Monday, January 28, 2008

Who Gets Free Samples? Not the Needy

A group out of the Cambridge Health Alliance at Harvard have published what appears to be the first population-based survey of the use of free prescription drug samples in the February, 2008 American Journal of Public Health (subscription needed to access on-line). To satisfy conspiracy theorists, I should admit up front that the notorious duo of Steffie Woolhandler and David Himmelstein, single-payer advocates and big honchos in Physicians for a National Health Program, are co-authors.

The authors took advantage of the fact that a large, detailed national survey, the Medical Expenditure Panel Survey (MEPS), asks several questions about receiving free samples, and allows those answers to be correlated with information about demographics, income, and insurance status.

The results: more insured than uninsured people received free samples in 2003, the year for which data were available. The poorest patients were less likely to receive samples. The authors note the likely dynamic--being given free samples by a physician usually requires that you were able to get inside the door of a certain type of office. Once you get inside that door, if you lack insurance, you may be more likely to be given a sample than your neighbor who has insurance. Within the confines of the office, that is, the docs may make decisions about distributing samples that are in keeping with an intention to serve the neediest. But whatever shift that produces toward the poor and uninsured getting more samples, is outweighed by the fact that the poor and uninsured usually cannot get inside that door to begin with.

The finding that most samples do not go to the medically indigent is no surprise; previous studies have shown similar findings, without the benefit of a national database. (This study could not detect an effect reported in previous studies, that as many as 1/3 of the samples may walk home with the physicians and office staff.)

The bottom line here seems to be that yet again, when we try to get straight on the various issues at the interface between medicine and the pharmaceutical industyry, we encounter layers and layers of rationalization before we ever get to enlightenment. Studies show that the majority of samples do not go to the indigent. It is not in the interests of the companies to give samples to the indigent. (Samples come out of the marketing budgets. The companies have separate programs to give away drugs for free as charity; how well those programs work is a matter for another post; but there is no benefit to the company in robbing its marketing budget to enhance charitable giveaways. As marketing, samples given to the poor are mostly a flop; you want to focus your marketing efforts on folks who can afford to buy your product.) Yet, as soon as a critic of the industry talks about samples, the industry apologists immediately trot out the canard about all the samples going to the needy.

Cutrona SL, Woolhandler S, Lasser KE, et al. Characteristics of recipients of free prescription drug samples: a nationally representative analysis. Am J Publ Health 98:284-89, 2008.

Friday, January 25, 2008

Do I Hate Capitalism? Wild and Crazy Accusations

Robert Goldberg of the Center for Medicine in the Public Interest was so kind as to include my name in a minor place in his diatribe:

He offers a psychological assessment of what really motivates those of us who "pile on" the drug industry and its supporters over issues of conflicts of interest--we really, at bottom, hate drugs and hate capitalism and hate profits.

Now, there is nothing original in his posting. Previously published commentaries by Richard Epstein and Thomas Stossel cover much the same territory. I have written a long and rather boring paper in rebuttal to what they say and have submitted it to an academic journal. (What can I say? It is what us academics do for a living.) I will try to provide here a much shorter, and hopefully much less boring summary.

First, this is good news. If I can further insult Mr. Goldberg by referring to him as a drug industry apologist, it is notable that he and his kin now think people like me worth powder and shot, in order to attack us. A few years ago they simply ignored us, because everything was going their way. So these attacks signal a bit of a turning point in the battle for public opinion.

Next, what are the specific charges lodged against me and others? They seem to be the following:

  1. We ignore the many other conflicts of interest that afflict academics and focus on the one conflict of interest, drug company money.
  2. We hate capitalism and really want to see government take over the drug industry and all technology-generating industries. (Stossel is kind enough to add that we are jealous of the pro-drug industry folks because they make more money than we do.)
The main point about #1 is that all conflicts of interest ought to concern us. Why do we pick on the drug industry specifically? First, because of overwhelming evidence of its deleterious effect on medicine and the public health--more on that later. Second, because as I argue in HOOKED, the conflict of interest is mostly unnecessary for medicine and science to proceed about their business. It is vitally important that medical scientists exchange information with the pharmaceutical industry and that physicians learn about new drugs; it is not at all important or necessary that either line their pockets with drug industry largesse. If we are going to do something about conflicts of interest, it seems to make good sense to start out by eliminating the unnecessary ones; then we can talk about how to manage the ones we cannot get rid of--such as the fact that somebody has to pay for the research and there is always the danger that scientists will be unduly deferential to the funders.

On to #2. I ask anyone to read HOOKED and then explain how it opposes capitalism and calls for a government takeover of the drug industry. Rather the book is written specifically to deny and avoid those unnecessarily extreme positions. (Goldberg mentions in passing that maybe I favor single-payer health insurance, and in fact I do, and say so frankly in HOOKED; but I fail to see how that equates with a nationalization of Pharma.)

To point out what's wrong with the relationship between medicine and Pharma today is one thing. To call for an end to capitalism and the government takeover of the pharmaceutical industry is quite another. To reply to your critics who are doing the first, by accusing them of doing the second, is simply to change the subject and to fail to recognize or respond to their real criticisms. It's as much of a straw man argument as the claim, "You critics must want all patients today to stop taking all pharmaceuticals and to die of easily treatable diseases just like patients did in the 19th century and before."

Also, I feel a need to repeat a point that I would think by now would be crystal clear. I would again defy anyone to read HOOKED and to say in the end that it is Pharma-bashing. My main target is not Pharma; it is my fellow physicians who act in ways I argue are unprofessional. (To be fair, Goldberg grasps this point; but he thinks that the "unprofessional" behavior I accuse my fellow physicians of is in fact exemplary entrepreneurialism.)

I'll end this perhaps overlong comment by using my own career as an example. I entered the field of medical ethics in 1972. In 1980, I made the personal decision not to meet with or accept most gifts/bribes from drug reps. At the time, I viewed that solely as a personal choice; I did not go around and tell my colleagues, who were seeing reps, that I thought them unethical. It never occurred to me to combine these two disparate parts of my life--my academic interest in medical ethics, and the personal choice I had made to avoid industry influence--until 1997, when I read Drummond Rennie's JAMA editorial, "Thyroid Storm." That editorial started me down the pathway that ended up in writing HOOKED and in starting this blog.

My point in recounting this story is that for all those years between 1980 and 1997, I agreed basically with Robert Goldberg. I did not see any need to "pile on" in criticizing the drug industry, or in criticizing my colleagues who accepted its favors. What changed me was simply the overwhelming evidence that we could no longer ignore the poisonous impact of layers and layers of conflict of interest on medicine's trustworthiness as a patient and public advocate. I defy anyone to read HOOKED, or the similar books by the likes of Marcia Angell, Jerome Kassirer, Jerry Avorn, John Abramson, et al. and deny that the evidence has piled up to the level I describe.

A Hidden Infomercial for Avandia and Zyprexa?

For a little sleight-of-hand drug marketing, see this opinion column (which I am grateful to fellow blogger Roy Poses for calling to my attention):

On its face, it seems pretty benign. That is, it bashes greedy lawyers, and so who can object to that? The claim is that beware the Internet, since you might go on line looking for serious medical information about drugs and diseases, and you may be seduced into believing junk that is actually posted by trial lawyers trolling for clients for class-action suits against big drug companies. Indeed, say the writers, the danger is that these junk websites will kill people by scaring them from taking life-saving pills that they really need.

Now, what is an example of this so-called junk information? Well, two drugs are mentioned by name, Avandia and Zyprexa. Both are portrayed as having bewen slammed by allegations based on dubious research methods, as really great drugs that have been unfairly tarred.

What are the facts? Avandia is said in the article to be thoroughly proven to be effective in treating diabetes, but only alleged to cause excess heart risks. That's a lot of a stretch. Avandia lowers blood sugar. But there is a lot more to treating diabetes effectively than lowering blood sugar--as much as the industry would like to sell us surrogate markers that in turn help them sell drugs. The real question is: does Avandia lower the risk of the serious complications of Type II diabetes, such as heart disease? The fact is, first, that Avandia has never been shown to be effective in this long term way; and second, that controlling blood sugar, per se, has been proven to be ineffective in reducing one's risks of almost all serious diabetic complications. So, if there is hardly any proof that Avandia is effective in lowering risk of diabetic complications, and now there is a suggestion that it might actually increase risk, and also just happens to be extremely expensive, why the heck would anyone take it? (Of course there are exceptional cases where it may in fact be an excellent drug, all things considered, which is why doctors were invented, and of course you should listen to yours.)

Zyprexa was heavily marketed for many years as the new generation antipsychotic. It was supposed to have two big advantages over the old-fashioned anti-psychotics. First, it was said to work much better. Second, it was said to avoid the horrible side effects of the older drugs, most commonly, the Parkinson's-like symptoms in the syndrome called tardive dyskinesia. It took a long time for the real scientific data to make its appearance through all the fog of company marketing; but it then developed that both of these claims were false. The new generation drugs work about as well as the old. The new drugs do cause some cases of tardive dyskinesia. But even worse, the new drugs cause you to blow up like a blimp with weight gain, causing very serious health problems especially in older patioents. (Many gain so much they become diabetic. But of course, not to worry in that case; you can just start taking Avandia.) There's worrisome evidence that the companies tried to suppress the bad news about Zyprexa and its cousins, just as we now know that the companies sat on the bad news about ezitimibe (Zetia, Vytorin) for lowering cholesterol.

Where did this report come from, on which the pro-drug op-ed is based? It's from Center for Medicine in the Public Interest: That organization is sort of a branch of a PR firm that handles numerous drug-company accounts, and says in its mission statement that it seeks to promote the positives of medical technological innovation. One of the positives of technological innovation in medicine is that it may or may not make patients better; but it sure as heck improves the bottom line of the company that can successfully market it to us.

(Now, just to provide a bit of balance here, I went on the CMPI website and I did see a couple of news items that were unfriendly to drug company interests. One reinforced the recent FDA advice not to buy over-the-counter cold preparations for little kids. The other admitted that drug company marketing had gotten a bit of a black eye over the way that Zetia and Vytorin were shilled.)

Monday, January 21, 2008

Going Pharm Free, with 20 Shopping Carts

USA Today reports on the efforts of SMDC Health Systems, based in Duluth, to implement its strict new no-Pharma-gifts policy:

Highlights: The clinics decided to get rid of all of what the reps call "reminder items" (pens, note pads, coffee mugs, etc.) along with samples. They disposed in the end of 18,718 items that required 20 shopping carts to haul off. The items are being donated to health facilities in Cameroon. (If, a year or so from now, we hear of a sudden and inexplicable downturn in the public health of Cameroon, we will know the cause.)

The always reliable spokesperson for PhRMA, Ken Johnson, admitted that the industry needed to do a better job of explaining and justifying its marketing practices, adding that until it does so, "Unfortunately there are a lot of cynics in America who want to think the worst."

Do tell.

More Conflicts of Interest--This Time, Not Pharma

See David Armstrong on the WSJ blog:

Just to make clear that the pharmaceutical industry does not have a corner on the conflict-of-interest market, Armstrong notes that two of the major authors of recent research studies advocating CT scans as a screen for lung cancer have undisclosed commercial ties, including patents held on the software that interprets the scans. The vast majority of journal articles that they have written do not disclose these ties, and some of the major journals in which the articles have appeared are investigating.

By way of background, I will simply note that lung cancer has historically been a disease for which no screening tests have been recommended--because there is no evidence that detecting the cancer at the point in which any screening test can see it, changes the actual outcome of the disease, which is generally pretty dismal. (Of course, prevention of lung cancer is relatively easy--don't smoke.) More recently, these gung-ho screening types have tried to persuade us that super-sensitive CT scans are the breakthrough that will detect smaller cancers at a point when they are still treatable, and so any patients at high risk (smokers, for the most part) ought to have annual CT scans. The data to date are underwhelming and seem to rely on flaky statistics to "prove" some survival benefit.

It's typical for the average joe, who hears that medical experts are against CT scanning as a routine screen for lung cancer, to imagine that it's all just an insurance company conspiracy to save money. What A.J. doesn't seem to grasp is that there are two obvious and serious personal harms that can result directly from a CT scan that is not really needed or helpful. First, these scans will have a huge false positive rate, meaning that many people will get their lungs cut open to get tissue for biopsy, just to find out that they do not have cancer. Second, we are waking up to the fact that a CT scan of the chest is no small deal when it comes to radiation exposure; so a few annuals scans and you could have been exposed to enough radiation to cause a new cancer if you did not have one already.

Nothing like knocking public trust in academic medicine and medical research down a few more notches.

Saturday, January 19, 2008

Can Anyone Explain the Nemeroff Phenomenon?

Please mosey on over to our distinguished neighbor blog, Health Care Renewal:

Scroll down to the January 16 blog entry, "Antipsychotic Drugs for Depression?" by Bernard Carroll. It's a long story, but very carefully documented, about a paper on the use of an antipsychotic medication, risperidone, for the treatment of refractory depression. The paper receives a label that I have not previous encountered in my reading, but is a brilliant neologism--Carroll refers to it as an "experimercial."

The senior author of the paper in question is Charles Nemeroff, MD, PhD, chair of psychiatry at Emory. Dr. Nemeroff's name will be very familiar to most readers of any materials critical of the medicine/Pharma relationship. As Carroll briefly relates, Nemeroff had to resign as editor of Neuropsychopharmacology because the journal published a paper, of which he was the chief author, that was another "experimercial" for a device (an implanted electrical stimulator), but did not reveal that Nemeroff was a paid consultant to the device's manufacturer.

The Wall Street Journal, widely known as a pinko-liberal muckraking scandal sheet, ran an article detailing Nemeroff's questionable activities. They received in reply a letter (Sept. 19, 2006) signed by 45 academic psychiatrists, praising Nemeroff effusively and bemoaning this undeserved calumny heaped on one of the shining stars of the psychiatric firmament. (In previous years, Nemeroff's coziness with industry, and willingness to line his own pockets with industry money, has received notice from other irresponsible scandal sheets such as the New York Times.)

My question is very simple. How can the field of psychiatry hold up its head and act as if its members are professionals, so long as Nemeroff remains an "opinion leader" in good standing? How can Emory University justify allowing such an individual to remain as a department chair? How can 45 other psychiatrists rush to his defense in print without having to put paper bags over their heads? What does this say about all of us in medicine, who claim to have some sort of connection with professionalism and ethics?

I did not set out, in writing HOOKED or in starting up this blog, to engage in personal attacks or character assassination. But there comes a point at which the so-called ethicists, if we are not willing to have the courage of our conviction and name names, are doing as much to obscure the issues as anyone with whom we disagree.

The Depressing Results of the NEJM Antidepressant Study

Do antidepressants work?

If you read the studies submitted by Pharma to the FDA, but never published, the answer is no.

If you read the published studies, the answer is yes.

As I reviewed extensively in HOOKED, it is old news that papers published in medical journals, of research funded by industry, disproportionately favor the company's drug; and that research studies showing the drug in a bad light have routinely been suppressed. What's newsworthy about the paper by Erick Turner and colleagues in the January 17 New England Journal is the breathtaking extent of the resulting bias.

The group had access to the FDA reviews of 74 company-sponsored studies of 12 different antidepressants. The data showed whether the study was viewed as positive or negative in terms of the drug's superiority to placebo; and the size of the positive effect if there was one. They then tracked down whether each study was eventually published in a journal, and whether one reading the article would classify the study as positive or negative.

Of 38 studies deemed positive by the FDA reviewers, 37 were published. Of 36 studies deemed to be negative or questionable, 22 were not published at all, and 11 were published with an interpretation that made them sound positive, so that the true negative outcome was concealed in one way or other in 33/36 studies.

There was also the interesting mystery of the effect size. The effect size reported in the published papers (which, remember, were virtually all positive) exceeded the effect size calculated by the FDA reviewers by an amount ranging from 11 to 69 percent. The median increase in effect size was 32 percent, meaning that on average, published papers made the drugs sound one-third more effective than the scientific data (at least according to the FDA) would support.

In other words, if we assumed that an evil demon was at work, trying to make it impossible for the readers of medical journals to know the truth about antidepressant efficacy, we would expect results precisely matching those actually uncovered by Turner et al.

So, can we give this evil demon a name? Turner et al. demur. They have no way of knowing whether all these papers were submitted to journals, and were turned down by editors because they were negative, and who wants to read a boring ol' negative study; or whether the drug company never submitted the papers for publication, or some of each.

Now, a couple of comments at this point. First, it seems that once we have identified this set of 74 studies, we have an extremely useful database for further inquiry. On patient investigation, it ought to be quite possible to determine the submission-to-journals track record (or lack of same) for each of the 74 studies (or rather, the 23 that were not published according to Turner and company). Since Congress is starting to interest itself in these matters, including such arcane issues as Robert Jarvik's qualifications to shill for Lipitor on TV, it's even conceivable that if all else fails, the 23 PI's of those studies could be subpoenaed to Capitol Hill to testify under oath. Then we would know a lot more.

Next comment--if a paper is not published, it may be the drug company not submitting it, or it may be the editor rejecting it. But if the paper is published, and the effect size has magically grown like Pinocchio's nose, can we really suspect that perhaps the editor personally rewrote the manuscript and made the company's drug sound better than it is? Or do we have to suspect the drug company in-house statisticians of doctoring the manuscript? To me, the company is much more likely to be the culprit. And, while awaiting further evidence, if the company is the culprit in that part of this intrigue, I have to be suspicious that non-submission to journals can be laid at that doorstep also.

Having said that, I still must admit that journal editors have not in the past acted in a way that would make them seem blameless in all this. In both the VIGOR and CLASS trials, as related in HOOKED, we have some strongly suggestive evidence that the editors of major journals (NEJM and JAMA) colluded with the academic authors of drug company sponsored trials, to make the results sound better and the risks sound less than they really were. Richard Smith, former BMJ editor, has written about the millions of dollars major journals can make when drug companies buy up reprints of highly successful clinical trials. So we need to keep in mind the possibility of collusion in the antidepressant trials as well.

Meanwhile, I have another question. One of my jobs is teaching medical students. Up till now, I have always taught them that a good doctor carefully reads the medical journals and decides how to treat patients based on what we read there. How can I go on telling them this, with a straight face?

Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 358:252-260, 2008.

Wednesday, January 16, 2008

Now That We've Been ENHANCED--What's the Message?

Since I last blogged about the ENHANCE trial:

...the big news of the week, that I'm a couple of days late commenting on, is the mind-numbing flop of the ENHANCE trial. When Merck and Schering-Plough started to do the usual Pharma tapdance, specifically calling in an expert consultant group to change the trial's endpoints before the results were announced (without the supposed principal investigator even being at the meeting), we all started to predict that the study results were not favorable to the companies' drug, and that skullduggery was afoot to re-spin the results to somehow make the sow's ear look like a silk purse. Few of us guessed just HOW totally disastrous the results actually were, as finally revealed this week-- that the drug ezetimibe (Zetia), added to a statin (as in the combination drug Vytorin), not only failed to improve arterial wall plaque in any demonstrable way, but may even have worsened it.

So what can we conclude from this?

First--we have really come a long way since when I first started seriously looking into Pharma issues along about 7-8 years ago. It was not all that long ago when ENHANCE would have fallen in the forest like the proverbial tree that no one ever hears, and the negative data about the drug would never have seen the light of day, period. By contrast, when Merck and Schering-Plough started playing games, the major media were all over them right away. I have no doubt that the unexpectedly sudden and total release of the negative results this week were a calculated decision by the companies, that the truth was bound to come out sooner or later and getting it all over with as soon as possible was their only possible survival tool. So the world is on to the sheninighans of the industry in a way almost unimaginable a few years ago.

Second--I think (as a very definite non-expert in cholesterol metabolism and heart disease) that this also throws a lot of the cholesterol story into doubt. We already know, as per my previous blog post, that statins do not act as we would expect them to, if the most important risk factor for later heart and vessel disease was a high level of serum cholesterol, and that lowering cholesterol (by whatever means) was therefore effective in preventing later disease. Now we have the added evidence that ezetimibe, another drug which is almost guaranteed to lower your cholesterol level by a significant margin if you take it, is either completely unproven as a heart disease preventive, or else in fact is demonstrably useless (if the surrogate markers used in ENHANCE are reliable). Sounds to me like we need to take the entire cholesterol-risk model in for repairs.

Third--and this is related to #2--we need to stand back and appreciate the subtle ways that pharmaceutical marketing (aided and abetted by other sources of irrational thinking in both medicine and in the popular culture) screws over a thoughtful and scientific approach to disease. Only in hindsight can we see how completely physicians in the US were sold a bill of goods about cholesterol. We were convinced, not simply by company reps but also by official guidelines, by tons of CME conferences, and you name it, that the secret of being a Good Doc is to measure everyone's cholesterol level, and then try to get it down within the pre-set target ranges, whether we tried to do that first with life style changes and only reluctantly added drugs later (the Really Good Doc), or went to drugs right off the bat (the Not Quite So Good Doc). We can now see that in all likelihood, this strategy is nearly worthless when it comes to preventing serious bad outcomes in our patients or extending their lives. But we can also see that it sure sold a whole sh*tload of drugs for the industry. In short, the have-your-cholesterol-level-checked model of preventing heart disease functioned much like the serotonin-deficiency model of depression--excellent for selling drugs, even if the final scientific evidence shows that it is a myth. When they come to write the history of medicine in the last decades of the 20th century, how much of our "science" is going to go onto the trash heap for this reason?

Now-- I just said that we cannot blame the industry solely for this debacle, that other sources of irrationality also played a role. Just what did I have in mind? How about American physicians' tendency on the one hand to rail against so-called "cookbook medicine" when ever some expert wants them to follow evidence-based guidelines, and yet secretly in their heart of hearts to yearn above all else for a cookbook that tells them how to practice medicine? (Who could write a better cookbook than the NCEP cholesterol guidelines?) How about the American public's deep yearning for the magic pill that will allow us to have the double cheeseburger with fries and escape the consequences?

Berenson A. Cholesterol drug has no benefit in trial. New York Times, Jan. 14, 2008.

Saturday, January 12, 2008

Guinea-Pigs for Pay: The Quality of Pharma Research

My friend Carl Elliott, who teaches bioethics at the University of Minnesota and who has written some of the most perceptive articles about medicine and Pharma, was kind enough to send me a copy of his recent piece in the New Yorker (Jan. 7), "Guinea-Pigging."

Most of what the article addresses is not directly pertinent to this blog. Elliott is concerned with the underclass in the US that makes a career of volunteering to participate in research trials for pay, and wonders about the ethical implictions of this system of populating research trials--and the adequacy of our present systems of oversight. The trials in question are for the most part Phase I trials if they involve drugs--trials of drug safety carried out on healthy subjects. (You cannot make a "career" of enrolling in Phase II and III trials because as a rule, you have to suffer from the disease in question to be eligible. )

Here and there, the article shines a light on issues that directly relate to the medicine-Pharma interface. The implication seems to be that when you take the existing stew of ethically suspect factors--cynical subjects doing it just for the money, and an equally cynical system of research review boards that are committed to pretending that it's not about the money and that people volunteer for research out of altruistic motives--and then add the incredible financial pressure that drug companies experience to enroll subjects as quickly as possible into trials, so as to extend the new drug's market and patent life--you get even more bizarre ethical challenges. Elliott reviews a number of recent scandals, commenting, "not all drug companies are especially selective about the researchers they hire. For example, the F.D.A. asked the drug company Sanofi-Aventis to perform new studies of the antibiotic Ketek, which was suspected of causing liver failure. Reports later revealed that the top-recruiting investigator...tested the antibiotic on clients in a weight-loss clinic that she ran in Alabama. She was sentenced to five years in Federal prison for fraud. Another top-recruiting investigator was arrested when the police found him carrying a loaded semiautomatic handgun, and hiding cocaine in his underwear." Elliott previously had described a psychiatrist who continued to supervise drug trials, receive payments from a dozen or more drug companies, and even receive a Distinguished Life Fellowship from the American Psychiatric Association--all after being disciplined by the Minnesota state licensing board over "reckless, if not willful, disregard of the patients' welfare" in the injuries or deaths of 46 research subjects in trials he was supervising.

When the industry, above all else, is paying for speed and not quality in research; and if you want to apply for a job doing research trials for drug companies, I guess you don't send in a CV or a resume; just send them your rap sheet.

Elliott C. Guinea-pigging. New Yorker, January 7, 2008: 36-41.

Sunday, January 6, 2008

More on Device Kickback Deals

Roy Poses' Health Care Renewal blog has very kindly cross-posted a couple of my recent entries on this blog, so now I need to return the favor by calling your attention to his excellent summary (click the link below and look for the entry dated January 4 and titled, "Neurosurgeon Admits Kickbacks from Medical Device Manufacturers"):

I offered my views a while ago ( on how devices were different from drugs in a couple of ways, that made it seem less reasonable to completely ban device reps from the hospital the way that many medical centers are now banning drug reps. While, if anything, leaning over backwards to try to be open-minded to what device reps might bring to the patient care arena that would uniquely benefit patients, I felt obligated to add the comment regarding the payments/gifts received by physicians from device reps: "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."

Dr. Poses offers excellent reasons in his summary as to why we should view the case of the neurosurgeon, Dr. Chan, as a tip-of-the-iceberg case rather than as a single-rotten-apple case--suggesting that kickbacks and bribes to surgeons for using one company's implanted devices are 1) very widespread, and 2) very commonly "disguised" as consulting fees and research grants.

I know this is no sort of controlled trial, but as I recall the various news accounts I have read over the years about docs who receive excessive gifts from drug reps in exchange for prescribing a certain company's drug, and contrast the stories about device manufacturers paying our similar bribes, the rule seems to be to take the amount of the drug company payoff and add a zero at the end of the figure, and you get the amount of the device company payoff. I don't know if that means that the device industry is that much more lucrative and so the companies can afford pricier kickbacks; or that surgeons make so much more money that it takes a bigger kickback to get their attention; or (more likely) both.

Saturday, January 5, 2008

Lobbying Congress on Anemia Drugs: How Not to Take Care of Patients

Here's a recipe for taking rotten care of some especially needy and vulnerable patients.

The first thing you do is set crazy reimbursement rules for cancer centers and kidney dialysis clinics. You promise to reimburse the physicians based on a percentage of the costs of the drugs that they administer by injection.

I think back to my days as a practicing family physician and wince. Suppose the people in control had told me that if I saw a patient, diagnosed an ear infection, and prescribed a cheap but ideal antibiotic like amoxicillin, I'd get paid $40 for the office visit. If I prescribed two different antibiotics, I'd get $60. And if I prescribed some unnecessary but very expensive antibiotic like Zithromax, I'd get $80. How would that payment system have distorted my prescribing habits? I am glad I never had to find out.

But my colleagues in kidney and cancer care have gotten used to such a reimbursement system--to the extent that for some cancer clinics, these drug administration fees account for fully 1/3 of their revenue. How likely are those physicians to recommend a shorter rather than a longer course of chemotherapy, or a less expensive rather than a more expensive drug, even if the patient would benefit?

Now, into this crazy reimbursement formula you add an anemia drug like Epogen or Procrit. These are very expensive drugs, made by a fancy recombinant-DNA biotech system. The drugs make up for the fact that patients with cancer or with kidney failure fail to make enough of a substance that tells the bone marrow to make more red blood cells, leading to an anemia that can make the patients weaker.

The good news is that in moderate doses, these drugs restore the red cell count and make the patients feel stronger. The bad news is that in higher doses, these drugs, we now know, increase the risks of stroke significantly, and also, in some cases, create a risk for faster tumor growth.

How likely are the docs who are paid on a commission basis--that seems to be what it amounts to, call it what you will--to cut back on the doses they administer, when dispensing higher doses means higher revenues for their clinics?

Medicare, that pays for all of dialysis care and the lion's share of cancer care, finally realized it had a real problem on its hands. So in 2007 they proposed a new rule--they'd pay only for the moderate doses but not for the risky, high doses of these anemia drugs. Which, from a medical point of view, makes perfectly good sense, across the board and in general.

That meant a financial hit to the companies that make the drugs--Amgen and Johnson & Johnson. Both, but especially Amgen, responded with an over-the-top lobbying effort. They complained that some patients, who actually needed the higher doses because of individual treatment factors in order to feel strong enough, would be denied what their doctors recommended for them under the new Medicare rules. (Federal bureaucrats tell doctors how to practice medicine! Film at 11!) They cranked up the "astroturf" (so-called "grass roots" organizations that supposedly represent patients, but that are in fact heavily bankrolled by the drug companies).

As the Wall Street Journal recently reported, the effects have been stunning. Amgen topped all the drug firms in its lobbying expenses for the first half of 2007 ($9.1M). In exchange, both houses of Congress have introduced legislation to overturn the Medicare rules. (Of course, the American Society of Clinical Oncology that represents the cancer docs has joined in opposing the new rules.) Congress tells Federal bureaucrats how to tell doctors how to practice medicine! Film at 11! (Actually, the fate of this legislation is hard to predict, since if it does not pass, Medicare will continue to bleed red ink and Congress will have to find some way to increase tax support for the program. The costs for these anemia drugs is one of the single fastest-growing items in the Medicare budget.)

So what would a person say who actually cared about what happens to patients--as clearly neither Congress, nor Amgen, nor the physicians any longer give a hoot about? It may be that the new Medicare rules are really too burdensome and too awkward to determine which patient needs what dose of these drugs. So maybe the rules are in fact a bad idea and need to be modified.

But pardon me if I believe that the underlying problem that has to be fixed is paying docs a commission for prescribing more and more expensive drugs to certain categories of patients. And if the oncologists and dialysis physicians are offended because I just said that they don't care about their patients any more, I reply--fine; if you want us to believe that you really care about the patients, then join us in changing the way you get paid. If you continue to demand to be paid by a commission formula, unlike most other medical specialties, who in their right minds would ever believe you, that you are truly patient advocates?

Timiraos R. Amgen spends big protesting curbs on anemia drugs. Wall Street Journal, Nov. 13, 2007:B1-B2.

Friday, January 4, 2008

What Are the True Costs of Drug Marketing?

A newly published study in PLoS Medicine provides very useful data on a long-contested question:

Marc-Andre Gagnon and Joel Lexchin teamed up to determine how much the U.S. drug industry actually spends on marketing as compared to R&D. They dismiss, as do most knowledgeable outsiders, the industry's own reports that it spends more on R&D than on marketing.

Let me provide some personal background. When I wrote HOOKED, I puzzled over the conflicting figures that Gagnon and Lexchin juggle with. I teamed up with two health economists and we spent a couple of years trying to develop a complete financial accounting of all the relationships between medicine and Pharma (ultimately failing). Nonetheless, bits and pieces emerged that seemed strongly to me to suggest that the "official" figures--usually those provided by IMS Health--must be far too low. (Gagnon and Lexchin used 2004 as their data year, and in 2004, IMS reported the total expenditure for pharmaceutical marketing in the US to be $27.7 billion.) For example, a few typical drug reps provided me with estimates of their annual budgets for physician gifts. If one were to multiply those figures by the total number of drug reps in the US, the result markedly exceeded any IMS estimates.

Therefore, when Marcia Angell claimed in her 2004 book, The Truth About the Drug Companies, that the real marketing costs were as high as $54 billion, I was quite ready to believe her estimates. In HOOKED, I hedged and estimated within the $40B range, lest I be thought to be too rabidly anti-industry.

If all you want is the bottom line, Gagnon and Lexchin estimate the total at $57.5 billion, which is 24.4% of total drug sales; R&D expenses account for 13.4% of sales by contrast. This works out to $61,000 spent on promotion for every US physician.

The details--Gagnon and Lexchin were able to contrast the IMS data with data from another firm, CAM, that gets information direct from physicians (while IMS gathers its data from the firms). Moreover, CAM has had the advantage of being able to compare its figures with industry data--the industry has been willing to open its books, at least partially, to CAM, which is quite an unusual situation. That allows CAM to estimate how much promotional activity is not captured in its physician data, and to make corrections accordingly.

Gagnon and Lexchin found that for 2004, the latest year for which they could get data from both companies, IMS and CAM agreed on how much was spent on direct-to-consumer ads ($4B) and medical journal ads ($0.5B). They disagreed markedly on the amount spent on detailing to physicians--$7.3B according to IMS, $20.4B according to CAM. The major difference seemed to be that IMS counted as the cost of a detail visit the rep's salary plus transportation. CAM added in the expenses of the entire management apparatus that backed up the rep, plus the costs of the promotional materials that the rep distributed. It seems obvious that the true costs of detailing are better represented by the CAM figures.

By contrast, CAM came up with a markedly low estimate for the value of "free" drug samples distributed to physicians, $6.3B vs. the $15.9B per IMS. Here the explanation was simple-- CAM used the average wholesale price while IMS used the retail cost of the same drugs. CAM also likely underreported the quantity of samples. Gagnon and Lexchin elected to use the IMS figures for two reasons--IMS got the data on quantity of samples direct from the companies; and the companies themselves, when they report on drugs that are given away for charity programs, use the retail price as the value of the drug. Since the industry itself favors the higher figure, Gagnon and Lexchin elected to go with it.

Angell based her very high estimate on the annual reports that the large drug firms make to the SEC. Gagnon and Lexchin offer several reasons why those reports are probably not accurate for our purposes. For instance, "marketing" costs for SEC purposes includes the costs of packaging and shipping the manufactured drugs from the plant to the pharmacy.

I should add that the estimate I provided in HOOKED for the cost of drug marketing per US physician was around $13,000. This is a many-years-old figure and so was most certainly too low. The $61,000 figure seems much more probable.

A final comment--think about what it means that the debate over the amount of money spent on marketing by Pharma has been going on for many years, and we are still trying to get the accurate figures on these expenses. There's a huge debate today about the price of gasoline; but I am not aware that there is any mystery over what a gallon of crude oil cost on today's market, or what Exxon's profits were in the most recent quarter. The fact that so many of these basic data points are simply not known, or are still contested, highlights the lack of transparency within which the drug industry does it business.

Thursday, January 3, 2008

Management Study: Docs Respond to Science, Not Marketing. Really?

As readers of HOOKED and this blog know, it is my view that the vast preponderance of the available evidence shows that physicians are influenced by drug company marketing--particularly contact with and gifts from drug reps--in ways that threaten the scientific integrity of their prescribing, and hence the well-being of the patient. According to a recent marketing study, this is simply not so.

The way a Duke University press release (sorry, I cannot find it on line) put it: When it comes to giving samples and writing prescriptions, doctors are swayed by science -- not by cozy relationships between themselves and pharmaceutical marketing reps or by advertising aimed at patients, new research shows.

The study itself is a bit more moderate, but still it makes rather sweeping claims and so requires careful analysis.

Sriram Venkataraman of Emory U. and Stefan Stremersch of Erasmus University-Rotterdam, the latter also being a visiting prof at Duke, developed a database that was basically designed to show that the impact of drug marketing varies by brand and according to the scientific data about the different drugs. Previous marketing research has tended to ignore these variables, assuming that you can sell pretty much anything to docs if you market the heck out of it.

If you read their references, there are relatively few to medical journals and most all the prior research cited is in the marketing literature. So the question obviously arises of how well these business-school folks understand the medical nuances of what they are studying.

To do their analysis, they needed basically three data sets--physician prescribing patterns associated with the number of detail visits and attendance at marketing meetings per physician for each brand of drug; the side effect profiles of each brand of drug; and the scientific data about the effectiveness of each brand of drug.

The first, major dataset the authors obtained from a drug company, who presumably obtained the data in turn from a commercial outfit that gathers such marketing data directly from physicians' offices. On the one hand this is a real strength, as most such data sets, being proprietary data that companies pay thousands of dollars to obtain, are not accessible to most academic researchers. But the downside is that these data came under a confidentiality agreement so that the authors cannot tell us which company, or give us many details about how the data were obtained, or even say what the drugs were that were studied--all they can say is that the drugs were in 3 classes: statins; ED drugs; and gastrointestinal drugs.

The other data sets came as follows. The efficacy data came from an excellent source--NICE in the UK, the official NHS group that assesses the effectiveness of treatments to allow decisions as to what the British health system ought to spend its money on. Still, the specific end points used to assess efficacy are not given, so we do not know if "effectiveness" of a statin means how well it lowers LDL cholesterol, or how well it prevents heart attacks. (The latter endpoint being obviosuly much more meaningful.) The side effect data set comes from the FDA label for each drug and consists of a simple count of how many side effects are listed.

Briefly, the authors found that some drugs were prescribed more often, and more samples were given out for them, if they were heavily marketed, and others not. The likelihood that marketing would lead to more prescribing was increased with the more effective drugs. It also was increased with the drugs with more, rather than fewer side effects. The authors theorized that this was because those side-effect profiles created excess physician uncertainty about using the drug, and detailing and meetings helped provide more data that then lowered uncertainty.

Do the conclusions follow from the data? Well, the first thing to note is that the side effect data are absolute garbage. The very idea that you could know something useful about the safety vs. the efficacy of a drug simply by counting how many side effects are listed--while knowing nothing about either their frequency nor their severity--would never have occurred to anyone with one brain cell worth of medical knowledge. So anything about side effects in this study is not worth discussing any further.

What about the efficacy conclusions? On the one hand, NICE is a highly regarded source for such data, but the need to keep us blinded to the actual drugs being talked about and to the endpoints used to determine efficacy, seriously undermines any value in this part of the study. Can we make any guesses? In the three drug classes that were studied here--statins, GI drugs (which I have to assume were probably proton pump inhibitors) and erectile dysfunction drugs--the current scientific literature would probably support the conclusion that these are, for all intents and purposes, me-too drugs--that the differences in real efficacy, brand to brand, will be very minor. So we can in turn guess that it is very unlikely that NICE found any serious differences in efficacy among these different brands, and therefore whatever differences in the effects of marketing turned up in this study are probably largely meaningless.

You are probably wondering--how come I said nothing about whether these authors received drug company funding for the study? The article actually does not say one way or the other, so we are left guessing. Here is my guess. The authors note that a large pharmaceutical company, with whom they then agreed to a confidentiality clause, kindly gave them the marketing and prescribing data. This is stuff, as I said, that normally one would pay thousands of dollars for, or even tens of thousands. They are also data that most drug companies keep very close to the vest. What sorts of investigators are such good pals with the drug company that these data would be made freely available to them? Draw your own conclusions.

Now, we have seen that there are serious reasons to doubt the validity of the major conclusions drawn in this study (quite contrary to the Duke press release). It is therefore interesting to see what recommendations these authors then offer for drug marketing:

As the prime need of physicians is information for which the manufacturer can be a useful source, public policy could actively restrict detailing to its purely informative role. Restricting the number of visits and further curtailing gift-giving are options one should consider. For managers, it supports the call for more evidence-based marketing.

In sum, even after massaging their methods like crazy to come up with industry-friendly results, the authors would still endorse some of the same lessons on drug company marketing preached by the industry's severest critics.

Venkataraman S, Stremersch S. The debate on influencing doctors' decisions: are drug characteristics the missing link? Management Science 53:1688-1701, November 2007. (Available on line only by paid subscription)

Wednesday, January 2, 2008

The Jarvik-Lipitor Connection

Since we are on the subject of Lipitor (as several recent posts have been), I am again grateful to Eric Jackson, PharmD, for pointing out to me the MSNBC coverage of Pfizer's extensive direct-to-consumer ad campaign for that drug, featuring as its pitchman Dr. Robert Jarvik:

MSNBC's science correspondent, Robert Bazell, makes a couple of observations. First, it is somewhat odd that Jarvik is being used as the "celebrity" in this ad, since by many standards he'd be seen as a total failure. Bazell reviews the trouble-laden history of the Jarvik 7 artificial heart which was introduced with tremendous fanfare and eventually dropped because of the multiple complications it caused and the miserable lives experienced by the few in whom it was implanted. (In my day job, medical ethics, we occasionally look back at those surgeries and wonder about the process of informed consent and ethical review, that led to those patients being victimized in the way that they were.) "Failure" is probably too harsh given the inherent uncertainties of medical research, but anyway you get the idea.

Second, and probably more pertinent, Bazell reviews Jarvik's training. He initially had inadequate grades to get into a US medical school, and finally did graduate with an MD, but never did an internship or residency and has never cared for patients as a physician. He's a biomedical engineer, pure and simple. So his ad is really quite reminiscent of the old ads featuring "Dr. Marcus Welby," the actor Robert Young, who said, "I'm not a doctor but I play one on TV..."

Tuesday, January 1, 2008

Kudos to "No Free Lunch" Pioneer, Dr. James Orlowski

The Prescription Project has kindly called our attention to a nice newspaper writeup about Dr. James Orlowski of Tampa:

The article credits Dr. Orlowski, a pediatrician, with being the only area physician listed on the "No Free Lunch" website (I assume, for having signed the pledge not to accept any gifts from drug reps).

What they could have said, but didn't, is that Dr. Orlowski did more than get listed on the site; he helped invent the arresting term "No Free Lunch" to describe drug company gifts.

As near as I can determine, the first published use of that phrase was in a paper that Dr. Orlowski co-authored while at the Cleveland Clinic in 1992: "The effects of pharmaceutical firm enticements on physician prescribing patterns. There's no such thing as a free lunch" (with L. Wateska, in Chest, 102:270, July 1992). This classic study looked at 20 staff physicians who attended two junkets at drug company expense, touting expensive drugs, showing that in the months following the junkets, the prescribing of those drugs at Cleveland Clinic shot up far out of proportion to any national trends--while when interviewed, the docs involved steadfastly denied that the junkets had influenced their prescribing.

Alleged Off-Label Lipitor Marketing--Further Details

In the previous blog post, I tried to summarize some of the background information about the evidence in favor of prescribing drugs for cholesterol. I am now able to relate the recent allegations against Pfizer, in the whistleblower lawsuit, to this body of information. I was very kindly sent a copy of the complaint filed with the US District Court for the Eastern Circuit of New York in the case of United States of America et al., ex rel. Dr. Jesse Polansky v. Pfizer, Inc. from which the rest of the information is taken.

Dr. Polansky, a former Pfizer manager, claims that the company engaged in a deliberate and sustained marketing campaign to encourage physicians to prescribe Lipitor for patients for whom the drug was not indicated according to the FDA label. According to these allegations, what, exactly, did Pfizer do?

The basic goal of the campaign (remember that this is all allegation, not demonstrated fact) was to greatly increase the number of patients with elevated cholesterol levels for whom Lipitor would be prescribed, beyond the limits suggested by the recent practice guidelines issued by the NIH National Cholesterol Education Project (NCEP). Now, this is already a tall order because many people claim that the guidelines themselves are overly generous in recommending statin therapy--I discuss this at some length in HOOKED. We'll see later why that may be so, as the vast majority of members of the NCEP panel are engaged in conflicts of interest and receive funding from Pfizer and associated entities.

However, even NCEP had to admit that for some moderate-risk patients, the evidence favored using diet and exercise to manage one's cholesterol, rather than drugs. Dr. Polansky now claims that Pfizer's marketing team set out to convince doctors, patients, managed care entities, and anyone else who would listen that most of these patients really needed drugs, not lifestyle changes. The claim alleges that Pfizer's off-label prescribing was so blatant that the company virtually admitted this transgression to its investors, bragging about how the campaign would drive up sales.

The centerpiece of this marketing campaign was a set of materials that was designed to create the clear impression that the viewer was seeing a summary of the NCEP guideline recommendations. But the Pfizer version deviated from NCEP in important ways. The most significant change was substituting one key number for another so as to favor drug prescribing.

The NCEP guidelines feature threshold values of cholesterol (specifically, LDL or "bad" cholesterol) that are supposed to be triggers for prescribing a drug if the patient's lab values exceed that number. Once a patient is placed on a statin drug, the guidelines then suggest target levels. This is the lab value you are supposed to be trying to reach with your drug, and you should adjust the dose of your drug and choice of drug to try to reach that target, according to NCEP. (I explained in my previous post that these "targets" are really based on no good evidence, according to my colleagues Jim Wright and John Abramson; but put that aside for now as we are discussing what NCEP actually claims and then what Pfizer construes NCEP as claiming.)

The allegations are that Pfizer's materials fail to mention the threshold values and instead focus exclusively on the target levels. The entire focus of the marketing campaign is to get the patient to achieve the target. Let's take an example of what this means. For some risk categories, the LDL level that provides the threshold for prescribing drug treatment is 160, and the target you then try to reach with the drug therapy is 130. The Pfizer materials ignore the 160 and only talk about the 130. What if you have a patient in that risk category whose LDL is 150? According to NCEP, that person does not need drug treatment. According to what Pfizer wants you to think NCEP says, this patient has not yet reached target and so you need to prescribe a drug (ideally Lipitor of course) to get the LDL down another 20 points.

But, one might say, why not use diet and exrcise to bring the LDL down that much? Pfizer's marketing materials are ready with the answers. Diet and exercise simply don't work the vast majority of the time, they emphasize. All they do is make patients feel guilty when they fail. You wouldn't want to do that terrible thing to your patients, now would you? So of course the best bet is to start off with the drug right from the get-go. Again, this advice is quite contrary to NCEP guidelines.

The allegations proceed to shine a light on two other questionable marketing practices. First, the complaint alleges that while the FDA is relatively strict about policing drug advertising that comes in the form of journal and TV ads (acually they are not, but save that argument for another time), they are very lax about other media such as web-based and hand-held computer calculators. So Pfizer created a number of computer decision calculators designed to be used by docs to figure out which patients needed to be put on drugs. The complaint alleges that these calculators use inaccurate numbers, not consistent with NCEP, to magnify the numbers of patients who end up "needing" drugs. If your friendly Pfizer rep gives you a nice handheld PDA with this calculator loaded onto it, and you use it to prescribe for your patients, your patients get more drugs than indicated and Pfizer gets more profit.

Second, the complaint goes into details about how Pfizer allegedly channeled a lot of money to support continuing medical education (CME) programs through three front organizations--National Lipid Education Council (NLEC--notice how easy it is to confuse with NCEP); Emerging Science in Lipid Management; and Vascular Biology Working Group. These impressive sounding entities could sponsor CME programs and spread the Pfizer marketing materials and messages while allowing the drug company to remain in the background.

Now we come to the conflict of interest matter--the complaint provides a nice table that lists all the big-time scientists who staff the NCEP guideline writing panel, along with their various roles in each of the three Pfizer-controlled and -funded "educational" organizations. The result is a nice checkerboard pattern with every one of the NCEP docs having at least one tie to another organization, and many having numerous ties. Assuming that these are paid consultantship-type relationships, it illustrates how members of NCEP all get some sort of drug company money, and in turn, how they make that money by "educating" physicians to prescribe more and more statins--even beyond what NCEP guidelines call for.

I am not a lawyer and so I cannot comment on any of the legal merits of this suit. Just looking at this list of allegations, I am worried. It seems that the case that is being made depends very heavily on a thorough understanding of the epidemiological data about heart disease risks and drug treatment. This is a tough enough task for a medical school classroom. What will it be like trying to teach an epidemiology course for non-epidemiologists in a courtroom? I will be very interested to see how this all unfolds.

NOTE ADDED 1/2/08: As I should have said as part of my analysis of Pfizer's marketing strategy: this example also shows how a drug company that positions itself properly can sell as many drugs by selling a lab test as it can by selling the drugs directly. Given that an awful lot of Americans have high cholesterol levels, once Pfizer has been successful in redirecting physicians' attention away from the threshold values for starting drug treatment and instead toward the target levels (as explained above), the best way to sell more Lipitor is to make sure that more and more people get their cholesterol checked. Hence the support for "health fairs" and other means by which lab tests will be "sold" to either the general public or to docs. John Abramson, in his Overdosed America, provides similar examples of how osteoporosis drugs are "sold" by encouraging more women to get bone-mineral-density testing. According to our cultural mythology, anyone who urges more and more people to go out and get tested for something "preventive" is a public health hero and so is immune from criticism--even if the motive and the result are higher profits pure and simple rather than any real patient benefit.