Hooked: Ethics, Medicine, and Pharma

Celebrity Shills for Pharma

2012-01-30T18:20:00.000-08:00

I was kindly asked by The Scientist to submit an opinion for their blog regarding recent news that Paula Deen, who I gather is a celebrity chef sort of person who has tended to advocate high-fat diets, has acknowledged having Type 2 diabetes and has shown up as a celebrity spokesperson for a diabetic drug for Novo Nordisk. So I figured why write two blog posts when I can write one:

http://the-scientist.com/2012/01/30/opinion-celebrities-pushing-drugs/

Ritalin: Is Drug Shortage or Drug Excess the Problem?

2012-01-29T15:39:00.000-08:00

Today's New York Times features an opinion piece by Dr. J. Alan Sroufe, emeritus professor of psychology at the University of Minnesota and expert on child development:
http://www.nytimes.com/2012/01/29/opinion/sunday/childrens-add-drugs-dont-work-long-term.html

Dr. Sroufe starts by noting that the news has lately been full of reports of serious drug shortages, leaving frantic parents and teachers worried that kids with attention deficit disorder will be unable to get their Ritalin (methylphenidate). Dr. Sroufe then offers the argument that instead of worrying that these kids might not be able to get their meds, we should be worried that far too many kids are getting medicated for ADD despite good evidence that any benefit from drugs is probably limited and short-term.

The piece basically falls into two parts. One addresses the actual evidence about the benefits of stimulant drugs like Ritalin in ADD. The other discusses the likelihood that ADD is not an inborn chemical imbalance and may be at least partly environmentally triggered, suggesting that a more complex approach is needed rather than just prescribing drugs. (Since psychiatrists tend to prescribe drugs for behavioral problems and psychologists tend to downplay the value of drugs and suggest various other forms of therapy and prevention, I fully expect to read angry psychiatrists attacking Sroufe's article in coming days.) And Dr. Sroufe defends his bona fides by noting that early in his career, he did research on Ritalin and helped show that it seemed to have benefit. Anyway, the first part of the article is what I choose to focus on as most pertinent to this blog's agenda.

Basically Dr. Sroufe disputes the initial claims that ADD kids have messed up brain chemistry because of an inborn problem, so that stimulant drugs have a paradoxical effect on them and settle them down instead of revving them up. There's no paradox, he says--anyone given stimulants, and then assigned to do boring, repetitive tasks (presumably like much schoolwork is) will be able to do the tasks better. The real issue is whether in the long run ADD kids improve on Ritalin, in terms of learning or life adjustment, and he claims that long-term studies show no difference and that any presumed benefit to stimulants disappears after a few years as the body develops tolerance. Because the body develops tolerance, kids do worse when the drug is stopped, so studies showing worsening of ADD symptoms on drug withdrawal hardly support the actual benefits of the drugs.

What these assertions have to do with our concerns is:

Stimulants, like many drugs used in mental health, look very good so long as you do your study for a 4-8 week period, and never look at long term outcomes. For this reason it is increasingly worrisome that so many studies of psychoactive drugs are roughly 4-12 weeks' duration. From an industry viewpoint this is good for two reasons--such studies are cheap and quick, and as noted their outcomes are much more likely to be positive. The rest of the world (the FDA included) needs to take note that such studies are also virtually uninformative about any drug intended to be used chronically.

To repeat a basic theme, drug marketing does not simply try to sell us drugs. Marketing tries to sell both physicians and the general public a way to think about drugs. We have recently discussed the popularity as well as the scientific defects of the low-serotonin theory of depression (http://brodyhooked.blogspot.com/2012/01/npr-forget-serotonin-theory-of.html). Telling guilty and frazzled parents and teachers that the child has an inborn brain disease is reassuring, while saying that something in the environment may be making them act that way just ramps up the guilt. So the public (and the physicians trying to reassure them) readily grab for a biochemical story to tell about ADD. So long as that story sells pills, Pharma wants to be sure we keep believing it, even if the science refuses to accommodate them.

We are also seeing here more signs of the worries raised in Robert Whitaker's controversial but probably mostly-on-target book, Anatomy of an Epidemic (http://brodyhooked.blogspot.com/2010/05/whitakers-anatomy-of-epidemic.html). Whitaker paints a bleak picture of modern psychopharmacology, while admitting that for the small population of people with really severe psychiatric symptoms, drugs are far better than no drugs. He claims as a general point about psychoactive drugs that the human body seeks to restore homeostatis, a fancy way of saying that if you give a drug that (say) raises your serotonin, the body thinks this is making things go out of kilter and sooner or later tries to lower its own serotonin production in response. If you then go off the drug for a while, you are left with a brain that is producing serotonin at even lower levels than normal, and you might well see withdrawal effects, which psychiatrists interpret as more evidence that you really need the drug and dare not stop it. So the bottom line is that we've gone way overboard in prescribing drugs that have dangerous and often unknown long-term consequences for people who have such mild symptoms that they would be much better off with no drug treatment--Sroufe notes that we now prescribe 20 times more stimulants for ADD than we did 30 years ago.

Another Planet Heard From: Sunshine Law is Useless

2012-01-24T08:19:00.000-08:00

I had not heard recently from Dr. Thomas Stossel of ACRE fame (see for example http://brodyhooked.blogspot.com/2010/04/federal-settlements-acre-perspective.html). However, the redoubtable Dr. Stossel now appears on the op-ed page of the Wall Street Journal ("Who Paid for Your Doctor's Bagel?" January 23, p. A17; subscription required), to inform us that the Sunshine Act provisions included in the Affordable Care Act, due to take effect later this year, are "toxic" and "inverts reality."

I have felt for some time that Dr. Stossel lives on another planet. On his planet everything is just fine between medicine and Pharma, at least so long as the evil government, and goody two-shoes folks like me, don't interfere. Docs get paid big bucks by Pharma. As a result they think fine thoughts and invent great new drugs. These great new drugs then make us all live longer and better. Eeveryone wins, and there's no downside. Dr. Stossel reports that medicine can today do wonderful things that we could not do when he graduated from med school in 1967--I didn't realize he was that old, I graduated in 1976 and feel pretty much fossilized myself--an assessment of progress with which I totally concur. He believes that all of it is due to the free enterprise business model that he advocates.

So what doesn't happen on Dr. Stossel's planet, that in my humble opinion happens on this one? First, drugs only help people and never hurt them, and companies never market potentially dangerous drugs to people who don't need them. Revelations such as Dr. Don Light's about the harm caused by prescription drugs apparently are irrelevant there: http://brodyhooked.blogspot.com/2010/08/how-many-new-drugs-are-lemons-ask.html.

But perhaps the most fascinating difference between the two planets is Dr. Stossel's claim, "Having failed to detect substantive corruption due to physician-industry relationships over a quarter century, [critics] will spend taxpayer-provided grant money" to keep searching for the supposedly non-existent corruption.

There's no "substantive" corruption because when the industry pays docs, it is always strictly on the up and up. Physicians are "compensated by royalties from useful inventions that they license to companies, or ...were paid consulting fees for advice concerning the optimal use of products, or for educating other physicians about products." On that other planet, docs are never paid bribes by industry to prescribe their drug or device, or to persuade their fellow physicians to do likewise. Funny how on this planet seldom a week goes by that I'm not blogging about some such corruption at the medicine-industry interface.

But then again, I suppose that the corruption that I have been blogging about all these years is not "substantive" enough. So just who "inverts reality"?

The Over-the-Top Prices for Cancer Drugs

2012-01-24T07:56:00.000-08:00

Our pal Merrill Goozner of GoozNews blog just posted this article in the Fiscal Times:
http://www.thefiscaltimes.com/Articles/2012/01/23/New-Cancer-Drugs-Affordable-by-the-1-Percent.aspx#page1

Gooz goes into the current problems caused by the high cost of new cancer drugs, relating facts such as:

84% of oncologists report that treatment recommmendations are modified due to the patient's out-of-pocket costs

Despite decreasing incidence of cancer, the National Cancer Institute projects a 27% rise in the cost of treating the 29 most common cancers by 2020

Typical price tags:

Johnson & Johnson's Zytiga extends life in advanced prostate cancer by 5-16 months, costing $44,000 per year

Bristol-Myers Squibb's Yervoy improves 1-year survival rate in metastatic melanoma from 25% to 46%, costing $120,000 for a 4-month treatment course

Gooz notes that neither the Republican nor the Democratic proposals for health care system changes address in any serious way what to do about this problem.

Back in HOOKED, I discussed the high price of some cancer drugs, noting that these prices were determined by one factor only--what the company figures it can squeeze out of the market. The price has nothing to do with either manufacturing costs or research costs--in this area, the bulk of the research on breakthrough molecules continues to be done in academic and not industry labs.

Until now, the industry has figured that a patient with advanced cancer would pay any amount for even a few more months of life, especially if newer drugs, as many promise, are much less burdened with side effects than old-style chemotherapy. Gooz's account shows that even if the patient has good insurance, the out-of-pocket copays may be so high that the patient and family decide that it's just not worth it. So as much as people want to sound off about "government death panels," here we have rationing of cancer care based on the private marketplace.

You could make the claim that when a new cancer drug might extend life by only a few months, and a patient decides they'd rather leave that much money to their grandkids rather than buy the medicine, it's a perfectly rational choice, and a good system that allows it to be made. I worry however that when the drug offers more substantial benefits than that, it seems less fair that the luck of the draw that is today's health insurance system might determine whether the drug is affordable. On the other hand, I have steadfastly proclaimed in this blog that there's no good, solid "ethical" answer to how much drugs should cost.

One point to note in pasing that as Gooz interviewed industry experts about why these drugs cost so much, one answer that came back is that the companies are trying to recoup their losses from so many blockbuster drugs like Lipitor all going off patent at about the same time, and that if you want to get this money back from cancer patients (there are reportedly about 887 new cancer drugs in some state of development), then you have to get as much of it as you can up front, because unlike patients taking Lipitor, these folks won't be around for that long. So the longer-term solution is likely to be refining the drugs and identifying the really promising compounds that truly keep these patients alive for a long time.

NPR: Forget the Serotonin Theory of Depression

2012-01-23T09:18:00.000-08:00

Alix Spiegel of NPR did a very nice story this morning on the serotonin theory of depression:
http://www.npr.org/blogs/health/2012/01/23/145525853/when-it-comes-to-depression-serotonin-isnt-the-whole-story

She quoted a number of notable psychiatric experts, but sadly not our friends Jeffrey Lacasse and Jon Leo, whom we have cited here previously:
http://brodyhooked.blogspot.com/2011/01/what-do-we-really-know-about-depression.html

Anyway the news report covered most of the bases--that scientists believe that attributing depression to a deficiency of serotonin is at best overly simplistic and at worst flat wrong; that the low-serotonin narrative for depression caught on with the public (and physicians) because it's simple, and no equally simple narrative is available to take its place; distressed patients really like simple narratives that promise to fix the problem, rather than complex narratives that may be scientifically more accurate; and the serotonin narrative has had both pluses and minuses--the plus being that many no longer see depression as something to be ashamed of or hidden, the minuses being that everyone now seeks a pill for depression despite the fact that pills work badly and have major safety issues, and many non-pill therapies work very well for mild to moderate depression.

Ms. Spiegel left out only one factor--what was the role of pharmaceutical marketing in selling all of us on the nice, simple serotonin narrative? And in making sure we still believe it even after it's debunked?

From Kalman Applbaum: How Pharma Does Business

2012-01-17T09:13:00.000-08:00

Thanks to my esteemed colleague Daniel Goldberg for alerting to to this post--
http://somatosphere.net/2012/01/the-banality-of-corporate-corruption-janssen%e2%80%99s-reimbursement-department-takes-the-stand-risperdal-on-trial-cont%e2%80%99d.html
--by our old friend anthropologist Kalman Applbaum, for example as summarized here:
http://brodyhooked.blogspot.com/2010/06/how-does-drug-industry-exert-power.html

Dr. Applbaum, showing us once again that academic research is far from glamorous, is apparently camped out in a courtroom watching the unfolding of the whistle-blower case regarding the antipsychotic drug Risperdol, Janssen/J&J, and the various state Medicaid agencies, primarily Texas and Pennsylvania, that the drug firms attempted to influence (or more bluntly, to bribe) to assure that their own drugs were promoted to physicians by getting written into the official treatment guidelines. To get a full sense of the case see the earlier posts in this series by Dr. Applbaum.

This particular post may not mean much if you've not been following the case closely, so I cut to the chase by appending his final comments. Dr. Applbaum refers here both to his extensive experience in interviewing pharmaceutical executives, and also the recently settled case regarding another antipsychotic, Seroquel:

While the scale of the organization of deceit revealed in the Seroquel documents astonishes, what should strike us the most in the depiction of the implemented marketing plans is how routine they appear to be. The spectacle of the court trial is in this sense a distraction, since it focuses our attention on violation, on breach. But while the actions under investigation may be legal contraventions, they are not managerial ones. On the contrary, the marketing practices conform to business and organizational norms that are positively embraced as sound managerial principles.

Because of this, the most florid violations lie on a simple continuum with all pharmaceutical marketing practices. The prosecuted cases are distinguished, if at all, by degree and not kind with other examples. If for no other reason than that competitive pressures drive companies to behave in similar ways, one can guarantee that the marketing strategies and tactics for drugs of a single class will resemble each other. When Vioxx blew, industry watchers knew that the other Cox-2 inhibitors (Celebrex and Bextra) were potentially not far behind. When Zyprexa [Lilly’s SGA] was called to account, informed observers knew that the other manufacturers of atypical antipsychotics (of which Seroquel is one) were guilty of similar crimes, which would become visible if the opportunity arose for opening up their marketing records.

Dr. Applbaum heads this post "The Banality of Corporate Corruption" which probably says it all.

Peddling Useless Drugs: Paying Journals to Publish

2012-01-06T17:32:00.000-08:00

I reprint the following from my post of November 21, 2011:

I've previously mentioned the Primary Care Medical Abstracts program run by my friends Rick Bukata and Jerry Hoffman, in which subscribers receive a CD each month with commentary on 30 recently published papers from medical journals. Since both Rick and Jerry are concerned about the impact of Pharma marketing on medical science and practice, it's not uncommon for several of the papers each month to address topics of interest to this blog. The October, 2011 issue had an especially impressive bumper crop. Here are capsule summaries of some of the papers.

Who's Marketing the Heck Out of Useless Cholesterol Drugs?

Before statins came along, an older class of drugs, the fibrates, was employed in attempts to lower cholesterol. Recent research has documented thoroughly that these drugs have no place in the medical armamentarium. Yet these authors noted a 117% increase in fibrate prescriptions between 2002 and 2009. Was this because physicians all on their own decided to go back to this old class of drugs? Hardly; the data show that newer brand-name fibrates are selling much better than older generics. So it seems that creative drug marketing has resurrected a class of drugs that should have been sent to the retirement home long ago.

Jackevicius CA, Tu JV, Ross JS, et al. Use of fibrates in the United States and Canada. JAMA 305:1217-1224, March 23/30, 2011

Okay, so you might ask, just how is Pharma going about twisting docs' arms to get them to prescibe more and more of these useless drugs?

Enter Marilyn Mann, who except for the fact that she reads this blog regularly is an eminently sane person. She posted a clue to this puzzle on her blog, which is called, for some strange reason, Marilyn Mann's Blog:
http://marilynmann.wordpress.com/2012/01/05/abbott-laboratories-sponsors-review-article-on-its-own-drug/

Marilyn, tipped off by Dr. Harlan Krumholz at Yale, provides links to a so-called review article on fibrate drugs. The fine print at the end of the article says that Abbott Laboratories, which by the merest coincidence manufactures two fibrates, paid the publisher to print this article. The disclaimer goes on to note that Abbott did not directly pay the authors. But the lead author is "medical editor" of the journal. I rather doubt that he does this out of the goodness of his heart, so I assume that the publisher pays him. So Abbott pays the publisher and the publisher pays the author, but Abbott does not pay the author. Okay, now it's all clear.

The tried and true tricks that the article trots out for our edification (hitting the high points only) are, first, including really glitzy graphics to illustrate what fibrates do at the chemical and cellular levels (a sure tipoff of generous Pharma funding; the average medical journal, unless they are high rollers like New England Journal, simply cannot afford cute color graphics)--thereby increasing the scientific panache of the paper without really saying anything important for clinical medicine; second, stressing surrogate endpoints--in this case, how much fibrates reduce blood levels of triglycerides, without mentioning that there's no correlation between making your lab numbers look better and your living any longer; and finally, omitting the key take home message, which is that all studies of actual patient outcomes in fibrates show that they reduce the rate of some cardiovascular events, some of the time, but don't budge the mortality rate. In other words, if you don't want to die of a heart attack, but would rather die just as quickly of something else instead, take fibrates. (In fairness, this point is mentioned, though effectively buried, in the text of the article, but is completely absent from the abstract--which is the only part of the article many, if not most, busy practitioners read.)

Marilyn wants to know why any physician would bother to read such drek, and why a state chapter of the American College of Cardiology would reveal its bottom-feeding tendencies by allowing its name to be attached to such a publication. She might as well ask why 85% of US docs see drug reps and use the industry as a source of information about pharmaceuticals. You can bet that Abbott did not merely pay the journal to print the article, they also bought a ton of reprints. Those reprints are handed to docs by the reps peddling the fibrates, and the docs have no time to read the reprint (except maybe the abstract as noted), but the reps point out the pretty pictures as evidence that the sales pitch they're delivering is "scientific."

(Hat tip also to Jerry Hoffman for helpful e-mail comments.)

A Voice from France on Device Scandals

2012-01-05T05:21:00.000-08:00

Most of you are aware of the current scandal in France over flawed breast implants (for example:
http://www.monstersandcritics.com/news/health/news/article_1684041.php/France-calls-for-new-rules-on-breast-implants-as-scandal-deepens)

Don't be surprised that this happened, says Dr. Alain Braillon, referring back to a commentary he wrote on how cozy the French device regulators are with the industry they supposedly regulate:
http://braillon.net/alain/medical_devices_approval_france_usa.pdf

Braillon, an MD/PhD, was fired from his post at the University Hospital of Amiens in 2009, despite strong peer support, as a result of his whistleblowing activities that angered the French Department of Health (see: http://onlinelibrary.wiley.com/doi/10.1111/j.1478-3231.2011.02723.x/full)

The French debate is of concern as the US medical device industry struggles hard to fight the latest efforts of the FDA to regulate them more stringently, playing the "jobs" card in Congress as aggressively as they can with both parties:
http://brodyhooked.blogspot.com/2011/10/more-on-device-industry-from-aslme-coi.html

From Health Care Renewal: Egregious Behavior of the APA

2012-01-04T10:19:00.000-08:00

Once again I am just the scounting party or the warmup act, whichever you prefer, for the Health Care Renewal blog, in this case Dr. Bernard Carroll:
http://hcrenewal.blogspot.com/2012/01/self-inflicted-damage.html

Dr. Carroll submits evidence that the American Psychiatric Association, currently under fire for the way that it is setting about revising its Diagnostic and Statistical Manual 5th edition (DSM-5)--see for example earlier posting:
http://brodyhooked.blogspot.com/2009/06/will-psychiatrys-dsm-v-be-huge-growth.html
--has now shut down a UK blog that was serving as a discussion forum for criticisms of the DSM-5 proposed revisions. APA threatened legal action based on copyright infringement if the blog did not close down its discussion of DSM-5. (Hey APA-- I just said "DSM-5" in this blog post--come and sue me too.)

Dr. Carroll makes a number of on-target observations in his post. He notes that this action by the APA amounts to what's called "SLAPP," which as I discussed in HOOKED means "strategic lawsuit against public participation." In this case it would be a threatened SLAPP rather than a true SLAPP, as no lawsuit was filed, but the fear of having to go up individually against the deep legal pockets of the APA forced the UK blogger to knuckle under promptly. A SLAPP is not a lawsuit that has merit that could win in a court of law--it's a power play in which the disproportionate ability of one party to pay for legal expenses without going broke is used to make the other party cease public criticism of the other party.

He also notes the divergence between appropriate professional standards and the behavior of the APA. Does the APA own psychiatric diagnosis? The organization makes huge bucks off selling the DSM which is effectively the Bible of psychiatric diagnostic labelling, whether your interest is clinical or financial in terms of billing for services. Dr. Carroll asks--why have we entrusted the APA with this publication? It can only be because society has confidence that an organization of physicians will carry out its mission with scientific integrity. Scientific integrity demands that if there's controversy, it is conducted openly and that what in the end gets published has withstood the most searching scientific criticism possible.

To try to shut down and stifle criticism because one hopes to make money off one's product is commercialism and not professionalism. That the APA appears to be acting in this crassly commercial manner would seem a severe indictment of what sorts of people are allowed to manage so-called "professional" medical societies in these times.

Previously I have taken off after my own professional society, the American Academy of Family Physicians, for behavior suggestive of commercialism and conflicts of interest:
http://brodyhooked.blogspot.com/2010/12/aafp-and-coca-cola-update.html
I would ordinarily not want to commit myself as to which society has sunk lower in the area of professional integrity, but I think the award has to go to APA-- at least if people disagree with what the AAFP is up to, the AAFP has not stepped in threatening legal action against their right to express their views.

Back to the Risks of Prescription Drugs

2011-12-24T07:17:00.000-08:00

The latest issue of the Medical Letter (Dec. 12/26, 2011; subscription required) is instructive in reminding us of an important theme behind the ethics of the medicine-Pharma interface. The biweekly newsletter for physicians, supported only by subscriptions and with no industry advertising, reports on two recently approved drugs (dabigatran and dronedarone) that turned out to have greater risks of serious bleeding than had initially been suggested by clinical trials. The newsletter then reviewed another new drug, rivaroxaban, a clotting inhibitor, which in early trials was shown to be somewhat effective (when added to other drugs) in decreasing the risk of future cardiovascular events, but only at the cost of increasing the risk of bleeding into the brain. The Medical Letter experts commented that this puts rivaroxaban in the same category with dabigatran and dronedarone, making one suspect that as more experience is gained, more will come to light about the actual risks of serious bleeding.

These reviews of new drugs reminded me of the fact I have previously blogged about (http://brodyhooked.blogspot.com/2010/08/how-many-new-drugs-are-lemons-ask.html), courtesy Dr. Donald Light’s important book, The Risks of Prescription Drugs. Dr. Light has reviewed data that indicate that each year, more than 100,000 Americans die of the adverse reactions from prescription drugs, properly prescribed in hospitals. That is, deaths from overdoses and due to errors in prescribing are not included in this total. If accurate, that would make adverse reactions from prescription drugs roughly the 4th largest cause of death in America. And those data exclude all deaths that might occur outside of hospitals.

I have to admit that when I first read that figure, I did not believe it, and I imagined that critics would come forward with different calculations to show that Dr. Light’s results were too high. So I consider it important that no such critics have, to my knowledge, come forward; and Dr. Light informs me that to the extent that he can double-check these calculations, they still appear to be valid, and have been buttressed by more recent studies. If anything, alternative methods of estimating the numbers (there are no direct data available that would give a precise figure) would lead to even higher totals. He also reminded me that the AARP featured these figures in their September magazine, warning about risks of prescription drugs:
http://pubs.aarp.org/aarpbulletin/201109_IL/?pg=14&u1=coverleaf&search=risks prescription drugs#pg14

Bear with me for some comments. We already put the American public at high risk of bad things happening to them when we prescribe drugs. Yet the Medical Letter shows that we persist in rolling out new drugs that add even more to the risks.

Pharmapologists will immediately protest that these risks are nothing compared to the wonderful benefits of all these new wonder drugs. So let’s think about those benefits for a minute. Let’s consider the new kid on the block, rivaroxaban, as one example. This drug (brand name Xarelto, manufactured by Janssen/Johnson & Johnson) is an anti-platelet agent (like low-dose aspirin) and is indicated for patients at high risk for blood clots that could cause strokes, heart attacks, and other bad stuff. Patients at that level of risk are typically now treated with two drugs, aspirin and clopidogrel (Plavix). So the research studies on the new drug compared patients taking those other two agents, plus placebo, with those taking the other two agents plus rivaroxaban.

When that comparison was made, the combined bad outcomes (death, heart attack, or stroke) happened in 9.1 % of those taking the three-drug combo (at the lower tested dose of rivaroxaban) compared to 10.7% of those on the two older drugs only. That calculates as best as I can tell to a number-needed-to-treat of 62. That is, you’d have to give 62 people the 3-drug combo for 2 years to prevent one case of death, heart attack, or stroke, in excess of what would happen with just two drugs only. At that dose of rivaroxaban, for every one person who avoided a bad event, another one would suffer a serious (but in this study, non-fatal) brain-bleed-type stroke.

Keep two things in mind. First, the advocates of rivaroxaban are proposing that we take what’s now a 2-drug combo and turn it into a 3-drug combo for treatment of the indicated conditions. We know that the more different drugs you’re taking, the greater the chance of adverse reactions. Second, these are the early data on the efficacy and safety of rivaroxaban. Recall John Ioannidis’s important work showing that we can bet dollars to donuts that the earliest studies of a new drug will show a substantially higher success rate, and a lower adverse-event rate, than the totality of all studies performed over a number of years (see previous post, http://brodyhooked.blogspot.com/2011/03/how-honest-reports-of-research-can.html).

To summarize, the US pharmaceutical industry, its pipeline running dry of really good drugs that are truly a major advance over existing drugs, is now busy flooding the market with drugs that offer very slight advantages and only at the cost of serious risk of harm. The total public health impact on the American public is increasingly negative, as Dr. Light’s figures indicate.

I am reminded of the old Harry and Louise ads, funded by the US private health insurance lobby to kill the Clinton health reform plan back in 1993-4. The couple sitting at their kitchen table, after listing all the terrible things that would happen if health reform was enacted, shook their heads and intoned, “There has to be a better way.” I think the same might be said of the way we discover, approve, and market new drugs today.

Painful to Report: ProPublica Skewers American Pain Foundation

2011-12-23T12:28:00.000-08:00

The most recent investigative reporting by ProPublica, who have done great work in exposing industry funding and related conflicts of interest, puts me personally in a bind because I have considerable sympathy with both sides:
http://www.propublica.org/article/the-champion-of-painkillers

Charles Ornstein and Tracy Weber detail the degree to which the American Pain Foundation has been funded by manufacturers of narcotic painkillers, including the notorious Purdue Pharma, maker of OxyContin, and how it then proceeds to stick up for widespread use of narcotics for treatment of chronic pain--even in the face of increasing evidence showing, first, that opiate drugs may not be very effective for chronic pain; and second, that overdoses and addiction from these drugs are growing to epidemic proportions.

So let me see if I can add any balance to the discussion.

First, let me speak in defense of the position taken by the American Pain Foundation. One of the big problems in pain research has been the lack of Federal grant dollars, since there is no National Institute of Pain at NIH, and the NIH has until very recently shown very little interest in funding pain research, despite estimates that around 75-100 million Americans suffer from some degree of chronic pain. In this funding vacuum, the analgesic manufacturers have often been the only possible source. As I detailed in HOOKED, this has led to the undesirable state of affairs, of many of the most prominent experts in pain management in the US being "on the take" with drug company money.

The critics of the Foundation that ProPublica spoke with all note the current dearth of solid evidence that opiates are good for treating chronic, non-cancer pain. It is true that the available studies to date have been discouraging. I think today, any physician who goes to narcotics and narcotics alone as the first line approach to treating chronic pain would be off base. But two important facts need to be put into perspective alongside these data from controlled trials. First, after you try all the various other modalities for pain management, virtually all physicians in this business would agree that you end up with at least some--more than just a few--patients who are still miserable and unable to function despite it all. These patients often get some relief, occasionally substantial relief, with opiates, and with proper management and monitoring the rate of addition or serious side effects is very low. Somebody needs to speak up on behalf of this group of patients and make sure that they don't lose access to the one thing that substantially helps them.

Second, the ideal way to treat chronic pain is through a multidisciplinary pain clinic that offers physical therapy, pain psychology, and generally a team approach alongside a willingness to prescribe appropriate analgesic drugs. Now, go try to find such a place. Not unusually, there's none within 250 miles. (Too many so-called "pain clinics" are basically procedure mills where anesthesiologists do mostly worthless injections for big bucks, then turn patients away as soon as their insurance benefits run out.) If you can find a truly multidiscioplinarty pain clinic, then ask if it accepts Medicaid. Chronic pain, not surprisingly, is concentrated in lower income groups, who often lack the good insurance that's the ticket into most of the really good clinics. So we are talking about an ideal mode of treating chronic pain that is simply out of the reach of way too many sufferers.

Are these clinical realities about treating pain reflected in today's media? All we read about is the epidemic of drug diversion, overdoses, illegitimate and illegal "pill mills" selling narcotics to addicts, and so on. Somebody needs to speak up for the legitimate pain patients who may need opiates as a part of a broader approach to pain management.

OK, that's the one side of the issue. Now let me speak with my usual hat on, opposed to conflicts of interest. Here we see the chickens that come home to roost when you feather your nest with industry cash. (Sorry for the fowl cliches.) There's that little question of public trust. It seems that whatever the American Pain Foundation set out to do, it has seriously compromised its ability to do it by getting in bed with the likes of Purdue Pharma.

Let me talk a minute about Purdue, whose record of wrongdoing is now legendary. They make OxyContin. Addicts found out about 5 minutes after the drug hit the market that the capsule had an unfortunate property--if you crush it, you got an immediate rush of the drug, rather than the slow release that the capsule was designed to give, and that it does give if you take it properly, without crushing. This set up the popularity of OxyContin as the infamous "hillbilly heroin." By contrast, another slow-release form of opiate, MS Contin, works just fine--even if you crush the capsule, the matrix that holds the active drug won't release it all at once. That's great for legitimate pain patients and bad for abusers.

So what would a decent drug company have done? I say--obviously, take OxyContin off the market, and don't bring it back on until you have redesigned the capsule to work in a way that doesn't help addicts get high. Instead Purdue did everything they could to keep selling OxyContin as originally formulated and also did everything they could to whitewash the problems. And the American Pain Foundation helped them out.

I strongly agree with my bioethics colleague, Dr. Ben Rich, who has written extensively about medicine's ethical obligation to do a far better job of treating pain. Sadly, well-intentioned organizations that take cash from Pharma and create serious conflicts of interest for themselves make this ethical job harder to do.

Why the Drug Pipeline is Dry: Another View

2011-12-23T11:15:00.000-08:00

In previous posts, such as: http://brodyhooked.blogspot.com/2011/07/drug-pipeline-not-so-dry.html, I have offered my opinions as to what's wrong with the research and development model favored by the drug companies over the past couple of decades, that has led to the notable dearth of important new drugs. As I myself know squat about drug research, I always offered these comments with trepidation. The post referenced above was reassuring in adding the opinion of two reporters; but now we have word from a medical expert who at least knows enough about the subject to get his stuff published in the New England Journal--specifically, Dr. Robert Schwartz of Tufts in Boston:
http://www.nejm.org/doi/full/10.1056/NEJMp1111377

Dr. Schwartz is focused on how best to find promising new cancer drugs, but I'll let him speak for himself:

“Targeted treatment” became the shibboleth of the pharmaceutical industry, spurring on a multibillion-dollar search for targets in other cancers. The quest began with an enterprise based primarily on industrial-strength methods of gene sequencing, gene arrays, and gene profiling, which allow rapid examination of thousands of genes in a cancer cell, potentially revealing the genetic profile (or signature) of a malignant cell. These profiles could, in principle, enable the design of a specific inhibitor of an aberrant cancer gene or its product.

But the idea of finding magic bullets by open-ended genetic screening that deliberately avoided any prior hypothesis was considered dubious by some. And ultimately, critics would complain that more than a decade of investigation with powerful technical methods and huge investments by the National Institutes of Health (NIH) and the pharmaceutical industry had yielded few useful drugs....The molecular labyrinth of the cancer cell guarantees that the odds of identifying a single useful and specific therapeutic target by mass screening are very low.

...[W]e [should] reconsider the way we organize cancer research. In Science-Mart: Privatizing American Science, Philip Mirowski concludes that today's system of big-time, industrialized scientific research is deeply flawed because of burdensome intellectual property rights and investors' management of research. Moreover, international pharmaceutical companies are cutting back their drug-development research owing to economic constraints, and the federal government probably can't make up the difference in these times of deficits and cutbacks.

To summarize, treating potential drug molecules like an assembly line making Model T Fords is maybe a model for drug R&D that is as out of date as the Model T. Maybe you actually have to have a clue as to what makes disease happen--the way academics have traditionally studied disease in the laboratory--before you can find drugs that actually show promise.

Here We Go Again, with the Form

2011-12-13T13:12:00.000-08:00

According to several press accounts such as:
http://www.startribune.com/local/135475788.html
--we can go back to our standard form and fill in the blanks (except to substitute devices for the usual 'drugs'):

Company: Medtronic
Devices: defibrillators and pacemakers
Settled Federal charges of: paying kickbacks to docs for using their brand of device ($1-2K per implantation)
Fine paid: $23.5M
Fine as % of Annual Sales during Peak Year: 0.4%
Company Admits Guilt?: Of course not

I calculated the percentage of sales based on last year's sales figures reported by the company of $16B, and their statement that 31% of their business involves cardiac rhythm devices.

As we have seen recently (e.g., http://brodyhooked.blogspot.com/2011/11/back-to-standard-form-again-merck.html) if anything, the trend within the drug industry has been for more substantial fines, so the pittance the Feds collected in this case seems a major step backward.

"Intellectual Conflict of Interest" Rides Again

2011-12-09T08:22:00.000-08:00

Dr. Roy Poses posted on his Health Care Renewal blog about Pharma critic Dr. Sidney Wolfe being denied a place on an FDA advisory committee--
http://hcrenewal.blogspot.com/2011/12/logical-fallacy-affecting-selection-of.html
--which prompted a response by a "Melissa Raven" and a reply from Dr. Poses (see same URL).

Dr. Poses was kind enough to reference two former posts on this site about "intellectual conflict of interest," of which the more pertinent and complete is:
http://brodyhooked.blogspot.com/2008/03/more-on-intellectual-conflict-of.html

I was about to add my proverbial 2 cents in the form of a comment on Health Care Renewal, but decided it would become too wordy, and I save wordy for this blog and the few long-suffering readers thereof, so here goes.

Mr. Raven sees value in excluding people with "intellectual conflicts of interest" from advisory panels and similar groups, and instead looking for methods experts who understand what counts as good and bad evidence, but who have not previously taken stands on the particular issue under review. Dr. Poses quotes objectors to the FDA action in the Wolfe case who say that eliminating "intellectual conflict of interest" amounts to excluding anyone who has previously thought carefully about an issue, which seems to be overkill on a scientific matter.

It seems to me that underlying this discussion is a possible confusion among three concepts-- disinterested; conflict of interest; and disclosure of conflict of interest.

Ms. Raven invokes the goal of the "disinterested" advisory panelist as her argument against seating somebody like Dr. Wolfe (whose specific sin, by the way, was having previously issued warnings, on behalf of the consumer organization Public Citizen, against the type of birth control pill that the panel was supposed to review). Now, there may be something to be said for this goal, and even taking it to the extreme of excluding academic types who have formed opinions on a matter previously. After all, a reason to exclude potential jurors is that they have preconceived ideas about the guilt or innocence of the defendant. But my point right now is that "disinterested" and "conflict of interest" are rather different concepts.

As I discussed in HOOKED, and in a subsequent publication referenced below, 'conflict of interest' is hard to define succinctly, but a good approximation is, "One has become party to social arrangements that would tempt a person of normal psychological makeup to neglect a duty to protect the interests of a person or group in favor of a secondary interest, in such a manner as to create a risk of loss of trust in one's social role." Illustrative example:

Medical scientist undertakes clinical study of a drug.

The medical scientist also becames a paid speaker and consultant to the company.

The company wants to publish data that would promote the use of the drug and suppress data hinting at problems with the drug.

A medical scientist has a (primary) duty to publish the scientific truth for the benefit of future patients.

The scientist now has a (secondary) interest in serving the goals of the company, which conflict with the goals of good science and patient benefit.

The secondary interest is of the sort that would lead a person of normal human psychology to be tempted to ignore the primary duty in favor of the secondary interest.

This social arrangement (accepting speaker fees etc.) is of the sort that could lead reasonable onlookers to lose trust in medical science.

Notice that this describes a pretty specific set of circumstances. On the other hand. "disinterested" is a much broader term, which does not necessarily implicate any conflict of interest or threaten loss of trust in a social role. Because I know somebody is interested and not disinterested, I may distrust a particular opinion that person offers, but that is not the same as losing trust in a social role.

The sorts of financial conflicts of interest that us pharmascolds have focused on are relatively easily avoided. One does not have to fill one's own pockets with Pharma cash to practice good medicine or do good science. On the other hand, in an academic venue or in medical practice, being truly disinterested may be well-nigh impossible.

Suppose that as a medical practitioner I tell my male patients that they should have PSA tests routinely. Studies now come out showing that PSA testing may be more harmful than helpful. I am hardly disinterested when I read those studies. If their conclusions are true I have been exposing my patients to potential harm out of proportion to their benefits. Of course I am "interested" in how I interpret those studies, how hard I try to find flaws in their design, and so forth. So find me a "disinterested" medical practitioner, let alone scientist.

I have previously stated, ad nauseam in fact, that disclosure of conflicts of interest is a necessary but often hardly sufficient response to the ethical problem posed by COI. But it is in the nature of financial conflicts of interest not to be generally known unless disclosed. On the other hand, the fact that an academic has taken a certain point of view on a scientific topic is usually self-disclosing. (Just listen to the guy for about 5 minutes.) Anyone wondering whether I have an opinion on most matters can easily do a PubMed search and see what I have published on the topic. Dr. Wolfe certainly does not keep his Public Citizen advocacy activities secret.

So I suggest we keep these distinctions in mind as we discuss such matters as whether the FDA was silly to exclude Dr. Wolfe, which I vote that they were.

Brody H. Clarifying conflicts of interest. American Journal of Bioethics 11(1):23-28, January 2011.

Supremes Look at Biotech Patents

2011-12-08T11:08:00.000-08:00

The Minneapolis Star-Tribune reports:
http://www.startribune.com/business/135202333.html
--that the U.S. Supreme Court heard arguments yesterday in a patent dispute between Mayo Clinic and a firm called Prometheus Laboratories. The case has implications for potentially reining in the overly broad patents now being issued for biological and medical discoveries, especially related to the genome.

The article is unfortunately not very specific about the diagnostic tests that are at the root of the patent dispute. We learn from another press source--
http://www.twincities.com/health/ci_19493210?source=rss
--that the test involves correcting the dose of thiopurine administered for various autoimmune disorders, especially in the gastrointestinal tract. Mayo previously used the Prometheus test to find out how much thiopurine stayed in each patient's bloodstream, until its own scientists came up with what they say is a better test, and then Prometheus sued Mayo to prevent their test from reaching the market. The lower court ruled for Mayo, a higher court reversed, and now the case is before the Supremes.

Mayo's case, which is backed by the Feds, is that the Prometheus patent is too broad, and would patent the idea of doing the sort of test Mayo has actually developed, even though Prometheus never invented that specific test. As I wrote in HOOKED, the patent system, which is an interference with the free market designed to trade off monopoly privileges for promoting innovation, is actually today squelching innovation because the patent office is willing to patent most anything, whether it has been actually taken to a realistic stage of development or not. The Supreme Court was told in argument that if they found for Prometheus, they would basically be saying that a manufacturer of a bad product could use the patent system to prevent a competitor from marketing a better product--hardly the sort of promotion of innovation the patent system as designed for.

I previously blogged about patents: http://brodyhooked.blogspot.com/search?q=patents
--in relation to pay-for-delay to prevent generic drugs from cutting into brand-name profits. Anything the Supremes might do to reduce overly broad patents, and to stop industry from "patenting the sun" in Jonas Salk's famous phrase, would be welcome.

Time Out for Some Drug Pricing Issues

2011-12-01T05:18:00.000-08:00

I try to stay focused in this blog on the ethics of the medicine-Pharma relationship and so as a rule steer clear of drug pricing issues as such. Of course drug prices indirectly affect the ethics of medicine as physicians try to figure out how an increasing number of their patients can gain access to needed medications.

Linda A. Johnson of AP did a recent story--
http://www.usatoday.com/money/industries/health/treatments/story/2011-11-29/Pfizer-maneuvers-to-protect-Lipitor-from-generics/51475288/1
--about Pfizer's struggle to keep making profits off its best-selling drug, Lipitor, which is about to go off patent. (Brand-name Lipitor sales at about $11B annually are now fully 20% of Pfizer's business.) Unfortunately her article obscures as much as it reveals. (Readers who understand the economics of drugs better than I do please feel free to chime in with comments.)

Quick recap of the generic weirdness according to the Hatch-Waxman act: As a method of incentivizing generic competition, Congress granted special privileges to the first generic manufacturer to come up with an FDA-approved bioequivalent product for the brand-name drug. The generic company that's first to the finish line gets a 6-month period of exclusivity before other generics can jump into the market.

That means that a brand-name drug goes from being a monopoly to being a duopoly for 6 months, then the real free market takes over. During the duopoly period, it is common for the generic competitor to be priced only a bit lower than the brand-name drug price. That means that the generic firm can make quite hefty profits off its drug for the 6 months, and the brand-name company can often extend its period of profits since it's not really being undercut all that much by the competition. Then 6 months later the price really falls as everyone and his proverbial duck can get into the game, and it's only then that consumers really benefit.

The company that's the lucky winner in the generic lottery, according to a press release just out, is Ranbaxy Pharmaceuticals, Inc. which is a wholly owned US subsidiary of the largest generic drug firm in India--itself a most interesting development, but that's for another post. Neither the press release nor the AP article says what Ranbaxy will charge for its generic atorvastatin (aka Lipitor) during its lucky 6 month window.

Now back to Johnson's report--she states that Pfizer is working hard to maintain brand loyalty among its customers, unlike the usual behavior of the brand name company which is to throw in the towel when the generic competition appears and profits drop. They are working as hard as they can to price brand-name Lipitor at lower than the generic price, at least during the 6-month window. That includes issuing copay cards for pharmacies allowing $4/month Lipitor prescriptions, and trying to lock pharmacies into special discounts on the condition that they don't substitute a different generic brand.

What's not clear to me at least is what the overall game plan is once the 6 month window is over. Does Pfizer figure it can lock in business during the time when the only generic competitor is relatively expensive, and then later reap the benefits when the generic competition becomes dirt-cheap? Or is it actually the case that Pfizer figures it can make decent money even selling its Lipitor at generic prices for the long haul?

What's also not clear is that it's hardly possible that this plan was Pfizer's Plan A. As we discussed in the past--
http://brodyhooked.blogspot.com/2011/10/what-to-do-about-pay-for-delay.html
--the usual Plan A of the brand-name firm is "pay-for-delay," cutting a sweetheart deal with the first generic competitor to lie low and not challenge the brand-name drug for an extra 6 months, assuring that the big profits keep rolling in for that half-year. It's not clear whether Pfizer tried various ways to buy off Ranbaxy and came up empty-handed, or whether the current sales strategy is in fact the result of a secret deal that Pfizer managed to cut. Hopefully we'll hear more on this soon.

Addendum 12/1/11: Apparently three US senators had some concerns similar to mine:
http://www.nytimes.com/2011/12/01/health/senators-question-plan-to-stall-generic-lipitor.html
Also in this news coverage by Duff Wilson at the NY Times, it's shown that I might have been in error above in saying that the first kid on the generic block was Ranbaxy, contrary to what their press release said. Watson Pharmaceuticals has FDA approval and is actually shipping generic atorvastatin as we speak. But Watson has a deal with Pfizer to make the "approved" generic. One press account says Ranbaxy has approval for its generic, another (Wilson-NYT) indicates that it's been held up, so I really don't know what the score is at this point. Stay tuned for further exciting adventures.

Addendum 12/8/11: Two more counties heard from... First, Merrill Goozner both on his Gooznews blog and in the Fiscal Times:
http://www.thefiscaltimes.com/Articles/2011/12/02/Pfizer-Maneuvers-to-Undermine-Generic-Lipitor.aspx#page1
--adds a bit more detail, and clarifies that both the Watson and the Ranbaxy generics are approved and out there, so it's both-and not either-or. Then a group in the New England Journal of Medicine, including our old friends Drs. Joseph Ross and Harlan Krumholz:
http://www.nejm.org/doi/full/10.1056/NEJMp1113112?query=featured_home
--provide a bit more detail, in the context of trying to calculate how much savings the US public could look forward to in coming years as a result of atorvastatin being available generically--they figure about $4.5B annually by 2014, assuming that full savings are realized. They then discuss how Pfizer could mess up the picture. Their worst-case scenario is that the sweetheart deals Pfizer has cut might discourage some generic makers from getting into the competition and that would be the main way prices would be kept higher than otherwise. So bottom line, still more questions than answers as to how all this will play out.

The "Emergent Patient-Industry Complex" and Regulatory Capture

2011-11-30T11:46:00.000-08:00

In HOOKED, I referred to the "Lotronex Story" and elsewhere talked of "regulatory capture," a term I first got from reading the work of British sociologist John Abraham (to describe how an industry that is supposed to be the subject of regulation ends up learning how to manage the regulatory process to its own advantage). Now Abraham and a colleague have gone into much more depth on the Lotronex case and reached some interesting conclusions (subscription required to access article).

Brief recap: alosetron (Lotronex), manufactured by Glaxo Wellcome (later GlaxoSmithKline) was put on the market in 2000, withdrawn later that year, and put back on the market with restrictions in 2002. It was marketed for irritable bowel syndrome, a common condition that is chronic and relatively mild in most cases but is quite disabling for a small percentage of sufferers. It was the first drug specifically aimed at IBS and so attracted a lot of attention because of its novelty.

The initial data presented to the FDA in support of approval were, in hindsight, remarkably skimpy. It seemed that alosetron worked only in women, and only in IBS patients who had mainly diarrhea as the predominant symptom. (When a disease occurs in both sexes but you find that a drug works in only one, that increases the chance that the drug does not really work at all and you're seeing a spurious finding.) At best the FDA data indicated a very mild if any benefit to be expected from the new drug. After it was approved on these skimpy data, reports emerged of ischemic colitis (segments of large bowel dying as a result of blood supply being shut off, due to severe constipation with impacted feces) occasionally requiring surgery and causing some deaths. Eventually the FDA allowed the drug to return to the market with serious restrictions on how it could be prescribed--a financial hit for the manufacturer, who saw a potential $5B blockbuster drug reduced to sales of only about $100M annually.

Let's now see what Davis and Abraham add to this brief recap. They obtained a trove of internal FDA documents via FIOA and also interviewed some of the FDA insiders who worked on the drug application.

They first note that when the reports of deaths from ischemic colitis started to roll in (and of course Glaxo denied at first that their drug had anything to do with these deaths, though virtually no one dies of IBS alone), FDA folks sat down with Glaxo folks and proposed a plan that was quite close to the re-marketing strategy that was finalized in 2002. But Glaxo elected on their own to pull the drug, arguing that ther FDA's restrictions were so onerous that the poor firm could hardly make a buck off the drug that way. The authors comment, "Evidently, providing the drug to the comparatively small number of patients most likely to benefit to reduce the risk to other patients less likely to benefit, together with research into how those risks and benefits could be better understood, was, according to GW, not commercially viable within the constraints of the U.S. capitalist market system." I have not seen a starker comment on the incompatiblility between good scientific medicine and drug marketing.

Once the drug was off the market, the FDA next heard from IBS patients, in a barrage of e-mails. As I reported previously in HOOKED, the barrage was launched by two patient groups, Lotronex Action Group and International Foundation for Functional Gastrointestinal Disorders. I quoted sources available then to report that the LAG appeared to be an independent grassroots organization while the IFFGD was openly and principally funded by Glaxo. However, Davis and Abraham quoted one of their FDA insiders that LAG raised all the red flags in his own mind of an industry-sponsored outfit, even though a connection was never proven.

Davis and Abraham noted that individual patient tesimonials from IBS sufferers who claimed to have had their lives dramatically improved by Lotronex dominated the FDA hearings to discuss re-marketing in April 2002. (No one testified who had nearly died of ischemic colitis.) They argue that despite the scientific nature of the FDA panel, the ensuing discussion within the FDA amounted to a sort of "regulatory capture" as a result of what they label the "emerging patient-industry complex." That is, the available scientific evidence provided no good way to identify either who stood a better chance than average of benefiting from alosetron (if you believed the data, the best guess would be nobody) or who stood at the highest risk of suffering harm. Indeed there was no good evidence that even carefully watching patients with an eye toward the signs and symptoms of ischemic colitis would allow identification of cases early enough to do any good by stopping the drug. Davis and Abraham allege that at this point, anecdotal patient testimonials trumped science in determining the FDA's agenda. And the further research that might have clarified therse matters was being resolutely avoided by Glaxo despite earlier FDA requests that the company proceed with those studies.

What I reported in HOOKED, that Davis and Abraham did not discuss, is how several FDA officers were outraged by bring overruled by agency higher-ups when the drug was re-marketed, and that other officers known to be critical of alosetron were summarily taken off the case.

In conclusion, Davis and Abraham conclude that alosetron generated a perfect storm of confluent forces--the FDA under fire from Republican-led congresses to show that they were not holding up the approval of innovative drugs; industry pressure; and patient advocacy lobbying that in all likelihood was funded and coordinated by industry. Scientific medicine didn't stand any chance in that environment. (The excellent policy question which the authors identify is what to do with patient testimony--it is clearly important in a democracy to validate and accept testimony of personal experience, yet we also know that no one can personally distinguish a drug from a placebo effect, which is worrisome when the "placebo" can kill you.)

Hat tip to my former graduate student and now esteemed colleague Daniel Goldberg of East Carolina University for alerting me to this article.

Davis C, Abraham J. Rethinking innovation accounting in pharmaceutical regulation: a case study in the deconstruction of therapeutic advance and therapeutic breakthrough. Science, Technology & Human Values 36:791-815, November 2011.

Back to the Standard Form, Again: Merck Settles on Vioxx

2011-11-23T14:52:00.000-08:00

Once again we can go back to the standard form:

Drug Company: Merck
Drug: rofecoxib (Vioxx)
Settled Federal charges of: Improper marketing (total settlement was a combined Federal and state action)
Fine paid: $950M
Fine as % of Annual Sales of Drug during Peak Year: 38%
Company Admits Guilt?: Can't tell from news report (see: http://www.latimes.com/business/la-fi-merck-vioxx-20111122,0,1295689.story)

In the previous post--http://brodyhooked.blogspot.com/2011/11/what-could-penn-state-scandal-have-to.html-- we reviewed the story of Merck's settlements of civil suits brought individually by patients who suffered heart attacks after taking Vioxx, noting that Merck ended up paying out about $7B in legal expenses and settlements in that set of suits. This means that if we add this new settlement, it may actually be the case that Merck has paid out in legal expenses just about as much as it made off Vioxx. (I could not quickly locate accurate yearly sales figures, but it seems that Vioxx sold less than $1B in 1999, then jumped to $1.5B in sales after aggressive marketing began in 2000, and reached peak annual sales of about $2.5B before being yanked off the market in September, 2004.) That would be a relatively new development.

Some Capsules of Recent Pharma-Related Escapades

2011-11-21T16:54:00.000-08:00

I've previously mentioned the Primary Care Medical Abstracts program run by my friends Rick Bukata and Jerry Hoffman, in which subscribers receive a CD each month with commentary on 30 recently published papers from medical journals. Since both Rick and Jerry are concerned about the impact of Pharma marketing on medical science and practice, it's not uncommon for several of the papers each month to address topics of interest to this blog. The October, 2011 issue had an especially impressive bumper crop. Here are capsule summaries of some of the papers.

Who's Marketing the Heck Out of Useless Cholesterol Drugs?

Before statins came along, an older class of drugs, the fibrates, was employed in attempts to lower cholesterol. Recent research has documented thoroughly that these drugs have no place in the medical armamentarium. Yet these authors noted a 117% increase in fibrate prescriptions between 2002 and 2009. Was this because physicians all on their own decided to go back to this old class of drugs? Hardly; the data show that newer brand-name fibrates are selling much better than older generics. So it seems that creative drug marketing has resurrected a class of drugs that should have been sent to the retirement home long ago.

Jackevicius CA, Tu JV, Ross JS, et al. Use of fibrates in the United States and Canada. JAMA 305:1217-1224, March 23/30, 2011

Data Dredging: Which Studies Do It the Most?

Here's a basic rule of statistics and study design--when you do a clinical trial, you are supposed to identify up front a handful of primary endpoints. You announce in advance that these are the outcomes you are going to be looking for to decide if your drug works or not. If you do it this way, and your results reach statistical significance, it's unlikely that any results you find are due to chance. But what if you then go back and look at your data to see if you can't find other associations--such as maybe older patients did better than younger patients, or those taking another drug did worse than those on the one drug only, or whatever? When you start doing these subgroup analyses, then you run a much higher risk of finding spurious associations. The common name for this practice is "data dredging" or "data snooping"-- it's a fishing expedition, not legitimate research.

These authors looked at 469 trials published in the supposedly best medical journals in 2007 to see how often data-dredging happened and what was associated with it. They found that the supposedly better the journal, the more likely data dredging was, and not surprisingly, drug-company-sponsored research was much more likely to engage in data dredging than other research. Also not surprisingly, if the primary outcomes were achieved, then data dredging was at a minimum, but it rose as soon as the primary outcomes failed to achieve statistical significance. In other words, when your study is a flop for your drug, then keep digging until you can find something good to say about the drug anyway.

Sun X, Briel M, Busse JW, et al. The influence of study characteristics on reporting of subgroup analyses in randomized controlled trials: systematic review. BMJ 342:d1569, March 28, 2011.

A Guideline Is a Guideline Is a Guideline--or Not

There's been a highly publicized difference of opinion over whether kids aged 2-10 need to be screened for cholesterol. Recently the American Academy of Pediatrics issued a guideline that said yes; but all along the U.S. Preventive Services Task Force has said no. In this paper members of the USPSTF fire back at the AAP. The USPSTF folks list a number of criteria that they use in writing their guidelines for preventive screening. They use a standardized approach to evidence and reject studies that are of poor quality. They rigorously exclude anyone with financial conflicts of interest from guideline-writing. They insist on using the actual evidence rather than relying on other previous guidelines that may not have been rigorously based. They also make public exactly who served on the guideline panel. The AAP guideline committee, these authors note, followed none of these criteria.

Grossman DC, Moyer VA, Melnyk BM, et al. The anatomy of a US Preventive Services Task Force recommendation: lipid screening for children and adolescents. Archives of Pediatrics and Adolescent Medicine 165:205-10, March 2011.

A Debate on Antidepressants

Finally, the British Journal of General Practice featured a pro-con debate over prescribing antidepressant drugs. Middleton and Moncrieff start off by noting that authoritative national guidelines suggesting that drugs be restricted to moderate-to-severe depression seem to have had little impact on profligate prescribing. They summarize recent research (as we have previously reviewed in this blog) that most antidepressants are nearly indistinguishable from placebo in their effectiveness, and that the theory that depression is fundamentally a disease of chemical imbalance in the brain has been vastly overblown. They conclude that since most of the good done by antidepressants seems to be a form of placebo effect, which relies on forming a strong therapeutic relationship with the patient and showing that one takes the patient's problem seriously, cognitive-behavioral psychotherapy is an excellent alternative to drug treatment and should be more widely used.

In reply, Anderson and Haddad basically change the subject and accuse Middleton and Moncrieff of saying a number of things that they don't say. From their doubting the serotonin theory of depression, Anderson and Haddad assume their opponents are guilty of mind-body dualism and dismiss entirely the role of neurotransmitters in mood. Responding to the claim that antidepressants show very little difference from placebo, Anderson and Haddad pounce on the fact that they show some difference from placebo and therefore the placebo effect cannot explain all of what they do. Anderson and Haddad then say, "[F]or individual patients who will not or cannot engage in other approaches, shouldn't this evidence allow at least a consideration of a trial of antidepressants?" This makes them appear reasonable and moderate and their opponents dogmatic, though Middleton and Moncrieff are far from ruling out antidepressant use in every case. Anderson and Haddad then add that psychological therapy will be a failure if you go to a lousy therapist--neatly ignoring all the evidence of the serious risks of antidepressants, in order to focus on the purported risks of psychotherapy!

Of these two sets of authors, one acknowledges receiving financial support from manufacturers of antidepressants. I'll let you guess which.

Middleton H, Moncrieff J. "They won't do any harm and might do some good": time to think again on the use of antidepressants? British Journal of General Practice 61:47-49, January 2011.

Anderson IM, Haddad PM. Prescribing antidepressants for depression: time to be dimensional and inclusive. British Journal of General Practice 61:50-52, January 2011.

Back to the Standard Form Letter: Abbott Settles for $1.3B

2011-11-21T15:34:00.000-08:00

In a recent post I was unable to employ my standard form to report legal settlements for corporate wrongdoing, due to the fact that many different drugs and several different allegations were all lumped together. Last month Bloomberg News reported--
http://www.bloomberg.com/news/2011-10-21/abbott-said-to-agree-to-pay-1-3-billion-to-end-depakote-suits.html#
--the following, which allows me to return to the standard format:

Drug Company: Abbott Laboratories
Drug: Valproic acid (Depakote)
Settled Federal charges of: Off label marketing (as well as state civil actions for inappropriate payments)
Fine paid: $1.3B
Fine as % of Annual Sales of Drug during Peak Year: 93%
Company Admits Guilt?: Can't tell from news report (the settlement was reported by "people familiar with the accords" and has not yet been officially announced)

What's notable about this settlement is both the fact that it topped $1B, though it's still only the third largest settlement; and the high percentage of annual sales the fine represents--we've seen from previous such reports that it's typical for the fine to be a mere 10% of annual sales.

Abbott is alleged to have heavily marketed valprioc acid, which is basically a drug to prevent seizures, for treating agitation and aggression in patients with dementia, autism, and various other disorders.

GSK To Set Record with $3B Settlement, and More on Avandia

2011-11-19T13:11:00.000-08:00

I usually use a standard form to report the latest drug firm settling with the Feds for wrongdoing, without admitting any wrongdoing, as in:
http://brodyhooked.blogspot.com/2011/09/same-song-i-lost-count-of-which-verse.html

The most recent report, however, won't fit my standard form for a couple of reasons. First, GlaxoSmithKline has apparently not yet actually settled, there are just rumors of a settlement. Second, they are settling three different actions on three different drugs, according to the reports. But in any event, if the rumors are correct then GSK will set a new record by settling for $3B, almost twice as much as the previous high, as Dr. Roy Poses reports over at Health Care Renewal:
http://hcrenewal.blogspot.com/2011/11/to-sir-andrew-with-settlement.html

The issues that got GSK into this much trouble are: alleged improper marketing of 9 of its best-selling drugs, including Avandia, Wellbutrin, and Advair; cheating under the Medicaid rebate program; and alleged improper promotion of Avandia for diabetes.

The settlement is tentative and reportedly would be concluded in 2012, so one might wonder why it is being announced now. The speculation Dr. Poses passes along is that GSK's UK CEO, Andrew Witty, is being pushed for a knighthood, and so the company wished to clear the decks and not have embarrassing news coming out later when it could interfere with Mr. Witty becoming Sir Andrew.

Along the way Dr. Poses cites a nice review by Deborah Cohen in the British Medical Journal (BSJ) on the ins and outs of the entire Avandia debacle:
http://www.bmj.com/content/341/bmj.c4848

Ms. Cohen's piece reviews the skimpy evidence presented to both the FDA and the European drug review agency that Avandia was safe and effective, even at the time it was first approved and before later evidence emerged on the extent of the heart disease risk that it posed. The reasons why it made it through approval on such a slim basis? Clearly smart drug company promotion and lobbying played a role. But at least a part of the problem was the diabetes-endocrinology community. The glitazone drugs represent a new pharmacological approach to diabetes treatment, unlike any existing class of drugs. They promise not to replace what insulin does, but rather to treat the insulin resistance of other body tissues that is a big part of type II diabetes. The first glitazone, troglitazone (Rezulin) had to be withdrawn when patients started dying of liver failure--though its maker, Warner-Lambert, lobbied like heck within the FDA to keep its drug on the market, as I recounted at length in HOOKED. So having another glitazone as an alternative was a big priority for endocrinologists. Apparently it was such a big priority that these smart specialists forgot to ask if there was any evidence that Avandia actually improved the long-term outlook of people with diabetes, instead of just making their numbers look better right now, and especially whether it actually prevented the heart and vessel disease which is the primary serious complication of Type II diabetes.

And here we return to another theme I harp on--why many within the FDA say they must ignore conflicts of interest because if they excluded all "experts" with COI from their scientific advisory committees, there would be none left to serve. My reply to this has often been that it depends on who you call an "expert," and why more of my own colleagues in primary care fields are not asked to serve on an FDA committee. I think here you have a case in point. Who is more likely to get all misty-eyed over the fact that Avandia works by a novel pharmacological pathway? An endocrinologist. Who is more likely to be skeptical and demand proof that it really helps patients? A primary care physician. I rest my case.

ADDENDUM 11/21/11: I erred above in saying that the GSK settlement was nearly twice the previous high settlement. I had thought that the most recent Pfizer settlement was in the middle $1B range, but according to the Bloomberg News coverage of another recent settlement, Abbott Labs (see post just above), Pfizer settled its charges over the marketing of the painkiller Bextra for $2.3B in 2009.

Will Brown University Investigate Keller?

2011-11-18T08:31:00.000-08:00

We've previously on this blog discussed the case of Dr. Martin Keller at Brown University and his study of Paxil (paroxetine) in children:
http://brodyhooked.blogspot.com/2008/06/alison-basss-side-effects-another-hall.html
http://brodyhooked.blogspot.com/2011/02/universities-corporate-influence-and.html

Now, thanks to our esteemed colleague Dr. Roy Poses from Health Care Renewal blog, we're provided with this article from the Brown newspaper in which he's quoted:
http://www.browndailyherald.com/prof-s-study-linked-to-child-suicide-1.2673693#.TsZ44VbfWSo

Seems that our other esteemed colleagues at Healthy Skepticism have been after Brown to get the University's help to withdraw the Study 329 claiming that Paxil was safe and effective in children. They argue that the article continues to be cited and can be implicated in suicides in children prescribed Paxil. Brown basically has gone into hiding and has not responded to these overtures.

Thanks to the exposes noted in previous posts on this blog, we know that Dr. Keller received huge sums of money from Pharma; that Study 329 was originally by scientific standards a negative study of Paxil in kids and was spun to make it sound like a positive study when it was published; and that the published version was essentially ghostwritten by a company hack. At least that's what's now on the public record (Dr. Keller routinely refuses to comment), and if Brown knows a different version, it's about time they let us hear it.

What Could Penn State Scandal Have To Do with Pharma?

2011-11-17T08:23:00.000-08:00

If you're tired of reading abbout the scandal at Penn State's football program (and the university that's a small branch of that program) and you came to this blog for a moment of respite, sorry to disappoint you.

As the extremely talented former NPR reporter Snigda Prakash writes in Slate:
http://www.slate.com/articles/health_and_science/medical_examiner/2011/11/sandusky_cover_up_why_is_kenneth_frazier_leading_the_investigation_at_penn_state_.html

--there is an unfortunate link between Penn State and Merck's Vioxx debacle, through the intermediary of Merck CEO and former chief legal counsel, Kenneth Frazier. Frazier is now a member of the Penn State board of trustees and was selected by his fellow trustees to head the University's internal investigation into the scandal involving the failure to report a former football coach for allaged child sexual abuse. The University has put out the usual word as to how this investigation will leave no stone unturned, let the chips fall where they may, and whatever the cliche of your choice.

So would you select Mr. Frazier to lead such an investigation? As Ms. Prakash reports in detail, let's follow his track record at Merck. First the company did its best to conceal the cardiac risks associated with its blockbuster drug rofecoxib (Vioxx), leading to an estimated 80-140K excess cases of serious heart disease during the years that the drug was on the market and after clear evidence of serious risk had emerged (as I discussed in detail in HOOKED). And Merck didn't just leave it on the market; they promoted the holy heck out of it (remember Dorothy Hamill skating on the TV ads?), milking it for every last penny before they finally had to pull the drug in 2004.

Now Mr. Frazier was in a top spot at Merck while this was all going down but probably he was not personally responsible. But he can take full credit for what happened next, in his post as chief counsel. Merck then went into lawsuit defense mode as all the people with heart attacks who had taken Vioxx started to sue. Predictions were that Merk would have to shell out $25 to $50B to pay all the settlements. But Merck decided instead on a bold defense strategy that Prakash describes as "scorched earth." They put out $2B to hire the best legal talent in the country and to fight every single suit. From an epidemiological standpoint it was smart. It's easy to calculate that 80-140K excess cases of heart disease were caused by Vioxx across the whole US population. It is nearly impossible to prove difinitively that any patient who took Vioxx, and then had a heart attack, had the heart attack because he took Vioxx and for no other reason at all. (If you want to read all about the Vioxx legal challenge, see Prakash's book, All the Justice Money Can Buy.)

So Merck fought every case, lost some but won a bunch of others, and in the end was able to wrangle a general settlement for a mere $5B. No doubt it was this brilliant strategy as chief counsel that Merck rewarded by making Mr. Frazier their CEO.

So Penn State wants to put its investigation into the hands of a guy who first, did his best (in company with all the corporate leadership) to conceal the truth to assure that a favored brand continued to make profits; and second, once the truth came out, fought like heck to make sure that the human beings who were harmed by those corporate actions didn't get a penny. Sounds like a great plan to restore trust in the university.

Shameless Commerce Division: New Book, THE GOLDEN CALF

2011-11-13T12:46:00.000-08:00

A while back I mentioned a forthcoming book:
http://brodyhooked.blogspot.com/2011/07/kid-gloves-on-corporate-crime-different.html

I'm happy to report that the book is now available in paperback, and soon to be released as a Kindle edition:
http://www.amazon.com/Golden-Calf-Economism-American-Policy/dp/1463762755/ref=sr_1_1?s=books&ie=UTF8&qid=1321217138&sr=1-1

To repeat my earlier brief description:
I have been spending time studying the origins and nature of a belief system that I think is most appropriately called economism. Economism is the belief in the all-powerful "free market," and the prescription that every problem in human life can be solved through the market, and that the only appropriate role of government in the market is to get out of the way and let it be "free." But economism is internally self-contradictory and so always ends up talking out of both sides of its mouth. In the case of "big government," economism desires half-powerful and half-powerless government. The powerless half is the part that could stand in the way of corporate profits--like too many DOJ or SEC investigators. But economism simultaneously desires all-powerful government when it comes to those aspects of government that can be tied to its own pursuit of wealth, and can secure monopoly privileges for those corporations now at the top of the heap. So, for example, making sure that Pharma continues to get huge tax breaks, and that the US government remains vigilant to protect its "intellectual property" so that no Indian generic firm can make AIDS drugs to sell in Africa at an affordable price, is a type of "big government" you never hear economism's boosters objecting to.

The main thrust of the book is that economism pretends to be a hard-headed scientific account of the real world, with which only irrational people could disagree. Yet any logical analysis of its thought structure shows that it functions as a religion and not as a science. Historically, I try to show that that's no surprise when you see where its ideas come from. Specifically, economism draws one strand of thinking--the idea that policies that favor the rich are good--from the "Protestant ethic" that grew out of American Puritanism in the 18th century and after; and the other strand--that policies that assist the poor are bad--from the British variant of evangelicalism that was prominent in the early 19th century. So when practitioners of economism--for example, today's "austerians" who insist that the Federal deficit must consume all of our attention, and who cares if Americans are unemployed and losing their homes--our politicians and media assume we are getting scientifically based economic advice, when in fact we are getting other peoples' religious beliefs shoved down our throats.

I ended up doing the inquiry that led to this book after studying the ethical issues around health policy, including the Pharma-medicine interface and health reform, and becoming persuaded that there was a deep level of resistance to policy ideas that otherwise made good sense. It was in search of this deeper level of belief, that declared so many promising reforms off the table from the get-go, that I came to find the phenomenon of economism. (It's been out there all along, and goes under various names--my political science and historian colleagues prefer to call it neoliberalism. But like the proverbial water that the fish swim in, it succeeds so well as a belief system that it manages never to call attention to itself.)

Why is it important to identify economism (first) and to note its logical resemblance to a religion (second)? As the Occupy Wall Street people are at least dimly aware, and are finally starting to create a relevant political dialogue about, economism has a paralyzing effect on democracy. It causes, in the name of the so-called free market and everyone's right to buy and sell without government restriction, incredible economic inequality and injustice both in the US and globally. But even more important, in a way, is how it stifles democracy by suggesting that the entire country is really nothing but a market, and the only people who can run markets are technocrats who should not be answerable to either the political system nor the public. Is it just by coincidence that the new rulers now slated to take over in both Greece and Italy are regarded as economic technocrats, and their rise to authority is being greeted by the European Union as a wonderful development--regardless as to what happens to the right of the people of both countries to control their own national destinies?

That's enough for here; check out the book if you want to learn more.

Important Conference on Future of FDA

2011-11-09T08:29:00.000-08:00

I've been asked to help publicize this conference and am happy to oblige:

http://www.ucsusa.org/scientific_integrity/solutions/agency-specific_solutions/fda-at-a-crossroads.html

FDA Commissioner Hamburg will be keynote speaker and bills in Congress regarding user fees for approval of drugs and devices will be the focus. Union of Concerned Scientists is one of the co-sponsors.

I'm happy to let all six readers of this blog know about it!

GoozNews on Guideline/FDA Panels: Yes, There Are Non-Conflicted Experts

2011-11-07T11:41:00.000-08:00

I've commented previously on the canard that the FDA must fill their advisory panels with docs paid by the drug industry, as those guys are the only real experts:
http://brodyhooked.blogspot.com/2011/08/nih-conflict-of-interest-rules-weakened.html

Our esteemed colleague Merrill Goozner addressed this head-on (in relation to recent discussions of NIH guideline panels) in his GoozNews blog--
http://gooznews.com/?p=3319

Let me turn the mike over to him:

That [you need to accept industry-funded people or else do without the real experts] is simply not true. When the Food and Drug Administration commissioned a study to see if it couldn’t make up its advisory panels with conflict-free experts, the outside consulting firm discovered that it would take about one week to find unconflicted physicians with the skills required to analyze clinical trial and other data needed to serve. Moreover, based on the publication records of the people turned up by such a process, the unconflicted physicians would have been more highly qualified than the “thought leaders” on drug or other industry payrolls who actually got the jobs.

Gooz identifies the critical point. In "opinion leader" circles it is simply assumed that "expert" means somebody who sits at a lab bench and discovers a new molecule, or else somebody who designs and runs clinical trials. These folks are no doubt commendable and knowledgeable, but they're not the people with the skills you most need when it comes to serving on an FDA advisory committee or writing clinical guidelines. Those tasks need different experts, people with training in fields like biostatistics and clinical epidemiology, who know how to sort through and weigh evidence from various sources. So sadly, when a mucky-muck at FDA or NIH says they need to include people with conflicts because they're the experts, they're not merely defending a flawed status quo; they're admitting that they don't understand what the real task at hand is.

More on Device Industry, from ASLME COI Conference

2011-10-29T03:53:00.000-07:00

Continuing my blogging post-conference for the American Society of Law, Medicine and Ethics, "Conflicts of Interest in the Practice of Medicine" (see previous post for link), two tidbits on the medical device industry. Two speakers addressed this topic, Dr. Rita Redberg, UCSF cardiologist and editor of Archives of Internal Medicine with its splendid "Less is More" feature, and Kelly Dineen, JD, St. Louis U law school. (Dr. Redberg was co-author of the excellent New England Journal commentary on the recent IOM report on FDA regulation of medical devices: http://brodyhooked.blogspot.com/2011/08/more-on-iom-report-on-fda-scrutiny-of.html.) I'm reporting my own impressions based on what they said, so don't blame them for what follows.

First, there was much discussion at the conference of the recent New York Times expose of the role of venture capitalists in lobbying against stricter FDA regs on devices, which is what the IOM recommended:
http://www.nytimes.com/2011/10/26/business/venture-capitalists-join-push-to-ease-fda-rules-for-medical-device-industry.html?scp=6&sq=health%20law&st=cse

The general comment was that it is notable how the device industry, and the venture capitalists that seek to profit off devices, have really taken the gloves off and come out swinging against the IOM and the scientific community generally. Dr. Redberg reported testifying on Capitol Hill and encountering Congressional committees that had been captivated by a device-industry-funded report that slammed "unnecessary" government regulation and threatened job losses of the FDA tightened its rules, and did not want to address patient safety or effectiveness at all. Apparently all patient concerns must give way before the almighty dollar.

Second, Ms. Dineen described in some detail the role of medical device reps in one area of medicine, neurosurgeons who specialize in implanting devices that give electrical signals to nerves (neuromodulation) for a variety of conditions. I have previously been fairly sympathetic to the difference between device reps and drug reps, based on the argument that devices need hands-on technical expertise that sometimes requires trained company reps to be in the operating room or at the bedside to advise the doc on how best to adjust the device. Ms. Dineen revealed an important qualifier I had not been aware of.

As I took her point, implanted neuromodulation device reps are functioning as basically unpaid labor for the neurosurgeons--a substantial company-funded subsidy for their practices. With device reps being ubiquitous, surgeons can turn to them for all the technical parts of the device, leaving their own role simply that of making the incision and sticking the device in. How the device is programmed to do its work, and what to do if something goes wrong later, can all be delegated to the company rep, who's more than eager to oblige, in exchange for the neurosurgeon's devotion to that company and its expensive products. In everyday practice the neurosurgeon can even "supervise" what the rep does (often from a considerable distance) and then proceed to bill hundreds of bucks for the visit. Now, the surgeons could take a course and learn how to do this programming function for themselves; or they could hire their own technicians to become part of their office and OR staff and do it for them. But why spend that time or money when the device company is eager to supply the reps for free?

End results: patients are cared for by staff who have the company's rather than the patient's interests at heart; neurosurgeons make more money for less work; and the device gravy train keeps rolling. Must keep those venture capitalists happy, after all.

The take-home message is that once again in medical devices, things are not as they seem. The "need "for hands-on assistance with the device, that justifies reps running free range through the hospital and clinic, may be more manufactured than real.

COI Update from the ASLME--Capsules

2011-10-28T18:00:00.000-07:00

I'm in Pittsburgh just having attended the conference, "Conflicts of Interest in the Practice of Medicine," sponsored by the American Society of Law, Medicine and Ethics, which you can read all about at: www.aslme.org/2011COIconference
ASLME also plans to publish all the papers from the conference in its journal.

So what's new in the field? The quick answer for regular readers of this blog is, apparently not much. There were few new issues and virtually no possible solutions raised that have not already been discussed here and elsewhere. The presentations were nevertheless interesting and the interplay between the legal and medical viewpoints was illuminating. I have listed a few capsules below of possible interest and will do at least one more post on a particular issue.

>>The conference began with the usual ceremony of the highly placed official welcoming everyone, and in this case it was the Dean of the Pitt School of Law. She began by saying that COI is "almost impossible to eliminate" and that the conference would address the "challenge of managing" COI. At that point I was getting worried that we were going to hear a rehash of really old ideas. Fortunately the subsequent sessions all paid appropriate attention to the desirability of eliminating and not merely managing COI.

>>Christopher Robertson, JD, PhD of U-Arizona law school was given the task if laying out the evidence for the seriousness of COI in medicine. He began by reviewing the evidence relating to physician self-referral (e.g., sending patients to the imaging center that the physicians' group owns instead of to get their scans at the local hospital x-ray dept.) and said what we all know, that evidence shows that the rate of ordering tests and procedures jumps astronomically with self-referral. I had generally not thought to connect the self-referral data to issues of COI at the medicine-Pharma interface. But I think Robertson raised a good point. Physicians commonly deny that they overorder tests and insist that when they send patients to the testing center they profit from, that either the patient benefits greatly from the test, or they have saved the patient a trip across town or to another city, etc. So we have clear evidence that 1) money changes physician behavior (duh) and that 2) physicians commonly rationalize that association away. I think one can reasonably argue that such is presumptively relevant to other money-laden relationships, until proven otherwise.

>>Bernard Lo MD from UCSF, a chair of the IOM panel that wrote their report on COI in medicine, was first to raise this issue but it was echoed by other speakers. As we enter the era of heightened, required disclosure, many physicians fear the liability of multiple, perhaps inconsistent disclosures, as different forms and bodies have different rules (such as whether to report relationships for the past 2 years or 5 years or whatever), and then providing fodder to investigative journalists who can check out all these disclosures on line and play "gotcha" with any inconsistencies that are revealed. Now the extreme pharmascold might say, so much the better, yet another good reason to divest oneself from these conflicted relationships. But the point the speakers made seemed very reasonable, that it would be far superior to have a single, uniform and common disclosure process so that each individual had to disclose in one place only for all purposes.

>>One of the most appreciated speakers was Sunita Sah, MD, PhD of Duke, who has co-authored several well-designed studies of how disclosure practices might impact physicians and patients. During the Q&A the point emerged of how reluctant patients are to appear to criticize their own physician's COI, assuming the relationship to have been established before the COI becomes known. Some studies that are cited to show that COI is no big deal for patients and does not decrease their trust are studies in which patients are basically asked about their own physician's COI. A fairer study design would be to get patients to imagine that they are seeking a new physician, and can choose among several physicians on a panel, some of whom are disclosed to have COI. The outcome of interest would be how willing patients are to select the physicians with COI, and at least some preliminary data, I understand, would suggest that they'd be less likely to select those docs.

>>A couple of speakers commented on the recent pullback at NIH in backing off proposed COI policies, that would have required academic medical centers to post faculty COI on accessible websites (http://brodyhooked.blogspot.com/2011/08/nih-conflict-of-interest-rules-weakened.html) Blame was placed on the White House, feeling under fire to do something about the supposedly out-of-control government regulations that the Republicans are raising Cain (no pun intended) about. The timing was bad; the time that the NIH stringent guidelines would have gone into effect was precisely the moment that the White House decided they had to make a show to scaling back on regulatory load.

Farewell to Xigris--Counting the Lessons

2011-10-25T12:30:00.001-07:00

One of my most faithful readers sent me a link to David E. Williams blogging on the Health Business Blog:
http://www.healthbusinessblog.com/2011/10/xigris-withdrawal-highlights-conflict-of-interest-problems/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+HealthBusinessBlog+%28Health+business+blog%29

Williams in turn comments on news that Eli Lilly has withdrawn its drug Xigris (recombinant human activated protein C) from the market after a new, major study failed to show any benefit in survival from sepsis:
http://www.medpagetoday.com/ProductAlert/Prescriptions/29250

The bulk of Williams' post is actually a reprisal of an old post, but it's still very timely, and for readers of this blog, provides a view of physician responsibility for drug industry marketing excesses from a vantage point outside of medicine.

I told the Xigris story in HOOKED as of 2006 or so. Basically Lilly gets credit for really trying to come up with a novel compound that attacked disease (life-threatening infection or sepsis) in a novel way. The sad news was that the initial trial showed that Xigris was only occasionally effective and also carried major bleeding risks.

The part of the Xigris story that especially caught my attention was how some of my colleagues in bioethics were caught up in the company's PR campaign without apparently realizing it--or else taking the money and not caring. As one prong of the marketing strategy, Lilly decided that since Xigris cost so much, and since so few ICUs were purchasing it (since the studies had been so equivocal), then there must be rationing of life-saving treatment going on. Of course one solution would have been to lower the price, but perish the thought. So Lilly instead forked over $1.8M to fund an "ethical" study of rationing in the ICU, with the intent of bringing pressure to bear on recalcitrant units with the dreaded "R word."

The part of the story that I did not cover in HOOKED, as Williams reminds us, was actually addressed in a 2006 commentary in the New England Journal (subscription required) by Eichacker and colleagues. Having managed to get the FDA to approve Xigris despite iffy data of efficacy and safety, Lilly bankrolled a big PR firm to do three things--set up the rationing "ethics" inquiry, and get major medical societies to write guidelines for sepsis care that included the use of Xigris (by funding the guideline panels and making sure that numerous docs with Lilly money in their pockets served on the panels). The third thing however was what made Eichacker and company worried. It was Lilly's subsequent effort to lobby the organizations that create quality indicators for hospitals and insurers to include those guidelines in their quality measurements. That is, if an ICU did not use Xigris, because they deemed it insufficiently useful and overly dangerous (a reasonable evidence-based position at the time), the hospital might get a lower score for quality of care and then have problems with insurance reimbursement as well as the bad publicity. Eichacker et al. very reasonably said this was a blatant hijacking of these quality indicators for commercial purposes.

I have commented numerous times on Kalman Applbaum's concept of controlling the drug channels. Lilly did this beautifully, gathering in its hot little hands all the threads that controlled the way hospitals were likely to use Xigris. Why bother sending drug reps into thousands of doctors' offices if you can buy off the people who write the guidelines and the people who ding the hospitals for bad quality of care?

So now we find out, at this late date, what many suspected from the start--that even the small degree of benefit for Xigris, that was seen in the initial study and that earned FDA approval, was probably a fluke. Farewell to yet another overmarketed and dangerous drug--though too bad that Lilly did not go back into the laboratory and try to use the basic understanding of the disease mechanism to find a better successor.

Here are Williams's take-home messages for the industry and for physicians, worth repeating here:

Here’s some free advice to the different players in health care:

--Industry: Feel free to market your products and services aggressively, but don’t take things too far. If you do you’ll end up killing the goose that lays the golden eggs. No one will trust doctors, guidelines or journals anymore
--Physicians: Remember that pharma and device companies are not stupid. If they spend money supporting your research or sending you to conferences or sponsoring continuing medical education it’s because they expect to get a return on their investment. It’s awfully hard to remain objective in such instances. Your job is to adopt the best medical practices and put the patient first –sometimes that requires expensive new treatments and sometimes old, cheap standbys are better

Eichacker PQ, Natanson C, Danner RL. Surviving sepsis--practice guidelines, marketing campaigns, and Eli Lilly. New England Journal of Medicine 355:1640-42, 2006.

The $43M Pill instead of the $800M Pill?

2011-10-24T13:02:00.000-07:00

I am worried about my friend Donald Light of University of Medicine and Dentistry of New Jersey/Stanford. First he came out with his book, The Risk of Prescription Drugs, in which he documented 100K deaths annually in US hospitals from prescription drugs taken properly as directed, making drug adverse reactions the 4th leading cause of death in the US. This finding would seem to challenge the standard industry line that discovering lots of new drugs and getting them onto the markket as quickly as possible means longer lives and more disease cures. Then, just to follow up that performance, Light and his colleague Rebecca Warburton of University of Victoria, BC decided to demolish the myth of the high R&D costs that the industry appeals to in justification of the out-of-sight prices charged for drugs nowadays (at least in the US where we refuse to follow the intelligent part of the world in using volume discount buying power to drive down drug costs). I am now worried that Dr. Light will be on Pharma's hit list. (See the end of the post for why I am actually not worried about any such hit list.)

I actually covered much of the ground that Light and Warburton traverse back in HOOKED, but since they provide additional details and calculations, and we have not discussed the issue for a while, I figured it was time for a revisit.

In 2004 Merrill Goozner, formerly economics reporter for the Chicago Tribune (and now blooger at GoozNews), published his expose, The $800 Million Pill. The title came from the research by DiMasi and associates at the Tufts Center for the Study of Drug Development, which is primarily funded by industry. That group published their estimates of what it cost industry to discover one new drug (that is, a novel molecule never before used) given all the dead ends that have to be navigated before one good drug emerges. They came up with the figure of $802M. Light and Warburton follow in the footsteps of Goozner and Marcia Angell (The Truth about the Drug Companies) in deconstructing this myth.

The brief highlights of their analysis:

The data DiMasi et al. used for their study was secret industry data that has never been revealed, so we have no way to check its accuracy. There are a number of sources of independent information that would call its accuracy and representativeness into question.

The costs of actual drug discovery are essentially unknown and highly variable. What did it cost Alexander Fleming to discover penicillin? Sometimes you just trip over a useful new drug by chance, sometimes a new drug emerges after 30 years of arduous research. Light and Warburton note in passing other findings that some 84% of new drugs are not discovered in house by the drug companies but by university and other noncommercial labs.

The drug industry rakes in considerable tax savings that represent as much as 50% of the actual costs of their R&D. Light and Warburton go into a long economic talk about this that goes way over my head, but seems to amount to noting that drug companies regard R&D costs as operating expenses and not capital investments for purposes of getting their tax breaks. Then when somebody asks why they don't deduct the tax savings from their reported R&D costs, they answer as if the R&D expenses were capital investments, so that tax savings if any would accrue only slowly over many years. They can't have it both ways.

As I noted in HOOKED, the industry then pads its R&D costs by adding in the profits that that same money would have earned had they invested it in the stock market for the same number of years, and saying that they deserve to be repaid for the foregone profits as well as for the actual costs. Light and Warburton note that no other research-intensive industry makes any such claim. If you purport to be in the business of discovering new drugs, of course you invest your money in drug R&D, and of course you don't put that same money in the stock market instead. Claiming that the company should effectively be reimbursed for profits forgone as well as for actual costs nearly doubles the estimated cost of discovering a new drug.

DiMasi et al. appear to have used unrealistically high estimates both for how long research trials go on and how many subjects are enrolled. Finally, instead of using median figures they use means, which can be inflated by a few high-end outliers.

Light and Warburton are so impolite to add that only a small proportion of the new drugs marketed by the industry are genuinely new molecular entities; and an even smaller percentage actually represent significant therapeutic over existing drugs.

So what does it actually cost to discover one new drug? I believe that in HOOKED I settled on the figure of maybe $100-200M. Light and Warburton suggest that the best answer is"we don't know" but did some calculations to show that the true number could even be as low as $43M.

I think the real take-home message is this: even if we don't know the exact right answer, there has been a lot of reason to regard the $800M as spurious practically from the moment it was released. It is surely at least twice the real figure and more likely, at least four times. Yet PhRMA and the media continue to bruit about that figure as if it were gospel. That just shows when you have a lot of money at your back, you can specify the "truth" to be pretty much whatever you wish.

So--why am I not worried about Don Light being on a Pharma hit list? The only example I know of, of the drug industry murdering people who they don't like, is John Le Carre's novel The Constant Gardener (and the film version). Le Carre was careful to document that all the industry skullduggery he used for the plot of his novel was based on real events, except for the murder part. When I met with a group of students recently who had seen the film, I asked them why they thought Pharma didn't actually go around killing people. The students immediately got the right answer--Pharma doesn't have to. They get what they want just fine, thanks, without the need for any such crude tactics.

Light DW, Warburton R. Demythologizing the high costs of pharmaceutical research. Biosocieties 6:34-50, 2011.

Light DW, ed. The Risk of Prescription Drugs. New York: Columbia University Press, 2010.

DiMasi JA, Hansen RW, Grabowski H. The price of innovation: new estimates of drug development costs. Journal of Health Economics 22:151-185, 2003.

Goozner M. The $800 Million Pill: The Truth Behind the Cost of New Drugs. Berkeley, CA: University of California Press, 2004.

Angell M. The Truth About the Drug Companies: How They Deceive Us and What To Do About It. New York: Random House, 2004.

What To Do about Pay-for-Delay

2011-10-18T12:59:00.000-07:00

Dr. Aaron Kesselheim and colleagues provide a useful review/commentary in last week's New England Journal (subscription required) on a problem I addressed in HOOKED--"pay-for-delay" when a brand name drug company and a generic company reach a settlement on the latter's patent challenge to the former, which results in a substantial delay in a cheaper generic drug reaching the market.

In quick summary, here's what happens in a typical case:

A lucrative brand name drug is about to go off patent. Typically, however, the company has a number of subsidiary patents on things like coating, etc. that have little to do with the actual active drug ingredient.

A generic company bids to come onto the market with the drug--by the Hatch-Waxman Act, the first company to do so gets a plum in the form of 6-month generic exclusivity, during which it can charge almost as much as the brand name price due to lack of competition from other generic makers.

The brand name company sues the generic company for patent infringement, often citing one or more of the subsidiary patents.

A major and potentiallly protracted court battle ensues.

The brand name company offers the generic a cash settlement, in effect paying them to drop their suit and take the cash, on the condition that they delay their product's marketing and preserve the brand name exclusivity for a longer period.

It seems at first that this process hardly serves the public interest. But the authors note that a prolonged court battle could just as easily keep the cheaper generics off the market even longer.

Kesselheim and colleagues make a number of good legal points and discuss some statutory fixes, most of which have little chance of passing the present Congress. But I think their most important argument is about the root cause of all this--silly patents. They propose two measures that could occur either at the Patent Office or at the FDA levels that would allow administrative challenges to minor patents that do not protect truly innovative drug development, leaving the courts free to decide the really tough cases, and industry free to patent and profit from real innovations. These reforms in my view should be the highest priority.

Kesselheim AS, Murtagh L, Mello MM. "Pay for delay" settlements of disputes over pharmaceutical patents. New England Journal of Medicine 365:1439-1445, Oct. 13, 2011.

More on the Medtronic-Yale "Model"

2011-10-18T12:11:00.000-07:00

A while back I commended Medtronic for agreeing to fund an independent review of its controversial bone-regrowth product:
http://brodyhooked.blogspot.com/2011/08/in-praise-of-good-corporate-behavior.html

More information on the model that Dr. Krumholz at Yale has pioneered in this case was recently provided in JAMA (subscription required) and also can be seen at:
http://medicine.yale.edu/core/projects/yodap/index.aspx

The model calls for the company to fund a study and to agree to turn over all their raw data, in a form that can be carefully reviewed for the quality of the research, to an independent organization. An steering committee (with public representation as well as experts) then oversees the creation of two separate academic teams to review and report on the data. Drs. Krumholz and Ross argue that the use of two separate teams both provides an accuracy check on each other's work and also further assures independence from the manufacturer.

We must of course await the results of the Medtronic study, but this model appears to be about the best that has yet emerged to restore integrity to the process of pharmaceutical research. An obvious question is how to address and assure integrity on an ongoing basis, and not merely once a scandal has arisen.

Krumholz HM, Ross JS. A model for dissemination and independent analysis of industry data. JAMA 306:1593-1594, Oct. 12, 2011.

Postcard from NPA Annual Meeting

2011-10-01T11:48:00.000-07:00

So long as the battery holds out and I don't lose the WiFi connection yet again, I'll send a brief postcard from the National Physicians Alliance annual meeting (actually from National Airport, on my way back home, as I unfortunately was unable to stay for much of the meeting). Those of you who don't know the NPA:
http://npalliance.org/
--should check out their excellent Unbranded Doctor Campaign that gives practitioners the resources to develop a drug-rep-and-sample-free office. The NPA has been very active in promoting health reform, physician professionalism, and physician-led cost containment. It was the latter issue that I was invited to speak about on a panel.

Among the many delightful people I met in person for the first time at the meeting, another panelist was Dr. Rita Redberg, the UCSF cardiologist who is editor of Archives of Internal Medicine and there pioneered the superb "Less Is More" feature, providing evidence in support of reducing the overuse of non-beneficial tests and treatments. NPA formed the Good Stewardship group that assembled panels from the three main primary care specialties and asked each to compile a "Top Five List" of the most frequently used interventions in each field that could be eliminated so as to improve the quality of patient care. The focus in that publication was quality, not cost--noting that when unnecessary and nonbeneficial tests or treatments are used, the patient may suffer harm without any compensating benefit.

What we learned today from Dr. Redberg is that in a new study, published on line today in Archives, Dr. Minal Kale and colleagues proceeded to do the cost calculations from the three primary care "Top Five" lists. (subscription required) They utilized conservative estimates to conclude that the total annual savings from eliminating these useless tests and treatments would be about $6.7B. There are two main take home messages in my view. First, this tends to support the view that primary care is not the cost-overrun problem in American medicine. Given estimates from groups such as the Institute of Medicine that we throw away annually some $760B in tests and treatments that produce no patient benefit, what primary care contributes is chump change. Still, if we want the big spenders like cardiology and orthopedics to mend their ways, it is very good that primary care looked at itself in the mirror first and called on the other specialties to do likewise.

The second take home message is that one single item on the Top Five list from internal medicine accounted for the lion's share of the total cost--the recommendation that physicians prescribe generic rather than name brand statins would alone save the country more than $5B. This in turn highlights the low-hanging-fruit issue, that it behooves us in cutting the costs of health care to make care more affordable for everyone to seek out these relatively small and simple steps that can save the most money without harming patients. It also reminds us once again how often picking the low hanging fruit will cause us to go contrary to the messages sent out by Pharma marketing.

We learned from Dr. Steve Smith, head of the Good Stewardship effort, that NPA now plans to produce videos for office use, helping physicians to explain to patients why they don't need some of these expensive but useless tests and treatments. This is a good example of NPA's view-from-the-trenches approach that picks out the critical steps needed to put good ideas into practical action.

Kale MS, Bishop TF, Federman AD, Keyhani S. Top 5 lists top $5 billion. Archives of Internal Medicine, doi:10.1001/archinternmed.2011.501, published on line 10/1/11

Good Stewardship Working Group. The top 5 lists in primary care--meeting the challenges of professionalism. Archives of Internal Medicine 171:1385-90, 2011;
http://archinte.ama-assn.org/cgi/content/abstract/171/15/1385?ijkey=5947b2777392ebfde658ef4eceb42ba0da248904&keytype2=tf_ipsecsha

Same Song, I Lost Count of Which Verse

2011-09-26T11:03:00.000-07:00

Time to get out the ol' standard form again:

Drug Company: Scios Division of Johnson & Johnson
Drug: Nesiritide (Natrecor)
Settled Federal charges of: Misbranding, off label marketing
Fine paid: $85M
Fine as % of Sales of Drug during Peak Year: 37% (2004)
Company Admits Guilt?: Can't tell from news report

The above from Bloomberg News:
http://www.bloomberg.com/news/2011-07-09/j-j-s-scios-unit-charged-in-misbranding-of-natrecor-drug-1-.html

Hat tip to the Health Care Renewal Blog which also provides good backstory analysis:
http://hcrenewal.blogspot.com/2011/09/johnson-and-johnson-pleads-guilty.html

Now, you may ask, why am I bothering even to mention this judgment involving the chump change of $85M, when the record for settlements in such cases is now well upwards of $1B? As HCR informs us, the reason is well summarized in two commentaries by cardiologist Dr. Eric Topol:
http://www.nejm.org/doi/full/10.1056/NEJMe1103116
http://www.nejm.org/doi/full/10.1056/NEJMp058139

What we have here is a drug (brand name Natrecor) that was approved by the FDA based on very slimsy evidence involving surrogate endpoints and despite considerable suggestion of risk of harm, for congestive heart failure, a condition for which many other treatment options exist. The company then aggressively marketed the drug for an off label use, weekly "tune-ups" by injection, and instructed cardiologists how to get big bucks in reimbursement for these "tune-ups," similar to what cancer docs get for injecting chemotherapy. Dr. Topol wrote in 2005 that more than 600,000 patients were getting these tune-ups despite the lack of any evidence that this use of the drug was helpful and despite these being off-label.

Finally, a company-sponsored trial was published in July, 2011, showing no excess deaths or cases of renal failure from nesiritide, but no benefits either when added to a regimen of other drugs. In short, Scios was making a lot of money for several years (before warnings such as Topol's took hold around 2004-5) on a drug that could not have helped and may very well have hurt a lot of folks.

If you wanted firm evidence of the Inverse Benefit Law in action--
http://brodyhooked.blogspot.com/2011/01/inverse-benefit-law-making-sense-of-how.html
--I can't think of a more obvious case.

The French Have Been Reading Our Blogs

2011-09-22T12:14:00.000-07:00

For a good while now I have been occasionally posting on a regular theme from Dr. Roy Poses's Health Care Renewal Blog, for instance:
http://brodyhooked.blogspot.com/2011/07/kid-gloves-on-corporate-crime-different.html
--that we cannot expect drug/device industry wrongdoing to cease so long as the corporation merely has to pay a fine for legal transgressions; they merely budget the looked-for fine as a cost of doing business and go merrily on their way. Only if individual execs are held accountable under criminal law can we expect behavior to improve.

Well, at least one French judge seems to have gotten the message (not sure if non-subscribers can access but here goes anyway):
http://www.theheart.org/article/1283233.do

Basic bottom line-- a drug (benfluorex) was approved for use in Europe but not the U.S. that seems to be a cousin of the fen-phen combo that I discussed in HOOKED, marketed as a weight loss drug and then shown to cause deadly adverse reactions including heart valve damage and pulmonary fibrosis. The head of Servier, France's second-largest drug company, has been charged with involuntary manslaughter, aggravated deception, and fraud for marketing the drug despite known risks. The CEO has had to post $5.5M bail (which, if French CEO compensation is anything like the U.S., he probably was carrying around as loose change).

My own comment is that the French more or less have the right idea, but I'm an old softie. I would have been happy with just the aggravated deception (whatever that is) and fraud charges. I would not have seen the need to add manslaughter.

From GoozNews: Doing the Right Thing on New Devices?

2011-09-12T08:02:00.001-07:00

Apologies if you cannot access this post by Merrill Goozner; I am not sure if you need to be a subscriber to reach his blog:
http://gooznews.com/?p=3156

"Gooz," author of the excellent book, The $800 Million Pill, offers a comment on the recent NIH study showing that stents for arteries in the brain do not prevent strokes and indeed worsen the stroke risk. The good news was that Medicare-Medicaid had held off paying for these stents even with an earlier, smaller study funded by the stent company (Stryker) that was much more promising. (The definitive study, that was stopped early due to the poor outcomes, was funded by NIH.) This was billed as a success story for evidence-based medicine. Medicare-Medicaid insisted that any patient who wanted such a stent had to be enrolled in a proper clinical trial so that the evidence could be collected.

Gooz says-- not so fast. Why wasn't Stryker required to do the large-scale study right from the get-go? He even suggests that the US taxpayers ought to get a refund for the NIH study.

Gooz may be counseling perfection on some matters, but I concur with his general point that the FDA requirements for approving new devices need to be tightened up generally, as we have addressed in previous posts such as:
http://brodyhooked.blogspot.com/2011/08/more-on-iom-report-on-fda-scrutiny-of.html

Colorado Institutions Riding Herd on Doctors

2011-09-08T10:35:00.000-07:00

I said in my last post to expect that local news media (at least the handful that still have an investigative reporter on staff) would be eagerly mining the ProPublica Dollars for Docs database to see what till their local physicians had their hands in. When I wrote that post I had not yet scrolled my e-mail down to my Kaiser Family Foundation Daily Health Policy Report. On that site I found just such a story by Michael Booth of the Denver Post:
http://www.denverpost.com/search/ci_18848973

What's most intriguing here to my mind is the reports of how two institutions, the U. Colorado School of Medicine and National Jewish Health, have taken on the task of prohibiting many practices that constitute conflicts of interest and demanding oversight of other relationships between their physicians and pharmaceutical companies. The U. was especially embarrassed by how many of their docs were listed on the first ProPublica database when it came out last year and so vowed to take action.

The upshot is that suppose you read on the database that Dr. House at one of these centers took $100,000 from Eli Lilly. You are not sure just what to make of that. But the institution can now tell you that it looked over the contract and that Dr. House is doing legitimate research with that money, not putting it in his own pocket, and not shilling for Lilly.

This seems to be another example to demonstrate that while mere disclosure of conflicts of interest cannot make everything ethically pristine-- a song I've been singing since this blog started--disclosure can lead to other steps that constitute a true ethical advance.

ProPublica's Updated Sunshine Database

2011-09-08T09:36:00.000-07:00

The good folks at ProPublica:
http://www.propublica.org/article/piercing-the-veil-more-drug-companies-reveal-payments-to-doctors
--announce that they have updated their "Dollars for Docs" database:
http://projects.propublica.org/docdollars/

They note that they are offering a sneak preview of 2013 when the Federal sunshine provisions in the health reform law take effect, and disclosures that are now semi-voluntary become required. (I say "semi" because some of the companies now disclosing are doing so under orders from court settlements.) The total database accounts for $760M betweeen 2009 and 2011. Given Gagnon and Lexchin's estimate several years ago that the US pharmaceutical industry spends a total of $57B annually on marketing, and given that at least some of the money on the database is in the form of research grants which at least officially is not marketing, we still have to ask how much of the total picture we are seeing.

To my mind the big news from ProPublica's initial analysis of their data is the possibility that sunshine is having an impact. There is some evidence of cutting back on the amount companies pay to speakers, in particular. The companies pitch this as a purely business decision, but it has several twists:

A mini-scandal erupted when the media noted that a number of drug company speakers were in trouble with their state licensing boards. This has led some companies both to pare back and also to be more selective about paid speakers. (They also mention it's smarter from a business point of view to pay fewer speakers to give more talks each; saves on training.) But that scandal was indirectly due to the sunshine of Dollars for Docs, as that provided the database for enterprising journalists to compare to the lists of in-trouble docs.

Some universities with policies prohibiting their faculty from being paid speakers had not been enforcing those policies, but Dollars for Docs makes them look pretty silly and has emboldened more of them to search the database for names of their own faculty. Apparently anticipating this scrutiny, some of those docs have chosen to withdraw from speakers' bureaus.

Indirect evidence that the Dollars for Docs is having an impact is the fact that PhRMA seemed to feel it necessary to come out with a preeptive-strike news release just before the update was announced, in which they defended their payments to physicians.

Expect to see more stories from the database as journalists around the country now start peering into their local doctors' names and tracking down what they are up to.

None Dare Call It Corruption

2011-09-07T09:15:00.000-07:00

Warning: Strident, intemperate post follows (at least at the end).

Exhibit A is a great summary from our friend Dr. Roy Poses at Health Care Renewal of the case of the contaminated heparin:
http://hcrenewal.blogspot.com/2011/08/jama-article-begs-key-questions-about.html

Bottom line: As most people have by now forgotten, 21 Americans died in 2007 due to contaminated heparin sold by Baxter Laboratories and made from ingredients manufactured in China. Dr. Poses shows that even recently written reports and news summaries dodge the tough questions of corporate responsibility. If a madman had slipped poison into bottles of an over-the-counter medicine and 21 people died, there would be a huge hue and cry and demands that heads roll. As Dr. Poses lays out in detail, various people made some important corporate decisions, all in the name of saving money, that predictably resulted in an unsafe drug being inflicted upon US patients. If you buy a Rolex at a certain discounted price, we all assume, with justification, that you ought to know that it's been stolen. Similarly, if Dr. Poses's summary is factual, anyone buying the heparin or the raw ingredients at the discounted prices being charged ought to have known that the chemicals came from unsupervised and unregulated workshops where purity and safety could not be assured. Not to have carefully tested and monitored the chemicals thus obtained, even assuming it was OK to get the chemicals from those sources at all, was another deliberate corporate decision. Yet no one, apparently, is accountable.

Exhibit B is an investigative reporting piece published by the AP today:
http://www.google.com/hostednews/ap/article/ALeqM5g5Jh7VmaKckgs3H035JJcYuzQttw?docId=d1b5a7b87097484b9b140838f50a88e7

Ricardo Alonso-Zaldivar, who's written many good pieces on the pharmaceutical industry, here reports on a recent study of campaign contributions to the twelve members of the Congressional "supercommittee" charged with coming up with a deficit reduction plan. Not surprisingly, deep-pockets health care interests, including Pharma and doctors, are near the top of the list. Not surprisingly, the offices of the involved congresspeople deny that any of these saintly individuals is ever swayed by mere campaign cash. Not surprisingly, if you believe that line, you have to believe that smart people who manage to make large bundles of money are completing wasting millions of dollars of it by giving campaign donations that produce no results for them at all.

As we have commented on previously:
http://brodyhooked.blogspot.com/2011/09/does-drug-industry-trust-super.html
--the smart Washington money is currently betting that these health-care special interests want the supercommittee plan to fail, based on their assumption that the across-the-board cuts that would automatically be triggered by that failure would be easier for them to live with than targeted and really smart Medicare and Medicaid cost reductions that were aimed at those things that don't help patients. (Given that doctors, hospitals, and drug and device companies all make billions off tests and treatments that fail to provide health benefits according to the best scientific evidence.) Is it possible that all the supercommittee members who take such major campaign contributions from these special interests are not going to be influenced by this preference of their corporate handlers?

The above was all reasonably temperate. Here comes the intemperate part. If all this was happening in Afghanistan or India, and corporations were getting away with murder and the media was keeping quiet about it just because it was corporate and not individual behavior, and politicians were being bought (or even appeared to be bought) by big money, the word we would use for it is "corruption." So my question is--why are people so reluctant to use this word when this happens right in front of us in the USA? Why don't we admit flat out that we have a corrupt corporate system, and that with the Citizens United Supreme Court decision opening the door wide to unrestricted corporate campaign contributions, we have let the corruption flow unhindered from the corporate world into government; and that the media, owned by large corporate interests, has little desire to shine much light at least on the corporate side of the equation?

Journal Conflicts: Drilling Down Farther

2011-09-03T14:18:00.000-07:00

When I was writing HOOKED, one of the most frustrating subtopics that I encountered was the financial aspect of medical journal publication. I found it nearly impossible to gather data about the degree to which most journals were entangled with the drug industry. Andreas Lundh and his colleagues at the Nordic Cochrane Center were able to do a better job than I at uncovering some key data but still came up partly empty-handed:
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000354

In this somewhat older article (hat tip to Primary Care Medical Abstracts and Drs. Bukata and Hoffman for pointing it out) the authors tried to gather data on how many studies in six of the top medical journals in English are industry-sponsored, what impact these articles have on the impact factor of the journal; and how much money the journals make from industry ads and from sales of reprints to drug companies. The impact factor is key; journals are in cutthroat competition over this measure of how widely cited their articles are in the rest of the medical literature. Impact factor plays a role in determining where important studies are submitted, how many libraries subscribe to the journal, and how easily the journal can attract advertising.

When Lundh and colleagues went looking for the financial data, they adopted the excellent initial strategy of asking. Of the six journals they were studying, BMJ and Lancet replied, while JAMA, Archives of Internal Medicine, New England Journal, and Annals of Internal Medicine refused to supply any data. When the authors then obtained tax reports and tried to calculate some of the relevant numbers, and sent their calculations to the publishing organizations for confirmation, American College of Physicians (publishers of Annals) responded but the others again refused to divulge any financial information.

Bottom line: most medical journals keep their financial numbers very close to the vest--even journals that have editorial policies that encourage full disclosure of financial conflicts among other parties.

So with what they could get their hands on, Lundh and colleagues noted that the percentage of clinical trials supported solely by industry varied from a low of 3% in BMJ to 32% in New England Journal. Industry-funded trials were more widely cited than other studies (a phenomenon noted in a number of previous surveys; being sure to write more articles that cite a successful study, and then placing those articles in turn in higher-impact journals, is standard industry marketing practice). Therefore as one would expect, publishing more industry-sponsored studies has an effect on the journal's impact factor. Had those studies not been published the impact factor would have dropped only by 1% at BMJ, the low end of the scale, but by 15% for NEJM. In other words, journals have a significant financial interest in publishing industry-sponsored studies on the grounds of impact factor alone even before we get to ad and reprint sales.

For the only two journals for which they could raise the data, Lundh et al. found that journal reprints made up only 3% of revenue for BMJ but all of 41% for Lancet. Tax returns indicate that the AMA, publisher of JAMA and Archives, derives 12% of revenue from reprint sales and a whopping 53% from ads.

The authors end with the following sensible recommendation: "We suggest that journals abide by the same standards related to conflicts of interest, which they rightly require from their authors, and that the sources and the amount of income are disclosed to improve transparency."

Placebo Effect and Adherence: A Challenge to Pharma?

2011-09-03T11:00:00.000-07:00

As all four of the regular readers of this blog are aware, I am an avid listener to Rick Bukata's and Jerry Hoffman's monthly audio recordings, Primary Care Medical Abstracts (free advertising for them: www.ccme.org). So here I am all innocently driving my car and listening to the CD for their August 2011 issue, when I am shocked to hear the CD shouting out my name. Jerry is asking that I respond to a query about one of the papers he and Rick had been discussing, in my capacity as someone who has a long-standing interest in the placebo effect.

So here is my answer to Jerry. You'll naturally wonder why it's here on this blog which is about ethics and Pharma and not about placebo effect. In the end I'll suggest an important connection.

The paper that started all this is a thoughtful editorial by Wilson (subscription required) about the placebo effect and adherence. There have now been a good number of studies that show that when you do a double-blind trial with a placebo arm, there is quite often (indeed rather consistently) a significant improvement of outcomes among those who take their placebos faithfully, compared to those who are relatively non-adherent to taking their placebos. Wilson does a neat analysis of what we know, and what we don't yet know, about this adherence phenomenon, and suggests linkages to what we are learning about placebo effects and why this phenomenon might be viewed (at least as a working hypothesis) as a variant of placebo effect.

Jerry then raises the question: what's the message here for clinicians? Should we give patients pep talks to try to both encourage and energize them about the treatments we're prescribing (whether drug or nondrug) to try to enhance their expectations of a good outcome, which has been shown to be positively associated with a placebo response? Should this pep talk include advice to be sure to take their pills (or other treatments) faithfully? Or might it be the case that the adherence research shows that what really matters is what's already inside the patient's head, not what we say--that those in the trials that were more adherent were simply that sort of person, and being that sort of person is what matters in terms of triggering a placebo effect--and our pep talk is worthless?

OK, Jerry, here's my answer, followed by my hunch.

My answer, as Wilson's nice review suggests, is: we don't know. No one has yet done the sort of fine-grained study of the more-adherent research subjects, analogous to some of the latest generation of placebo-effect research done in the last decade with brain imaging etc. So the underlying psychological and neurochemical factors that might explain the adherence-placebo effect link are unknown.

Now my hunch. The placebo effect is almost certainly multifactorial. Indeed, Fabrizio Benedetti of Turin titled his excellent 2009 book Placebo Effects (rather than Placebo Effect) to make the argument that continued research will almost certainly reveal multiple underlying mechanisms that may operate in different diseases and different organ systems.

The best available evidence that we have suggests two very general psychological mechanisms for most placebo effects--expectancy and conditioning. Expectancy is basically forward looking--your body is likely to heal itself when you think it will get better in the future. Conditioning is backward--your body is more likely to heal itself when you associate the circumstances you're in now with circumstances in which your body experienced healing previously.

The adherence effect probably partakes of both. Subjects who take their medicines regularly probably anticipate a good outcome with greater confidence. These same people probably got better in the past when they religiously took their pills, and so conditioning can contribute to their getting better this time by reactivating the same neural pathways.

Now what happens if a physician acts enthusiastic and encouraging about the nature of the treatment? This is likely to increase both expectancy and conditioning effects--expectancy for obvious reasons, conditioning because the patient probably associates an emotionally supportive environment with past healing (going as far back as when Mommy kissed your boo-boo and it got better afterwards). So I cannot see how the encouraging physician could detract in any way from the patient's inner tendency to experience an adherence-placebo reaction, and I can see several ways that the former might enhance the latter. So: bring on the pep-talk.

I have recently become interested in the connection between placebo response and medicine viewed as ritual/performance/theater. We scientific types are used to dismissing ritual as meaningless superstition, but the current placebo research indicates the neuroanatomical and neurochemical reasons why ritual can be efficacious in changing bodily function as well as in altering our cognitive and emotional views of the world. Much of medicine, when we think about it, is ritual and/or performance. (Science writer Nicholas Wade once wrote something like, "All medicine is a form of theater.") Rituals include taking one's pills once or several times a day and can readily trigger both expectancy and conditioning responses. Smart physicians who prescribe exercise and other lifestyle changes try whever possible to suggest rituals to patients to increase adherence, in some cases going so far as to write the instructions on a prescription pad, which when in practice I always found especially powerful. All of these measures seem well calculated to increase placebo effects, as well as to make patients healthier by way of the drug or the exercise or whatever.

I promised in the end to bring this back around to Pharma, so here goes. I suggest that you read Wilson's article and look especially at the effect sizes reported for the adherence-placebo effect. Just for example: Mortality difference between adherent and nonadherent placebo group subjects in the Coronary Drug Project (1980): 15% vs. 25%. More recently, adherence effect in mortality in heart failure, based on the SOLV-TT and SOLV-PT trials: hazard ratio 0.52 (Avins 2010). And remember, according to the body of data Wilson reviews, these are not one-time flukes. And remember too we are talking here about people keeling over dead, not some meaningless surrogate endpoint.

Why is this of importance? The drug companies would kill to come up with a new drug that had efficacy numbers this good. So you could spin this in a pro- or anti-industry fashion. On the side of the industry, have a pity--look what they have to overcome to show that a new drug is better than placebo, when the placebo effect alone can be this powerful. But on the other side of the coin, when mere encouragement and positive thinking can have this much beneficial effect on patient outcomes, why in heaven's name would we want to give drugs that have dangerous side effects and that cost an arm and a leg, unless the drugs had been clearly shown to be really superior to cheap and safe encouragement?

Wilson IB. Adherence, placebo effects, amd mortality [editorial]. Journal of General Internal Medicine 25:1270-1272, December 2010.

Avins AL, Pressman A, Ackerson L, et al. Placebo adherence and its association with morbidity and mortality in the studies of left ventricular dysfunction. Journal of General Internal Medicine 25: 1275-1281, December 2010.

Does the Drug Industry Trust the "Super-Committee"?

2011-09-02T17:19:00.000-07:00

The New England Journal of Medicine's online-first includes an opinion piece--
http://healthpolicyandreform.nejm.org/?p=15246&query=home
--by former Clinton health adviser Christopher C. Jennings, on why a lot of special interests in the health field will do their best to torpedo any proposals coming out of the Congressional "super-committee." The political wisdom seems to be that the threat of $1.2 trillion in automatic budget cuts, that would be triggered by a rejection of the committee's proposals, is so scary that everyone will rush to embrace what the committee proposes, Jennings says--no, if you go by the old adage of better the devil you know, then most healthcare special interests have every reason to choose the fallback across-the-board cuts.

Jennings proceeds to list all the various special interests and explain why they'd be better able to cope with the fallback cuts, from their self-interested point of view--despite the fact that public policy and public health goals would clearly be better served by avoiding such cuts and adopting proposals that the super-committee is likely to propose. (In other words, our dysfunctional political process, far from having discovered the way to get beyond the present partisan impasse, has once again assured gridlock.)

What role does the drug industry play in all this? Jennings has little to say about them as a specific player in this game except to point out that there seem to be two options open. One is the automatic fallback cuts. These are likely to amount to 2% overall in Medicare, but Medicaid would be protected from these cuts. The other option would be a sensible plan to reduce costs of both Medicaid and Medicare without cutting useful services for patients, and almost for sure, any such deal would call for extending to Medicare the privilege now enjoyed by Medicaid of using its bulk purchasing power to force discounts in drug prices. The specter of Medicare being able to bargain from a position of real strength has always sent shivers of the spine of the drug industry. So they'll take the fallback cuts, thank you very much.

Accuracy of Drug Ads: Glass Half Full?

2011-09-02T15:01:00.001-07:00

A recent study in PLoS One by Korenstein and colleagues:
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0023336
--addresses how well drug ads in major medical journals adhere to FDA guidelines, and whether, secondarily, the ads tell physicians what they need to know to prescribe properly. Is the glass half empty or half full? You be the judge.

The authors looked at 83 unique ads appearing in 9 high-impact medical journals during November 2008. They found that only 18% clearly met all the FDA criteria, 49% were clearly nonadherent in at least one criterion, and the rest were uncertain due to missing information. (half empty) But the articles that were clearly nonadherent failed, on average, to meet only 1-2 of 21 FDA guidelines. (half full)

Where were the ads most likely to fail? The chief deficiencies identified by the authors were:

Unbalanced literature citations making the drug sound better than the evidence shows

Misleading use of headlines or pictures

Implying doses recommended for one class of patients also safe and effective for other classes

One example given of a misleading photo is an ad for a drug recommended in advanced lung cancer, showing a hunk windsurfing.

The authors went on to assess whether the ads provided important prescribing information. They found few ads that met this goal, mostly due to failure to quantify either safety or efficacy. (half empty)

So, what's the take-home message? The ads may be deficient according to FDA guidelines but most ads seem adherent to most of the guidelines. On the other hand, any physician trying to figure out how to prescribe drugs for patients should never trust drug ads to tell what she needs to know. On the other other hand, who didn't know that?

A few comments. First: the FDA is probably always destined to be toothless regarding ads unless it were to be equipped with SWAT teams. Ads have a natural and limited life cycle, somewhere just upward of the May fly. They are run for a few weeks or months and then replaced by a new round of ads. Almost always, by the time the FDA gets wind of a major violation in an ad and can gather itself to take formal action, the ad has already run its course and the damage is done.

Second: As I tried to describe in HOOKED, drug companies never market a drug in just one way. A drug marketing campaign is a carefully orchestrated symphony. Not only are there a lot of sections, but great care is taken to precisely coordinate the timing of all the different elements. So looking only at one section of the orchestra--the journal ads, the TV DTCA ads, the drug rep visits, the dinner talks, etc.--is almost certainly to miss the forest for the trees (to mix metaphors shamelessly).

Third, having said all that, it would be wrong to blow off journal ads as not worth powder and shot. Korenstein et al. cite industry data to show that the drug companies estimate return on investment for journal ads at $5 in drug sales for every $1 spent on ads, making this one of the best returns in any area of marketing.

FTC Goes After New Generic Sweetheart Deals

2011-09-01T13:46:00.000-07:00

In HOOKED I described one way that the brand-name drugmakers collude with generic drugmakers to "evergreen" a lucrative blockbuster drug about to go off patent. The process starts with the usual abuse of the patent system that seems standard these days, where the original company patents every aspect of the drug they can think of down to the color of the capsule. When the first generic manufacturer appears, the brand-name company immediately sues them for patent infringement, threatening to tie the whole thing up in court for years and keeping the price of the drug for consumers high. But (knowing that they are unlikely to win any of these basically frivolous patent claims) the brand-name company then offers a deal to the generic company--just delay the entry of your cheap drug into the market, and we'll pay you a sum about equal to what you could have made by selling the generic for that many months (but well below the profit we expect to make with the brand-name drug having no competition during those months). The winners--both drug companies. The loser--US consumers and taxpayers.

According to Duff Wilson at the New York Times:
http://www.nytimes.com/2011/09/01/business/ftc-criticizes-agreements-that-delay-generic-drugs.html
--the FTC has just reported that companies have figured out a new twist. To evade regulations, apparently, the brand-name firm no longer comes out with a blatant payoff to the generic firm. Rather the payoff is indirect. The brand-name firm simply agrees to postpone for the requisite length of time its own generic version of the drug. I know this gets complicated when we start talking about the apparently self-contradictory term "brand-name generics." The FTC claims in its report that when in the first 6 months of competition (during which by law a single generic firm can have a monopoly on the generic side of the trade), if the brand-name company (the only company legally entitled to compete during that time window, as I gather) puts it own generic out on the market, the overall cost savings to the consumer is 4-8%. So if the brand-name company can promise the generic company that it won't compete, that amounts to the same thing as handing over cash, but without handing over any cash.

At least I think that's the way it works. Anyone among the four regular readers of this blog who understands the law better than I or who can explain it better, please send us a comment.

The FTC report struck a nerve because both the brand-name drug industry, in the person of PhRMA, and the generic industry association are grousing. Each insists that agreements that prevent extended patent fights in court are good for consumers and the FTC should take a hike. Of course they are partly right--if the patent laws were effectively enforced as they were intended, all of these lawsuits would get tossed out of court from the get-go. But the FTC is certainly right in claiming that sweetheart deals by which both drug firms make a bundle at the consumers' expense is not the answer.

Pharma, Science, and Drug Reps--an Update

2011-09-01T05:50:00.000-07:00

I commend to your attention a blog post and the related comments--
http://go.neiglobal.com/Blog/tabid/83/EntryId/16/Are-future-psychiatric-treatments-doomed-Be-careful-what-you-ask-for-you-just-might-get-it.aspx

Dr. Stephen M. Stahl, "award-winning author and psychiatrist" according to the website, founded the Neuroscience Education Institute and is a paid consultant and/or speaker for numerous pharmaceutical firms. He wrote the initial post bemoaning the activities of "pharmascolds" and accusing them of causing drug companies to be putting less research effort into finding valuable new paychiatric drugs because of the grief they are causing the industry.

This led Dr. Danny Carlat, of Carlat Psychiatry Blog and a well-known critic of Pharma, to comment that Dr. Stahl was not quite correct on a number of his facts, and that the real reasons why there are not more new and powerful psychiatric drugs now on the market is because the drugs being promoted by the industry don't work very well, and the companies prefer financially less risky me-too drugs over genuine innovation.

So that has led to a lot of back-and-forth commentary and I don't want to get involved in who said what to whom or who called whom what name, but I do want to pull out a couple of comments from the blog that struck me as illuminating.

First: One of the regular bloggers on Dr. Stahl's site is Dr. Debbi Ann Morrissette, a medical writer who I gather is employed by their firm. Dr. Morrissette took issue with a number of Dr. Carlat's objections to Dr. Stahl's statement. Here is a part of her comment:

CARLAT ASSERTION:3. Drug companies have introduced many psychiatric medications over the last two decades, but they have made the business decision to invest heavily in me-too agents, some of which, such as Pristiq and Invega, are embarrassingly blatant patent-extenders with no clear advantages over existing agents. Perhaps if companies had invested more resources into developing truly novel compounds, they wouldn’t be in the pickle they are in.

FACT: THE SUBSTANCE P ANTAGONISTS WERE NOVEL, AS WERE THE CRF1 ANTAGONISTS, NEUROKININ 2, NEUROKININ 3, BETA 3 AGONISTS, AND MANY OTHERS THAT FAILED TO SHOW CONSISTENT EFFICACY. AGOMELATINE IS NOVEL AND FACES AN UNCERTAIN FUTURE IN THE US BECAUSE OF POTENTIAL HEPATOTOXICITY. OVER A DOZEN NOVEL MECHANISMS WERE ADDED ON TO ANTIPSYCHOTICS TO TEST COGNITIVE IMPROVEMENT, FROM 5HT6, TO NICOTINIC AGONISTS, AMPAKINES, MANY MORE. THE FACT IS THAT INDUSTRY IS PUNISHED FOR PURSUSING TRULY NOVEL COMPOUNDS AND REWARDED FOR ME TOOS.

Okay, so let me see if I get this. Here is a highly trained medical writer trying to defend the drug industry from the supposedly uninformed anti-psychiatry rants of Dr. Carlat. She lists a variety of novel compounds being studied recently by the drug industry, that involve molecular mechanisms different from existing psychiatric drugs. (Real innovation--so far, so good.) She then lists the unfortunate fate of these compounds in clinical trials--they don't work very well, or they cause nasty adverse reactions. She then makes the astounding claim, that on this basis, "industry is punished for pursuing truly novel compounds and rewarded for me toos."

If you consider discovering a new chemical, subjecting it to clinical trials, and finding out that it does not perform as well as you have hoped "punishment," then you seem to be saying that normal, routine clinical research is punishment--which makes Pharma's claim that that's the business they are in rather odd. Are you saying that Pharma ought to be "rewarded" by being allowed to sell useless and dangerous drugs for huge profits? Pharma is indeed "rewarded" when it makes and markets me-too drugs, but the reward is solely economic; by definition, patient care is not significantly advanced. So are you saying that Pharma is really all about profits and not about patient care? Funny, that's what the pharmascolds have been saying.

Second: Here is a comment signed "Former Pharma sales rep":

As a former sales representative for a major international pharma company, I learned firsthand clinician and patient attitudes toward the pharma companies. Patients eyed pharma reps suspiciously in waiting rooms, the front-desk staff treated us miserably, and the doctors refused time with us. Even my acquaintences, some of whom owed their lives to modern pharmaceuticals, could not understand why pharmaceutical companies promote their products or sell them at any significant price. All education efforts, sales efforts, or marketing was considered questionable. As sales representatives, we had a hard time recruiting attendance for educational events because by this time, we were prohibited from providing lunch to go with the presentation. Soon, sales reps were banned from most clinics in the area, and we could no nothing more than drop off copies of clinical studies with scowling front-desk staff. It wasn't long before my entire sales team was laid off due to shrinking sales budgets. Any luxury item is heavily promoted and nobody complains. But a drug that saves lives is expected to be available for free and without sales or marketing behind it. I feel that the clinics in my sales territory did get what they asked for. The absence of up-to-date drug information and education from live representatives.
I am unable to say whether this is an accurate report of the status of being a drug rep in today's world, or some combination of bellyaching and sour grapes, or some of each. But if this is even partly true then I think the important take-home message is the incredible attitude shift that has occurred in this whole field since I started doing the research for HOOKED a little more than a decade ago. Back then the drug rep business was flying high, physicians rolled out the red carpet for reps, and the whole crew was fat and sassy and thought critics of these arrangements were completely crazy. If things have changed as much as "former rep" says, can we pharmascolds actually be responsible? As Dr. Carlat suggests in his reply to Dr. Stahl, it would seem odd that a bunch of generally powerless folks like us could have somehow engineered such a huge change. But hey, we'll take it.

This former rep says that the downside of these changes has been "The absence of up-to-date drug information and education from live representatives." Is that so? Of course this is nonsense in terms of the reps being a reliable source of up-to-date information, or that docs don't have far better evidence-based sources than reps. But that would take us back into far too many previous posts on this blog about how the industry thinks marketing is education.

J&J CEO at the White House: The Wider Message

2011-08-29T14:32:00.000-07:00

Once again our good friends, in this case Dr. Roy Poses, over at Health Care Renewal provide grist for our mill:
http://hcrenewal.blogspot.com/2011/08/why-cultivate-weldons-confidence-ceo.html

This instructive post first notes how Mr. Bill Weldon, CEO of Johnson & Johnson, was one of eight business leaders invited by President Obama to the White House to give advice in the economy and in particular, to tell the Administration how it could restore their confidence. The remainder of the post is a litany of all the illegal behavior that has earned J&J fines and censure in the past several years, and how Mr. Weldom has been given hefty annual raises despite presiding over this string of disasters. Dr. Poses naturally asks why any Administration would want to gain such a person's confidence.

We could dig into this a little deeper and ask whether this interest on the part of the White House in making nice with big business--potential source of huge piles of campaign cash as the 2012 election looms--has anything at all to do with the Feds doing a one-eighty on some "get tough" conflict of interest provisions, as we discussed recently:
http://brodyhooked.blogspot.com/2011/08/integrity-in-government-forget-about-it.html
http://brodyhooked.blogspot.com/2011/08/nih-conflict-of-interest-rules-weakened.html

We could also ask about the timing of this sudden desire to regain the "confidence" of big business. It seemed to come right after the Democrats took a whupping in the 2010 elections. From a purely political point of view that timing may have made sense. From a policy point of view it is hard to get away from the fact that we were, in 2010, in the middle of a very deep recession, brought about by the irresponsible behavior of that same big-business community--who continue to tell us that the best way toward future economic prosperity is the same set of policies that got us into that recession--that is, shrink big government, don't regulate business, and above all else don't tax the rich. And, as Charles Ferguson showed dramatically in his brilliant documentary, Inside Job--
http://www.insidejob.com/
--Obama proceeded to appoint to his own economic team almost all of the major architects of the previous disaster.

More on the Effects of Samples in the Doctor's Office

2011-08-27T13:16:00.000-07:00

It's nice to be able to come back to a topic we have not addressed in a while, the good ol' down home matter of the doctor's office sample cupboard. Dr. Richard G. Pinckney and colleagues from the University of Vermont (subscription required to access article) noted that previous attitude surveys about how samples impacted on prescribing practices had usually been restricted to just a few office sites and so set out to do a broader survey, taking advantage of a Vermont statewide primary care database. Now you could immediately object that if you had to survey docs in any state of the US, Vermont might well be the greatest outlier, especially since they are now considering something akin to a single-payer system. Be that as it may, in Vermont they had their database and in Vermont they did their study, which got in the end a 35% response rate, fairly typical for today's world.

Along they way they cited a Kaiser Family Foundation poll that showed that 92% of US physicians reported that at least once in their careers, they'd received samples from a drug rep. I interpret that to mean that 8% of physicians are either liars or have rotten memories.

Pinckney and friends found in this particular instance that about 3/4 of their responding docs had samples in their offices, and they proceeded to compare that group with the remainder who did not. They provided two vignettes involving patients with no insurance and with hypertension and depression, respectively. The majority of docs got the right answer--use a cheap and effective thiazide diuretic for the first-pass treatment of the hypertension, and if the depressed patient needs drug therapy, pick a cheap generic. But there were significant differences between their two groups. Only 70% of the sample-docs picked the thiazide while 91% of the no-sample-docs did, and while 91% of the sample-docs went for the generic antidepressant, every single one of the no-sample-docs did.

They also asked those folks about attitudes toward samples, and again not surprisingly, the sample-docs were significantly more likely to believe that samples expedite treatment, make patients happy, help the indigent, and allow the docs to check out which meds work best. The no-sample-docs were more likely to believe that samples distort treatment plans, increase the costs of care, and lead to overuse. Pinckney et al. noted that actually a majority in both groups agreed that samples increase the costs of care and can affect physicians' prescribing habits.

What's cart and what's horse? It could be of course that docs who have certain attitudes are more likely to elect to dispense with the traditional sample cupboard, or that docs who have samples around all the time end up getting certain attitudes, or a bit of each. From such a study one can only hypothesize associates and not causes. Still this is just a bit more support for the already-fairly-well-documented idea that "free" samples in the office do more harm than good.

(Hat tip to Primary Care Medical Abstracts for the citation.)

Pinckney RG, Helminski AS, Kennedy AG, et al. The effect of medication samples on self-reported prescribing practices: a statewide, cross-sectional survey. Journal of General Internal Medicine 26:40-44, January 2011.

Maybe Starting to Get It: Neurosurgeons on COI in Research

2011-08-27T12:27:00.001-07:00

An article and accompanying editorial in the Journal of Neurosurgery back in January are instructive in regard to our present level of understanding of the threats to medical research integrity posed by conflicts of interest.

Dr. Alpesh A. Patel and co-authors, a group of academic orthopedists:
http://thejns.org/doi/full/10.3171/2010.8.JNS091834
--discuss various recent cases of conflicts of interest in medical research and publication, many of which we've addressed here. They start off with this list of problems raised by these instances:

Calling into question the ethics and motives of the involved individuals

Creating public distrust of science

Calling into question academic medicine's "honor code"

Disrupting relationships with patients

"They offer salacious opportunities for the lay press to decry the rampant corruption in health care"

"Lastly, and most ominously, they draw the attention and scrutiny of the government and politicians"

In the remainder of the article they sort of tack back and forth between the themes they list at the beginning-- that is, sometimes they are worried most about the patient and about the integrity of the science; other times they seem more concerned about what the press will write about us and how the politicians will come in and tell us what to do. When they get around to proposing solutions, they mention several times that eliminating commercial sponsorship of key research would be the ideal. They state that this seems unrealistic in the short run and therefore ways are needed to "manage" COI. The "management" tools they propose are hardly novel but reasonably strict. They advise their colleagues, "...some [clinicians] view any mandatory COI benchmarks as a personal affront. However, rather than contest the imposition of these restrictive regulations, it is imperative that physicians take the lead and accept that they are subject to a higher standard than others..." They focus on the responsibilities of physician-scientists and of the medical journals, respectively.

Dr. Joseph H. Piatt, Jr., a Delaware neurosurgeon, takes up in the accompanying editorial--
http://thejns.org/doi/full/10.3171/2010.1.JNS10152
--the prevarication in tone in Patel et al's paper. He's stronger about the extent of the problem: "By corrupting the scientific method, commercial bias contaminates our knowledge base and deflects us from the objective best interests of our patients." He then scolds the other authors for placing so much emphasis in professional self-regulation when it has failed thus far to solve the problem: "The challenge of commercial bias in clinical research is not new, and the profession has made sincere but largely toothless attempts to contain it over the years. Patel and coauthors do well to exhort us neurosurgeons to take ownership, but none of their suggestions are game-changing. Look for expanded governmental control of the clinical evaluation and marketing of new medical technologies, particularly as the imperative for the containment of the growth of health care spending by any and all means becomes more acutely felt in the next decade." (The editorial includes a reply from Patel et al. who basically don't disagree with anything that Piatt says.)

What's the take-home message? I propose that we can see the slow evolution of attitudes within academic medicine, in specialties like neurosurgery and orthopedics that have not historically been at the very forefront of ethical advances (if I may express my bias):

COI is not a problem.

COI is a minor problem and we can easily manage it with a few tweaks.

COI is a serious problem and we had better do more to eliminate it, else the dreaded government will take over and tell us what to do.

COI is a serious problem, we had our chance to eliminate it and we failed, so we might as well make up our minds that the dreaded government is going to have to come in and fix it, even though there is still much we could do ourselves if we'd grow a bit of backbone.

And backbone, I may add, is what these orthopedists and neurosurgeons claim to be experts in.

(Note: I'm grateful to Rick Bukata and Jerry Hoffman of Primary Care Medical Abstracts for alerting me to this paper, though what I say above is a slightly more sympathetic take on the article than suggested in Jerry's recorded commentary.)

Controlling the Channels: Pushing the Pharma-Friendly Model of Diabetes

2011-08-25T18:03:00.000-07:00

In keeping with my lazy habit of letting others write this blog for me, I will talk about a couple of commentaries included in the July, 2011 edition of Primary Care Medical Abstracts by my friends Rick Bukata and Jerry Hoffman. The first, I will argue, illustrates the concept previously blogged about by the anthropologist, Kalman Applbaum, on the idea of drug "channels" and how drug company marketing works to control these channels effectively. The take-home message in each case is how medical journals have been harnessed to the cause of selling drugs, despite lack of sound evidence, in ways that are usually opaque to the average reader.

Exhibit A for this commentary is a so-called expert consensus panel (McInnes et al., subscription required) on diabetic foot care, published in the British journal Diabetic Medicine. The panel appears to be what evidence-based gurus call BOGSAT, or "bunch of old guys sitting around talking," rather than a systematic evidence-based review with proper methods. The funding for the "old guys" came from a firm called SSL International, which has since been bought out by another firm, which makes a variety of health-related products, mostly for nonprescription home use. I don't see offhand that they make any diabetes drugs. Nothing is said in the article about conflicts of interest, or lack of same, among the authors.

The authors set out to answer the question of what kind of foot care should be provided for diabetics considered to be at relatively low risk. I was puzzled because the article does not say whether they are talking about Type 1 or Type 2 diabetes, so I have to imagine they mean both. It is therefore important to keep in mind that about 90 percent of patients seen by adult practitioners have Type 2 (adult onset) diabetes. As we have discussed in several previous posts, there is at present no compelling evidence that tight control of blood sugar levels (trying to get the hemoglobin A1c blood test within normal limits) effectively prevents the major complications of Type 2 diabetes, in particular diabetic neuropathy which is the cause of most foot problems.

So the "old guys" list four things that they think physicians should advise patients as part of good diabetic foot care. The second is: "maintaining adequate glycaemic control." They proceed to explain: "Numerous clinical studies have demonstrated the positive relationship between reductions in HbA1c and reduced risk of microvascular complications of diabetes, including neuropathy and foot ulcers." Now, this is sort of half right. Numerous studies have shown that if you have two groups of diabetics, one with high levels of A1c (poor control) and others with low A1c (good control), the first group will have many fewer complications. What has never been shown is that giving medicines in Type 2 diabetes to lower A1c reduces the incidence of complications.

So what evidence do these "old guys" cite to prove their point about better control leading to fewer complications, especially in the feet? They mention two references. The first, as Jerry pointed out in his commentary on the paper, was to the DCCT trial published in 1993, which showed that tight control reduced complications in Type 1 diabetics--that is, irrelevant to the vast majority of adult diabetics. The second reference is a paper by Boyko et al. in 2006. This paper has nothing to do with diabetes treatment or the prevention of complications. Rather it is the development of a prediction tool to show which diabetic patients are most likely to develop foot ulcers. Not surprisingly, one of the risk predictors is elevated HbA1c--though interestingly enough, this single factor increases one's risk of foot ulcers by only 10% above baseline, while other predictive facts double or triple the risk. But the Boyko et al. paper says nothing whatever about whether better glycemic control will prevent neuropathy or ulcers.

So what we have here in this journal is a supposed "expert consensus" on preventing foot complications in diabetics, claiming that better blood sugar control is a critical component of this prevention, but unable to cite a single clinical trial showing this to be true for the most common type of diabetes. So long as physicians think that the best way to prevent the complications of Type 2 diabetes is to lower HbA1c, they will write a lot of prescriptions for expensive medications, making the drug companies richer--but doing very little actually to prevent diabetes complications. In this way even an article that seems to be not at all about drug therapy manages to convey a drug-industry-friendly message--and the evidence be damned.

McInnes A, Jeffcote W, Vileikyte L, et al. Foot care education in patients with diabetes at low risk of complications: a consensus statement. Diabetic Medicine 28:162-167, 2011.

Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine 329:977-986, 1993.

Boyko EJ, Ahroni JH, Cohen V, et al. Prediction of diabetic foot ulcer occurrence using commonly available clinical information: the Seattle Diabetic Foot Study. Diabetes Care 29:1202-1207, 2006.

Want to Wreck Things and Rake In Millions? Become a Pfizer CEO

2011-08-23T18:38:00.000-07:00

Let me tell you a little story, that has very broad implications about national economic policy, and eventually get around to saying something that relates to the pharmaceutical industry.

Andrew Carnegie, who in his day was sort of Bill Gates and Warren Buffett wrapped into one, wrote an essay called "The Gospel of Wealth." As rich guys go Carnegie was not a bad sort; he believed that the rich should give away most of their wealth to community charities such as libraries and museums. But Carnegie also had pretty strict views about why you should not give direct charity to the poor. He described an instance in which a philanthropist he knew gave a quarter to a beggar. Carnegie was outraged, and insisted that that single stupid act was bad enough to undo all the good work this philanthropist had achieved over a lifetime. First, he was quite sure that the beggar would use that quarter for some immoral purpose--and those were the days when a quarter would actually buy something. But more important, Carnegie was sure that giving assistance to a poor person was a sure way to sap that individual's sense of responsibility, and lead inexorably to what today people would term the "culture of poverty," always waiting around for a handout and doing nothing to pull oneself up by those proverbial bootstraps.

I don't think that Carnegie had a name for this phenomenon, but when conservative economists started creating the theories that led to Reaganism and supply-side policies in the late 1970s, somebody came up with the term "moral hazard." The basic idea is that if people are in unfortunate straits and you give them some sort of aid, all you do is increase the rewards for being in those straits and make that behavior even more attractive in the future, which works directly against the unfortunate bettering themselves. So basically any federal program to help the needy in any way is a bad idea.

Okay, now back to Pharma. Dr. Roy Poses over at Health Care Renewal--http://hcrenewal.blogspot.com/2011/08/what-pfizer-iii-enormous-pay-for-poor.html--
in turn drawing on a report in Fortune magazine/CNN Money--http://hcrenewal.blogspot.com/2011/08/what-pfizer-iii-enormous-pay-for-poor.html--
tells us about the deeds and reimbursement of the most recent crop of CEOs at Pfizer. The basic bottom line is that the investigation viewed their performance as abysmal; their annual pay was in each case in excess of $10M; and during the time they were doing their best to ruin the company, they were actually granted annual raises. One former CEO, "Hank" McKinnell, more or less threw up his hands and declared his job impossible in 2002. He then sort of went missing and left a power vacuum that created severe headaches in the upper reaches of the company until he finally was forced to "retire" in 2006. He was paid $10.7M in 2003, $11.3M in 2004, and $12.8M in 2005.

This says something about bloated CEO pay throughout US corporations. This also says something about ineffective leadership at some large drug firms. But the particular lesson I wish to draw is about moral hazard. Notice that according to the gurus of our economy, if you give a poor man a quarter, you will probably ruin him for life and incidentally cause the collapse of Western civilization. If you pay a CEO extra millions of dollars every year for destroying his company, however, you are apparently following good economic principles; no "moral hazard"
here.

In other words, there are rules for the rich and rules for the poor. And the rich are in charge. And don't you forget it.

NIH Conflict of Interest Rules: Weakened

2011-08-23T18:30:00.000-07:00

I recently recapped fears that "get tough" moves at NIH, FDA and DHHS/DOJ regarding conflicts of interest were all being retracted or watered down. I then described some pushback on the FDA front, but according to our friend Dr. Bernard Carroll writing for Health Care Renewal:http://hcrenewal.blogspot.com/2011/08/quis-custodiet-ipsos-custodes-redux.html, the announcement from NIH earlier today on their new COI rules leaves considerable disappointment.

Dr. Carroll notes two major issues. One, that I summarized in my earlier post--http://brodyhooked.blogspot.com/2011/08/integrity-in-government-forget-about-it.html--is that universities are no longer required to post information about investigators' conflicts of interest in an easily accessible public website. (If you want you can write the university a letter and they are supposed to reply within 5 days.) The second is that the loophole that allows a conflicted investigator who was sanctioned at one institution simply to jump ship to another bottom-feeder university and start applying for NIH grants again right away, remains more or less wide open.

Pressure Builds on FDA to Maintain New COI Rules

2011-08-22T18:35:00.000-07:00

In the previous post, I discussed briefly the FDA's apparent desire to retreat from the tough new conflict of interest rules it had earlier announced, particularly, excluding "experts" funded by industry from its advisory committees. Numerous examples have occurred where industry-supported votes made the difference between keeping a dangerous drug on the market and pulling it, for example. But the FDA is now claiming that it simply can't find any real experts who are not in the pay of the industry.

Enter our old friends, journalists Shannon Brownlee and Jeanne Lenzer. Jeanne authored a news item in last week's BMJ (subscription required) highlighting the entry of our other friends, the National Physicians Alliance, into the fray. The main point raised by Brownlee, Lenzer and the NPA is that they had worked hard a little while ago to compile a list of expert physicians who take no industry cash. They were able to come up with a list of over 100 such individuals (full disclosure: I'm on the list, though just what I am an expert in remains to be determined). The NPA and the journalists objected that despite their having been supplied with this list, there's no evidence that anyone at the FDA made any effort to contact any of those physicians. How, then, said the FDA's critics, can anyone claim that these experts are too hard to find?

There is some tentative evidence that the FDA may be backpedalling on their backpedalling, so stay tuned for further exciting adventures.

Lenzer J. Doctors join protest over change to FDA rules on conflicts of interest. BMJ 2011; 343:d5269.

Integrity in Government? Forget About It

2011-08-15T15:23:00.000-07:00

Once again I can sit back and let others do all the heavy lifting for this blog, in this case Dr. Roy Poses at Health Care Renewal:
http://hcrenewal.blogspot.com/2011/08/retreat-back-to-regulatory-capture-us.html

Dr. Poses conveniently combines three breaking news stories, each of which features an unfortunate retreat from integrity by an arm of the Federal government, where previous action that showed a commitment to integrity is in danger of being reversed:

The FDA is telling Congress that it cannot find real medical experts who are not in the pay of drug companies, so please excuse them from their goal of excluding these industry shills from FDA advisory committees

NIH is now saying that academic medical centers cannot find the resources to maintain websites that list the sources of payment for faculty members with financial conflicts of interest, so it cannot implement a previously announced transparency plan

DHHS earlier threatened to exclude Forrest Laboratories CEO Howard Solomon from further dealings with Federal health programs (the so-called fiscal "death penalty") after his firm was found responsible for repeated violations committed on his watch. This was initially hailed as a step to show that finally DHHS was serious about punishing companies that repeatedly broke the rules. Now DHHS says--sorry, we were just kidding; after the U.S. Chamber of Commerce and PhRMA raised a howl. (Forrest hired former Sen. John Breaux as its lobbyist to fight the exclusion.)

See Dr. Poses' long post for details and additional links on each of the three actions, but if there's a summary message, it seems to be a cynical one--the election is approaching and with the US Supreme Court removing all limits on corporate cash flowing into campaign coffers, don't expect either the executive or the legislative branches to stand up to the aggressive corporate lobbying of the drug industry and its cronies. In the case of the NIH my feelings are more mixed due to my own conflict of interest, as a faculty member at an academic medical center. I've seen up close and personal the damage being done to our institutions as both state funds and NIH grants are cut back and every medical school is expected to do more with less. So I have a bit more sympathy there. Still, given the hoopla with which the new NIH COI transparency rules were announced, it is deeply disappointing to see the full-scale retreat with hardly a whimper. Moreover, one has to wonder--is it really the gripe of the academic medical centers that they don't have the resources to staff the websites? Or is it rather that they'd prefer not to interfere with the corporate grant machine that their conflicted faculty help to fuel with the industry's largesse?

More on IOM Report on FDA Scrutiny of Devices

2011-08-12T11:02:00.000-07:00

We posted previously on the device industry pushback against the new IOM report urging major reforms of how the FDA regulates medical devices:
http://brodyhooked.blogspot.com/2011/08/medical-device-industry-to-iom-drop.html

Now the New England Journal of Medicine:
http://healthpolicyandreform.nejm.org/?p=15108&query=home
--in a "Perspective" authored by their executive editor, Dr. Gregory Curfman, and Dr. Rita Redberg, the editor of Archives of Internal Medicine, adds their word of support to the IOM proposal. Some highlights from the Perspective:

Despite its reasonable (and relatively modest) recommendations, the report has been aggressively attacked by the device industry and by politicians from states where device companies are located. In fact, the attacks began even before the report was released, which is highly unusual for an IOM report.

We believe that the IOM report is insightful, judicious, sensible, and long overdue. ... Unfortunately, the FDA leadership has already suggested that it does not intend to implement this key recommendation of the report, although it may be open to other changes. As the best long-term improvements are contemplated, there are important steps that the agency can take now.

We strongly believe that, in the interest of advancing human health, patients must have easy access to innovative medical devices and that the approval process needs to be sensible and efficient. But no one’s interest is served by putting defective medical devices onto the market where they cause harm to patients, waste health care dollars, and may kill jobs when they are withdrawn. It is essential that the FDA be adequately funded to carry out its mission to ensure the safety and effectiveness of medical devices. The IOM report charts a path that is right for the future, and despite well-financed outside pressures, we urge the FDA to initiate an action plan with congressional support to adopt these important recommendations.

Sunshine Laws Having an Effect? Maybe

2011-08-12T10:43:00.000-07:00

A stray e-mail that came across the ol' transom today seems to hint that sunshine laws, requiring the public disclosure of names of physicians who receive payments/gifts from the pharmaceutical industry, might actually be changing the landscape. At least a consulting firm called Alliance Life Sciences thinks so:
http://www.alscg.com/company/events/kolwhitepaper

Alliance, their website explains, currently works with 8 of the 10 largest pharmaceutical firms around sales and marketing. They have produced this new white paper on what's new with physician Key Opinion Leaders (KOLs) in an era of sunshine. From their e-mail/press release:

“Firms may wish to embrace new marketing paradigms, such as disease-centric product offerings that enhance value propositions for physicians, patients and payers, to compensate for KOL physicians that may no longer be willing or able to collaborate with them,” says Ed Masterson, senior vice president, consulting operations, ALSCG. ... “The new marketing paradigm won’t come from having renowned academics simply present a firm’s PowerPoint deck to auditoriums of doctors,” says Masterson. “It will be based upon research demonstrating improved patient outcomes and avoided costs associated with better compliance that delays or reverses disease progression and acuity.”

What a revolutionary idea--to successfully market new drugs, you might actually have to show that they work. Not simply bribe a famous doctor to show slides over dinner.

The debate over sunshine laws, as we've discussed in numerous previous posts as well as in HOOKED, is how much mileage you get purely out of disclosure. Disclosure of unethical behavior does not turn it into ethical behavior, so if physicians continue to take freebies from industry, and don't care if their names show up on a public website or not, nothing may change. The theory behind the sunshine laws is that if physicians know their names will be made public, they may think twice about their relationships with industry and actual behavior may improve. Alliance Life Sciences seems to be betting that this likely effect is real.

In Praise of Good Corporate Behavior: Medtronic

2011-08-07T18:42:00.000-07:00

I last spoke of Medtronic's shenighans with their spinal surgery devices and products here:
http://brodyhooked.blogspot.com/2011/06/taking-professionalism-seriously.html

It's critically important that if this blog is to be about ethics at the interface between medicine and for-profit industry (drug or device), that I am equally attentive to good corporate behavior as to scandals. This can be challenging as we've seen numerous examples of egregious corporate behavior spun by creative PR so as to appear virtuous. But if it really seems that a company has seen the error if its ways, we should take note and be appropriately respectful.

So is Medtronic now in this august category?
http://tcbmag.blogs.com/daily_developments/2011/08/medtronic-pays-yale-to-review-controversial-bone-product.html
Two things make me accept this account as indicative of genuine corporate responsibility. First, the person who sent me the link is a hard-headed critic of industry and has often seen through PR fluff in the past when I could have been fooled. Second, the person selected to do the study of Medtronic's products, Dr. Harlan Krumholz, has what I believe to be an unassailable position as an independent industry critic. If you want somebody to paper over your misdeeds, he would be a pretty pooor choice.

If we ever want to have a relationship between the medical profession and the industry that takes full advantage of the benefits of collaboration while avloiding the ethical cesspool of today's conflicts of interest, we need models of effective neutral turf where industry and professional folk can foregather to address the issues and see what sorts of new developments might be proposed, without the setting itself creating new conflicts of interest or dangers of one side controlling the discussion for its own ends. I am not sure that this Yale study will be a model applicable to other such settings, but it's certainly a welcome development if it is what it seems to be.

Econ 101 and Drug Patents

2011-08-05T17:11:00.001-07:00

I know that all of you out there keep a copy of HOOKED at your bedside and read a chapter each night before retiring. But in case you've not yet committed the volume to memory, I can take the opportunity of these news items to do a bit of review of a basic concept:
http://keionline.org/node/1147
http://www.guardian.co.uk/commentisfree/cifamerica/2011/may/31/healthcare-pharmaceuticals-industry

The latter article, from The Guardian, is a commentary by economist Dean Baker (whom I quote in HOOKED) on legislation proposed by Sen. Bernie Sanders (I-VT), which is summarized in the first link.

Here's how Baker starts off his commentary: "Drugs are cheap. There are few drugs that would sell for more than $5-$10 a prescription in a free market. However, many drugs in the United States sell for hundreds of dollars per prescription and, sometimes, several thousand dollars per prescription. There is a simple reason for this fact: government-granted patent monopolies."

Now, this comment may strike you as strange, especially if you were to check out the Pharmaceutical Research and Manufacturers of America website (http://www.phrma.org/about/phrma) There you will find the following statement of the drug industry's core values:

PhRMA's mission is to conduct effective advocacy for public policies that encourage discovery of important new medicines for patients by pharmaceutical and biotechnology research companies. To accomplish this mission, PhRMA is dedicated to achieving these goals in Washington, the states and the world:
• Broad patient access to safe and effective medicines through a free market, without price controls;
• Strong intellectual property incentives;
• And transparent, efficient regulation and a free flow of information to patients.

In case you don't know what "intellectual property" is, read "patents." So how can it be that an economist explains that in a free market, drugs would be really cheap, and the reason they cost so much is because of patents that amount to government monopolies (which are of course a violation of the free market); yet PhRMA insists it is for the free market (and against price controls), yet also for patents?

I mentioned in passing (http://brodyhooked.blogspot.com/2011/07/kid-gloves-on-corporate-crime-different.html) that I hope soon to be able to announce the availability of a new book on the subject of economism. Economism, briefly, is the worship of the "free market" as an item of religious faith, though it disguises its religious nature by posing as hard-headed science. Economism, I hope to show, is shot through with internal contradictions and inconsistencies, explaining why its believers have to be faith-based, because neither facts nor logic would support it. PhRMA's two claims of being pro-free-market and pro-patent is just one tiny example of the sorts of contradictions that economism generates--yet at the same time obscures, so that most US politicians and policymakers repeat this nonsense without realizing that it's nonsense.

Baker goes on to explain that a patent is a government-granted monopoly based on a hunch that the extra cost to the public, forced to pay monopoly prices for goods until the patent expires, is a good trade, because the patent forms an incentive to innovate and invent which in turn is a public benefit. This hunch could be well or poorly grounded. Baker argues that right now, we are paying a lot more for drugs through patent monopolies than we are getting benefits from real innovation. If you don't think this is true, you have not been following this blog.

Enter Sen. Sanders. There are wo possible solutions to the mismatch between drug patents and real public benefit. One would be a strictly regulatory approach--change the rules regarding granting patents for new drugs. Demand more evidence of real benefit before granting a patent, or shorten the period of patent protection, or some such. The other approach, which is what Sanders actually has proposed, is a quasi-market approach, using financial incentives rather than regulation. The idea is to impose a tax on both public and private health insurers. The money from the tax would create a prize fund. The prize fund would be used to buy up patents for really useful drugs, as opposed to "me too" drugs. These useful drugs would quickly become generic drugs and would be available cheap.

This, say both Sanders and Baker, would be a win-win. The insurers would more than save in lower drug costs what they paid in the new tax. Drug companies would then have a powerful incentive to discover really useful new drugs, because then they could easily sell the patent for a tidy profit. Baker is perhaps overly sanguine in imagining that in this new system, drug companies would gain no benefit from deceptive marketing of marginally useful or harmful drugs, so they'd simply quit doing that.

Since true believers in economism hate government programs and hate new taxes, and probably hate Bernie Sanders, you can bet there will be little support in those quarters for this proposal. But thanks to Dean Baker for again revealing the hypocrisy of the drug industry's wrapping itself in the "free market" mantle.

ADDENDUM 8/6: A reader much more alert than I was when I wrote this post last night informed me that I had inserted the word "patient" when I obviously meant "patent." This has been corrected above.

Ghostwriting, Again: This Time, Consequences

2011-08-05T10:54:00.000-07:00

Some time back--
http://brodyhooked.blogspot.com/2010/07/still-awaiting-academic-physician-to.html
--I mentioned that we were still awaiting a case where an academic physician suffered clear, negative consequences as a result of being guest author on a ghostwritten paper, though I described a case that provided circumstantial evidence of such consequences. (That particular physician had two strikes against him, of which involvement in ghostwriting was just one, so it was not clear just what offense produced the consequences.)

Thanks to a regular reader of this blog, I now can report what seems a clear case of cause and effect re: ghostwriting and guest authorship, from our neighbors to the North:
http://www.montrealgazette.com/news/montreal/McGill+reprimands+prof+over+ghostwriting+scandal/5209461/story.html
This case involves a punishment meted out in 2010 (apparently, as it was not then publicly announced) by McGill University for a paper published in 2000. We need to note that while on the surface, it might seem unduly vengeful and petty to look back so far for a punishable offense, in reality this is often what the academic medical center has to work with. It is often the case that revelations about ghostwriting come to light only following litigation and the release of internal company documents, which most often occurs many years after the actual incident.

A possible defense of this academic was that back in 2000, this sort of behavior seemed routine and noncontroversial, and it was only years later that all the attention began to be paid to the ethical issues related to ghiostwriting. That is, in my view, a fair comment, and if you read the Montreal article closely you'll see that the level of punishment meted out was consistent with that level of seriousness (in my view).

Even More on Ghostwriting, Or, They Don't Get It in Toronto

2011-08-04T13:15:00.000-07:00

Two big questions this time around--first, can academic medicine police itself regarding ghostwriting, or do we need to invoke the law? Second, does the Toronto Globe and Mail get it, or rather, who got to them?

First, on how to police ghostwriting, we start with an article by our old friends Jonathan Leo and Jeffrey Lacasse, this time aided by Andrea Cimino (subscription required). This group tells us that there has been a lot of huffing and puffing among academics and editors as to why ghostwriting really is not that at all, or if it is, well, it's still okay. So the authors try to simplify for us by saying--this is ghostwriting, and if it happens, then it's wrong and you should be throwing the book at somebody. They argue that the essence is: "If a person who should have been listed as an author was left off the byline, then the paper has been ghostwritten."

This would be a nice, concise formula if it were acceptable. I am fearful that it's not. As to why, stay tuned. But anyway, Leo et al. are optimistic that if we academics could just get clear on what ghostwriting really is, we could manage to police it properly. Now along come Simon Stern and Trudo Lemmens from Toronto:
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001070
--to say, no way. They review the various conflicts of interest that both journals and academic medical centers have with the drug industry, making it unlikely that either would find the backbone really to put an end to ghostwriting-related practices. They suggest that the only thing left is legal remedies, and they then develop specific legal arguments as to why ghostwriting is fraud, and drug companies conspiring with medical writers and academic "guest authors" is racketeering under the law. (Along the way, they dig up an interesting case from 1944, said to be the only U.S. Supreme Court decision on ghostwriting--it involves a patent on glass manufacturing, of all things.)

Okay, so there you have the debate on the first question. On to the second question. It is pretty unusual for the local newspaper to come out with an editorial that says that a paper just published by two members of the local university faculty, in an academic journal, is all wet. But that's just what the Toronto Globe and Mail did with the Stern-Lemmens paper: http://www.theglobeandmail.com/news/opinions/editorials/in-praise-of-ghostly-scribes-for-scientists/article2118829/

Now, this editorial is such a serious misrepresentation of all the ethical issues in ghostwriting that you have to wonder what prompted it. The point of the editorial is that ghostwriting is good because academic physicians can't write worth beans (mostly true), so if professional writers take over and render one's article readable, then they are doing a great service, and how can you call this fraud and racketeering, etc. They admit grudgingly along the way that "guest authorship" is of course wrong, and if you did not truly contribute to the research or the writing, your name doesn't belong on the paper. But they act as if the ghostwriter is the innocent victim in such a case. They totally fail to address the basic problem, that ghostwriting and guest authorship, together, are part of a larger system by which the drug industry can manufacture "science" to its marketing specifications. They say they are opposed to this, and make this incredibly naive comment: "If, on the other hand, pharmaceutical companies are paying, in whole or in part, for the research, and they supply the ghostwriters, there is a need for particularly vigilant reading of the draft by the researchers, so that no advertising spin creeps in." This of course ignores the reason that the entire process exists, and that the money needed to hire the ghostwriter fell out of the sky to begin with--that "advertising spin" is not an accidental byproduct but the entire intent.

So where did such a wrongheaded and ignorant editorial come from? I can only relate back to our earlier post:
http://brodyhooked.blogspot.com/2011/06/ghostwriting-bolder-than-ever.html
We saw that the medical communications companies that supply the ghostwriters for industry, and that helpfully coordinate the care and feeding of the guest authors, are tired of being sneered at and are launching their own PR blitz (which is, after all, what they are supposed to be good at), trying to take back the ethical high ground. All I can imagine is that some of these dudes captured the ear of a gullible editor at the Globe and Mail and managed to plant their own advertising spin into the editorial. Which tells you a little something about the ethical integrity of that industry.

Back to my comments on Leo et al, in case you're not asleep yet. Why do I doubt that they got it right on their crisp definition of ghostwriting? Here's a case we talk about in an "Ethics of Scientific Research" course we teach here. Prof A goes to do a sabbatical in Prof B's lab. He does an experiment there, using Prof B's lab equipment and support team. Later he goes back home and then works with Prof B to write up the results of his experiment. When he gets the final draft of the paper for his review, he's shocked to see Prof C's name on it, who works at a distant university and had nothing to do with the experiment. Prof B explains that he and Prof C have a deal. They worked together in the past and they simply agreed always to list the other as co-authors of any future papers. When Prof A objects, quite correctly, that this is an unethical violation of the rules of authorship, Prof B retorts that if Prof A will not honor his deal with Prof C, then the B lab will simply take A's name off the paper and publish the results themselves.

Okay, imagine that B carries out his threat. C is a guest author, which is unethical. A, who should ethically have been listed as an author, is not so listed on the paper. Does this make the paper a ghostwritten paper? There is no ghost writer. The people who wrote the paper, B and his colleagues (except for C who's being included unethically), did in fact do the experiment along with A, and legitimately are part of the scientific team responsible for the data. Plus, the case has nothing whatever to do with commercial spin. Yet by the Leo et al. definition, this is an example of ghostwriting. So I think their definition needs more work.

Leo J, Lacasse JR, Cimino AN. Why does academic medicine allow ghostwriting? A prescription for reform. Society (epub July 21, 2011)

Medical Device Industry to IOM: Drop Dead

2011-08-02T08:39:00.000-07:00

The Institute of Medicine (IOM) of the National Academy of Sciences recently issued a report on FDA regulation of medical devices--unfortunately only a brief summary, which is frankly not all that informative, is available:
http://www.iom.edu/Reports/2011/Medical-Devices-and-the-Publics-Health-The-FDA-510k-Clearance-Process-at-35-Years.aspx

As explained in the press coverage:
http://seattletimes.nwsource.com/html/health/2015771871_medevice30.html?syndication=rss
--the FDA had commissioned this review by the IOM a couple of years ago, and the IOM now argues that the entire system that the FDA uses to regulate and evaluate devices is seriously flawed and should be replaced. As I said, it's hard to get the whole picture from the 4-page summary of the report released thus far. As best as I can tell, the issue is with the so-called 501(k) process, which is based a law passed between 1976 and amended in 1990 and 1997.

By this process, a device can largely escape the need to prove that it's both safe and effective for human use if the company can demonstrate that it's "substantially equivalent" to an already approved device, known as a "predicate device." The IOM committee seems to have two problems with this approach. First, in many cases, the "predicate device" itself was never proven to be safe and effective. Second, the IOM report calls for a continuum of pre-and post-market surveillance for safety issues, and feels that the current 501(k) system fails to address that continuum adequately.

Bottom line, says the IOM: stop tweaking 501(k) and figure out a new regulatory framework to replace it. Problem: the FDA has never gathered enough data about the practical impact of 501(k) to determine what would be a better system; so step one called for by the IOM report is to do that study.

Full disclosure: I am a member of the IOM. IOM is part of the National Academy of Sciences and is supposed to represent an elite cadre of medical thinkers, working independently of government, to address pressing issues in a scientifically informed manner. The IOM's earlier report on medicine and the pharmaceutical industry has generally received the high marks typically granted to the IOM's work, as we summarized: http://brodyhooked.blogspot.com/2009/05/iom-report-on-coi-yes-we-really-mean-it.html

So, if the IOM says that the regulation and safety monitoring of medical devices is in serious trouble, you'd imagine that the device makers would, if not exactly kissing the hem of IOM's gown, at least feel some need, strategically, to offer an appearance of deference before they start to beat up the findings. But, as Steve Martin might say--naaaah. Matthew Perrone reported for the AP: "The device industry's chief lobbying group also dismissed the proposal, saying its conclusions 'do not deserve serious consideration from the Congress or the administration.'"

Now, just where did that "also" come from? Funny, it seems that the FDA is not itself very pleased with the report that it comissioned. Dutifully, FDA announced they'd convene a public meeting and take comments on the IOM recommendations. But in their press release--
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm265908.htm
--Dr. Jeffrey Shuren, head of the device agency within FDA, was quoted, “Medical devices in the U.S. have a strong track record of safety and effectiveness. The 510(k) program has helped support a robust medical device industry in the U.S. and has helped bring lower-risk devices to market for the patients who need them.”

Are you having difficulty telling who's a flack for the industry and who's speaking on behalf of the government agency that's supposed to be regulating the industry? Hmmm. In defense of the FDA, they have been busily at work proposing refinements to their 501(k) process, and basically object that we should give them a chance and see how these improvements work before we set off the more arduous and politically fraught process of trying to rewrite the legislation.

So that's where we are with the IOM report. I mainly want to note the arrogance of the device makers. As we have previously summarized. In some recent press coverage that I now see I may not have gotten around to reporting on this blog, it seems clear the device makers are feeling their oats. They are throwing around their big donations to key Congresspeople, and threatening to take US jobs offshore if the FDA tightens up on device regulation. And this despite major recent revelations about the rampant corruption of medical science and practice by major device manufacturers, as we have noted:
http://brodyhooked.blogspot.com/2011/06/whos-at-fault-company-or-physicians.html
http://brodyhooked.blogspot.com/2011/06/taking-professionalism-seriously.html

So when you have government in your back pocket, I guess you can thumb your nose at the IOM with impunity.

Epocrates: Having Your Cake and Eating It Too

2011-07-29T13:15:00.000-07:00

Duff Wilson in the New York Times did a nice job of shining a spotlight on a phenomenon that has lurked for too long in the shadows:
http://www.nytimes.com/2011/07/29/business/the-epocrates-app-provides-drug-information-and-drug-ads.html?_r=1&hp

Epocrates, an increasingly popular information service for physicians, has been scoring big with its free smartphone app that allows physicians to pull up drug prescribing infomation in the midst of a patient visit. Here's what one of my colleagues in family medicine says about this service:

"Dr. Robert M. Schiller, chairman of family medicine at Beth Israel Medical Center in New York, said he often uses Epocrates to look up drugs and advises medical students to use it, too.

“I have it on my iPhone,” he said. “It’s great for the convenience, being in a room with a patient and checking a medication. But the biggest problem is that it’s supported by the pharmaceutical industry.”

Drug companies, Dr. Schiller said, sponsor information that favors them. “To extent that this is a product that will influence physician prescribing behavior because it’s so efficient and useful, it really needs to have minimal bias,” he said. “And how do you assure that?”

Ah yes-- how do you assure that? Here's the dilemma-- as a seasoned physician educator notes, this type of service fills a real need, and yet there's the downside of commercial bias. So just how good a job is Epocrates doing in balancing those objectives?

Well, on the one hand, Epocrates acknowledges at least the marketing value of not being beholden to industry: “The credibility of our brand is dependent in large part on the medical community’s continued perception of us as independent from our health care industry clients, particularly pharmaceutical companies,” the company said in a securities filing this year.
... “Our first commitment is the value to the physician,” Rosemary A. Crane, president and chief executive of Epocrates, said in an interview.

So that's what they say to the docs. What do they say to the drug firms that buy their ads?

"Epocrates says drug makers get $3 in increased sales from every dollar spent on DocAlerts. The claim comes from comparing prescription records of doctors who see DocAlerts with those who do not, company officials said. But they declined to share the research, saying it was paid for by drug companies and was confidential. ... Pfizer, the world’s largest drug maker, has certainly found the marketing channel to be an effective way to reach doctors. “The beauty of the work we do with Epocrates is that we literally put ourselves in the palm of their hand,” said Dr. Freda Lewis Hall, chief medical officer at Pfizer."

By the way, what was Epocrates' CEO Rosemary A. Crane's last job before she took over the firm? Oh yes--she worked for 26 years as a Pharma executive (Johnson & Johnson, Bristol-Myers Squibb).

Docs love Epocrates because its smartphone app is free. What else is available? "UpToDate, from Wolters Kluwer Health, has a Web-based disease reference guide that, it emphasizes, does not accept money from pharmaceutical companies. But UpToDate costs $395 to $495 a year, and its first iPhone app just became available on Monday."

There you have it. The drug companies have recently been cutting back on their drug rep sales force, both to reduce costs as fewer brand name blockbusters remain on the market, but also because they see a greater marketing advantage in Internet and electronic approaches to practitioners--like Epocrates. Epocrates seems to be talking out of both sides of its mouth when it comes to who it works for--the docs or the drug industry. Which side is winning? Well, who's paying the piper?

How long are we in medicine going to keep thinking we can get goodies for free and yet we won't be biased and that the real goal is education, not marketing? And just who's in the palm of whose hand?

SLAPP and Stem Cell Clinics

2011-07-22T16:39:00.001-07:00

For this item I'm indebted to my distinguished bioethicist colleague Art Caplan:
http://www.msnbc.msn.com/id/43760409/ns/health-health_care/

In HOOKED I discussed how Pharma had occasionally made use of SLAPP, or "strategic lawsuit(s) against public participation." The basic idea behind SLAPP is that there are two parties to a dispute, one with a lot of power and money, the other with little of either. The weaker party has a legitimate gripe against the stronger. If it actually went to court, the weaker party would almost surely prevail. The stronger party then pre-emptively files, or threatens to file, a lawsuit against the other, knowing that while the suit is a sure loser in the long run the weaker party would be bankrupted by the legal fees required to defend itself. The stronger party then says it will make nice and drop the suit, so long as the weaker party agrees to be quiet and not get in the way of the stronger party's plans. Ideally the SLAPP has two outcomes. First, the party that is actually creating trouble for the stronger party's plans will go away. Second, other potential critics who might be waiting in the wings will be silenced out of fear of a similar action being taken against them.

Caplan tells us how commercial stem cell clinics, many located outside of US jurisdiction and taking full advantage of lax oversight, are promising totally unproven cures. The International Society for Stem Cell Research, a group of scientists, has been worried about these practices and initially responded by posting on its website a list of the available body of evidence to show what is known about what stem cells have so far been proven to do (thus far, very little). But that part of their website came down when a group of clinic operators threatened them with an expensive lawsuit, far beyond the budget capabilities of the scientific nonprofit organization.

Just a small comment about what happens when commercial interests take over medical care...

Kid Gloves on Corporate Crime: A Different View

2011-07-18T17:02:00.000-07:00

The following post takes off on Roy Poses' post on Health Care Renewal:
http://hcrenewal.blogspot.com/2011/07/case-of-bleeding-heart-prosecutors-how.html
--which in turn is heavily based on a New York Times account by Gretchen Morgenson and Louise Story:
http://www.nytimes.com/2011/07/08/business/in-shift-federal-prosecutors-are-lenient-as-companies-break-the-law.html

As I've demonstrated many times, Roy and I almost always have the same general take on an issue, albeit me more with a focus on Pharma and Roy on the corporatization of health care more generally. Here I find myself differing from Roy's analysis. So rather than simply appending a comment to his blogsite, I will take advantage of my own bully pulpit to make several points that seem to me pertinent.

First, the brief summary, though I recommend both of the above links to get the full picture. The U.S. Justice Dept. is said to be going soft on corporate wrongdoing, in terms of criminal prosecutions of corporate execs. They are increasingly using a tool called "deferred prosecution agreements," which advocates say gives them a bigger bang for the buck, getting companies to investigate themselves and to clean up their acts quicker than would be the case in a prolonged legal fight. Critics say that this is a form of mollycoddling white collar criminals and note that since the Great Recession, hardly any Wall Street execs have faced legal penalties.

Roy has for some time been harping on the need for CEOs to actually suffer consequences if the current wave of corporate wrongdoing is to stop. And he has a lot of ammunition in terms of the various corporate settlements we've reviewed here at nauseam, where a drug company can simply break the law so long as it has a blockbuster drug that brings in lots of cash--allowing it to set aside a big legal payout as simply a cost of doing business, after which it goes back on its merry, illegal way.

But I believe that Roy misses a deeper message in the NYT article. He says in his post that the new, softer policy was adopted by DOJ "for reasons that were not explained." But the real reasons seem to be staring us in the face in several places in the Times story. For instance:

Still, some lawyers applaud the closer relationship between the government and business. “Given the scanty resources that have been committed to corporate crime enforcement, I think the government’s leveraging of its prosecution power from corporations and their lawyers has been critically important,” said Daniel C. Richman, professor of law at Columbia and a former assistant United States attorney in New York.

But Professor Richman added that the government should have “a much more developed, funded and empowered S.E.C., Federal Reserve, E.P.A. and other agencies to do regulation, to do enforcement and feed cases where necessary to criminal prosecutors.”

Here, I think, is the answer. We've just had more then three decades of so-called leadership where Republicans and Democrats have vied with each other in their eagerness to "shrink big government." Just as we've seen here before that the FDA doesn't have enough inspectors to be sure that drug ingredients imported from China are safe, the Feds apparently lack the investigators to police corporate wrongdoing. The "deferred prosecution agreements" essentially outsource the Federal investigation--the company has to hire a big law firm to find out what it did wrong and then come up with a supposed promise-to-be-good-in-the-future plan. And as the critics note, the corporation is much more likely to resort of this strategy, and to be frank about what the problem is, when some underlings can he hung out to dry, and not when the criminality resides in the executive suite. But what can DOJ or SEC do when they simply have to few trained staff to run their own investigations, with real teeth?

This leads to an announcement I hope to be able to make soon about a new book that I have been working on for some time. It's about US policy, and not about pharmaceuticals, so I plan to take little space here to talk about it. But I have been spending time studying the origins and nature of a belief system that I think is most appropriately called economism. Economism is the belief in the all-powerful "free market," and the prescription that every problem in human life can be solved through the market, and that the only appropriate role of government in the market is to get out of the way and let it be "free." But economism is internally self-contradictory and so always ends up talking out of both sides of its mouth. In the case of "big government," economism desires half-powerful and half-powerless government. The powerless half is the part that could stand in the way of corporate profits--like too many DOJ or SEC investigators. But economism simultaneously desires all-powerful government when it comes to those aspects of government that can be tied to its own pursuit of wealth, and can secure monopoly privileges for those corporations now at the top of the heap. So, for example, making sure that Pharma continues to get huge tax breaks, and that the US government remains vigilant to protect its "intellectual property" so that no Indian generic firm can make AIDS drugs to sell in Africa at an affordable price, is a type of "big government" you never hear economism's boosters objecting to.

So, if I could wave my magic wand and make the corporations and the wealthy pay their fair share of taxes, and then we'd have enough government gumshoes to bring the corporate wrongdoers to justice, would I then be in favor of unleashing them mercilessly on the industry? Well, not exactly, which is my next-to-last point for this overly long post. I was quite persuaded when I wrote HOOKED by the Australian sociologist, John Braithewaite, who back in 1984 wrote an interesting and prescient book, Corporate Crime in the Pharmaceutical Industry. Braithewaite was an advocate of turning where possible to a cooperative rather than a big-stick approach to corporate wrongdoing, arguing that each corporation contains within it people who want to see the right thing done, that those folks are often better placed as insiders to see what is really going on, and that finding ways to form alliances with those people might actually pay off better in the long run in terms of responsible corporate behavior and safe and effective drugs. Braithewaite was a firm believer that sometimes you had to hit the proverbial mule over the head with the 2x4 to get its attention, and so he argued that focused prosecutions were a very good tool to use along the way. But he also argued that a policy simply of "throw the rascals in jail" was not the way to get what we want either. So I can see an argument for some balance here despite the fact that the situation as described by Morgenson and Story sounds way out of kilter on the mollycoddling side.

Final point: back to economism again. One of the main tools for economism's advocates in the last three decades or so has been the concept of "moral hazard." According to this so-called economic theory, you should never help the poor, because if you help them you reward their behavior, and that makes them just do whatever made them poor in the first place more often. But again economism talks out of both sides of its mouth, and here proves a point wittily made some time back by J.K. Galbraith: "The poor don't work hard enough because they're paid too much, and the rich don't work hard enough because they're not paid enough." (Quote courtesy Steve Keene, Debunking Economics, Zed Books, 2001.) In other words, so long as we are talking about the poor, then "moral hazard" is a universal law of human pychology, but economism changes its tune abruptly when we are talking about the rich. If the poor commit a crime, we lock them up for life under a 3-strikes law. But if the rich commit a crime, then we talk about deferred prosecution agreements.

Backpedalling in Maine

2011-07-15T10:04:00.000-07:00

It's sad to read the latest news from Maine, thanks to our friends over at PostScript:
http://postscript.communitycatalyst.org/?p=2939

Here's what journalists call the "lede" from Kate Petersen's interview with Democratic state Rep. Sharon Treat: "The new Republican governor and majority in the Maine Legislature have together now repealed not only the state’s gift disclosure law, but nearly every progressive prescription drug policy we have, including our pharmacy benefit manager (PBM) law, and pricing transparency. This is not surprising as there are very close ties between the pharmaceutical industry and the Republican party in Maine. None of these laws were easy to pass in the legislature even when Democrats had the majority, because the drug industry is very powerful when it comes to influencing politicians."

The Sky Is Falling--What if New Drugs Actually Had to Add Value?

2011-07-13T14:39:00.000-07:00

John C. Lechleiter, CEO of Eli Lilly, warns us in a Wall Street Journal op-ed (subscription required) of a truly terrible fate that might befall the U.S., if only American policymakers are so misguided as to follow the example now being set in Germany.

And just what are those terrible Germans doing? I hope you're sitting down when you hear this. They seem to have an effective system in place to require that new drugs do something of value before they'll pay for them.

According to Mr. Lechleiter, you can kiss drug innovation goodbye if this thing were to happen in the US. The scenario that he depicts is a bit hard to follow but let me see if I can hit the high points. First, he makes a claim that most regular readers of this blog will find hard to swallow--"Contrary to myth, so-called blockbuster medicines are not the result of slick marketing campaigns but of demonstrated success in the actual practice of medicine." For a different perspective see: http://brodyhooked.blogspot.com/2011/01/inverse-benefit-law-making-sense-of-how.html But for now, let that pass. The next step in the reasoning is that a drug may be a really fine drug but you cannot tell that when the drug is first introduced; it is only with extended clinical experience that you can see how really fine it is. Now, this reasoning runs contrary to what John Ioannidis has cogently argued: http://brodyhooked.blogspot.com/2011/03/how-honest-reports-of-research-can.html (showing mathematical reasons why the early reports of a drug's efficacy almost always overestimate its benefits compared to later data). So now we come to Mr. Lechleiter's grand conclusion, which is that if we did what the Germans are doing, then promising and powerful new drugs will get nixed right out of the starting gate and will never show us their real potential.

So the reasoning about the future public being robbed of valuable drug advances turns out to rest on some pretty shaky premises. Plus Mr. Lechleither--as typically occurs with those who try to market drugs-- seems to focus solely on efficacy and to dismiss concerns about safety. I'm grateful to my colleague Don Light, author of The Risks of Prescription Drugs that's mentioned in one of the above posts, for recently calling my attention to some published work by Mary Olson on the relationship between quicker FDA approval and greater risk of later adverse reactions (which I may detail in a later post). Olson has actually calculated an increase in the hospitalization and death rates due to adverse drug reactions for each so many months that the FDA approval time is shortened.

In sum--Mr. Lechleiter is upset that a careful pre-marketing vetting of new drugs will stifle valuable innovation. This fear seems to ignore two things. First, if we demand that drugs prove their mettle first, and then agree to pay for them, it is unlikely that we'll keep very many useful new drugs off the market, but we can save a ton of money on not-very-useful drugs. Second, if we took longer before we allowed new drugs to be marketed, evidence available today suggests that the safety factor would be enhanced. It is quite possible (see Don Light's book) that more lives are lost today in the US due to adverse reactions to prescription drugs than are saved by truly lifesaving new drugs (which are reliably estimated to be a tiny fraction of all new drug approvals).

Now we come to what may seem a gratuitous ad hominem attack--but I am sorry, if somebody treats me as if he thinks I am a complete idiot, then I am likely to get my back up. Mr. Lechleiter spends most of his article decrying the terrible model provided by Germany and hoping that the US will never follow that lead. (Don't worry, Pharma is spending every lobbying buck they can lay their hands on to make dead sure of that.) Then at the end he has the nerve to say: "We share Berlin's goals of generating value and limiting unnecessary costs in health care. We see ways of harnessing and improving health-outcomes research."

Come again? You have just trashed Germany's system precisely because they do certain things, and apparently very effectively--and then you have the gall to tell us you share the same goals? And this is supposed to make the pharmaceutical industry trustworthy brokers in our eyes?

Lechleiter JC. An ObamaCare drug preview in Germany. Wall Street Journal, July8, 2011, A13.

The Drug Pipeline--Not So Dry?

2011-07-12T16:30:00.001-07:00

Keeping up with today's theme, which is what's happening over in the pharmaceutical industry these days, an encouraging article comes from Jonathan Rockoff and Ron Winslow in the Wall Street Journal (subscription required). The article raises an interesting possibility--that despite all that I don't know about the science of drug discovery, I may actually have been right in HOOKED when I charged the industry with pursuing a dysfunctional model of R&D.

First the good news--20 medicines deemed truly innovative (though not necessarily shown yet to be better than existing medicines) have been approved by the FDA so far this year, compared to only 21 all last year. A Credit Suisse analyst predicts that in the next 3 years, more than 20 innovative drugs that will be good enough to earn blockbuster sums ($1B annually or more) are likely to see approval. Two recent breakthrough drugs for advanced melanoma, two new drugs for hepatitis C, and the first new drug for lupus in half a century are given as examples of recent advances.

Why? Rockoff and Winslow say that Pharma has wised up and realized you cannot make useful new drugs by a science assembly-line approach--the model I derided in HOOKED. You actually have to understand the mechanism of the disease. Hence a new era of partnering with university scientists and small biotech startups. (It also works financially because the big brand-name company can let the small firm assume all the risk, and then come in later and scoop up the drug if it seems promising. For one of the new melanoma drugs, ipilimumab, Bristol-Myers paid a biotech firm, Medarex, about $250M when doing the same drug discovery process totally in-house could have cost it $1B.)

The reporters also state that the more cost-conscious, generic-friendly environment works against the so-called drug discovery model that made profits in the past few decades--just tweak an existing molecule and make a me-too drug like The New Purple Pill. So companies are actually today trying to find diseases that don't already have a good treatment, and look for one. They count on the fact that while insurers in the future may not pay for the next Purple Pill, they will probably pay for the only drug that treats a deadly disease, even if it's priced very high. (Bristol-Myers intends to sock it to patients or their insurers to the tune of $120,000 for a full course of ipilimumab, which they will make pronouncible with the brand name Yervoy. How much they intend to make is shown by the fact that they purchased full control of Medarex for $2.1B.)

The news in this article, if accurate, is hardly the end of all that has been wrong with the drug industry that promotes a lack of professionalism on the side of medicine, and that hurts the public health in the name of profits. But it may be a sign that at least one aspect of the industry is moving in a direction that may actually help future patients, and that may gradually return the industry to an ethic of promoting health more than relying on slick marketing.

Rockoff JD, Winslow R. Drug makers refill parched pipelines. Wall Street Journal, July 11, 2011, A1.

What's Pharma Up To? Profits vs. Safety

2011-07-12T11:09:00.000-07:00

A couple of news items these past couple of days reveal what the drug industry is up to--and what it isn't. (A reminder for newcomers--this blog is not about industry-bashing, it's mostly about medical-profession-bashing, arguing that many of the ethical problems at the interface between medicine and the pharmaceutical industry could best be resolved by a higher level of professionalism, and less greed, on medicine's part. But every once in a while we need to take a look on the other side of the fence to see what's going on there.)

First we see from the LA Times--
http://www.latimes.com/health/sc-dc-0709-debt-pharma-20110709,0,1832507.story
--how the industry is busy pulling out all the lobbying stops to make sure that any budget deal that passes Congress will not put a crimp in their profits. Some folks in Congress who want results and not political posturing have noted that demanding what seem to be reasonable discounts for government health care programs, for escalating drug costs, could save $112B over the next decade. The industry wants to put a quick stop to any such talk. So far, it's working.

The next question is what the industry is doing with its profits. Apparently, not assuring drug safety, according to a report recently released by the Pew Health Group and kindly summarized by our friends at PostScript:
http://postscript.communitycatalyst.org/?=2922
Basic bottom line is that a bunch of people died from contaminated Heparin a few years back, traced to shoddy ingredients from a Chinese factory. Since then everything has gotten worse--40 percent of all finished drug products, and 80 percent of the ingredients used to make drugs for the US market, now come from overseas, yet the industry's ability to trace the origins of those ingredients, and the FDA's ability to inspect the plants that make them, remain virtually nonexistent. You'd expect Congress to be indifferent when people in other countries die because of bad drugs, yet to sit up and take notice when some Americans die. Apparently that wake up call didn't happen. Certainly, left unregulated, the industry has no intention of changing present practices. As the Community Catalyst group that worked with Pew reported with a quote from a major brand name drug firm, it's all about how cheaply one can make the product.

Outsourcing Trials: An Ethics Vacuum?

2011-07-11T11:53:00.000-07:00

A report from the 7th World Congress of Science Journalists, courtesy The Guardian in the UK--
http://www.guardian.co.uk/global-development/2011/jul/04/ethics-left-behing-drug-trials-developing
--raises a specter that we've addressed previously, that by moving clinical trials to developing nations, the pharmaceutical industry is making use of a setting in which protection of human research subjects may not be as stringent.

The developing-world advantages for the contract research organizations (CROs) that run these trials for Pharma are first, lower costs, and second, readier availability of subjects who are not already taking a bunch of meds.

The article states, " 'Less stringent ethical review, anticipated under-reporting of side effects, and the lower risk of litigation make carrying out research in the developing world less demanding,' said Ames Dhai, director of the Steve Biko Centre for Bioethics at the University of Witwatersrand, South Africa.

"While many countries have set ethical standards for clinical trials, this is not a guarantee they will be respected by those who perform the trials. 'The problem is implementing these [ethical] guidelines and the imperialistic attitude of researchers and sponsors who come to the country and frequently disregard our process,' Dhai added."

The article goes on to mention both South Africa and India as two research settings in which subject abuse can readily occur.

PS: Before we go tsk-tsking about the low ethical standards in other countries, we also have to ask if US institutions are up to the task of protecting subjects-- for example, http://brodyhooked.blogspot.com/2010/08/continuing-our-all-carl-elliott-issue.html

Taking Professionalism Seriously: The Editors of The Spine Journal

2011-06-29T08:35:00.000-07:00

"Scathing" was the way that Kerry Sheridan of AFP:
http://news.yahoo.com/us-bone-growth-studies-under-fire-alleged-bias-222210731.html
--described the editorial that's just now appearing in The Spine Journal, authored by a number orthopedists plus Dr. David J. Rothman of Columbia. (Note: The article is apparently to appear in the June issue of the journal which seems not yet to be up on the journal's website. One needs a subscription to access the site.)

Necessary background--this brings us back to our old friends the device company Medtronic (see most recently http://brodyhooked.blogspot.com/2010/12/in-defense-of-paranoia-suspecting.html). In previous posts I discussed in very general terms the fact that this firm sells "hardware" for spinal fusion surgery and has been implicated in a number of shady practices that have been exposed by John Fauber at the Milwaukee Journal-Sentinel, among others, and also earned them the close interest of Sen. Charles Grassley's subcommittee. I have not as yet focused on a specific product called Infuse (or generically, rhBMP-2). This chemical is a bone growth factor that is applied to bone to make new bone grow. It is supposed to be enclosed in a little cage so that it causes the bone to grow only where the surgeon wants it to. The big advantage is to cause new bone to grow, for example to fuse two vertebrae togerther, instead of having to make a separate incision and take a bone graft from another site (like the hip) for the same purpose.

The authors of this editorial begin by noting a series of 7 published reports (one of which was published in their own journal) about Infuse, all by authors with significant financial ties to the manufacturer--they state that one trial in particular apparently paid its investigators a cool $26M. These reports are quite remarkable in one way--not a single adverse reaction is attributed to the product. Think of that. Ever heard of anything in medicine that never, ever, produces even one adverse reaction?

Not surprisingly, as soon as articles began to be published by those not in the pay of Medtronic, toxic effects began to be reported--the short list includes inflammatory reactions, persistent pain, inability to urinate, inappropriate abnormal bone growth, and displacement of the implanted apparatus. The major systematic review published in the same issue of the journal estimated that actual complications and adverse events "are perhaps 10 to 50 times the original estimates calculated from industry-sponsored studies" by the FDA.

The editors now face squarely the implications for their own practices. They allude to what they call the "choirboy defense" that all physicians are of stellar integrity, potential conflicts of interest are only potential, etc. This defense, they conclude, won't pass muster, either inside or outside of medicine. Add to this is the problem that "disclosures in our journals are more often than not self-contradictory blurbs of improbable nonsequiturs bracketed by misdirection." They use as an example a published disclosure statement which is actually a denial rather than a disclosure, stating both that the manuscript is not about medical devices or drugs, and that "no benefits in any form have been or will be received from a commercial party." The editors then state, "Even a most cursory review shows that this was all about devices and drugs used in an off-label manner and reported by authors who, by conservative estimates, have tens of millions of dollars of financial association with the sponsor."

The editors conclude, "The core of our professional faith...is to first do not harm. It harms patients to have biased and corrupted research published." Saying "We all must do a better job going forward," they promise a series of later changes to be announced to improve their editorial policies.

Comment: First, kudos to the editors of The Spine Journal for so frankly throwing down the gauntlet for themselves. Second, I am not a business ethicist, but I have to borrow a note from my old friend Leonard Weber in his nice book about the pharmaceutical industry, Profits Before People? I believe that Professor Weber would ask--how can it possibly benefit Medtronic to run its business in this fashion? How could any business plan, other than the most cynical short-term stockholder gain (maybe with the CEO exiting via the famous golden parachute), include exposing one's firm to this barrage of apparently-fully-justified criticism and condemnation? Or has the idea of "in the long run" so totally ceased to function in American culture?

Carragee EJ, Ghanayem AJ, Weiner BK, et al. A challenge to integrity in prine publications: years of living dangerously with the promotion fo bone growth factors [editorial]. Spine Journal 11:463-68, 2011.

Lightning Strikes: AMA Adopts Strong Statement on Commercial CME

2011-06-25T06:54:00.001-07:00

According to our friend Dr. Danny Carlat (as passed along by PostScript):
http://carlatpsychiatry.blogspot.com/2011/06/ama-votes-to-discourage-commercial.html
--an unprecedented event occurred on June 20 in Chicago at the meeting of the AMA's House of Delegates. A bit of background to explain this (unfortunately, background not fully provided in previous blog posts here).

For a number of years the Council on Ethical and Judicial Affairs (CEJA) at the AMA has been proposing new opinions on the ethics of the relationship between physicians and the drug industry, along the lines of the reforms advocated in this blog. The existing AMA opinion on the topic is, in my own view, quite wimpy and offers all sorts of loopholes to excuse docs taking bennies from the drug industry. You can read it here:
http://www.ama-assn.org/ama/pub/physician-resources/medical-ethics/code-medical-ethics/opinion8061.page?
That opinion dates from 1992. Several times in recent years, CEJA has offered revised and updated opinions that come down more strictly on policing the conflict of interest inherent in docs accepting gifts/bribes from Pharma. Each time the report was sent to the House of Delegates, and each time the HOD slapped it down and sent it back to CEJA for rewriting. This is a perennial problem in the AMA--in this sense the HOD is too democratic. It seems that if CEJA tries to say something is ethically improper, and if any significant number of Delegates currently do it, the question shifts from the reasonableness of the ethical principle to "how dare my AMA tell me that I'm unethical!" So it can become an ethical race to the bottom instead of aspiring to higher levels of professionalism. (PS: Since the AMA seems to employ a webcrawler to alert them to any mention of their organization on the Internet, you can expect a comment to appear below from the AMA president, in about 3.6 seconds, informing us that what I just said is unfair and not representative of the AMA's good works. For previous comment like that see:
http://brodyhooked.blogspot.com/2011/04/supremes-to-hear-challenge-to-vermont.html)

In a similar vein, CEJA proposed back in 2009 a report specifically on commercial sponsorship of continuing medical education programs:
http://brodyhooked.blogspot.com/2009/06/ama-council-cuts-cme-baby-in-half.html
--which the HOD rejected, presumably on a matter of technical language. But some inferred from the HOD action that really, the organization was not all that interested in ending the commercial sponsorship gravy train, that currently keeps many state medical society meetings (for example) afloat financially.

So when CEJA came back with a revised CME report, this time really strict on cutting the financial ties with industry, I would have guessed it would get the same frosty reception from tghe HOD. To my surprise Dr. Carlat tells us that the new report actually passed and has become official AMA policy. Not only that, but because of the relationship betweeen the AMA and the Accredition Council for Continuing Medical Education, the national group that certifies CME programs for official credit-granting status, this change immediately impacts ACCME policy as well. The CEJA opinion (see link on Dr. Carlat's blog) cites particularly the recent Institute of Medicine report on conflicts of interest that similarly proposed elimination of commercial funding for CME, as we reviewed:
http://brodyhooked.blogspot.com/2009/05/iom-report-on-coi-yes-we-really-mean-it.html

Dr. Carlat adds some notes of caution, in that the report does allow for some commercial sponsorship to continue. The exceptional case they seem to contemplate is when a new medical device is introduced, which is very expensive, and the only people who really know how to train docs in its use are the employees and consultants of the company that manufactured it. They give a number of reasonable precautions to keep commercial sponsorship limited to these unusual types of situations, and also to further mitigate the biasing effects of that sponsorship even when it is allowed. In short, I think Danny Carlat is right to call this a very significant breakthrough from an unexpected quarter.

Supreme Court Strikes Down Vermont Anti-Data-Mining Law

2011-06-24T18:39:00.000-07:00

Well, I sort of called it: http://brodyhooked.blogspot.com/2011/04/supremes-to-hear-challenge-to-vermont.html I said it was a foregone conclusion that the US Supreme Court would side with IMS Health and the pharmaceutical industry against the state of Vermont, and rule against its anti-data-mining law. (See previous post for background.) But I did not bargain on the sweeping nature that some observers have attributed to this ruling. NPR, for example--http://www.npr.org/2011/06/23/137376149/top-court-rules-in-favor-of-drug-companies-in-two-cases
--suggested that two legal challenges are sure to follow. Drug firms will attack the FDA's power to make them desist from marketing off-label uses; and the tobacco industry will fight the new "scare labels" being proposed for cigarettes. On the other hand, law professor Kevin Outterson:
http://theincidentaleconomist.com/wordpress/sorrell-v-ims-health-6-3-for-the-companies
--argues that Vermont can revise its statute rather easily to meet the constitutional requirements set down by the majority ruling, and that indeed that ruling is a sort of recipe for how the statute might be modified.

As a nonlawyer reading the Supreme Court opinion, I was struck by the very different logics applied by the majority and the dissenters. (By the way, in my prediction, I foresaw a 5-4 vote, but the actual vote was 6-3, with Justice Sotomayor going over to the conservative side--so much for "liberal" justices.)

The majority opinion, written by Justice Kennedy, starts with the now-widely argued position that "commercial speech" is nearly as well respected as a First Amendment right as is any other form of speech. The question then is whether the Vermont law is written narrowly enough, and cites a sufficiently compelling state interest, to justify its interferences with commercial speech. (Which in the old days we used to call "advertising.")

Based on the fact that pharmaceutical marketers find the prescriber data sold by the respondent, IMS Health, to be sufficiently worthwhile to pay big bucks for, the majority hold that drug detailing is commercial speech, and that the Vermont statute burdens this commercial speech (by interfering with the data mining that makes the speech more effective). It is at this point that the majority get their knickers in a knot, because the Vermont law would allow the selling of prescriber-identifying data for other purposes, such as public health monitoring or research. The offense here, in the view of the court majority, is that Vermont will allow speech when it likes the message, and disallow speech when it does not like the message (that is, when the speech favors prescribing high-price drugs). This seems too much like censorship and raises all the First-Amendment hackles of the justices.

An example Justice Kennedy offers seems to hint at what most offended the majority. They note that in Pennsylvania, this same sort of prescriber information was used by a state agency engaged in counter-detailing--that is, going to doctors with a message about prescribing cheaper generic drugs. This usage of the data would also be allowed by the Vermont law (though as Justice Breyer wrote in his dissent, there's no evidence that any such counter-detailing is actually going on in Vermont). So we have a situation where the use of a type of information is prohibited by law when the drug companies wish to sell their products, and is allowed by law when somebody wants to come to docs with a message not to prescribe the drug company's products. This seems to the majority to be so unfair on its face that the law is proclaimed to be unconstitutional. As typically occurs in legal decisions that by the merest chance end up serving the interests of powerful corporations, the relative power and economic muscle of the two parties being discussed here does not enter into the equation at all.

Speaking for the three dissenting justices, Justice Breyer offers a contrary view which seems to have the virtue of logic and good sense on its side--but that's probably just me. Breyer asks: exactly what is it about the Vermont law that interferes with drug companies getting their marketing message out? They can print ads, advertise on TV, hold dinners to push their drugs, and send as many detailers to docs' offices as often as they wish. All the law says is that companies cannot sell a type of data that makes these marketing efforts especially effective. Basically Breyer is saying that the whole framing of the issue by the majority, as interference with speech (commercial or otherwise) is bogus. He goes on to say that the stated goals of the law--improving public health, reducing health costs, and protecting doctor privacy--are fully sufficient to justify the law, and that there is no narrower way to write the law that would properly protect these legitimate state interests.

The majority objected to the Vermont law because its restrictions were "content-based" and "speaker-based." That is, the law censors speech based on who says it and on what it says, which violates First Amendment protections. But Justice Breyer replies that what we have here is commercial activity, and the right of the state to regulate commercial activity, which no one (openly) disputes. And any regulation of commercial activity must by its very nature be content- and speaker-based. For example, the FDA is allowed by law only to regulate drug companies and similar firms, and only to regulate marketing about drugs. Well, duh.

So in my biased view, the logic is all on the side of the dissent and not the majority. But I would lose an opportunity to repeat the basic message that runs throughout this blog if I did not fully agree with one argument made by Justice Kennedy: "Physicians can, and often do, simply decline to meet with detailers... Doctors who wish to forgo detailing altogether are free to give 'No Solicitation' or 'No Detailing' instructions to their office managers or to receptionists....If pharmaceutical marketing affects treatment decisions, it does so because doctors find it persuasive."

In other words, if physicians behaved like professionals instead of industry patsies, then Vermont would not need any such law. If physicians tomorrow refused to see detailers, then IMS Health would go out of business, at least so far as its business involved data-mining.

Supreme Court of the U.S., Sorrell v. IMS Health, decided June 23, 2011, no. 10-779.

Old Pharma Wine in New Democrat Bottles

2011-06-22T10:21:00.000-07:00

Sebastian Jones over at the Washington Monthly--
http://www.washingtonmonthly.com/magazine/julyaugust_2011/features/friends_like_these030379.php
--tells us the background on the New Democrat Coalition, a group of 42 House members who are poised to give the Obama administration major headaches.

A brief digression--a fight is brewing in Washington that in many ways is all about the future of health care cost containment in the US, whether or not "Obamacare" goes forward or is shot down in flames. The fight, which is getting much less media attention than it deserves (except for demogoguery about "death panels"), addresses Medicare's proposed Independent Payment Advisory Board (IPAB). The health reform law calls for a 15-member appointed board, made up of medical experts, to recommend to Congress how Medicare can cut costs. The goal was to re-0create for health care the Pentagon's base-closure commission, that managed to create a rational system to replace the old district-by-district Congressional bickering.

When Obama was challenged with the Ryan Plan from the House GOP, claiming to do a better job of Medicare cost-cutting (a claim later shown to be mostly smoke and mirrors), he responded with his own proposal to strengthen the role of IPAB.

Time out for a health policy announcement. If you are like any of my health-policy-wonk friends, you realize that there are basically two ways to trim Medicare costs. One is the IPAB way--try to decide on a scientific basis what works and what does not, and selectively eliminate payments for what doesn't work. Best estimate today is that if we fully implemented such a scheme we could save 20-30% of Medicare costs. The other way is the usual Congressional way--wait till a last-minute crisis, then impose an emergency across-the-board cut of so many percentage points, and don't worry if useful care gets eliminated alongside useless "care."

The predictable response of the GOP has been to denounce the IPAB as unelected bureaucrats who want to kill Grandma. But what has thrown the media for a loop (when they pay attention at all) is the group of Democratic congresspeople who have joined in GOP calls to repeal IPAB.

Jones tells us just who these "New Democrats" are--they basically have sold themselves to two major interest groups, the financial services and the health care lobbies. Their buzzword is "innovation," and they oppose meassures that are said to stifle innovation--but by the merest coincidence, what they oppose is regulations that would cut into the profits of their corporate handlers. And according to Jones, guess who's heavily investing in these House members from the industry side--Big Pharma leading the pack. Every deep-pockets interest group that now sells a lot of stuff which would not stand muster if Medicare monies were spent in accord with the best scientific evidence are lining up to try to kill IPAB, and the New Democrats are scarfing up the campaign cash.

Jones goes on to tell us how the media get suckered by people like the New Democrats because they've drunk the same Kool-Aid that Obama has, and go into raptures over anything that even vaguely looks bipartisan. But what is really bipartisan over the fact that special interest groups have bought a small bunch of Democrats retail, in the same fashion that they've bought the Republicans wholesale?

Finally, Jones reviews several political scenarios for future votes on IPAB and issues this dire prediction: "It’s hard to imagine, then, that the New Democrats will be able to repeal IPAB before the 2012 election. But, by joining with Republicans in the attempt, they may well succeed in turning Medicare from a winning issue for Democrats into a losing one." And, if that happens, look for boom times for Pharma, device companies, hospitals, and procedural subspecialists, while Medicare costs continue to bankrupt the nation (http://brodyhooked.blogspot.com/2011/06/cut-health-costs-not-in-us-of-thank-you.html).

Drug Industry Buying Up Academic Research Partnerships

2011-06-22T09:44:00.000-07:00

Heidi Ledford in Nature--
http://www.nature.com/news/2011/110622/full/474433a.html
--describes Pfizer's June 8 announcement that it was spending $100M on a research partnership with eight Boston area academic institutions, and adds that this is only one of a number of recently announced partnerships between drug firms and academic labs. (Yours truly is quoted briefly toward the end of the article.)

The article notes a number of important issues. In recent years, as described in HOOKED, the drug industry has been pulling research support out of the academic medical centers that used to do the lion's share of the late-stage clinical trials of new drugs, electing instead to go with commercial contract research oprganizations (CROs) that can do the job quicker and without academic-administrative red tape, especially if they can outsource the trial to less-developed nations where ethical oversight may be much looser. This more recent trend, however, is to link up even more tightly with academic centers for the earlier, molecule-discovery stages of drug development: "[T]hese relationships are becoming more important as the industry closes its research labs in response to falling profits." The loss of revenue due to the drying-out new drug pipeline (see for instance http://brodyhooked.blogspot.com/2011/04/why-pharmas-new-drug-pipeline-is-dry.html) has crimped the big firms' research budgets, it seems, and sent them looking for more partners in academe.

Now, as I made clear also in HOOKED, it is nothing new for academic labs to discover promising new molecules and drug mechanisms, then to have industry swoop down later and scoop up the findings for commercial development. So why does Pfizer want to put $100M up front instead of just sitting back and letting the scientists in Boston chug along as they always have? Both sides, it seems, have realized that the old system was suboptimal. Ledford quotes Mark Pepys, an investigator in London:

"Yet industry's need for secrecy, and its tendency to change its research focus abruptly, can conflict with the more open and stable academic environment. Pepys experienced this first-hand in the 1990s when the Swiss drug-maker Roche abruptly terminated its collaboration with his team. He faced a long and costly battle to retrieve the intellectual-property rights to a compound developed during the project. A little later, Roche agreed to work on the compound with him again, only to prematurely end the collaboration a second time. Once more, Pepys had to fight to continue his work. 'It was a very expensive and tedious process that has delayed the drug by about ten years,' he says. 'And the clock on the patent is ticking.'

"Nevertheless, Pepys notes that without Roche's help, he would not have been able to develop a compound that, he hopes, will soon be ready for clinical tests in people with Alzheimer's disease. 'Nobody except big pharma can make a medicine effectively,' he says."

From their side, industry has been frustrated with previous, hands-off deals with academe:
"Shiv Krishnan, a senior director at French drug-maker Sanofi's branch in Bridgewater, New Jersey, notes that Hoechst, a German life-sciences company that Sanofi acquired, paid $70 million in the 1980s to fund research at Massachusetts General Hospital. In the end, however, the firm had little to show for it, Krishnan says. 'And why?' he asks. 'Because it wasn't collaborative. It was: I'll send you the cheque and you let me know when you have something.'"

So how do the drug companies propose to fix all this? "Pfizer says it will set up a lab in Boston that will house about 50 researchers — half of them Pfizer employees, the rest Pfizer-funded postdocs from participating academic labs. The team will work on projects selected by an oversight board comprised of academics and Pfizer executives. ... The various deals also aim to smooth over tensions between industry and academia. Duncan Holmes, who heads GSK's Discovery Partnerships with Academia initiative, says that the company will give research partners a year's notice if it chooses to end a collaboration and that, if it that happens, academics would be free to continue with the project. To ease worries about publication restrictions, many agreements stipulate the terms for publication ahead of time."

As we have described at length in previous posts, research funding, per se, seems less corrupting than arrangements that put money directly into the pockets of investigators, like consulting and speakers' fees. Moreover, as Kenneth Kaitlin of the Tufts Center for the Study of Drug Development (heavily funded by industry) adds, the universities now have a stronger bargaining position due Pharma's financial stresses: "Earnings at these companies are falling through the floor and investors are losing confidence."

While I applaud the increased attention to issues that have led to loss of trust in the past, I still agree with Harvard sociologist Eric Campbell: "You should not in any way accept the notion that these giant institutional agreements are without tremendous danger." In general Ledford's piece describes most of the dangers accurately, but one could have used greater emphasis. If university labs start acting more like the drug companies' in-house research labs, we can be pretty sure what will happen to the scientist who's on the verge of discovering a new drug to treat malaria or African sleeping sickness. She'll be told to drop that project and work instead on something that grows hair on bald men, or eliminates wrinkles.

Old News, but Still Important: The Selling of Risperdal

2011-06-21T11:29:00.000-07:00

In the previous post I mentioned Kate Petersen at PostScript:
http://postscript.communitycatalyst.org/?p=2840
--who in turn cites Ed Silverman at Pharmalot:
http://www.pharmalot.com/2011/06/jj-risperdal-project-subverted-scientific-integrity/
--who in turn gives credit to--but I don't have all day, sorry.

Anyway, the short version. In 1995, Johnson & Johnson funded a project led by three prominent academic psychiatrists to write Schizophrenia Practice Guidelines. Things being pretty loosey goosey back then regarding conflicts of interest, no one really made any bones about these guidelines being a tool to market the drug Risperdal (risperidone). The academics freely consulted the J&J staff and shared drafts with them. J&J for this privilege paid a total of $515K to the three medical schools where these psychiatrists were based.

Now, how to get folks to read and follow these wonderful new guidelines? The three docs then proceeded to establish a firm called Expert Knowledge Systems. EKS was set up to take drug company money, use it to publicize and advocate for the new guuidelines, and incidentally to pay some cash to the three docs, now that they had their own organization and were no longer getting the grants through their medical schools. EKS ended up taking in more than $900K from J&J.

Still back around 1996-7, EKS launched an effort with the Texas Medication Algorithm Project to help them design a drug protocol to assist state Medicaid mental health programs in designing (presumably) cost-effective ways to treat their patients with drugs. Not surprisingly, the TMAP protocol, which was then heavily peddled to other states, ended up recommending Risperdal a good percentage of the time, over cheaper generic alternatives that have since been shown to be just as effective and perhaps safer.

As I discussed in HOOKED, in 2004, a former Pennsylvania state investigator (who was fired when he started raising inconvenient questions) blew the whistle on how TMAP was really a drug-selling scam. In 2006 the Texas attorney general joined this suit, which is scheduled finally to come to trial in November.

So why all the fuss here and now? Some of the documents related to this whole debacle are only now coming to light--what I said above comes from a report from David Rothman at Columbia prepared last October (see link in Pharmalot post), though the bulk of the relevant documents in this case remain sealed. One regularly encounters objections from Pharma when we accuse them of sleazy practices--this is all old news; this stuff happened in the 1990s for heaven's sake, of course we gave up doing those things years ago. And indeed that may be true. But here we come to my old refrain--just how would we know? When only now in 2011 are we starting to find out about stuff that happened back in 1996, on the basis of what sort of faith are we to accept the assertions that nothing like this happens today? Ed Silverman points out that if J&J settles the case pretrial, one result could be that the other documents will remain out of the public eye. And Kate Petersen focuses her analysis on whether today's more stringent conflict-of-interest rules would have prevented all this from happening, and concludes that it's iffy.

Finally, a footnote. One of the three academic psychiatrists who started that ball rolling in 1996 was Dr. Allen Frances, chair of psychiatry at Duke. We have encountered Dr. Frances in these pages before: http://brodyhooked.blogspot.com/2009/06/will-psychiatrys-dsm-v-be-huge-growth.html. In that post, about psychiatry's DSM-V controversy, Dr. Frances was on the side of the angels as I depicted him, criticizing the aspects of the new DSM-V from the vantage point of his own role as a chief architect of DSM-IV, and accusing DSM-V of being way too ready to add new, dubious psychiatric diagnoses which are almost sure to increase drug prescribing across the board. For his pains, Dr. Frances was immediately condemned by his peers at the American Psychiatric Association, and accused of being motivated by conflict of interest because he had authored a book that was based on DSM-IV. Back then I trusted the statements of people like Dr. Danny Carlat that Frances was the good guy in this dispute. Had I known about this older history, I would at least have seen the logic of suspecting that Dr. Frances might have been motivated by money in the stand that he took. Whether Dr. Frances is a reformed former offender who has now seen the light, and has come over to the right side, I will leave to my psychiatry colleagues to determine.

The Wisconsin Pain Initiative: Caught in the COI Trap

2011-06-21T10:45:00.000-07:00

One of the problems of being a so-called "ethicist" is that occasionally you stake out a position based on what you think are valid principles; and then somebody you agree with and whose work you admire turns out to have crossed the line you've drawn. Ethics, of course, requires that you show them no favoritism and condemn their behavior equally with those lower down your likeable list. But it can still be painful.

I have for many years been drawn to the arguments that the prescription use of opiate drugs for chronic, non-cancer pain needs to be liberalized. That is a hard case to make in our society for several reasons. One is that we live in a society that has so demonized addiction that anything about using opiates draws immediate resistance and condemnation. Another is that there is a lack of solid data, in large part because "pain" is not a disease. Most diseases have a National Institute of Health devoted to their study, but pain does not. For a long time it has been extremely hard to get research funds to really study how well opiates work for this sort of pain. We do know, however, that an incredible number of Americans say they have longstanding pain that is not being adequately treated--up to 75 million according to one survey cited by the AMA.

In HOOKED I commented on journalist Barry Meier's book, Pain Killer, about the epidemic of OxyContin abuse. Meier did a reasonable job of giving a balanced presentation of the legitimate medical uses vs. the abuses of opiates. But he came down appropriately hard on Purdue Pharma, OxyContin's manufacturer. More to my chagrin, as I admitted in HOOKED, he listed a number of national pain-management authorities whose work I had long admired, as having gotten substantial research funding from Purdue Pharma and other firms. One could make the excuse that if you wanted to do any sort of research on opiates, that might have been the only game in town, with Federal grants so hard to get. Still there was no question but that this financial tie cast a shadow on those who advocate more liberal use of opiates.

Now the other shoe has dropped. John Fauber, author of an important series of investigative pieces in the Milwaukee Journal-Sentinel, that we have previously cited several times, more recently targeted the University of Wisconsin Pain and Policy Studies Group, in an article from April that was just alluded to by Kate Petersen at PostScript:
http://www.jsonline.com/watchdog/watchdogreports/119130114.html

The Wisconsin group have been national leaders in the struggle to get physicians to prescribe opiates more freely for chronic pain, and to alter government policies to reassure physicians they will not face licensing or criminal actions for responsibly prescribing opiates for legitimate pain patients. Fauber targets two leaders of the UW group, Aaron Gilson and David Joranson. He documents that both have received finding from Purdue Pharma and other drug firms that goes beyond research support and even general program support, working as paid consultants and speakers. Documents that they contributed to on pain policies often did not acknowledge that financial tie. In short, the same old incestuous relationship we've seen with so many other academics in this blog.

Fauber tries to put all this in perspective by painting a picture of a society that is now suffering huge burdens from the abuse and diversion of prescription opiates, due to the misguided prescribing practices of doctors who use OxyContin and its cousins for headaches and back pain, when the medical literature provides no sound basis for such use--an epidemic of drug problems aided and abetted by the reports and articles published by the Wisconsin pain center. Now this is partly true--there is indeed a serious increase in the abuse of prescription opiates, and in to some degree thay have become more popular among some user populations than older drugs of abuse like heroin. (And there are some reports that the use of heroin is rising again now that Purdue Pharma has done what it should have done many years ago, and reformulated the OxyContin capsule so that it can no longer give the abuser a high by crushing it instead of swallowing it.) And it is true that some studies of the chronic use of opiates for long-term pain have not been as promising as people like me would have hoped. But it still seems to me that there are a lot of patients with severe, untreated or undertreated pain who could benefit from the use of opiates combined with other modalities in a carefully monitored program. And in today's climate where all we hear about in the media are "pill mills" and abuse, it's very hard to get physicians, especially in primary care, to consider such an approach.

So the people at the Wisconsin pain center have unfortunately cast an even deeper shadow over the cause they had hoped to advance, through their willingness to compromise themselves for cash. Even after we consider all the good reasons they may have thought they needed to take the Pharma dollars to get their work done, we see that in the end the risk of taint significantly outweighed whatever good they were able to do. And while you may feel the need to take research and program support funds just to be able to do your work, even that does not justify a personal enrichment relationship such as consulting and speaking.

Cut Health Costs? Not in the US of A, Thank You

2011-06-14T15:28:00.000-07:00

If you want to know the prospects of trimming out-of-control health costs in the US in our lifetimes, you can read the depressing forecast in three articles from the media, all noted in today's Kaiser Family Foundation health policy report.

First let's check out the good news:
http://www.minnpost.com/medcitynews/2011/06/13/29088/new_report_finds_health-care_market_awash_in_opportunity
--where we learn that there's huge opportunity for profit in the future of health care in America, according to a new report from PricewaterhouseCoopers (linked in the article). Tellingly, the article is titled, "The New Gold Rush." Several types of companies are poised to share the wealth, say the gurus. Some promise actually to help save money through innovative strategies for better management and information flow. But one of the four groups is called "retailers." The description: "Retailers prosper in high-volume, standardized markets with low margins. They use their deep customer relationships and ubiquitous access to serve new markets..."

Sound like anyone we know? Notice there's no mention among this group of any contribution to cost containment.

Now, you may ask, just why are "retailers" facing a New Gold Rush? And what's this about their "ubiquitous access"? For an illustration we next turn to Oregon:
http://www.oregonlive.com/health/index.ssf/2011/06/provision_to_curb_drug_costs_f.html

Nick Budnick at The Oregonian tells us about the failure of a legislative provision to try to trim $17M out of the total $240M savings the state needs to achieve in Medicaid. The proposal is consistent with a pile of scientific evidence we've reviewed in several posts here--the general equivalence of older, generic psychiatric medications to newer, more expensive meds.

Defenders of the provision note several things. Other states have developed formularies to cut costs through generic substitution and have achieved similar savings with no apparent downside. It's true that once a complicated patient is stabilized on a particular drug combo, most psychiatrists are leery of messing with success by then trying to switch drugs--so the provision called for exempting patients now on meds and applying only to new patients just starting.

But those sensible observations, and the solid science, could not hold sway against a determined drug industry lobby and their cronies. The industry contributed more than $300,000 to candidates for the state legislature; and to be sure that the so-called patient advocacy groups were on board, the industry also gave $23M to the National Alliance on Mental Illness between 2006 and 2008 (though the state NAMI chapter says it's independent and gets nowhere near that much money). Eventually defenders of the cost-saving provision figured this fight was not worth it and moved on. And this was in Oregon, generally considered one of the most progressive states in the nation.

And why does the public continue to play into the hands of the New Gold Rush gang, rather than insisting on sensible, science-based reforms? A clue is found in the third article:
http://blogs.ajc.com/jay-bookman-blog/2011/06/13/why-free-market-isnt-answer-to-health-care-costs/?cp=7

Here, Jay Bookman in a blog at the Atlanta Journal-Constitution notes that all the opposition to "Obamacare" relies on the ideology that the so-called "free market" will save money for Medicare a lot better than any government plan. So he trots out the data on how free-market systems compare to government run systems in the cost control area, and finds predictably, as any respectable health economist would tell you, that they do much worse.

One telling graph, showing that costs have risen much faster in private insurance than in Medicare between 1969 and 2009, is taken from economist Paul Krugman's blog. Bookman obviously fears a backlash here so he says carefully: "Some will no doubt attempt to discredit the above chart by noting that it originated with Paul Krugman, a Nobel-winning economist and a columnist with the New York Times. However, Krugman built the chart using publicly available and noncontroversial government data, referenced in the caption. If you have grounds to question the accuracy of that data, please do so. Otherwise, you’re attempting to sidestep the issue."

So guess what one of the first comments I saw below the posting said? "Get Real" commented, "You are right Jay; you should have stopped after the words Paul Krugman and the NYT…."

I gather that means that for "Get Real," and others of her/his ilk, the mere fact that something was said by Krugman, or even appeared in the NY Times, is sufficient grounds to dismiss it. When that is what passes for political discourse in the US, then none of the rest of the news we've reviewed here should be of any surprise.

When "Professional" Societies Become an Industry PR Apparatus

2011-06-13T15:57:00.000-07:00

I have delayed posting about this matter and as a result can simply point to several earlier posts by our various colleagues:
http://hcrenewal.blogspot.com/2011/05/medical-societies-paid-to-do-corporate.html
http://pogoblog.typepad.com/pogo/2011/05/another-doctor-bought-by-big-pharma.html
--as well as Alicia Mundy's report in the Wall Street Journal (subscription required):
http://online.wsj.com/article/SB10001424052702303654804576343753512740330.html

Short version: Sanofi-Aventis makes a drug called Lovenox (enoxaparin), given by injection. This drug is one of a class called "low-molecular-weight heparins." Heparin is a drug to prevent clotting (a so-called "blood thinner" which is a misnomer as it does not thin the blood) that also carries with it a number of problems, including a need to have its effect on the body closely monitored. Lovenox and its cousins can be given safely without that close monitoring, meaning that some conditions that used to require hospital stays now can be handled in an outpatient setting. Lovenox is one of the relatively small number of drugs that could legitimately be argued to have saved money, even though the drug itself is very expensive--if it keeps people out of the hospital and allows home treatment instead.

But all good things must come to an end, and in this case the good thing, for Sanofi-Aventis, is Lovenox's patent. The possibility of competition from cheaper generic drugs cutting into Lovenox's $4B in global sales had the usual effect on the company. Their response has been to launch a massive PR campaign aimed at the FDA, arguing that the data do not demonstrate the safety of the generic versions, raising the fear that patients might die if given cheaper drugs.

As Roy Poses noted in the Health Care Renewal post, a typical PR move in such circumstances is to play the "third-party tactic"-- send the company's message to the FDA but as if it was coming spontaneously from another party entirely, without any prompting from the firm. Now, enter the Senate Finance Committee, where drug industry foe Sen. Charles Grassley hangs out. The committee has issued a report naming two medical societies (Society of Hospital Medicine (SHM), North American Thrombosis Forum (NATF)) and Duke University prof Dr. Victor Tapson as accepting large payments from the company and then sending supposedly independent letters to the FDA challenging the safety of the generic drugs. Internal company memos clearly indicate that the company, at least, thought that it had a quid pro quo from these folks. Between 2007 and 2010, Sanofi-Aventis contributed more than $2.6M to SHM, $2.3M to NATF, and $260,000 to Dr. Tapson. Dr. Tapson was apparently a bargain for the company; he wrote multiple letters to the FDA. Paul Thacker at Project on Government Oversight reports that Dr. Tapson, in an e-mail to the Wall Street Journal, characterized the Senate Finance report as "very incorrect," but did not explain in what way. Thacker throws in as a bonus a copy of one of the letters Dr. Tapson wrote to the FDA (http://pogoarchives.org/m/ph/lovenox-senate-report/tapson-letter-duke-letterhead-20100528.pdf).

And of course in none of the communications from the above three parties was any mention made of receiving funding from Sanofi-Aventis. Earlier, before the Senate Finance report, leaders of one of the medical societies explicitly denied any relationship between the company funding and their letters to the FDA.

Beware Surrogate Endpoints: Yet More Evidence

2011-06-10T11:43:00.000-07:00

Thanks to my pals Rick Bukata and Jerry Hoffman over at Primary Care Medical Abstracts for telling me about this study (subscription required). A team from Naples, Italy led by Dr. Pierluigi Costanzo did a meta-analysis of 41 randomized trials, all of which allowed a comparison between carotid intima-media thickness (IMT) and cardiovascular outcomes.

Let's stop for a plain-English break. You can do a fairly simple, noninvasive ultrasound test and measure thickening in the wall of the carotid artery in the neck. This measure has for a long time been viewed as an aspect of atherosclerosis, or hardening of the arteries--and indeed, if you divide a large population into those with a lot of thickening and those with a little, the former group ends up showing more heart disease in the end. This has led investigators who want to test whether their drug or other treatment works to lower cholesterol and to prevent cardiovascular disease like heart attacks and strokes to measure IMT as their favored outcome measure. The theory is that it might take many years to see a difference among your treatment groups in heart attack, stroke, or death rates; but within a few months to a year you might be able to measure changes in IMT, so it's much quicker and cheaper to measure IMT than to wait for the "hard" clinical endpoints.

The Costanza group sugegsts that there's only one problem with this quick-and-cheap approach. Their meta-analysis showed that there is no consistent relationship between improvements in IMT and any of the outcomes that really matter. In short, IMT is just like too many other "surrogate endpoints" in medical research--just because it gets better, you cannot assume that what really is of interest gets better too. Costanza et al continued to agree with what we thought we knew in the past--that a high IMT at baseline is a risk factor for worse heart or vessel disease on a population basis. It's the later change in IMT that seems not to be correlated with anything of importance. (Just why this is so, they offer a number of possible explanations for, which need not concern us here.)

I have to note in fairness that these meta-analysis results can cut both ways. Guess who wants to do quick and cheap studies to show that a drug works for reducing your cardiovascular risk? Our old friends the drug industry, of course. So showing the lack of any linkage between IMT improvements and real risk reduction means that a number of studies that seemed to show great promise for any given drug are of no real scientific value--no matter how many drugs may have been sold to unwary docs based on those findings. But it also means that a drug that fails to improve IMT could, presumably, still end up being valuable in reducing heart risk. Consider Zetia or ezetimibe (http://brodyhooked.blogspot.com/2008/01/now-that-weve-been-enhanced-whats.html). The manufacturer got stung because they put a lot of weight on a study, ENHANCE, trying to show that their drug reduced IMT, and it ended up maybe making it worse. We now can see that those findings may not have really told us much about whether or not ezetimibe is a good drug. (I understand that the manufacturer is now sponsoring a longer-term study to measure actual outcomes--which of course is what they should have done from the get go.)

In a way this is all a crying shame. It makes really good sense that IMT ought to be a reliable measure of the progression or improvement of atherosclerosis. Physicians and scientists who thought this has to be true are not smoking something; the hypothesis seemed to make excellent physiological sense. And this in turn illustrates a point that's becoming an old refrain in this blog. The Pharma marketers very seldom tell docs something that we all know to be untrue and get us to swallow it. They are, on the other hand, extremely adept at taking something we already believe to be true, even if it isn't, and then using that belief to manipulate us into a course of action that ends up with more revenue in their pockets. So the problem is us fooling ourselves as often as it is them fooling us--or more accurately, us helping them to fool us.

Costanzo P, Perrone-Filardi P, Vassallo E, et al. Does carotid intima-media rthickness regression predict reduction of cardiovascular events? A meta-analysis of 41 randomized trials. Journal of the American College of Cardiology 56:2006-20, 2010.

Keeping KOLs Fat and Sassy: These Consultants Can Help

2011-06-10T10:58:00.001-07:00

I am not usually pestered with e-mails from consultants who serve the pharmaceutical industry, and so it was an interesting experience to get one e-mail directly and have another forwarded to me by a colleague, within 24 hours. As I described last month--http://brodyhooked.blogspot.com/2011/05/on-care-and-feeding-of-kols-attend.html
--the care and feeding of KOLs ("key opinion leaders" for those who just joined us, aka paid physician shills for industry) seems to be a hot topic just now.

I received this message:

Howard,

I hope things are well at University of Texas Medical Branch. As you may already know, the Sunshine Act is the most pressing set of regulations that will impact how companies approach KOL compensation. University of Texas Medical Branch will need to start implementing aggregate spend tracking processes now, because in January 2012, your company will be required to disclose all payments for key opinion leaders' services. Companies like University of Texas Medical Branch need to have a progressive and compliant infrastructure in place to establish fair-market value compensation and meet regulatory challenges. Regulatory agencies that have focused heavily on top drug makers have begun to turn their attention toward mid-size and smaller companies' KOL compensation practices. Cutting Edge Information’s latest study, "KOL Fair-Market Value and Aggregate Spend: Documentation, Tracking and the Sunshine Act," is designed to help companies of all sizes compete in today's highly regulated environment.

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These folks appear to think that the academic medical center I work for is a mid-sized company that sells drugs. We do, I suppose, employ "key opinion leaders" but we call them faculty, and expect them to teach students and do research and take care of patients, not sell products for us. (There is the whole debate about whether academic centers are becoming too commercialized, but that's a different post.) They also seem to suggest that the threat of shining the light of publicity on KOL-related activities will have us running scared and hence in need of consultant assistance.

Meanwhile a colleague of mine received this e-mail solicitation:

Dear XXX,
I wanted to get in contact, as we're organizing speakers for a very focused and unique conference looking at the important issue of:

KEY OPINION LEADER & STAKEHOLDER MANAGEMENT IN
SPECIALTY & ORPHAN THERAPEUTICS
Integrating innovative communication approaches and new best practices to reinvigorate the pharma high-value commercial model
Miami, USA 14th-15th November 2011

This will be the only focused event looking at the latest "best practice" approaches to selling and marketing high-value specialty drugs to distinct consumer groups, and working in partnership with therapeutic specialists & pharmacists as well as with hospitals & healthcare providers to provide real value and to improve patient access.
One of the goals, will be to improve seamless coordination between all internal & external stakeholders in strategic, operational and tactical roles. Such roles would typically include marketing, commercial operations, sales, sales force effectiveness, talent development, training, market access, pricing and reimbursement, product and brand management, as well as medical affairs & liaisons. As specialty & orphan marketplaces are growing rapidly, with a lot of new, high cost therapies entering a saturated market, where payers are more risk averse and budget-conscious, most would agree this topic deserves specific and detailed attention and discussion.
Would you perhaps be interested to speak/present there? If not, perhaps you could recommend somebody or a specific organization who we could invite?

Possible topics will include:
· Specific examples & focused case studies from across Specialty disease & medical areas i.e. Oncology, Orphan, Inflammatory, Pediatrics + others.
· What do specialist prescribers want and how can we better communicate value?
· New approaches to customer-centric, ethical, trust-focused, value-based sales of innovative drugs in the face of increasingly available and lower-cost generic products
· Best practices in specalist account management
· Mapping and targeting Key Opinion Leaders, payers, and today's new stakeholders
· Understanding, adapting to and selling in, the new cost containment, health technology assessment, evidence-based environment
· Interacting with specialists treating multicultural populations
· Increasingly important role of the Medical Science Liaison to engage KOL
· Marketing approaches to: Healthcare providers, Hispanic, African- American, Asian-Americans, Women, Parents, Elderly
· Digital and social media advances and how to adapt marketing methods to communicate effectively with specialists
· Benefits from supporting investigator initiated trials & publications
· Responding to the growing need of gathering & presenting real world data to demonstrate product value and acheive market access
· How to best incorporate all stakeholders' insight and analysis into company activities
· What differences exist for marketing specialty products to niche & emerging markets?

Consultants and solution providers please note: As we have a high demand for speaking positions and very limited positions available, solution providers who sponsor/exhibit will be given first right of refusal for limited speaking opportunities.

Thanks and best regards
Geraint Collingridge
Event Producer
T: +381 690 307 462
www.nextlevelpharma.com
"Knowledge Solutions for Life Sciences"

I am thrilled that "ethical" got thrown into their laundry list. As best as I can tell, these various firms want to assist companies who now employ KOLs to keep doing what they are doing, which presumably includes making a lot of money, despite a hostile environment in which some people are mean enough to say that the odor arising from these activities is starting to seem a bit rank. There seems to be no one considering telling us that maybe the reason there are problems and stresses is that KOL-related activities are inconsistent with medical professionalism and should be curtailed or completely rethought.

By the way, if you don't know the classic joke about consultants, see http://daveola.com/Resume/Joke.html.

The Bottom Feeders Are Out In Force: Physician-Owned Device Distributorships

2011-06-09T13:51:00.000-07:00

John Carreyrou in the Wall Street Journal online--
http://online.wsj.com/article/SB10001424052702304778304576373592455703056.html

--tells us that 5 senators, including our old acquaintance Chuck Grassley of Iowa, have asked the Inspector General of DHHS to investigate physician-owned distributorships. These PODs are owned by physicians and act as middlemen, buying medical devices such as spinal surgery implants from the manufacturer and selling them to hospitals. They apparently are sometimes able to offer the device at a slight discount, which the owners claim makes them a good thing.

The senators are prompted by press coverage of a Portland, OR case in which a neurosurgeon was charged with doing a lot of unnecessary surgery, which could have been motivated by his being an investor in a POD and making more money the more devices the POD sold (to the tune in that case of a cool half million a year). He denies thart he did any unnecessary surgery but he has lost his privileges and is being investigated by the state medical board. A telling point is that once the POD had the media spotlight shown on it, device manufacturers stopped doing business with it and it had to shut down.

The senators' concern is also prompted by the apparent near-exponential growth in PODs, even though they exist in a "legal gray area" according to Carryrou. (Besides the PODs themselves, another growth industry seems to be law firms promising that they'll help you set up your POD in a way that protects you from the legal system coming down on your head.)

Does anyone recall the olden days, when it was sometimes necessary to explain to physicians why they should not own a drug store on the side, and then send their patients to that drug store with their prescriptions? Maybe time for a refresher course...

Who's at Fault: The Company or the Physicians?

2011-06-06T08:57:00.000-07:00

For this sad tale of woe and intrigue check out the Health Care Renewal post by Roy Poses--
http://hcrenewal.blogspot.com/2011/06/stealth-marketing-of-medical-devices.html
And then the New York Times article by Barry Meier that Dr. Poses links to:
http://www.nytimes.com/2011/06/01/health/01device.html

Quick summary and attach "allegedly" in front of everything as none of this has been proven--a relatively small German firm, Biotronik, that makes pacemakers and implantable defibrillators, is now answering questions based on a trove of internal documents sent to the New York Times by a disgruntled former employee--an employee who claims he was fired because he complained about the corporate wrongdoing that his documents demonstrate. (The company protests that he's cherry-picked and that the documents don't tell the whole story.) PS-- a little change here in the usual script; usually it's a lawsuit or a Federal investigation for fraud that triggers release of these hidden documents.

The documents reveal a pattern of payola to get cardiologists to use Biotronik devices rather than one of their competitors'. The payola takes the form of "seeding trials"-- trials of no scientific value that are really excuses to get practitioners to enroll "subjects" for fees, and to promote the wider use of the company's product. (Biotronik sales officials even referred to these trials candidly in their internal documents as "unscientific studies.") Hiring physicians or their family members as "consultants" based solely on volume of product used or referrals for product use is the other major activity documented.

Here's a typical passage from Meier: "An implant specialist in Fullerton, Calif., Duane E. Bridges, became a consultant to Biotronik in mid-2008, company records indicate. The monetary volume of company products used by Dr. Bridges from early 2008 to early 2009 reached about $360,000, then jumped to $1.6 million over the next 12-month period, a greater than fourfold rise, the company data indicates. Dr. Bridges did not respond to comment; also a lawyer, Anthony Willoughby, who said he represented Dr. Bridges could not be reached for comment."

Also: "For example, in plotting strategies to gain sales at one California hospital, Biotronik officials suggested that an implant specialist, whose son and wife both worked for a competitor, might be wooed if Biotronik offered him concessions “such as studies or even the hiring of his son,” according to an internal company report."

The article also details a non-implanting cardiologist in Tucson, who was hired on as a Biotronik consultant and immediately informed his colleagues that he would not refer patients to them for implants unless they agreed to use Biotronik stuff. One of the area cardiologists to whom this doc referred patients (who was not apparently a paid consultant himself) increased his use of Biotronik devices eightfold, netting the company $1.1M in revenues.

Dr. Poses offers two astute comments. First, he notes that even people critical of financial ties with the drug and device industries tend to be less concerned about consulting relationships, and willing to give the doc the benefit of the doubt that the "consulting" is real and involves a true contribution of expertise in exchange for reasonable pay. He then notes that memos like those exposed here show that from the industry's point of view, "consulting" looks like bribery pure and simple. I would add a footnote--I expect if anything, and some of my surgeon colleagues agree, this is even more true in the device industry than in drugs. Why? Since device makers virtually never sponsor head to head trials, there's no scientific data as a rule as to which device is better. So if three firms sell similar devices, it's a wide-open arms race to get the docs to use your device and not the other guy's. The Biotronik memos seems to make clear that competition with other, bigger firms was the main driver behind these activities. (And incidentally reveals that almost for sure, the other firms were using the same tactics.)

Second point: Dr. Poses notes the by-now-pretty-tired excuse, that financial ties between docs and industry are required to promote scientific advance and innovation. It's quite clear that nothing about this entire Biotronik episode relates in any way to innovation.

Let me add my own two cents and bring up another huge point. Here is how Meier began his story: "The message from cardiologists was loud and clear, according to a top executive at a heart device company. The doctors wanted implant makers to produce more clinical trials of devices to help them generate income from research fees. To compete, 'we must be able to "answer the bell," ' wrote Thomas V. Brown, an executive vice president at the American subsidiary of Biotronik..."

In HOOKED I wrote about what seemed to be to be the saddest depths of professional ethics that physicians could fall to--not drug reps tempting physicians with generous payola to prescribe their products, but greedy physicians actually shaking down the reps for even more goodies and threatening to stop prescribing their drugs if they didn't come across. (To the point where even the drug reps felt ethically offended by the docs' behavior!) One has to conclude that a number of the cardiologists who ended up in the pockets of Biotronik were not seduced there by the big bad corporation; they pretty freely and eagerly crawled in. And what does that tell us about the state of professional ethics when these practices are permitted to flourish?

Pro-Con: Off-Label Anti-Psychotic Drugs for the Demented Elderly

2011-06-02T17:54:00.000-07:00

Here's the pro-con debate from CNN:
http://www.cnn.com/2011/OPINION/05/31/levinson.nursing.home.drugs/index.html
http://www.cnn.com/2011/OPINION/05/31/carlat.nursing.home.drugs/index.html

Daniel Levinson, Inspector General of DHHS, weighs in on their recent report viewing with alarm how many demented elderly are receiving atypical antipsychotic drugs, which Levinsom notes are not approved by the FDA for this use, and can pose serious risks, including a higher death rate. On the other side is Dr. Danny Carlat, whose work has often been noted in this blog.

Dr. Carlat is no slouch when it comes to revealing the misbehavior of the pharmaceutical industry and of physicians who do its bidding (for just one example, see http://brodyhooked.blogspot.com/2009/07/more-on-psychiatrys-dsm-v-mess.html). So it's significant that in this debate, he goes toe to toe with OIG-DHHS and defends the use of these drugs.

Dr. Carlat makes a number of good points. He stresses, as I have tried to myself, that "off-label" does not necessarily equal "wrong use" or "bad use" of a drug. He makes the important point that as of now no drug is approved specifically by the FDA for treatment of agitation caused by dementia, despite the way this condition can make life miserable for both patients and families as well as for staff. Moreover, he notes that several clinical trials support this use of antipsychotic medication. He therefore concludes that it's a matter of individual medical judgment whether for any given patient, the potential harms of these drugs are outweighed by the benefits--and OIG should back off.

Given Dr. Carlat's excellent record I hate to quibble with him, especially in an area where his psychiatric smarts trump any medical knowledge that I possess. But I would pose just one question. The atypical antipsychotics seem to pose one unique risk that especially is worrisome for the elderly--weight gain that could trigger diabetes--that is not shared by the older antipsychotics. And recent literature reviews (see for instance http://brodyhooked.blogspot.com/2009/01/are-second-generation-antipsychotic.html) have demonstrated pretty convincingly, I would judge, that there's no real benefit of the newer antipsychotics over the older, to the extent that calling them "second-generation" or "atypical" is probably a serious misnomer. So given that all drug use for this unfortunate problem is going to be off-label anyway, why not use a cheaper, older drug that many primary care physicians understand much better?

More Signs of the Empty Pipeline

2011-06-02T14:57:00.000-07:00

I have referred at various times to the problem the drug industry faces of the empty research pipeline, with fewer useful new drugs coming out of their research labs, meaning that if they want to continue making the profits they (and their stockholders) have grown accustomed to, they have no choice but to market the hell out of less-satisfactory drugs. I have also referred to the Medical Letter, a long-term standby for non-commercial drug information for practicing docs, tho sadly so few US practitioners subscribe to it.

The pipeline problem is, I believe, well illustrated by two items from recent Medical Letter issues (May 2 and May 16):

Duloxetine (Cymbalta), basically an antidepressant but one that has been viewed as having a specific anti-pain component, has just been approved for treatment of chronic musculoskeletal pain. ML notes that the mechanism by which duloxetine might relieve pain is unknown, and that the studies supporting its efficacy were all performed by employees of the manufacturer. All studies are placebo-controlled; there is no comparison with either commonly used over-the-counter analgesics, or with other (cheaper) antidepressants. A 30-day supply of Cymbalta costs $160. The reviewers conclude that if duloxetine has any superiority over placebo, it seems to be "modest at best."

Medoxomil (Edarbi) is the 8th drug of the angiotensin receptor blocker class to be marketed. (There is one, losartan, that is now available generically, but interestingly its cost is not that much lower than all the brand name drugs.) Like all other ARBs it works for hypertension. ML admits that medoxomil "might" be more effective than some other ARBs for that condition. But it also has a major practical disadvantage--the tablets are sensitive to light and moisture and so cannot be taken out of their original container until you swallow them. Just why we need yet another ARB, and one that is so difficult to use to boot, is never explained.

I think these examples highlight what the drug industry is up against, due to the lack of real breakthrough drugs these days. While we might have some pity for the poor marketers who have to convince us that these pigs look good in lipstick, that still does not justify the shady marketing practices that we discuss in this blog practically every week.

Ghostwriting: Bolder than Ever

2011-06-01T16:27:00.000-07:00

The current status of ghostwriting seems well summarized by an article on a blog of UK's Guardian:
http://www.guardian.co.uk/science/2011/may/20/drug-companies-ghost-writing-journalism

What we have been calling "Medical education and communications companies" (MECCs) on this side of the pond seem to be called "publication planning agencies" in the UK, but other than that there does not seem to be any trans-Atlantic difference.

The Guardian blogger discovered a considerable degree of what some would call chutzpah among the "publication planners" he spoke with. They talked about providing a real service and moving their activities from the realm of marketing into the realm of science. (Remember the drug rep's, and the physician apologist's, chorus: "It's not marketing, it's education"?) They spoke of a new level of openness in their activities.

All of which was quickly debunked by various expert commentators. The replies included:

Dr Leemon McHenry, medical ethicist at California State University: "They've just found more clever ways of concealing their activities. There's a whole army of hidden scribes. It's an epistemological morass where you can't trust anything."

Alastair Matheson, British medical writer: the planners' claims to having reformed are "bullshit...The new guidelines work very nicely to permit the current system to continue as it has been. The whole thing is a big lie. They are promoting a product."

So just what is going on here? My interpretation: Demands for disclosure appear in this case actually to have backfired, to some degree. The ghostwriters and their handlers used to work strictly in the dark. It then became obvious to them that the very fact that they operated out of sight gave credence to charges that they were up to no good. So they decided that the wiser strategy was to pretend to come out into the daylight. They talk more openly about what they do and crow about what a valuable service it is, thereby creating an aura of transparency.

But there is still no real transparency. They say that they simply "help" the academic guest author to write the paper, when in actuality, it's the same ol' same ol'--the company-directed ghostwritwer writes a detailed draft and if anything, the academic (who's of course "too busy" to be bothered with the whole thing, except to pocket his fee) maybe changes a few words here and there to keep up appearances. And what ends up published is the company's chosen spin, with the academic credibility of the supposed author and his institutional affiliation pasted on. What is never disclosed is the actual amount and type of work on the manuscript that the "ghost" and the "guest" each contributed, or what each was paid by the drug company for their deeds.

Two lessons here--first, demanding disclosure, rather than an end to nefarious practices, may not be a half-way step toward a solution but actually a regressive step. Second, when enough money is involved, expect quick adaptation to new realities, but no basic change in behavior or attitudes.