to favor the company's drug. So commercial bias has been shown to be real and substantial. Against that empirical proof, we are being invited to dismiss commercial bias as no big deal, but to quake in our boots at the possibility of "intellectual bias."

The implicit subtext, as best as I can read it, is that people ("academic intellectuals") who work at NIH, or at universities that believe in avoiding conflicts of interest with industry, are some sort of ivory-tower, goody-two-shoes weirdos. They think they are intellectually superior to the rest of us mere mortals, and the best thing to do with these insufferable twits is to ignore them. By contrast, scientists who jump into bed with industry at the first opportunity are regular people just like us, and are hard-headed, pragmatic realists. Their take on the world is much more reliable.

Stay tuned. I expect to see charges of "intellectual bias" repeated regularly whenever Pharma feels that it is being placed on the defensive by demands for reform.

Eichacker PQ, Natanson C, Danner RL. Separating practice guidelines from phramaceutical marketing [special letter to the editor, with reply]. Crit Care Med 35:2877-80, 2007.

A Couple of New Blogs/Sites

This is a quick message to alert readers to some sites I just became aware of today. First, anyone lusting for an illustrated inventory of all the goodies that drug reps leave for doctors can find it at:

http://drugreptoys.blogspot.com/

You might want to do your on line Christmas shopping here.

Next, it seems that some HIV physicians have taken off the gloves and gone after their peers who are scarfing up the big bucks from the drug industry. The site is not afraid to name names:

http://www.shillfactor.net/writereport.html

It has long seemed a problem to me that being a paid shill for the industry is apparently a no-consequences move for an academic physician. A few more websites like this one and that could change.

Are Devices Different from Drugs?

John, Swen, a Pfizer VP, asked a very good question at a health policy forum in Minneapolis last month. Minnesota, as I have noted in earlier posts, has one of the most stringent programs in the country for recording and publicizing the money that physicians in the state get from drug companies. So why, said Swen, do the device companies get a pass? Why does the law only apply to drug manufacturers? The Pioneer Press reported on the debate:

http://www.twincities.com/ci_7505789?IADID=Search-www.twincities.com-www.twincities.com&nclick_check=1

Essentially two answers were given in the article, neither satisfactory. First, it was admitted that when the current laws were written, device makers were simply not on anyone's radar screen. Second, many medical device companies are based in Minnesota and have a lot of political clout.

The question, "Are devices just like drugs or not?" keeps popping up and so I am going to restate the case without offering a definitive answer--and invite comments from you readers.

I can think of two ways in which the device industry differs in some basic way from the pharmaceutical industry. Please bear a couple of things in mind as I explain these two things. I am, by training and experience, a family physician. We family docs are not big-time device users. So I am left at a disadvantage in talking about this topic compared to surgeons, cardiologists, and other specialists whose bread and butter involves medical devices. Also please bear in mind that the end result of all this talk is supposed to be the benefit of the patient. We are not trying to rein in pharmaceutical industry influence, and get greedy docs to clean up their act, simply so we can all get gold stars in the teacher's grade book. We are trying to reform this system because of our conviction that at present, it is not serving the patient.

So, my nominations for how devices are legitimately different from drugs and so may mandate a somewhat different regulatory approach:

1. Several academic medical center policies that basically ban drug reps outright do not ban device reps, and I think that is justifiable. I don't need a drug rep on site to show me how the patient is supposed to swallow a capsule. Virtually all the information that I need to know about how to prescribe a drug could be provided to me in writing. For many devices this is not true. The company rep may be in fact a skilled engineer. Many devices need fine adjustments to work properly and the company staff may know much more about how to make these adjustments than anyone else in the hospital. And the adjustments may well require a hands-on demonstration if the physicians and nurses are to become adequately skilled at using the device.
2. Just as device reps have knowledge that physicians really need to take good care of patients, some physicians have knowledge that device manufacturers truly need to design the next generation of devices. In today's world, I doubt that a single drug is ever discovered or developed as a result of a practitioner calling up the drug company and saying, "I sure wish I had a drug that I could give my diabetic patients who have foot pain." The company's in-house scientists know far better than any practitioner what classes of molecules are out there that could become new drugs, and what bodily functions those molecules affect. But I assume that many medical devices are developed because, say,. an orthopedic surgeon calls up the company and says, "This artificial hip that you make is pretty good but I find it a bit awkward to apply the cement. Now, it dawned on me that if you modified the surface where the prosthesis attaches to the femur, the cement would go on a lot easier and you could have a much more secure attachment." (Or however they attach the danged thing--I have no clue.) So there is much more room for legitimate consulting between the company and a group of medical specialists in the device than in the drug case.

That said, there is one obvious and glaring similarity between gifts and consulting/speakers fees paid from device companies and drug companies to docs: at least some of these payments, if not the majority of these payments, are thinly disguised bribes to use the drug/device rather than an equally good drug/device made by a competitor company.

I would invite the executives of the device companies, if they want transparency and reform as much as some of them have said in Minnesota, to help legislators and regulators decide which payments are which. I also propose that medical professionalism remains an important part of the equation here because it is often the case that if there is a difference, the physician who gets the fee knows it--though the ability of physicians to go into rationalization-and-denial mode when their gravy train is interrupted is probably just as great on the device as on the drug side. Meanwhile I invite readers to comment at will.

"The Intimidation of Dr. John Buse"--Some Further Lessons

The recent report by the staff of the Senate Finance Committee on how GlaxoSmithKline tried to silence an early critic of Avandia who called attention to the drug's cardiovascular risk in 1999 has received some play in the press and among my esteemed fellow bloggers. I'm grateful to have had my attention called to the complete text of the Finance Committee report, as it raises some issues that may not have been fully exposed:

http://finance.senate.gov/press/Bpress/2007press/prb111507a.pdf

The basic story mirrors a previous case, Dr. Gurkirpal Singh of Stanford University, whom Merck tried to warn off from making critical statements about Vioxx's heart risks. Dr. John Buse is a distinguished research endocrinologist at the University of North Carolina. In 1999, Dr. Buse gave several talks at national conferences in which he warned of increased heart risks from the diabetes drug, Avandia--risks that this year led to the FDA requiring a black box warning, though it seems only fair to say that the case has not been definitively proven. GSK (back then, SmithKline Beecham) went into frenzied activity to shut him up. The consultations on how to manage the Buse problem went all the way to the CEO. Dr. Tachi Yamada, the company's research director (and now research head of the Gates Foundation) was directly involved in talking both with Dr. Buse and with his department chair. The end result was that the company drafted a letter which Buse referred to as a "clarification" and the company internal memos call a "retraction," and Buse effectively was silenced from making any more claims in public, though he continued to express his reservations in private.

So now we have the standard melodrama--GSK is the dastardly villain and Dr. Buse, plus all the patients who may have sufered from heart disease from taking Avandia, are the innocent victims. Or does this script hold water? Specifically, what made GSK so outraged that Buse had spoken up; and what made them think that they could succeed in reining him in?

A close reading of the documentary record that the Senate Committee staff compiled yields a number of facts. Dr. Buse was a consultant (presumably paid) for both SmithKline Beecham who made Avandia, and its competitor, Takeda-Lilly, that makes the closely related diabetes drug, Actos. (Actos seems to be sufficiently different in its chemical mechanism that it does not create the same heart risk that is seen with Avandia.) When for example SmithKline Beecham executives labeled Buse, in a series of internal e-mails, the "Avandia Renegade," were they referring to an independent academic stating his scientific views--or were they referring to the fact that one of their paid agents seemed to be turning on them? Or suggesting that Buse was a double agent who was now in the pay of their rivals and therefore tearing down Avandia to boost Actos sales?

In 2000, Buse seemed to be doing all he could to be conciliatory to the company. He even proposed to GSK that they give him money to sponsor a continuing medical education program about the use of all drugs in the same class, and that he had similarly approached Takeda for their financial support. He argued in his message that it would be a good thing for both company's marketing of their drugs that they were seen publicly as burying the hatchet, and that such a joint CME program had the potential to "grow interest in the class [of drugs] as a whole"--that is, that more doctors would prescribe both Avandia and Actos. An interesting posture, it now seems, for a doctor who is supposedly a hero for trying to call early attention to the risk of heart disease among patients taking Avandia.

In 2002 the internal GSK memos are singing a different tune. The company is worried because he was becoming the "most powerful Endocrinologist in the Carolinas," so that extending more olive branches (and money) in his direction would be a good move. GSK was trying to launch a new combination drug that combined Avandia with metformin, an old standby generic diabetes drug. In one memo a GSK official asks another, "It looks like marketing would like us to move forward using Dr. Buse as an investigator in the Avandamet program. Are you OK with this?" (That is truly an interesting question. Why is marketing, not research, deciding who should be an investigator in what is supposedly a research program? Say goodbye to any pretense that these firms are about science and not about sales.) The Senate Committee documents do not say if Buse became an Avandamet investigator and how much more he might have received in research grants or consulting fees.

I agree that it is bad when companies try to intimidate scientists to keep quiet about potential drug risks. But what about the academic physician-scientists, who think that they can ride the tiger and still stay in control? Dr. Buse, it appears, thought that on the one hand he could pocket his consulting fees (and perhaps speaker fees as well; we are not told) from these drug companies; and on the other hand could freely speak his mind as an academic scientist. His new owners told him in no uncertain terms that once the business deal had gone through, he had better remember who was calling the shots. Buse himself seems to have gotten the message as to who owns his opinion--when the press approached him recently to say something nasty about GSK, he refused, saying that the matter was over years ago, that they had apologized to him, and he was eager to let bygones be bygones.

My central message in HOOKED is: when we physicians are lacking in our own professional integrity, pointing fingers at the bad drug companies is hardly an adequate ethical response.

Carlat's "Dr. Drug Rep"--Some Further Possibilities

Dr. Danny Carlat, editor of the Carlat Psychiatry Report and keeper of another great blog on the problems with industry influence in medicine, has written a must-read article in the New York Times Magazine. I'll let his blog entry tell you about it and guide you to the article itself:

http://carlatpsychiatry.blogspot.com/2007/11/dr-drug-rep.html

Very briefly, the article tells about Dr. Carlat's saga into and out of the world of paid drug company speaker--how he was initially wooed, wined and dined; how he rationalied the message he was giving to his medical colleagues (while pocketing a cool $30K in extra income); how he began to have doubts about the ethics of his role as he saw new research data showing that the drug he was shilling for was not all that great; and how he eventually regained his integrity and parted company with the company.

It may seem like piling on to pick any holes in Dr. Carlat's riveting and well-told story; and indeed he provides an excellent model of how good doctors ought to read the medical literature with a critical eye. Here I just want to add an angle that he appears to have left out.

Dr. Carlat initially assumed that he was "hired" by Wyeth for one reason--they wanted to "educate" other physicians in his area about why Effexor XR was the best antidepressant and why they should prescribe it as their first choice. As a physician he could command more credibility than a mere drug rep, and so of course his talks were of great value to the company. That explains why it was worth $30K to them to have his services.

In what way did he come to change his mind? At first, Dr. Carlat was himself a true believer--the data seemed to support Effexor's superiority. Later, he became a relative skeptic about Effexor, and perceived that as his enthusiasm for the drug slacked off, his Wyeth handlers were quick to point out his deficiencies as a speaker. In other words, his opinion changed about the ratio between real education and pure marketing contained in the talks he was giving.

What no reader of the article will take away is the possibility that the real reason Wyeth hired Dr. Carlat was to pay him $30K in bribes to get him to prescribe more Effexor in his own practice.

That sounds crazy, right? How can it be worth it to a drug firm to pay a single doc $30K just to prescribe more to his own patients? But consider two facts.

The first fact is sort of buried in Dr. Carlat's article. He mentions that we do not really know how many physicians are paid drug company speakers; but some data are consistent with it being 25 percent. A quarter of U.S. physicians are paid speakers? A quarter of us are really talented and entertaining educators? A quarter of us are so good with statistics that we can make sense of the most complicated research studies? Get real. If fully a quarter of us are out on the road giving talks, who's staying behind to hear the talks?

How about nurses? See my earlier post about what happened in Minnesota when they actually clamped down on the free dinners to docs (http://brodyhooked.blogspot.com/2007/10/if-you-dont-feed-them-they-wont-come.html). The drug companies could no longer get away with taking docs out to a lavish dinner to hear the spiel from one of their paid speakers. And without the free food the docs would not show up. So what did the companies do? Tell the speakers, sorry, we can no longer uise your services?

Hardly. They started inviting nurses to the talks instead of doctors. You might think, well, that makes sense; the nurses often have some influence over what medications the docs prescribe so this is a good indirect way of influencing the physicians. But Gardiner Harris, who wrote this up for the New York Times, made it clear that that was not the drug company's angle.

The point was, the speaker-docs were the local high prescribers of the company's product. It was essential for the companies to reward them for their good behavior. They were going to go on paying them to speak, come hell or high water, even if they had to fill the seats with life-size cardboard cutouts of people. (Harris, by the way, also pointed out that Dr. Carlat needed a better agent. The Minnesota top speakers easily pull down $100K a year.)

I know nothing about Dr. Carlat's own practice. But it seems reasonable to conclude that somebody at Wyeth added up the numbers and figured out that if they paid him to speak about Effexor a couple of times a week, somebody might listen to him and somebody might not. But the bottom line was that Dr. Carlat himself was going to find it very hard to prescribe anything except Effexor to his depressed patients. And those extra scripts were worth a certain amount to Wyeth.

And many of our colleagues still regard all this as "education."

Ghostwriting: Some Updates

Ghostwriting, as I discuss in HOOKED, is one of the hardest practices at the medicine-Pharma interface to get a grip on. All parties to the transaction--the academic physician whose name appears as the author of the article; the medical writer who actually wrote the article; and the drug company that funded everything--either are paying good money, or are paid good money, not to talk about any of it. Yet if anything at all in the medicine-Pharma relationship ought to be an ethical no-brainer, this is it. It can never be right for people to lie, in print, in the pages of medical journals, about who did or did not write something. And for the academic physician, accepting money to put your name on an article you did not write, and henceforward listing that article in your curriculum vitae as if you had written it, has to be the slimiest of unprofessional behaviors.

For all these reasons, even brief anecdotes about ghostwriting are worth taking note of. Here are a couple (one thanks to Roy Poses' excellent Health Care Renewal blog-- see Links).

Most recently, Jean E. Sealey, professor emerita of physiology and biophysics at Weill Cornell Medical College, went public with an approach she had received to "write" a review on the new anti-hypertensive drug nebivolol (Forest Laboratories):

http://blogs.wsj.com/health/2007/11/21/odd-ghostwriting-offer-raises-researchers-blood-pressure/

One of the commentators astutely asked why the Wall Street Journal placed this news item on its blog instead of doing an in-depth story in its print edition.

Going back a little ways, Danny Carlat, in his own excellent blog on psychiatry issues (http://carlatpsychiatry.blogspot.com/), reported on a paper for which one of the listed co-authors is Dr. C. Lindsay DeVane, Professor of Psychiatry and Vice Chair for research at the Medical University of South Carolina. The paper is a summary of a discussion that occurred as part of an "Expert Roundtable," and was published in the May 2007 issue of CNS Spectrums, where it was listed as eligible for CME credit:

http://carlatpsychiatry.blogspot.com/2007/09/author-calls-his-own-cns-spectrums.html

Dr. DeVane told Dr. Carlat that this paper is a "piece of commercial crap" and that the views expressed there are not his. He had not read the final version before it was published. The article was written after the discussion by a medical writer hired by i3 CME and funded by Bristol-Myers-Squibb. Dr. DeVane told Dr. Carlat that he found the draft text, which he was shown, "inaccurate, simplistic." He did not say whether he requested or demanded the right to edit "his" article. Neither Dr. DeVane nor Dr. Carlat addressed the question of 1) why Dr. DeVane allowed his name to appear on this article if it is untrue with regard to his views on the subject; and 2) whether any money changed hands at any point in the process. (One would assume that Dr. DeVane was paid expenses plus an honorarium to speak at the symposium, at the very least).

Just by way of further illustration of how hard it is to get a handle on the ghostwriting issue, I recently told a colleague of mine, who spends a lot more time than I do hanging out with journal editors, that the highest amount that I had ever been able to find in print, for the sum paid to the academic "author" of a ghostwritten paper for the privilege of using his name, was $1000. My colleague merely snorted.

Here We Go Again: Everything That's Wrong with Industry Sponsored Trials, Chapter 77

Alex Berenson wrote recently in The New York Times about the delay in reporting the results of the "Enhance" trial of the cholesterol-lowering drug, ezetimibe. His article contains a quick review course of most everything that is wrong with company sponsored clinical trials of drugs, in case you came in late.

Ezetimibe is currently sold by Merck and Schering-Plough, alone (as Zetia) and in combination with a statin drug (as Vytorin). The two drugs together sell about $4B annually. Ezetimibe's claim to fame is that it does not work like statins, so patients unable to tolerate statins can usually take it safely. It also is better at selectively lowering "bad" (LDL) cholesterol than statins alone. Proof that it lowered LDL was enough for the FDA to approve it. Yet there have been no trials demonstrating that ezetimibe, either alone or in combination, actually prevents serious disease or saves lives. (Lesson One) Three such trials are underway with results expected perhaps in 2010.

In the meantime, a lot has been riding on the Enhance trial, which is designed to measure the growth of atherosclerotic plaque ("hardening of the arteries") in patients taking only a statin vs. patients taking both the statin and ezetimibe. The thickness of plaque is still a "surrogate endpoint" rather than an actual disease outcome; but many believe that it's a reasonable predictor of whether the drug will actually work. Berenson reports that there is therefore considerable concern among cardiologists that the results of Enhance, initially expected to be presented in March 2007, will not be ready till March 2008.

The official word from the lead investigator, Dr. John Kastelein of Amsterdam, is that no one knows what the results are yet because no data have been released, and the data are still being analyzed. The delays were routine problems that arise when you have as huge a body of data as was generated by this trial. Kastelein strongly denied that there was anything fishy going on.

But besides this suggestion of normal delay, there were two worrisome features of Enhance reported by Berenson. First, it turns out that the companies have sole control of the data, and until they analyze it all and elect to release it, Kastelein himself has no way to access it. (Lesson Two.) Second, it turns out that the companies have decided to change the study's primary endpoint. Initially they had planned to focus attention on a combination of plaque thickness measuements at three different points in the carotid (neck) artery. They now intend to report as the primary endpoint the thickness at onely one point. (Lesson Three) This, they claim, will allow faster reporting of the results and will be just as reliable. They say that they will still report the three separate places in the carotid, but as a secondary and not as a primary endpoint.

Kastelein hinted in the interviews that he was personally not very happy with the change in endpoints. To determine that this was the right thing to do, the companies brought in an outside expert advisory panel. The panel concluded that the endpoint should be changed. The companies refuse to say who was on the panel. (Lesson Four)

Trial expert and industry critic Dr. Bruce Psaty is quoted by Berenson as highly critical of the endpoint shift. As a rule such a shift is very suspicious because it raises fears that you are deciding what counts as a successful trial result only after you know what some of the data show. It is analogous to hitting a bull's-eye with a bow and arrow by first shooting the arrow, then drawing the bull's-eye around the arrow wherever it happens to land.

So, in summary, here is the set of rules for drug companies as to how to make the scientific community--at least that part of it that has not been bought off with your consulting fees, speakers' fees, research funding, etc.-- most suspicious that you are pulling a fast one:

1. Seek to get your drug on the market before we know whether it actually makes us live any longer or prevents real disease.
2. Keep all the data under your strict control; don't even let the (so-called) lead investigator see it.
3. Change the primary study endpoint in the middle of the trial.
4. Keep all the processes as secret as possible at each step of the way.

Now, there may, in fact, be perfectly innocent explanations for all of this. (After all, Saddam Hussein turned out to have no WMDs.) Given the past track record of industry behavior in like circumstances, how many people are willing to bet in this case that the explanations are entirely innocent?

Berenson A. After a trial, silence. New York Times, Nov. 21, 2007: C1.

NOTE ADDED 11/26/07: I'm grateful for an e-mail from Matt Herper at Forbes who informs me that they got to the ENHANCE story first-- see:

http://www.forbes.com/home/healthcare/2007/11/19/zetia-vytorin-schering-merck-biz-health-cx_mh_1119schering.html

Great Article on Company-Sponsored Statin Comparison Trials

I really should be in another line of work. I am embarrassed that this paper came out in June and I am only now getting around to posting about it.

Lisa Bero, of the pharmacy school at UCSF, and her colleagues have come out with another gem on industry-sponsored clinical trials:

http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pmed.0040184

In one way this is old news because it adds to the long list of papers documenting that studies funded by drug companies turn out very often to conclude that the company's drug is best. But this paper extends the findings to a particular class of studies, those comparing one statin with another--the coveted head-to-head trials that we say the industry funds far too few of. And especially the paper gives us new insights into how the bias creeps in. (Or, in this case, the bias does not creep in; it walks right in the front door, sits down, and demands dinner.)

Because statins are such big business, Bero et al. were able find 192 studies comparing one statin to another. No surprise--in almost all cases, the end result was that the sponsoring company's statin performed better than the competitor statin. The authors found a 20-fold increased likelihood that the actual results of the trial would favor the company's own statin, and a 35-fold increased likelihood that the study would end up recommending the company's own statin. Note those numbers--obviously, in many (almost half) of the papers in which the authors confidently recommended the company's statin, the actual study results did not support that recommendation. (This is a fairly usual finding for industry-sponsored studies--that almost always there's a blatant marketing message added in amongst the scientific reporting. A pox on the journal editors and reviewers who lack the gumption to insist that such messages be excised, since it takes no advanced biostatistical smarts to figure out when the study results don't support the recommendations.)

Of even more interest were the reasons why these studies showed such disproprotionate results. Bero et al. were able to identify almost all the study design factors that accounted for the results that favored the company's drug--in this set of studies, the big culprits were inappropriate dosing of the comparator drug, and incomplete blinding. It does not seem to extreme to say that in summary, when the study results of a company-sponsored trial end up favoring the company's drug, it happens because the study was deliberately designed from Day One to assure that their drug came out on top. Again this is no surprise for an industry that makes it more clear all the time that it views its so-called scientific research enterprise as nothing but an extension of the marketing department.

Looking Over the Shoulders of the Drug Reps: Who Are They?

Some colleagues of mine on the Healthy Skepticism listserv have lately been commenting on some postings on the "Cafe Pharma" blog (warning: it's at least PG-13 if not R):

http://www.cafepharma.com/boards/showthread.php?t=226949

I am not sure just how this changes over time; but when I logged on, the discussion thread had to do with some reps sharing stories of how they had deliberately contaminated the food they brought into physicians' offices to "get even" with various people who gave them a hard time or who did not value their services. Others took issue with such behavior. One resident, who maintains his own blog, wrote to say that now he had yet another reason not to take any food from reps, thereby setting off a torrent of abuse from the reps directed at the resident, replete with suggestions as to with whom his wife was sleeping when he was on duty.

I was guided to this blog one time before by an in-the-know acquaintance, and after 10 minutes of reading gave up in disgust. I chose at that time not to mention this blog or its contents in any of my writing on ethics and the industry, as it seemed way too cheap a shot to take at the reps as a group.

On this occasion as I read the postings I am struck by the range. Some of the reps seem thoughtful and decent and trying to maintain integrity. Others are embarrassingly juvenile, obscene, and just plain mean in their postings.

I have tried hard in my own work never to villainize reps. As I see it, reps have an impossible job. From the company's point of view, they have one function only, to move product. I ask at every opportunity for someone to tell me about a single rep who was ever paid a single bonus for anything other than quantity of drug sales--and no one has ever given me an example.

The other part of their job is to lie about this. They have to lie to two people. First they have to lie to us, because we demand it. We will not easily and comfortably take all the goodies they shove our way, unless they keep repeating over to us the soothing rationalization, "It's education, not marketing." Second they often have to lie to themselves because they can live with themselves much easier if they can see themselves as educators and not as mere salespeople. Or at least they can lie to us more glibly if they lie to themselves first.

In one respect, I can concur completely with the blog postings, as much as I am repulsed by the packaging. If I sort through the obscenities, one basic idea seems to stand out. These reps despise docs and office staff who first scarf up their food and other goodies whenever they get the chance, and then believe that they can turn around the treat the reps who brought the stuff like dirt.

I agree totally. Whether that means it's ethical to deliberately sneeze in their lasagna is an issue we can take up at another time.

The Drug Industry: Business is Bad

In the Epilogue of HOOKED I reviewed evidence that shows that the glory days of the pharmaceutical industry may rapidly be coming to an end. Further evidence of this may be found in a recent article from The Economist (http://economist.com/business/displaystory.cfm?story_id=10026788&CFID=24605387&CFTOKEN=99289234).

The article describes the same tale of woe--many of today's blockbuster drugs are about to go off patent; Pfizer for instance is looking to lose a cool $13 billion in annual revenue when Lipitor goes off-patent around 2010. The pipeline that was supposed to be producing the next generation of blockbuster drugs has suddenly dried up--notwithstanding heavy new investments in research by most of the leading companies. More and more of the drugs the companies have been relying on for revenues have developed safety problems, either before or after FDA approval.

In an odd turn of events, The Economist reports that even safe drugs are being axed by the companies when their sales are disappointing. Exubera, for example, Pfizer's inhaled insulin, has been one of those poor revenue performers, but has shown no safety problems. Nevertheless Pfizer CEO Jeffrey Kindler decided to pull Exubera around mid-October in a bid to cut costs. (Just what do you say to thousands of patients who have been taking your drug, presumably doing fine with it, and having no bad side effects, when you suddenly yank it off the market?)

One thing that's new, says The Economist, is that the industry leaders have stopped bluffing their way through this downturn. You can now hear such folks as Novartis CEO Daniel Vasella admit openly that the industry has to change its business model in a basic way, and can no longer thrive solely on its top-heavy marketing operation.

But just what is this new business model that will come along and save the industry? The article is pretty thin on those details. Drug firms are starting to buy up biotech firms and medical-diagnostics firms in hoping of adding research muscle and diversifying. Beyond that there is really no news here as to what the industry might have up its sleeve--if anything.

In HOOKED, at the end, I try to make a case that these industry woes might provide an opportunity for meaningful reforms, in the direction of enhanced medical professionalism, if the companies feel vulnerable and are willing finally to admit that they have a problem. Certainly if the only result of these bumps in the road is that the industry goes down the tubes, that would be an outcome that cannot possibly help anyone. Poetic justice may be emotionally satisfying but never made a sick patient better.

Are We at a Turning Point on Drug Company Gifts/Bribes to Docs?

Eric G. Campbell, PhD, of the Institute of Health Policy, Massachusetts General Hospital/Harvard Medical School, has published two major surveys of relations between physicians and pharmaceutical companies so far this year--first, on individual physicians (http://brodyhooked.blogspot.com/2007/04/new-england-journal-study-shows.html), and then on medical school departments and department heads (http://brodyhooked.blogspot.com/2007/10/academic-departments-lots-of.html). In the latest issue of the New Enland Journal, Campbell summarizes the current scene:

http://content.nejm.org/cgi/content/full/357/18/1796

Campbell first notes legislative efforts at both Federal and state levels to require reporting of all company gifts to physicians. Then, after reviewing the reasons why marketing influence can harm patients' interests, he notes the increasing number of academic medical centers that have enacted strict policies banning drug reps and their gifts. He offers the opinion that maybe we are coming to a turning point when more and more physicians and medical centers will choose to divest themselves from the industry gravy train, and that either new laws, or the threat of them, might stimulate more aggressive internal measures by medical groups.

In the end Campbell offers some suggestions to individual practitioners, to "maximize the benefit for patients and minimize the risks associated with their own industry relationships."It may be worth assessing the value of these recommendations by comparing to material discussed in HOOKED:

1. Recognize that relationships with industry have one goal, to influence their prescribing behavior in industry-friendly directions, and assess the impact of these relationships on one's patients-- this is certainly good basic advice. I would add--all practitioners need to be regularly sensitized to the prevalent rationalizations that their colleagues use to justify the status quo and that industry sources are only too happy to reinforce vigorously: "it's education, not marketing"; "others may be influenced but I am a scientific reasoner and cannot be influenced"; "it's insulting to think that I can be boiught for a donut or a coffee mug"; and so on as we have extensively reviewed in this blog. After a while, no physician should be able to repeat these rationalizations without blushing.
2. Be familiar with policies and codes of ethics of one's medical institutions and professional societies-- this will be good advice for docs who happen to work for the forward-looking centers that have banned reps and their stuff. If the doc works for one of the majority that are not yet that enlightened, instiitutional policy won't help much. Ditto, as HOOKED shows, for most association codes of ethics. Most are based on now-discredited ideas that gifts are OK so long as they are of low monetary value, are "modest" meals, are aimed at patient care, and so forth.
3. Remember that ultimately the patients pay for all this junk--This also seems like good advice, and indeed, based on purely anecdotal evidence, this realization has provided the "aha!" moment for at least some physicians who ended up dissociating themselves from the reps' grip.

How Pharma Pads Its Research Costs

In HOOKED I mentioned in passing that the drug industry claims that it spends more on research and development than on marketing, while virtually all independent economists put the figures at roughly 12% of revenues going to R&D while as much as 30% of revenues go to marketing. Besides that little white lie, the industry routinely pads its research numbers by slipping into the research column activities that really cannot be construed as research by any fair-minded criterion. The only specific example I was able to give, however, was "seeding trials"-- pretend post-marketing clinical trials which are really more disguised bribery, in which physicians are paid to give the drug to patients and to fill out meaningless "data" forms, the whole idea being to get practitioners to get used to prescribing the drug more and more.

I recently received from Donald Light, health systems professor at University of Medicine and Dentistry of New Jersey and an affiliate of the University of Pennsylvania Center for Bioethics, a copy of a recent book chapter he wrote. Among many other good things he provides a very handy list of these fake "research" budget items. Besides seeding trials, his list includes:

• executive costs of negotiating with other firms for new product licensing
• costs for medical writers and PR staff to write media stories about trials while they are in progress, to stimulate market demand
• support for medical journal supplements and ads in those journals, as those are often the venue where lower-quality clinical trials can get published
• lectures and CME courses to inform practitioners about current research
• legal fees related to patents and licenses, and other research-related matters
• land and construction costs for buildings in which some research is done, even if only a small amount of space is devoted to research
• company-wide technical upgrades such as new computers or software

Light D. Basic research funds to discover important new drugs: who contributes how much? In: Burke MA, de Francisco A, eds. Monitoring financial flows for health research 2005: beyond the global numbers. Geneva, Switzerland: Global Forum for Health Research, 2006.

Today's Integrity Award: A Pakistani Psychiatrist

I cannot promise that each day I will issue an Integrity Award (let alone post a blog entry), but such as it is, today's award goes to Dr. Murad Moosa Khan, professor of psychiatry at Aga Khan University in Karachi, and author of "Why I declined an invitation to a drug company seminar":

http://www.bmj.com/cgi/content/short/335/7625/887?etoc

There are several reasons why Dr. Khan seemed to merit special recognition:

1. He referred to the invitation to the seminar, at a 5-start hotel in Pakistan, as "a form of bribery" (see my other post today on that topic).
2. He is alert to the negative consequences of pushiong psychiatric drugs in his country, both for the patients who might be better served by a different form of treatment, and the excessive costs of the drugs that could better be invested elsewhere.
3. Dr. Khan emphasizes the social circumstances of psychiatric illness. He notes that most of his patients with the worst mental health problems are poor, and that Pakistan has no effective public policy for dealing with mental illness. He also berates the medical schools in Pakistan for failing to teach most physicians about any form of psychiatric management.

Consumers International Report: A Must-Read

In my recent post on bribery I mentioned the new report from Consumers International:

http://marketingoverdose.org/documents/ci_pharma_2007.pdf

This 44 page report focuses on how drug marketing to physicians in the developing world seriously distorts health priorities. CI concludes that industry self-regulation is a flop, and calls for strict legal bans on "gifts" from drug companies to doctors in developing countries, with severe sanctions for violators.

ADDED 11/4/07: Here are a few more details from this important report. CI notes that most developing countries have effectively abandoned regulation of pharamceutical marketing to the industry. In turn, industry has blatantly violated many of its own claimed ethical codes. Advertisements to physicians in developing countries often leave out even the limited information that is required for the same drug in the developed world, and give blatantly misleading impressions about a drug. CI estimates that up to 50% of medicines in developing countries are irrationally prescribed. In these countries, people may pay a much larger percentage of their extremely limited health care dollars for medicines, so when an expensive drug does not work or is dangerous, the damage is doubled--both the direct effects of the drug, and the waste of money that could have been so much better spent on something else. While the amount of business done in the developing world by the major international drug companies is a small percentage of their total, this small sum is increasing much faster proportionally than most other sectors of the company's business, making it very tempting to keep on doing what drives the most profits. "Gifts" to physicians are often thinly disguised payoffs for the quantity of prescriptions written. Cars and televisions are not uncommon gifts received by high-prescribing doctors. (Popular gifts noted in a Pakistani survey included air conditioners, cars, cash, home appliances, and domestic cattle--the last a nice homey touch, don't you think?) Other popular gifts are air tickets, hotel and meal expenses to attend CME conferences, which are simply outside the affordability range of many practitioners in these nations without company funding.

CI notes that there are already laws and regulations against many of these practices; they need to be enforced. They call for a total ban on gifts; transparency in all industry marketing practices; and more government efforts at making CME and unbiased drug information available to their doctors.

A sad anecdote from Kenya--medical students have been spotted wearing white coats with drug company logos on them. When U.S. educators see residents going around with a lot of drug company pens and other gimmicks sticking out of all their pockets, they often try to shame them by asking, "Would you sell the company advertising space on your white coat?" In Kenya the answer seems to be "yes." CI reports that the same rationalizations that are in common usage among U.S. physicians to excuse taking company largesse are in evidence all around the world--only perhaps more understandable in nations where physicians are paid a relative pittance compared to their American income.

The Framing Problem, and Physician Bribery

First, and apparently (but not really) off the subejct--if you do not know about the Rockridge Nation website and blog, you should. Here is a great recent piece on children's health insurance:

http://www.rockridgenation.org/blog/archive/2007/10/26/schip-and-the-rigged-health-insurance-game

The point of this "progressive" website is all about framing. As linguist and Rockridge founder George Lakoff has written about for some time, political discourse in the US has deteriorated because one side of the political spectrum has been amazingly successful in framing many issues in such a way that the words used to describe the issue pre-determine the conclusions. There cannot be an honest political debate because one side of the issue never gets under the spotlight for discussion. For that reason we must be extremely careful of the language used to frame any policy discussion, and to be sure that it enhances rather than retards understanding of what is at stake.

Now, back to Pharma. I thought of the framing issue yesterday when two headlines came across the ether:

Name and shame 'bribed' doctors
Tamara McLean, Herald Sun (Australia), Oct. 31
http://www.news.com.au/heraldsun/story/0,21985,22679124-5005961,00.html

Drug firms try to bribe doctors with cars
Sarah Boseley, The Guardian (London), Oct. 31
http://www.guardian.co.uk/print/0,,331116619-103681,00.html

(Both these stories relate to the recent Consumers International report, which I will address in a second posting.)

Did you say "bribe"?

I thought--in HOOKED, I refer all the way through to "gifts" given to physicians by pharmaceutical companies. The companies themselves try not to go so far as even to say "gifts"--they call the small stuff with company logos, like pens and mugs, "branding items" or "reminder items," and they try to label all the big stuff as some sort of "education" or other.

These recent newspaper headline writers, apparently emboldened by the tough new report from Consumers International, had no problem calling the practice by a more proper, accurately descriptive name. (Dictionary.com tells us that "bribe (noun)" means: money or any other valuable consideration given or promised with a view to corrupting the behavior of a person, esp. in that person's performance as an athlete, public official, etc. All we have to establish for "gifts" from the drug industry to physicians to become "bribes" is that the commercial influence has the view of "corrupting" and that the behavior of a physician is analogous to that of a public official with regard to public trust. I offer arguments in HOOKED to show that those things are so.

So, if the goodies dangled before physicians by the drug companies are in fact bribes, why have we been giving them a free ride for so long and using euphemisms?

(I cannot help adding as a footnote that when I showed my wife the headline from The Guardian, her reply was: "So--they are not trying to bribe doctors who don't have cars?")

Retinal Specialists Get the Integrity Award--Genentech and Avastin

I am rather shocked to look back in the blog archives and see that I have not yet addressed the Avastin-Lucentis controversy. So I need to provide some background before handing out today's integrity award.

Quick overview--Genentech, the biotech firm, is maker of a very successful drug (brand name: Avastin) that is quite useful in colon cancer. The drug works by counteracting the tendency of tumors to create a lot of new, small blood vessels to keep the growing tumor supplied with blood. Some smart person figured out that the eye disease called wet macular degeneration is caused by a similar proliferation of new blood vessels and so the same sort of drug might help that condition too. (Wet macular degeneration occurs mostly in older folks but is not the most common sort of macular degeneration, a common cause of progressive vision loss. Still it affects a large number of people.)

So some retinal specialists tried Avastin by injection into the appropriate area of the eye and found that it really worked just great--highly effective and apparently very safe. The special bonus was the price. Avastin is extremely expensive for colon cancer, costing many thousands of dollars for a course of treatment. But the dose you need to treat an eye is a tiny fraction of the dose you need for colon ancer. So a single very expensive vial of Avastin can produce hundreds of relatively cheap doses for eye use.

Genentech had figured out the marketing angle on this pretty early on. They first did the usual "evergreening" trick, figuring out what portion of the Avastin molecule was the business end and creating a smaller molecule that contained that active portion. (Brand name for the new fragment of the old drug: Lucentis.) They then, based on some suspect animal data, declared that they just knew, without doing any further studies, that Avastin was too large a molecule to penetrate into the eye where it was needed. That was the excuse they used for not subjecting Avastin to any formal scientific trials to see if it worked in the eye. Then they did studies of Lucentis and showed that (surprise) it did work pretty well in the eye, and so they marketed Lucentis with a specific label saying this form, and only this form, was for eye use. Of course, since Lucentis was intended for eye use only, they prepared it in very tiny vials, each containing enough for one treatment, and priced each vial at a hugely expensive figure. Somebody calculated that at the price charged for Lucentis by Genentech, if all people with wet macular degeneration got treated with that drug, the entire present-day Medicare budget for eye treatment would go into the pockets of Genetech.

Now, stop for a minute and think what the average retinal specialist out in community practice is facing in the choice between Avastin and Lucentis. All the Genentech reps are heavily pushing Lucentis and giving a whole slew of phony reasons why Avastin is no good for eye use. We presume that there was all the usual bribery with fancy "educational" conferences at plush resorts for those who prescribed Lucentis. Coupled with all that marketing pressure is the threat that if any of them use Avastin in the eye, and there are any bad consequences, they'll have the pants sued off them for using an off-label drug that was not FDA approved for this purpose.

So if the retina guys acted like most docs act most of the time, when faced with the juggernaut of Pharma marketing, they would all be using Lucentis, and the patients and Medicare would be going bankrupt.

But that is not what happened. Despite all this pressure, the obvious rightness of using the good, cheaper drug continued to win out, and a significant number of specialists were using Avastin for wet macular degeneration and passing the savings along to the patient or the insurer.

Genentech was furious that the docs were refusing to be bribed, as usual. They cranked up their campaign, threatening to cut off supplies of Avastin to anyone who was making it available for eye use. They did this of course not for slimy financial reasons, but for good scientific reasons because they wanted to promote the very best quality of care.

On October 29, the American Academy of Ophthalmology put out a news release:
http://www.aao.org/advocacy/avastin20071029.cfm

The AAO and the American Society of Retina Specialists sent a high level delegation to meet with the Genentech bigwigs. Genentech agreed to hold off its threatened sales embargo, not to impede physicians or pharmacies seeking to use Avastin, and to seek advance comment from the two societies before putting out any new statements comparing Avastin to Lucentis. (Genentech, for its part, indicated that it was working in tandem with FDA guidance and that depending on what the FDA did or did not approve, it might later rescind this agreement.)

It is not clear what will happen in the future. A clinical trial to compare Avastin and Lucentis head-to-head for wet macular degeneration is now underway, with neutral funding I believe. In any event it seems that retinal specialists have as a group been singularly impressive and successful in standing up for the patient.

Yet More Evidence Linking Industry Funding to Biased Research Outcomes

HOOKED contains a considerable discussion of the evidence that pharmaceutical trials funded by industry are substantially more likely to favor the company's drug than studies funded by neutral parties (by about 4-fold). However, if people are going to prove it some more, I'm game, especially if they help us see how it's done.

A team of investigators hailing from Spain, Mexico, and Wisconsin reviewed 275 studies of inhaled corticosteroids that were company-funded and compared 229 studies of the same class of drugs that were non-industry-funded. The specific question they explored was how likely the study was to report significant adverse effects.

They discovered that only 34.5% of the industry-funded studies reported any adverse effects compared to 65.1% of the neutral studies. Once they adjusted for important features of the study design, the difference was no longer significant. This in turn indicated that the way industry-sponsored studies underreport adverse effects is by being deliberately designed with trial methods that are likely not to detect such events--such as by using the study drug in very low doses.

HOOKED explains that according to the best thinking in today's drug industry, research is a marketing tool--in fact, if the company CEO allows the scientists to design trials without the marketing depatrtment looking over their shoulder at every step of the way, the CEO should be fired. Here we see just one more example of this philosophy in action.

Nieto A, Mazon A, Pamies R, et al. Adverse effects of inhaled corticosteroids in funded and nonfunded studies. Arch Intern Med 167:2047-53, Oct. 22, 2007.

Newsweek Reports Fewer Docs Seeing Reps

Newsweek, this week, reports a trend among physicians and medical centers away from talking with reps and accepting company gifts (see the article: http://www.newsweek.com/id/57342). The article, of course, is music to my ears; but it would have been nice had it included just a little bit of data--any data--to back up the assertion that such a trend exists.

NEJM: Conflicted Editorialist?

I must have been taking an extended nap the week the May 3 New England Journal of Medicine came out, or curiosity alone would have prompted me to look up an article that claimed you only had to treat patients with a once-a-year dose of a drug. A group calling itself HORIZON, which stands for Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly by some alphabetical legerdemain that I cannot fathom, reported that when 3889 women with postmenopausal osteoporosis were randomized to either a once-yearly IV infusion of the drug or placebo, and followed for 3 years, the drug group showed significant reductions in both hip and vertebral fractures. The only downside was an increase in serious atrial fibrillation in the drug group. No surprise that the study was funded by the maker of the drug, Novartis.

Fortunately this study was pointed out to me by my colleagues Rick Bukata and Jerry Hoffman in their Primary Care Medical Abstracts monthly tapes (www.ccme.org). They went on to point out the editorial that accompanied the HORIZON paper, by Dr. Juliet Compston of Cambridge, England. The editorial reads like a long, glowing advertisement for zoledronic acid. Besides being sure to include the glitzty acronym HORIZON in the title of the editorial, she gushes about the relative risk reductions instead of the more informative absolute risk reductions (e.g. noting a 70% reduction in the rate of vertebral fractures, which translates into an absolute risk reduction of from 10.9% to 3.3%). The fine print at the end lists a number of drug companies for which Dr. Compston consults and speaks, and notes among other things that she serves on data and safety monitoring boards for Novartis.

At one time the NEJM prided itself on having strict policies that prevented editorials from being written by those with financial ties to the makers of the drug being studied. Apparently such policies are old-fashioned.

Rick Bukata also chided NEJM for leaving out the key fact that a single IV dose of zoledronic acid runs about $1000, independent of any administration fees or physician costs.

Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809-22, May 3, 2007.

Compston J. Treatments for osteoporosis--looking beyond the HORIZON. N Engl J Med 356:1878-80, May 3, 2007.

Conflicts of Interest Rife at IOM? Maybe Not

One of the writers whom I have relied on in the past is Merrill Goozner, who works with Center for Science in the Public Interest and wrote an important book on the drug industry, The $800 Million Pill, exposing the inflated claims made by the companies for their costs of doing research. He maintains a list called "GoozNews" for his personal views. So when I read his concerns about a new conflict of interest panel being assembled by the Institute of Medicine, I took notice:

http://www.gooznews.com/archives/000842.html

The prestigious IOM appointed a 15 member committee to produce model guidelines for dealing with conflicts of interest with industry. The committee, Goozner noted, was charged with developing guidelines that would not interfere with industry relations. So right away Goozner smelled a rat. The rat got more odorous when he discovered that 3 members of the committee had to have waivers to be allowed to sit on the panel due to their own ties to industry.

Goozner went on to give a list of prestigious members of the IOM who were not invited to serve on this committee despite having written important works on conflict of interest with industry, such as Jerry Kassirer, author of On the Take. (He left me off the list but that is neither here nor there.) Why, he asked, were IOM members known for their expertise on COI not appointed to the committee, while those known to be in bed with industry were?

While I was initially alarmed, I decided to check out Goozner's link to the committee composition. I was mainly interested in whether some of the very distinguished medical ethics folks who are members of IOM were appointed to that committee. After all, a 15 member committee can afford to have a handful of people who represent the pro-industry end of the spectrum, and probably needs them for balance if their final product is to be credible. But if people with expertise in ethics are left out, then I would be really worried.

So I was relieved to see that the chair of the committee is Bernard Lo, author of the textbook of medical ethics that I use with my students; and another committee member is Jim Childress, who is co-author of the best-selling textbook of bioethics. Also a member of the panel is Dennis Thompson, who wrote a seminal piece on COI several years ago for the New England Journal (though in HOOKED I found reason to dissent from the definition of COI that he offered there).

I then went down to the list of COI waivers/disclosures and found that Jim Childress was one of those listed as having conflicts. Now, call me naive if you wish; but when someone of his stature and reputation is named to a committee like this, I am inclined to give him a pass even if he has on occasion consulted with industry.

So all in all, I believe that the IOM may have appointed a reasonable panel to address COI issues and to develop model guidelines. I agree it would have been better had at least one of those known for writing specifically about Pharma, such as Kassirer, Lisa Bero, or yours truly, been asked also to serve. But the IOM process frequently has other members review a draft report after a committee has finished their work; so we may well be asked to be reviewers at a later time.

I am most worried about the apparently slanted charge to the committee, stressing making nice with industry over scientific and profesional integrity. I hope that the ethicists on the committee will make sure that balance is restored during their process.

Bashing Head-to-Head Drug Trials--from a Conflicted Source

This post is thanks directly to Dr. Roy Poses's "Health Care Renewal" blog, and indirectly thanks to the Prescription Project whose "weekly reader" directed me to it.

http://hcrenewal.blogspot.com/2007/10/whose-opinions-did-new-york-times.html

Dr. Poses quotes from a New York Times op-ed (Oct. 18) by Peter Pitts, writing on behalf of the Center for Medicine in the Public Interest, which the paper identified as "a nonprofit organization that receives financing from the pharmaceutical industry." (Try to find something that they have printed or disseminated that is not favorable to the drug industry.) Left unsaid by the Times is the fact that Pitts is also a senior vice president for a PR firm that includes many pharmaceutical giants among its accounts.

Pitts is upset that the SCHIP bill (health insurance for children) may not be dead despite Congress's failure to override the Presidential veto. The bill has a lesser known provision that would create a Center for Comparative Effectiveness for Medicare. This Center would have a $300M budget to do what the popular parlance calls "head-to-head" trials of drugs to see whether expensive new drugs are truly better than older, cheaper drugs.

Pitts proceeds to give several reasons why comparative effectiveness research is really a rotten idea--the studies may be flawed; and we cannot trust the government to do them fairly, as Medicare has a vested interest in cutting costs and not in finding out which drug is truly best.

Poses then goes on to dismantle these arguments detail by detail, and to note what Pitts leaves unsaid--that the current system is that no such head-to-head trials are done, or if they are done, they are done on the company dime and are aimed at providing marketing advantage, not at getting the best scientific answer. It is a far stretch to imagine that Medicare's conflict of interest would be worse than the industry's.

Poses leaves out yet another argument against Pitts. Medicare is a government program. For all the flaws that this might give it, the bottom line is that it is of necessity fairly open and accountable. If Medicare manipulated studies to be sure that the cheapest drug "won" all the time, there is a pretty good chance that somebody would get wise and blow the whistle. By contrast, the drug companies own their research data as proprietary, and HOOKED recounts numerous instances where if those data don't support the company's marketing message, they never see the light of day--or do so only after somebody files a lawsuit and company documents become discoverable in court.

The shamelessness with which the industry continues to put forth its preferred message, despite all logic and science to the contrary, via its numerous paid minions, continues to astound.