Yet More on the Broken Serotonin Model of Depression

A psychiatrist colleague sent me, with his endorsement, an article in the New York Times Magazine on the science of depression:
http://www.nytimes.com/2012/04/22/magazine/the-science-and-history-of-treating-depression.html
--whose author is Dr. Siddhartha Mukherjee of Columbia, whose recent book, Emperor of All Maladies: A Biography of Cancer was very well reviewed.

Since I have previously been dismissive of the serotonin theory of depression, Dr. Mukherjee's account of the history of the science of depression provides some potential balance. Dr. Mukherjee's basic hypothesis is that while it's clear that the idea that serotonin is a sort of magic bullet for depression is deeply flawed, two things are probably true--first, that serotonin plays an important role in at least some cases of depression in one way or another; and second, that drugs that change depression levels have been extremely helpful in our understanding of depression, not as cures, but as chemical probes that help us better understand what's going on in the brain--so long as we understand properly what the probes are telling us.

So I recommend the article, but I did find myself hiccuping at two places where I thought the author deviated from the careful and balanced tone he had established. The first such passage that caught my attention was: "But such a line of inquiry can’t tell us whether the absence of serotonin causes depression. For that, we need to know if depressed men and women have measurably lower levels of serotonin or serotonin-metabolites (byproducts of serotonin breakdown), in their brains."

Now, asking that question gets us a part of the way to an answer, but it's quite misleading if taken to represent the full answer. This is the old confusion between association and causation. Answering this question might reveal an association between serotonin levels and depression, but tells us nothing about whether that association plays a causal role, or whether some other thing is causing both the depression and the serotonin variations. Getting us messed up between association and causation is one of the primary ways that Pharma marketing manages to sell us a lot of ineffective and potentially harmful drugs.

The other passage that disturbed me relates to the newer theory of depression that excites Dr. Mukherjee the most, though he admits that depression is still very complicated and there may be no single "answer." The new theory is that while in most of the adult brain, no new cells grow, there seems to be an exception and new cells can grow slowly in one portion of the hippocampus, which seems to be related to mood. Experiments in mice show that behavior changes that are depression-related can be caused by enhancing or blocking the growth of these cells; and in humans, brain scans seem to indicate some similar function for cell growth in this region. Dr. Mukherjee then states about this cell-growth theory: "Nor does the theory explain why “talk therapies” work in some patients and not in others, and why the combination of talk and antidepressants seems to work consistently better than either alone. It is very unlikely that we can “talk” our brains into growing cells."

This passage seems a retreat back into another mode of flawed thinking that Pharma marketing exploits to mislead us--the old-fashioned mind/body dualism, which persists in treating the mind as foreign from the body and made up of different sorts of stuff, so that things that influence the body cannot affect the mind and vice versa. Dr. Mukherjee had just finished explaining to us that when mice are put in an enhanced environment with fun new stuff to explore, they become more adverturous and less depressed-seeming, and their brains also grow new cells in the hippocampus. He apparently forgets for a moment that if an enhanced environment can grow new brain cells in mice, then the enhanced environment provided by "talk therapy" in humans might have the same effect.

Despite these bumps in the road the article seems thoughtful and I commend it to your attention. I'll await the comments of more expert readers than I as to how good the science is that Dr. Mukherjee refers to.

Yet More on The Broken Disease Model of Diabetes

In the past I've ranted about how in dustry marketing helped to sell both docs and the general public on a flawed model of what "diabetes" is, for example:
http://brodyhooked.blogspot.com/2011/08/controlling-channels-pushing-pharma.html

Again with a hat tip to my esteemed colleagues Drs. Rick Bukata and Jerry Hoffman, I was informed of this study by a multi-national team, one of whom is an excellent person, Dr. James Wright at U-British Columbia, whose work on evidence-based prescribing I have long admired:
http://www.bmj.com/highwire/filestream/388629/field_highwire_article_pdf/0.pdf

These folks looked at 13 randomized controlled trials of type 2 diabetes, involving a total of 34,533 patients, which should be reasonably big numbers to be able to draw conclusions. These studies randomly assigned patients to either standard treatment or super-wonderful-tight glucose (sugar) control. According to our preferred model of diabetes, if you can lower the blood sugar, so that nice little machine Wilford Brimley tries to give away on TV will show better numbers, then of course you'll live longer and be healthier.

So what did these studies show? First, overall death rate was no different in tight sugar control vs. less tight control. Second, deaths from cardiovascular causes (mainly heart attack and stroke) were no different in the two groups.

Was anything different? Two things. First, one good thing-- the tight control people did have statistically fewer non-fatal heart attacks--maybe a 15% reduction in the risk of having one of those. Second, the bad thing-- your chance of having a severe episode of low blood sugar, which could lead to seizures or coma, was more than twice as great in the tight control group. For every one person you'd save from having a non-fatal heart attack, you would have about 5 who suffered severe attacks of low blood sugar.

So what's going on here? We have been brainwashed that diabetes treatment is all about controlling blood sugar, which is certainly the case in juvenile onset or type 1 diabetes. In the much more common adult or type 2 diabetes, the evidence is overwhelming that tight control is not the answer, and that our disease model should be all about blood vessel damage prevention and not about tight sugar control. So what does help in diabetes? First, good ol' diet and exercise. Second, quit smoking. Third, control high blood pressure. In short, treat diabetes as a disease in which you need to prevent further vessel damage. (One drug, by the way, is quite good for type 2 diabetes--metformin, a cheap generic, that helps prevent heart disease and also lowers blood sugar, but the two effects seem to be unrelated.)

But you'll never hear that message from drug companies who make drugs that do a wonderful job of lowering blood sugar, but don't do squat to make patients live any longer or healthier. Or from the device and supply companies that make a mint charging Medicare for the test strips that go in that cute little machine.

Cancer Care Study: The Shadow of Pharma

Check out the story in these two places:
http://gooznews.com/?p=3843
http://www.reuters.com/article/2012/04/09/us-cancercare-idUSBRE8380SA20120409

Thanks to Merrill Goozner at GoozNews, we read about a study recently published in Health Affairs by health economist Tomas Philipson at U-Chicago:
http://content.healthaffairs.org/content/31/4/667.full

This study purports to show that the US spends $70,000 per cancer case compared to $44,000 in Europe, and the US rate is climbing much faster than the European--but it's all worth it because US patients live an average of 11.1 years after diagnosis compared to the Europeans' 9.3.

Gooz reports that critics were all over this study as soon as it came out, for what I believe are quite valid reasons, indeed raising the question of how such a study came to be published in an excellent journal. There are two huge sources of error in a study done the way this one was.

One is called lead time bias. Suppose you have two patients with the same cancer at the same stage and there's no effective treatment for this type of cancer. One patient is diagnosed in 2012 and lives till 2016. The other patient is not diagnosed till 2014 and then dies in 2016. The cancer killed both patients at the same rate and at the same time. But because we diagnosed the first patient 2 years sooner, it falsely looks as if whatever we did added 2 years of life.

The second source of bias is becoming rampant in the US as we aggressively screen for more and more cancers, and is very well described in W. Gilbert Welch's wonderful book, Overdiagnosed. This is definitely true today for a lot of prostate cancer. Now that we are typically doing PSA screening on men starting practically from birth, we are diagnosing a lot of cases of prostate cancer. In olden days, if a man was diagnosed with prostate cancer, he probably had something seriously wrong with him because he managed to come to the physician's attention to begin with. Based on that population of patients we decided quite reasonably that "prostate cancer" was a big deal. But now we are finding very healthy men who have a few funny looking cells on a biopsy which they never would have had if their PSA test had not been a bit high, and if we followed those men without any treatment for decades, we'd see that these microscopic "cancers" never cause really serious disease. In other words, "prostate cancer" today means something quite different than what it did some years ago. But of course if you diagnose a lot of men with this sort of not-really-cancer, and see how long they live, you'll get very impressive survival statistics--which only proves that we do way too many screening tests, not that the money we spend on cancer is well spent.

So why is this important to us? As Gooz informs us, "Philipson is a fellow at the conservative American Enterprise Institute and at the Manhattan Institute, served in the administration of President George W. Bush and was a healthcare adviser to Sen. John McCain’s 2008 presidential campaign....The Philipson paper was supported in part by Bristol-Myers Squibb Co, whose cancer drugs include Yervoy. A drug for advanced melanoma, it costs $120,000 for a full course of treatment. Clinical trials showed that Yervoy produces a near-miraculous cure for some patients, with a median increase in survival of 3.6 months."

Golly gosh. I wonder of the sources of funding had anything to do with the conclusions of this study.

"Balance" in the Defense of Poor Arguments Is No Virtue

Some time ago I was driving somewhere with my car radio tuned to the local NPR news station and heard a portion of a discussion regarding one of the services that is supposed to call out falsehoods that appear in media news stories. The discussion immediately turned into a defense of the service against accusations of bias by showing that they had attacked roughly equal numbers of statements by Republicans and Democrats as being false.

My reaction to this weird discussion was: wait a minute, I thought the reason for this service was to tell us what's true and what's false, not to be "balanced" between the two major parties. What if one party told lies 90% of the time and the other one 10%? Is the service then supposed to be "balanced"?

Naomi Oreskes and Erik M. Conway, in their fascinating book Merchants of Doubt, tell us how a small group of scientists has managed to cast doubt on a series of well-established scientific conclusions ranging from tobacco causing cancer to climate change (and what's especially fascinating is that it's many of the same scientists in all these cases). They point out along the way how the "fairness doctrine" in the media works against accurate reporting, since news outlets act as if there's one scientist saying it ain't so while the vast majority of credible scientists in the field say is is so, then they have to give equal time to both viewpoints.

And what does this have to do with the topic of this blog? Be patient, I'm getting there.

A group of three has published a letter to the editor in Nature Biotechnology (subscription required). The three are:

• Roman Lesko, of Navigant Consulting in New York (a firm that does management and economic consulting for various industries, including healthcare systems)



• Samuel Scott of the University of Baltimore Law School



• Dr. Thomas P. Stossel of Harvard and ACRE, whom we last heard from in this blog at: http://brodyhooked.blogspot.com/2012/01/another-planet-heard-from-sunshine-law.html

They start by citing three articles that demonstrate advantages of close associations between the drug and device industries and academic medical centers. The first such article is by our old friend Frank Lichtenberg, the flaws in whose economic research we discussed a while back:
http://brodyhooked.blogspot.com/2008/02/defending-free-lunch-mistakes.html

They then ask whether top-tier medical journals present a fair assessment of the pros and cons of relationships with industry, or whether they rather have an anti-industry bias. They proclaim the latter. They did a study in which three readers, whom they don't name but I would have to guess are the authors, read all articles looking for a variety of characteristics: did they cite evidence; did they address opposing viewpoints, etc. They concluded that the anti-industry articles were seriously inferior in quality to the pro-industry articles--for instance, the former addressed an opposing point of view only 44% of the time while the latter did 100% of the time. They concluded by calling on editors of these journals to present a more balanced picture.

OK, where to start... First of all, most of their measures of the quality of the articles would seem to be quite subjective, and how much trust would one have in the combined judgment of this group of three individuals that they assessed these articles in the same way the thoughtful, average reader would? Second, I don't see how the editors of these journals could be faulted if they were to conclude, for all the reasons repeated ad nauseam in this blog, that there was a much stronger case to be made on the side of skepticism toward industry engagement.

Along the way, the authors repeat the common ACRE lament that there's really no solid evidence that docs' relationships with industry have ever harmed any patients. As I discussed when the article was first published:
http://brodyhooked.blogspot.com/2010/10/major-new-study-published-in-plos.html
--the article by Geoff Spurling and the group from Healthy Skepticism in Australia is probably the best current review of the available facts on this point. If one of the pharmapologist papers ever cited the Spurling study and explained any flaws in the data analysis, then I might credit that gang with actually looking to see what the evidence might be. I have yet to see one of these papers, however, engage or even mention the Spurling study.

The high-tier journals are pretty one-sided right now on the value to physicians and patients of close financial ties with industry. These same journals are also pretty one-sided right now on the value to patients of treating bronchitis with antibiotics. The latter is because the evidence is overwhelming that antibiotics don't make bronchitis better. Maybe the same reasoning applies to the coverage of industry relationships. Sometimes being one-sided can be good.

Lesko R, Scott S, Stossel TP. "Bias in High-Tier Medical Journals Concerning Physician-Academic Relationships with Industry." Nature Biotechnology 30:320-322, April 2012.

ADDENDUM 4/13/12: Either not wishing to pile on the authors of this research letter, or else suffering from momentary brain absence, I did not check out the report of "competing financial interest" for which I had to go back to the on-line version of the above paper. I thought it was interesting enough that I will reprint it here:

Competing financial interests
T.P.S. has been awarded a grant from the Searle Freedom Trust to study physician- and academic-industry relationships. The Trust had no participation in the conception, design, performance or reporting of the study. Although T.P.S. has various industry relationships, the paper does not address any topic relevant to these relationships. R.L. and S.S. received funding from the Association of Clinical Researchers and Educators to participate in the analysis. The Association had no input into the conception, design, performance or reporting of the research described.

So Dr. Stossel has "various industry relationships." (When he gives lectures, he quite proudly fills an entire PowerPoint slide with his list of relationships.) And he has here written an attack on major medical journals for being negative toward physicians who have relationships with industry. But his relationships are not relevant to the topic of this article. Hmmm.

Topping the Pentagon's $500 Hammer, or, Back to the Basement of the YMCA

Many moons ago, there was a flap about a cost study that showed that the Pentagon had paid $500 for a hammer, and this was widely quoted as an example of bloated government spending and waste. Now we discover that whoever ordered that hammer quit working at the Pentagon and is instead in the CME business.

Still catching op on older articles, I come to the study by Dr. Jeffrey Tabas and colleagues at UCSF: http://archinte.ama-assn.org/cgi/content/full/171/9/840
--looking at physicians' attitudes toward commercial funding of continuing medical education. The main take home message is that these docs, surveyed as they attended CME programs, agreed that when companies paid for CME, they introduced bias into the program, and that was not good. But the docs also shied away from paying any more themselves for CME registration and basically shrugged and said that CME could not survive without commercial sponsorship.

What most grabbed me, however, about the article was their observation that docs tended to way underestimate the actual cost of running a CME program. As an addendum the authors checked out the costs of various stuff at different cites in the US, presumably looking at big hotels or convention centers where CME events are often held. Taking Atlanta as a mid-range example, the costs per cup of coffee worked out to $7.47 and of a bagel, $5.05. If you wanted to splurge for lunch it would be $49.41. On the non-food side, the cost of getting a room set up with a screen, laptop, projector, and cables was $1520, not counting the cost of the technician.

So this led to a train of thought. We have to recognize (as was of course the case with the infamous hammer) that all these numbers reflect not the actual costs of the specific items, but what other charges and profits the business decides to tack onto that part of the tab; if we insisted on paying no more than $3 for coffee, the place would surely oblige, but simply add on the equivalent cost someplace else on the total bill. That being understood, I still have to wonder--if docs saw these figures, would they still agree that CME should proceed in the same way it always has, and that commercial sponsorship, while perhaps unfortunate, is nevertheless essential? Or would the light dawn that as long as a sugar daddy has been willing to pay the freight, others decided to take advantage, and so there's been an unjustified cost escalation in CME?

One of the quotes I most cherished when I was working on HOOKED was from a top dog at the American Psychiatric Association, who when asked by a reporter writing about their 2002 annual convention why they took so much Pharma money, protested that without Pharma bucks, they'd "be sitting in the basement of the YMCA." (Since then APA has made considerable strides in ridding their meetings of commercial money.) I had to wonder--has anyone asked the YMCA lately what they charge for a cup of coffee?

Yet More Ways the Literature Can Mislead Us

I'm back to pearls from recent issues of the "Primary Care Medical Abstract" program run by Drs. Rick Bukata and Jerry Hoffman, this time to touch upon some articles that add depth to our understanding of how the published medical literature can give a misleading impression of the world of human health. You may detect a certain for-profit industry footprint in some of these techniques for obfuscation.

• A group at Freiburg, Germany compared the original research protocols of 52 randomized controlled trials with 78 journal articles reporting the trial results. Their concern was with eligibility criteria--which types of patients were included in the study or not. They found that only about half the time, the eligibility criteria reported in the final paper actually matched the original protocol; in the other instances the criteria were either not mentioned or were modified. The net result was often to make it appear that a treatment good for a small segment of the population was useful for a much wider group of patients. However, in their sample, this did not vary according to who funded the study, so non-industry researchers seem to be just as guilty as industry-sponsored folks. (http://www.bmj.com/content/342/bmj.d1828?view=long&pmid=21467104)


• John Ioannidis, a frequent flyer in this blog with numerous highly revealing statistical analyses to his credit, who has now apparently forsaken Greece and gone to Stanford, reports with his colleagues on biomarkers--measures that purportedly signal level of disease risk or severity. As they note, new biomarkers are constantly being discovered and tested but relatively few ever end up influencing clinical practice. They looked at biomarker studies that appeared in high-impact journals like New England Journal, JAMA and Lancet that are most frequently read and cited, studies in less known journals, and meta-analyses of all known studies. They discovered that if you only read the articles in the high-impacty journals, you'd conclude that biomarkers were much more useful than they turned out to be according to the total mass of data. More suspiciously, the articles published in the high-impact journals, that showed the most favorable pictures of the biomarkers, were often not the largest studies in terms of numbers of subjects; the larger studies often showed less favorable outcomes. It looked very much like cherry-picking--either be sure to get your best-looking study in the highest impact journal and bury the less-good studies elsewhere; or else the editors of the highest-impact journals accept only the most favorable papers and turn down the others. But the bottom line for physicians is don't believe it just because you read it in a major journal. (http://jama.ama-assn.org/content/305/21/2200.long).


• Another group of authors with John Ioannidis among them looked at cost-effectiveness analyses of various versions of the Pap test for cervical cancer, with many new (and of course much more expensive) variations being promoted by industry as superior to the standard Pap test. By the merest coincidence, in looking at costs and benefits of the newer test vs. the old Pap, not a single industry-sponsored study found that the old Pap was better. Also, the assumptions used in the industry-sponsored studies, in order to prove the superiority of the newer test, estimated the sensitivity of the old Pap test at an average of 10% lower than the assumptions employed in non-industry-sponsored research. Jerry Hoffman likes to say that we should simply throw out any industry-sponsored cost-effectiveness analysis without bothering to read it because you can fudge the assumptions any which way you please, and no one has yet discovered an industry-sponsored CEA study that did not conclude that even though the treatment or test promoted by industry is much more expensive up front, in the end it actually saves money (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071415/?tool=pubmed).

Sismondo on How Pharma Disguises Interest as Science

I've reviewed the work of philosopher Sergio Sismondo of Queen's University, Kingston, Ontario previously, for example:
http://brodyhooked.blogspot.com/2009/11/inside-belly-of-medical-communications.html

Thanks to my esteemed colleague Daniel Goldberg, I learned of a recent paper by Dr. Sismondo (subscription required), which offers a number of observations about drug industry activities and also a bit of philosophical analysis. While many of the factual observations have previously been discussed here and other places, I thought a few tidbits were worth mentioning before I get to the philosophical part:

• Dr. Sismondo extends the concept of "ghostwriting" medical journal articles into the more general practice of "ghost managing" entire publicity campaigns, and medical communications companies market their wares to big drug companies based on their success in doing this. While major medical journals commonly reject 90% or more of all submitted manuscripts, several top communications companies claim that they have a nearly 80% success rate with manuscripts they produce. This is not surprising, he notes, when a firm such as Complete Healthcare Communications can draw on the talent of more than 50 medical writers and editors and more than 30 publication planners, plus numerous other staff. No academic author doing legitimate research publishing without industry support can draw upon anything like that battalion of resources.


• Dr. Sismondo takes us behind the scenes at a 2-day conference sponsored by ExL Pharma, a "KOL Relationship Summit" to discuss how to best utilize physician-scientist "key opinion leaders." One KOL, Dr. Michael Thase, noted how difficult it had been for him when he served as an expert witness in a court case and the attorney for the opposing side hit him with documents describing the drug company's "individual management plan" for him. Thus, he said, it's problematic when companies talk about "managing" KOLs. This led to a long discussion of semantics in which phrases such as "opinion leader engagement" were tossed about. Dr. Sismondo noted that there was a lot of debate on what to call the behavior but no one suggested changing the behavior itself.

Now for the more general philosophical point, which I shall modify somewhat from Dr. Sismondo's rendition. Many pharmapologists accuse pharmascolds like me of creating a straw man argument when we talk about "conflict of interest." They claim that after all, we are here dealing with scientists doing science. All human beings have various biases and prejudices that influence how they think and act. But the norms and methods of science are designed to transcend those personal quirks and assure that the outcome is valid and "objective." To claim that a scientist produced bogus data because he had a conflict of interest is a sort of ad hominem argument--we cannot dispute the science and so we resort to name-calling to discredit the author.

The point I take away from Dr. Sismondo's discussion is that whatever the rest of us may think about interests and science, when one reads the internal documents of the drug industry and attends conferences such as the ExL Pharma KOL management conference, it's quite clear that "interest" describes exactly the way the industry thinks and behaves. They believe that they've bought and paid for the science and the scientists and therefore they can expect the scientists to dance to their tune and the science to translate directly into sales and profits. And if it doesn't work out that way they figure they've been had.

A point Dr. Sismondo does make is that the industry shows how much it believes in the idea of "interest" by realizing that if it wants to sell drugs using science, it has the go to great lengths to disguise the "interest." So the industry values KOLs, ghostwritten articles, and the entire "ghost management" process precisely because docs can easily be made to believe that what they get from these sources is disinterested science, and not industry interest.

Sismondo S. "Corporate Disguises in Medical Science: Dodging the Interest Repertoire." Bulletin of Science, Technology & Society 31:482-492, 2011.

Yet Another Evergreening Ploy--More on Peddling Useless Drugs

I will introduce this topic with a fictional story, about a drug company, Scam Pharmaceuticals. This company managed to get FDA approval for its wonder drug, Placebo Plus, whose contents, in generic terms, consists of 100 milligrams (mg) of lactose (milk sugar). During the period of patent protection, Scam can market this drug at whatever they wish to charge without any generic competition, so they sell their drug at $5 per pill.

But all good things must come to an end, including patent protection, and a generic company now files with the FDA to market an equivalent 100-mg-lactose product. Scam immediately does what it's entitled to do under current law and regs--file a lawsuit against the generic firm claiming patent infringement. This suit may not have any chance of succeeding, but merely by filing it, Scam earns a 30-month reprieve from any generic entering the market.

Now, as the 30-month grace period winds down, Scam announces that it's discovered a superior version of its drug, now named Placebo Plus One. This new wonder drug also contains lactose, but this time it contains 99 mg, not 100 mg. Scam can easily get FDA aproval because it does not need to do any clinical trials of Placebo Plus One. All it has to do is show that in the human body, 99 mg of lactose acts just about the same as 100 mg does (bioequivalence). Placebo Plus One now has patent exclusivity for another period of time and cannot have any generic competition. Because it's new, it must be better, so Scam prices this new brand-name drug at $6 per pill.

Pharmacists are in a bind. By now, there are generic equivalents of the old Placebo Plus formulation, 100 mg lactose. And the FDA has just gotten finished saying that that formulation is virtually the same as 99 mg. But no pharmacist can substitute the generic lactose for Placebo Plus One because of the 1-mg dose difference. Officially, doing that means changing the dose of a medicine, which no pharmacist can do without a doctor's prescription.

Well, once again the clock ticks down, and Placebo Plus One is about to lose its patent protection. And indeed an eager-beaver generic firm files to provide a 99-mg pill. So again Scam files a countersuit and wins its automatic 30-month extension. At the end of this 30 months, Scam proudly announces that it has made yet another breakthrough discovery, which it calls Placebo Plus Two. And this new drug product also consists of lactose, but this time the dose is 101 mg, and it costs $7/pill. You get the drift.

Now, this must be pure fantasy, right? No drug company could be so blatant as to engage in such sleazy behavior that so obviously does nothing whatever to improve patients' health, right? And if they did, no docs would be so lemming-like as to actually prescribe all the "new" products, right?

At this point I thank faithful reader and fellow blogger Marilyn Mann who sent me a copy of a paper just out on line (subscription required) by Nicholas Downing , co-authored by our old friends Drs. Joseph Ross and Harlan Krumholz. And the story of Abbott Laboratories and its versions of the drug fenofibrate, a drug intended to lower cholesterol and triglycerides, just about exactly parallels my fictional story of Placebo Plus (though I did not check the actual prices). Abbott managed to market sequentially three versions of fenofibrate, Tricor-1, Tricor-2, and Tricor-3. The lowest-dose capsules of the three drugs respectively contained 67 mg, 54 mg, and 48 mg of the active compound. For the fourth interation, the people at Abbott were apparently bored out of their minds and wanted at least to go into the lab and clink a few test tubes together. So the latest brand-name version is called Trilipix and contains not fenofibrate, but fenofibric acid--which just happens to be the natural metabolite that the human body makes when its swallow fenofibrate.

As you would guess, the improvement in patient's health from any of the new formulations compared to the original version is nil. The cost, of course, is far otherwise. The authors state that the current annual bill for all versions of fenofibrate and its cousins is $1.4B and if instead, docs prescribed the equivalent generic forms, the savings would amount to $700M.

As you might also guess, the people footing the bill for Abbott's shenighans have not failed to notice what's going on, and several antitrust lawsuits have been filed. The cost to Abbott for settling all these suits to date has been around $300M, which, as the authors note, comes in at about 4% of total sales so far for all the fibrates.

Now, critics of my little story about Scam would say that I unfairly stacked the deck by calling my pill "Placebo Plus," since placebos supposedly do nothing for your health, while fibrates lower cholesterol and triglycerides. But the critics would be premature, which gets us back to the work of another co-author of the paper, Dr. Cynthia Jackevicius, whose work we previously encountered:http://brodyhooked.blogspot.com/2011/11/some-capsules-of-recent-pharma-related.htmlIn her previous work, Dr. Jackevicius reminded us that if we're now spending $1.4B annually for fibrate-type drugs, we're probably throwing all that money down the drain--since no research study has ever shown that actual patient outcomes like death, heart attack, stroke, etc. are improved by taking fibrates. As was said in that earlier article, the fibrates should have been added to medicine's trash heap years ago. Yet prescriptions are actualy on the rise, showing the effectiveness of Abbott's marketing campaigns.

At the end of the present article, the authors list the various policy changes and could prevent this sort of scam in the future. (Obviously the 30-month extension comes in for some attention.) But the one that mostly jumps out at me is--how about us docs following the example of the Scarecrow in the Wizard of Oz, and going out to get ourselves a brain, instead of being led around by drug reps?

Downing NS, Ross JS, Jackevicius CA, Krumholz HM. Avoidance of generic competition by Abbott Laboratories' fenofibrate franchise. Archives of Internal Medicine (e-pub April 9, 2012).

ADDENDUM 4/10: Drs. Bruce Psaty and Rita Redberg commented in Archives in an editorial on the Downing et al. paper reviewed above. Their remark on the evergreening technique employed by Abbott Laboratories is telling: "Without endorsement, we note the methodological artfulness." They cite with approval the various policy changes Downing et al. propose to prevent such skullduggery in the future, but also add that the blame for lemming-like behavior should be extended from physicians to medical guideline committees, since several practice guidelines recommended fibrate treatment for high triglycerides despite lack of evidence of change to any outcomes that matter to patients. The whole episode is yet more evidence of both physicians' and patients' fixation on surrogate endpoints like blood test numbers instead of on actual improvements in health, playing right into the hands of "artful" pharmaceutical marketing.

Psaty BM, Redberg RF. Evidence of pharmaceutical innovation and therapeutic enthusiasm [editorial]. Archives of Internal Medicine, e-pub April 9, 2012.

A Potpourri of Recent Research on Improving Patients' Health Sensibly

I've had occasion several times to shout out for my friends Drs. Rick Bukata and Jerry Hoffman's Primary Care Medical Abstracts. It slowly dawned on my dim wits recently that it had been several months since I had gotten my monthly audio CD in the mail, and I had to have a talk with their normally on-the-spot crew at their headquarters at Creamery, PA (I have always imagined that your cholesterol goes up 50 points just by entering the city limits). But all is now well and a backlog of several months' CDs duly arrived, which I am working my way thru. Several papers they discussed specifically about the Pharma-medicine interface will be the subject of later posts. But the theme for this post is several studies they reviewed in a 3-month period about non-drug management of common medical problems, as summarized briefly below (journals require subscriptions for access).

• A Swedish randomized trial in irritable bowel syndrome showed that a program of regular physical activity, instructed by a physiotherapist, dramatically reduced symptom scores, and three-quarters of the patients were able to stick with the program (Johannesson E, Simren M, Strid H, et al. Physical activity improves symptoms in irritable bowel syndrome: a randomized controlled study. American Journal of Gastroenterology 106:915-922, May 2011).


• A randomized trial out of Pittsburgh involved older adults (mean age 72) with chronic insomnia--an important age group both because insomnia is common and because the risks of side effects of drugs is higher. The experimental group were given 2 sessions with individualized instructions regarding behavior changes to manage insomnia. The number reporting no insomnia at the end of the study were 55% who got the experimental intervention vs. 13% for the controls (Buysse DJ, Germain A, Moul DE, et al. Efficacy of brief behavioral treatmen for chronic insomnia in older adults. Archives of Internal Medicine 171:887-895, May 23, 2011).


• A Brazilian group looked at a meta-analysis of 47 previous trials of exercise in Type 2 diabetes. (Another meta-analysis recently showed that almost all drugs now prescribed for diabetes reduce glycohemoglobin, the standard measure of blood sugar control, by about 1 point at best.) If physical activity was of greater than 150 minutes per week duration, it reduced glycohemoglobin by 0.89 points, while lesser amounts of exercise reduced glycohemoglobin on average by 0.36 points (Umpierre D, Ribeiro PA, Kramer CK, et al. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA 305:1790-1799, May 4, 2011).


• A group at the American Cancer Society looked at a group of folks who reported in 1992-3 whether they adhered to cancer prevention guidelines calling for weight control, exercise, diet, and moderate alcohol consumption. The authors excluded tobacco avoidance since we all know how huge that is in preventing cancer. They then looked at the 14 years of follow-up and found that among those reporting a high level of adherence to these guidelines, the chance of dying of any cause was reduced by 42%, the chance of dying from a cardiovasculoar cause was reduced by about 53%, and the risk of dying from cancer was reduced by about 27% (McCullough ML, Patel AV, KushimLH, et al. Following cancer prevention guidelines reduces risk of cancer, cardiovascular disease, and all-cause mortality. Cancer Epidemiology, Biomarkers, & Prevention 20:1089-1097, June 2011).

These studies remind me of an old friend, Dr. David Sobel, who for many years did preventive medicine with the Kaiser organization in California. He would do talks for physicians and say something like,"I want to tell you about a new pill that has just been developed. If you give it to people with irritable bowel syndrome, their symptoms will dramatically decrease. And the pill has almost no side effects, and it's very cheap." The docs would jump up and down in their chairs and demand to know more. Then Dr. Sobel would deliver the punch line: "Oops, I made a mistake. It's not a pill after all. It's a simple exercise program." At this point the docs would groan and shake their heads and lose interest.

One of the standard rationalizations that physicians report when asked about bias from getting most of their information from drug reps is, "But I cannot be biased. I see reps from all the different companies, so whatever bias each one introduces must be cancelled out in the end." I will lay dollars to donuts that none of those reps came by the office touting exercise or simple behavioral treatment for irritable bowel or insomnia or diabetes. Yet the effect sizes seen in the studies above are so impressive that any drug company would kill to have one of its drugs perform anywhere near so well in a controlled trial. The conclusion that our society is overdrugged and that we underuse nonpharmacological tools for disease management and prevention seems hard to avoid.

Consumer Reports on the Device Mess

Consumer Reports magazine (May issue) has a mostly nice article on the problem of unsafe medical devices and inadequate FDA testing requirements:
http://www.consumerreports.org/cro/consumer-reports-magazine/May-2012/medical-devices.html

So why is the article mostly nice and not completely nice? The article explains, as we have in this blog, how the Institute of Medicine says that present-day device testing is inadequate (and an editorial in the magazine agrees). The article explains how the FDA continues to protest that everything's okay. The article also mentions in passing, "Congress is now debating a new law that would keep the present system virtually intact..."

What they don't provide is the missing piece of the puzzle, as we have discussed:
http://brodyhooked.blogspot.com/search?q=device+capitalists
http://brodyhooked.blogspot.com/2011/08/medical-device-industry-to-iom-drop.html
That is, the magazine does not tell us how vigorously the device industry, and the venture capitalists who get rich off it, have lobbied Congress, claiming that American jobs will flee overseas if the rules get even a tiny bit tougher. When the pockets of Congresspeople are filled with lobbyists' cash, funny how persuasive that argument becomes. Fortunately, the editorial opinion adds, "Consumers Union's Safe Patient Project is organizing patient-safety activists to speak up to Congress."