Back to the Risks of Prescription Drugs

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

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

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

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

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

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

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

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

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

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--
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

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?

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?

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

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

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

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

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

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

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?

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

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"

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

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

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.