Wednesday, November 30, 2011

The "Emergent Patient-Industry Complex" and Regulatory Capture

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recap: alosetron (Lotronex), manufactured by Glaxo Wellcome (later GlaxoSmithKline) was put on the market in 2000, withdrawn later that year, and put back on the market with restrictions in 2002.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.

Wednesday, November 23, 2011

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

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:,0,1295689.story)

In the previous post-- 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.

Monday, November 21, 2011

Some Capsules of Recent Pharma-Related Escapades

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

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--
--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.

Saturday, November 19, 2011

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

I usually use a standard form to report the latest drug firm settling with the Feds for wrongdoing, without admitting any wrongdoing, as in:

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:

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:

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.

Friday, November 18, 2011

Will Brown University Investigate Keller?

We've previously on this blog discussed the case of Dr. Martin Keller at Brown University and his study of Paxil (paroxetine) in children:

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:

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.

Thursday, November 17, 2011

What Could Penn State Scandal Have To Do with Pharma?

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:

--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.

Sunday, November 13, 2011

Shameless Commerce Division: New Book, THE GOLDEN CALF

A while back I mentioned a forthcoming book:

I'm happy to report that the book is now available in paperback, and soon to be released as a Kindle edition:

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.

Wednesday, November 9, 2011

Important Conference on Future of FDA

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

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!

Monday, November 7, 2011

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

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:

Our esteemed colleague Merrill Goozner addressed this head-on (in relation to recent discussions of NIH guideline panels) in his GoozNews blog--

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.