Friday, July 30, 2010

Big Pharma on the Hill: Still Plenty of Clout

A recent Senate committee action gives us a chance to see how Big Pharma is doing these days in terms of political clout:

This ought to be one of those no-brainers--should we continue to allow the brand name drug companies to employ a loophole in the generic drug laws, and pay off generic drug companies not to compete with them by bringing their alternative drugs onto the market as soon as the law allows? It's estimated that the big companies take us for $3.5B/year through this ploy, called "pay-to-delay."

Sen. Herb Kohl, D-WI, co-sponsor of the Sunshine Law to require disclosure of drug industry payments to physicians, authored the measure to close this loophole. It passed the Senate Appropriations Committee.

It's interesting to see how close it came to not passing. Sen. Arlen Specter, D-PA, who until recently was an R instead of a D (and who has lost his primary bid to stand for re-election), started the bidding for Pharma by introducing an amendment to strike this provision from the larger bill of which it is part. The AP reports that the drug lobbyists who filled the audience thought they had it made when they picked up four Democratic votes in Specter's favor, including Frank Lautenberg (D-NJ) and Barbara Mikulski (D-MD), both representing states with a lot of drug-related jobs. The drug lobby figured it had all the Republican votes on the committee in their back pocket.

They were thwarted, however, by Richard Shelby, R-AL, whose vote on Kohl's side deadlocked the panel at 15-15. As a majority vote was needed to kill the Kohl provision, the industry's move failed.

Bottom line: In the Senate, the drug lobby can commandeer virtually all the Republican votes and usually also enough Democratic votes to get whatever they want.

Thursday, July 29, 2010

What's Playing in Peoria? Commercial Influence over CME Is Alive and Well

One problem I continually run into as an academic-type physician is to get a fix on what's happening out there in the "real world." We've seen on this blog recently how if one only looks from the vantage point of the ivory tower, it would seem as if pressure is mounting to free continuing medical education from commercial influence. Authoritative groups such as the Institute of Medicine have called for a complete rift betwen CME and industry funding:

The real-world perspective was brought to my attention today by some colleagues who have been pioneers in creating CME venues that support themselves completely with registration fees and accept no industry cash. Names will be changed to protect the guilty, so let's just say we are going to talk about a certain state-level medical specialty society in an unnamed state.

My friends had entered into some discussion with that state society to see about offering their CME program in connection with a society meeting. There was some hemming and hawing--amidst profuse expressions of approval for the excellent way that the CME program had been organized and its superb content. When they asked folks to please fish or cut bait, they were able to get the following statement from a Deputy Executive Vice President of the organization: "I can't say 100% no, but I seriously doubt we can use this format for our annual meeting. We use our meeting to launch many of our national initiatives, and they all have commercial support. If we were to use this format/meeting, it would have to be at a different time of year, and I do not think that's an option for us right now. Will chat with X about this...but don't get [your] hopes up."

Reading just a bit between the lines, somebody else involved in the negotiations translated the above as: "They won't offer a good course with proven reviews because they risk offending their commercial support?"

So from one vantage point we seem to be making real progress. From another vantage point, not only can we not get rid of commercial report for CME and other medical organization "initiatives," but we cannot even offer a commercial-free CME program at the same time as the meeting where the commercial folks show up, lest the commercial people take offense.

All of this led one of the parties to this discussion to conclude: "I don't know how we ended up in such a sleazy business."

Deja Vu All Over Again Department: Did you think you heard this story somewhere before? Well, you did. A few years ago, as I described in HOOKED, Dr. Bob Goodman tried to purchase display space in the annual meeting exhibit halls of both the American Academy of Family Physicians and the American College of Physicians, to set up a table for his "No Free Lunch" campaign and distribute buttons. Both groups initially refused to allow him into their exhibit halls, obviously out of fear that he'd offend the really well-paying customers.

Tuesday, July 27, 2010

Still Awaiting an Academic Physician to Suffer Consequences for Ghostwriting...

A plaint that regular readers of this blog have now heard several times: when is an academic physician going to suffer any bad consequences as a result of being exposed as having been the putative author of a ghostwritten article? When is one of our great academic medical centers, that huff and puff about how unethical ghostwriting is, going to prove it actually means business?

Just maybe we are a step closer.

A story was unfolding right in my own Texas back yard, which i was unaware of till tipped off by the redoubtable duo of Jonathan Leo and Jeffrey Lacasse, who have continued their anti-ghostwriting crusade in the Chronicle of Higher Education:

Not much new ground was covered in that article, that we have not already looked at previously:

However, they mentioned in passing that on July 12, Dr. Steven M. Haffner was accused in a letter from the U.S. Senate Finance Committee (read: Sen. Charles Grassley, R-IA) of having allowed his name to be placed on a ghostwritten article at the behest of GlaxoSmithKline, in that instance about Paxil. According to Sen. Grassley's folks, Haffner was a part of the CASPPER program revealed in internal GSK documents released by litigation, the program that won the award for "cute name" after it was edged out in the "professional ethics" category:

Hmm. Steven Haffner--where have we heard that name before? Sonofagun--that was the same guy who leaked the Nissen-Avandia research manuscript to GSK, in violation of the New England Journal's editorial policies (and all professional ethics):

Putting all that together led in turn to a recent article in The Daily Texan:

--and Ed Silverman at the Pharmalot blog:

--and finally an article by Paul Basken in Chronicle of Higher Education, July 16 (subscription required). Interestingly, neither the Chronicle nor the Daily Texan connected the dots; each reported the ghostwriting claim but not the NEJM leak.

What can we learn from all of this? The following seems to be the overall chronology based on what's been made public:
  • 2007: Dr. Haffner is on the faculty at University of Texas-San Antonio medical center. If you Google him you'll see right off the list of drug companies for whom he's a paid speaker and consultant. Being a GSK paid consultant, one day after being sent the manuscript of Nissen's paper on Avandia by the NEJM, he faxed a copy of the "confidential" manuscript to his pals at GSK.
  • 2008: Brian Vastag writes about the Haffner case for Nature (see: Haffner tells Vastag he's really sorry for the slip-up; he was not feeling well that day and he made a bad decision.
  • 2008-2010: There is some muffled noise about both NEJM and UT-San Antonio investigating Dr. Haffner for this breach of editorial ethics. If there is any outcome, nobody says anything.
  • 2009: Dr. Haffner "retires" from UT-San Antonio. Possibly this has something to do with the above investigation? If so nothing is said.
  • 2009: Baylor College of Medicine in Houston hires Dr. Haffner as a part-time assistant professor. A Baylor spokesperson, in the context of the more recent flap, says that Baylor knew about the NEJM leak matter when they hired him and accordingly, hired him only part-time and only for limited activities related to his special expertise in clinical epidemiology of cardiac risks. Here we have some evidence of real consequences, even if people are not saying why. At San Antonio, Haffner had apparently held the rank of (full) professor, having been on their faculty since 1981. To be hired on by Baylor at the rank of assistant professor would seem like a pretty severe slap in the face.
  • July 2010: The Grassley subcommittee accuses Haffner of ghostwriting, and Baylor says it will investigate. (GSK, as you'd expect, claims that Haffner "contributed substantially" to the article he was said to have ghostwritten and so no ghostwriting occurred.)

So there is at least a chance that up to this point, Dr. Haffner has actually suffered some significant consequences; and there's a fair chance he stands to suffer more. In which case he'd be first case I know of that we can report thusly.

A personal disclaimer: some might imagine that I get my jollies from berating and outing my fellow academic physicians, not to mention those who are fellow members of the U-Texas System faculty. The fact is that any such naming of names is extremely distasteful and I wish I could see my way clear to avoiding this aspect of the whole mess. Why can I not see my way clear? Because if the root problem is that people engage in these unethical actions but nevertheless advance in their climb up the academic ladder; and in academe, one's good reputation is the main coin of the realm; then if you are not willing to name names, you are unfortunately perpetuating the very problem you seek to ameliorate. I heartily wish it were otherwise.

Sunday, July 25, 2010

AAFP and Coca-Cola, Continued: How I Just Spent $100

Let me recommend to you that you consider spending a bit of your own money in the way that I just spent $100.

I received an e-mail from Richard Bruno, med student, Class of 2013, Oregon Health & Science University. He responded to my recent published commentary on the AAFP-Coca-Cola controversy and added that he was a member of a group of students, representing a number of medical schools, that are planning an action at this weekend's meeting of students and residents interested in Family Medicine at the AAFP headquarters in Kansas City. He asked me to donate $100: "Specifically we want to set up a table, pass around a petition, have buttons and stickers, and have people sign postcards that we will send to the AAFP board of directors. We are very passionate about ending this conflict of interest and exploring healthier partnerships for the sake of our members and our future patients....$100 could provide us with 300 postcards, 100 buttons, and 100 stickers to pass out at events and at a table."

When I replied to indicate my interest, he informed me of two ways to get him the money: 1) send a check to Richard Bruno, 2164 NW Aspen Ave, Portland, OR 97210; or 2) send the money via PayPal to

Now, I am an old-fashioned skinflint, and generally parting with a hundred bucks would not leave me in a good mood. So why am I so upbeat about this particular expenditure? First, I am quite impressed (as readers of this blog know) at the immense power that med students have exerted in the conflict-of-interest debate generally, as evidenced most impressively by the AMSA Pharm-Free campaign and their brilliant PR ploy of "report cards" giving med schools failing grades if they allowed too much coziness with the drug industry. I can testify as to how much stock AAFP puts in the student/resident contingent, as that is the entire future of our specialty, so these folks can get the attention of the AAFP leadership in a way that old fogeys like me never could. Finally there is the donation multiplier effect of the fact that med students work incredibly cheap. A dollar donated to a student group goes a long way farther than a dollar donated to a group of, well, people like me.

So go get 'em, Richard and friends, and let this blog hear from you how the meeting goes in Kansas City!

Friday, July 23, 2010

What's New In Pittsburgh? Current Status of Physicians and Drug Industry Cash

So--for the past few years some of us have been hammering away at why it is ethically bad news for docs to take cash from drug companies for activities such as speakers' bureaus. How are we doing? A longish report by Kris Mamula in the Pittsburgh Business Times:

--provides us with some clues.

First, Mamula is able to report payments to docs in the Pittsburgh area made by four large drug companies that either voluntarily released data or are doing so under legal pressure from litigation. It's noted that 8 other large drug firms currently have no such disclosure. The article as a whole in my view is reasonably balanced but with a slight tilt against the practice of commercially-paid speakers.

What seems to give us a clue as to the current situation is some of the comments from docs, handing out the same tired rationalizations we have been hearing for decades. Dr. Anthony Gentile, an ob-gyn and top pocketer of company funds ($89K) in the Pittsburgh area, said: ...the notion that drug companies could influence doctors’ prescribing practices [is] “total, unequivocal hogwash.” “People think we get up there to push this drug or that drug,” Gentile said. “That’s not what we do. We just say this is something you should consider. We educate, and that’s what I have a big passion for.”

From Dr. Lawrence Glad, a Uniontown-area gynecologist who came in at third-highest-paid at $74,916: “Yes, it’s promotional, but it’s educational...I think we have some critical skills for our patients beyond who bought my last bagel.”
Glad made presentations in small towns, including Parkersburg, W.Va., where doctors have few opportunities to learn about the latest developments in medicine. These aren’t people “who can walk down the hall and hear nationally known doctors,” he said. “These are people who are lucky if they can get to one conference a year.”
At least Dr. Glad was willing to admit that it's both promotional and educational--that's a step ahead of the old bromide, "it's not marketing, it's education."

Said Dr. Michelle Roberts, an endocrinologist and faculty member at the University of Pittsburgh School of Medicine: she takes her teaching role seriously at drug company sponsored sessions and always receives approval from her supervisors. Last year, Roberts received $8,525 to discuss the Lilly drug Forteo, used to treat people with severe osteoporosis.
Her purpose during the session was teaching, not selling, she said.
“I’m an educator, and my role is to better educate physicians about how to care for women with osteoporosis,” she said. “I would not compromise my job or integrity to sell drugs for Eli Lilly. I’m not a puppet for the drug companies.”

Psychiatrist and Allegheny County Medical Society President Dr. John Delaney, who received $69,350 from Lilly last year, said the money he receives from Lilly doesn’t affect his prescribing practices.
“The transparency has made it look like a bad thing, but I’m not embarrassed about it. I’m a big speaker for them....You end up prescribing the best drug at the time, regardless of the affiliations you have. I think all of us feel that way.”

Unfortunately, if these local docs seem to be in denial about the likelihood that their taking company money might influence their own prescribing or the message that they "educate" about, the official policies adopted by the local medical centers seem to compound the problem. For example, the University of Pittsburgh Medical Center's conflict of interest policy says: faculty members “may participate as speakers, provided that they prepare their own content without any control or approval of the content by industry.” What the policy ignores is that any faculty who actually follow this advice are likely to be in serious hot water with the Feds. If you take money from the company, you're considered a company employee, and are bound by the same rules for what you can and cannot say in marketing a drug--especially about off label uses--as is the company as a whole. Get off message and you're likely to find yourself facing Federal criminal charges. So the idea you have have your cake and eat it too--take the money but also maintain your independence as an academic physician--is sadly mythical.

The better advice comes at the very end of the article: For many years, Dr. John Walsh, distinguished service professor of urology at Johns Hopkins Medical Institutions and a critic of some drug company funding to physicians, said he has long told students, “You can have your money or you can have your reputation, but you can’t have both.” If the remainder of the article is any indication, many docs in Pittsburgh have not yet gotten the message; and their likelihood of having gotten the message seems inversely proportional to the amount of money accepted from drug firms.

Wednesday, July 21, 2010

Docs for Sale: The FDA Advisory Panel on Avandia

Thanks in part to Postscript, I was guided to two articles by Alicia Mundy in the on-line Wall Street Journal:

It appears this story has kept investigative reporter Mundy quite busy in the wake of last week's FDA advisory committee hearings on Avandia. Most of you know from the popular press that the committee voted 20-12 to keep Avandia on the market, though 17 of the 20 favored stronger warning labels or other measures to restrict use of the drug.

First Mundy found out that Philadelphia endocrinologist David Capuzzi, who was one of the three lonely members of the committee to give Avandia a free ride (keep it on the market without any extra warnings), had received $14,750 as a paid speaker from Avandia's manufacturer, GlaxoSmithKline. He argued that he had no conflicts of interest because he never gave any talks specifically about Avandia; instead he spoke about a different GSK drug.

Hardly was the ink dry (metaphorically; I know nobody writes with ink anymore) on that report than Mundy was out there again telling us about Abraham Thomas, head of endocrinology and diabetes at Henry Ford Hospital, Detroit. Thomas had been one of the 12 votes for taking Avandia off the market. He'd given two talks for Takeda, the manufacturer of the diabetes drug Actos, on behalf of that drug and made $2000-3000, between 2007 and 2008. Actos is the rival to Avandia that is the drug most patients are likely to be switched to if their physicians take them off Avandia and look for a similar drug to replace it. Dr. Thomas said he told the FDA all about his Takeda money and noted that the conflict-of-interest screening he'd been put through before this committee met was "extensive."

By way of exploring the dynamics of drug company funding of medical KOLs ("key opinion leaders"), consider what Dr. Capuzzi had to say to Mundy in his own defense. First, he said that even though he had voted in the most pro-Avandia way possible on the panel, he really did not think very much of that drug. He told Mundy "he isn't a fan of Avandia and uses metformin, an older diabetes drug, in his practice." [Hooray! An endocrino9logist, finally, who actually believes that you should treat diabetes patients with a drug that has been well-documented, in controlled studies, to reduce the risks of the serious complications of diabetes; and that's available generically to boot.] So why then did he vote to be so careful not to upset Avandia's role in the marketplace? Well, he said he was worried about Actos. He's worried that the rival drug may also have safety problems, and that switching patients from one to the other would do them no good.

Now, we can note two things about this line of reasoning. First, his opinion about Actos-related dangers is definitely a minority opinion; the panel overwhelmingly voted that Actos was safer than Avandia. Second, a standard industry ploy, when your drug is accused of causing bad side effects and your previous efforts to ward off attention to those effects have all failed, is that as a last-ditch effort you try to claim that so what, all the rival drugs cause the same risks. (That's why we now have a totally ridiculous warning label on Naprosyn claiming that it increases the risks of heart disease, because that was supposed to divert attention from whether Celebrex caused almost as much heart risk as Vioxx.)

Bottom line: Can we prove that Dr. Capuzzi voted the way he did because he was paid by GSK? Of course not. Can we claim a certain association between a doctor taking money from a drug company speaker's bureau, and the doc demonstrating patterns of thought that happen to resemble how industry marketers think about drugs? You be the judge.

Bottom bottom line: What is it going to take to get my fellow physicians, when a drug company waves dollar bills at them and invites them to join the speakers' bureau, to say, "No thanks, who needs that grief"? So that when Alicia Mundy goes to write her next story about unseemly behavior among highly-regarded professionals, she has to go write about lawyers, or politicians, or somebody other than doctors?

Tuesday, July 20, 2010

More on the AAFP-Coca-Cola Controversy

Since last fall I have been conducting my debate with the leaders of my own medical professional society, the American Academy of Family Physicians, within full sight of the readers of this blog. I submitted a long article (just out this week) to the AAFP academic journal, the Annals of Family Medicine, explaining at some length my disagreement with the leaders' decision to accept funding from Coca-Cola for patient education materials on obesity prevention:

Not unreasonably, the Annals elected to offer the AAFP leadership, namely President Lori Heim, a chance to respond, which she did:

I was not able to review the contents of Dr. Heim's rebuttal until the publication date earlier in the week. I then prepared my response which I have submitted to the journal's on-line TRACK discussion feature (meaning that if there is further give and take you can follow it on the Annals website, which has free open access). As the journal has to make up its mind before they decide whether to publish my response, I append it below.

A Reply to Dr. Heim

Dr. Heim (1) takes issue with my criticism of the AAFP and its leadership for accepting Cola-Cola funding for patient education materials (2) on the following grounds: It cannot be the case that appearance of a conflict of interest (COI)—“a person’s perception of another’s behavior—even absent relevant information related to the behavior or its outcome” (1, p. 359), is ethically the same as an actual COI. It must be the case that an appearance creates nothing more than a rebuttable presumption of possible ethical misdeeds. In the AAFP’s case, the careful and responsible way that the organization went about dealing with the funds—full disclosure, demanding editorial independence, etc.—successfully rebuts any presumption of unethical action. So, in accusing the AAFP of an ethical lapse, my criticism is not suitably evidence-based (“Dr. Brody has failed to bring forth evidence that the TCCC contract interfered with the AAFP’s ability to meet its mission”; (1, p. 360)).

On its surface this rejoinder appears quite reasonable, so it will require a bit of stepwise analysis to show why I believe that it ultimately fails to prove the point that Dr. Heim wishes to argue.

In my essay (2) I offered a definition of COI: that it arises “when individuals or organizations enter into a set of arrangements which under usual circumstances would lead to the reasonable presumption that they will be tempted to put aside their primary interests…” (2, p. 355, emphasis added). If this happens, according to the definition, we have not an apparent COI but an actual COI. Notice that part of what makes it a COI is that a reasonable onlooker would reasonably judge that the arrangements entered into by the organization would normally and naturally tempt it to forgo its primary commitments (in this case, to promoting the public health). It is not enough that the onlooker has a mere uninformed “perception” as Dr. Heim puts it (1, p. 359).

The majority of the people I am aware of outside of the AAFP leadership who have heard about the Coca-Cola deal concluded immediately that the arrangement could not pass what would vulgarly be called the sniff test. That is, they decided that receiving a “strong six figure” sum from Coca-Cola would reasonably be expected to cause an organization like AAFP to deviate from its mission of strong advocacy for the public’s health. Put another way, they wondered why Coca-Cola would spend that much money to support a patient-education program that AAFP supervised. Coca-Cola is not, after all, a non-profit or a charitable foundation. One could argue that the company is obligated to its shareholders not to spend that sort of money unless they could be quite sure that something of benefit to company sales was going to result. In effect, Coca-Cola was saying through their corporate behavior that they expected commercial benefit from this deal, whereas AAFP was insisting that no such benefit would accrue and that the result would be strictly a contribution to the public’s health. The onlooker might well decide that of these two accounts, Coca-Cola’s was the more plausible.

I assert that the fact that the AAFP entered into this arrangement with Coca-Cola, when reasonable onlookers would reasonably have this reaction, constitutes an actual COI. The reason is because of the link that I described between COI and one’s ability to maintain public trust (2). By entering into this deal, AAFP knew or should have known that it was placing itself in a position where the public’s trust could easily be compromised.

To risk public trust in this fashion is to take a serious gamble. We next need to ask what prompted AAFP to take such a gamble. If the only way to secure support for patient education materials was to get the funding from Coca-Cola, then we might have a reasonable rebuttal to the charge of COI. But the AAFP has come nowhere close to showing that it had no other choices of where to raise the funds.

Dr. Heim goes on in her commentary to list things that AAFP has since said about the dangers of drinking beverages that contain too much sugar. Presumably those statements count as actual “evidence” on the basis of which AAFP should be judged, while the criticisms lodged against AAFP last fall, when the deal was first announced, count only as “early, uninformed reaction” (1, p. 360). She adds that I “[offer] no evidence of long-term harm resulting from” those “uninformed” reactions (1, p. 360).

As a long-time member of AAFP, I am frankly delighted that I can offer no hard evidence of long-term harm to the trust that the public presumably feels toward AAFP. In the past year or so we have had two examples of organizations that have discovered “evidence of long-term harm” in terms of widespread public distrust created by their actions—Toyota and BP. I presume that Toyota and BP have each discovered what most of us already know, that it takes much less time and effort to lose public trust than to regain it once it is lost.

Last fall AAFP took a gamble with its reserve of public trust by signing the “six-figure” deal with a soft drink company. So far, the gamble appears to have worked out all right. Could one have been so sure, back in the fall, that this would have been the outcome? What sort of pressing need could have justified AAFP taking this sort of gamble with its most precious resource? Since it has been lucky so far, what sorts of even riskier gambles will it decide that it can take in the future? My argument is that AAFP is ethically accountable for such decisions, and that its ethical reasons are wanting thus far.

1. Heim L. Identifying and addressing potential conflict of interest: a professional medical organization’s code of ethics. Ann Fam Med. 2010; 8:359-361.

2. Brody H. Professional medical organizations and commercial conflicts of interest: ethical issues. Ann Fam Med. 2010;8:354-358.

Are DSMBs Independent? NEJM Worries Not

In previous posts, such as:

--I have expressed the opinion and concern that the data safety and monitoring boards (DSMBs) that are supposed to be an independent check on the conduct of a randomized controlled trial--for example, stopping a trial early if there is excess mortality among one study group--may not be as independent from the commercial sponsor of a trial as is officially stated. The reasons I thought this might be true were:
  • Anecdotal comments from friends closer to the ethical review of clinical trials than I am
  • The strange coincidence that a number of recent decisions by DSMBs to stop trials early seemed suspiciously favorable to the marketing aims of the drug company paying for the trial
As neither of the above is any sort of solid evidence, I had no really good grounds to express concerns. I therefore am happy to see that I appear to be in good company. The New England Journal of Medicine (subscription required) has published an editorial on-line by its editor, Dr. Jeffrey Drazen, and by drug industry expert Dr. Alastair J.J. Wood. The editorial describes two specific instances in which the integrity of the DSMB process appears to have been compromised. The editorialists therefore call for new steps to assure stricter firewalls between the management of the DMSB and the trial sponsor. They conclude, "For too long, sponsors of trials have considered the DSMB a necessary nuisance whose strings they can pull at will."

Drazen JM, Wood AJJ. Don't mess with the DSMB [editorial]. New England Journal of Medicine (10.1056/NEJMe1007445), epub July 7, 2010.

Monday, July 19, 2010

Watch Out When These Foxes Guard the CER Henhouse

I've been getting e-mailings recently about a conference to be held in Washington, on July 22, called "Delivering on Patient-Centered CER" (Comparative Effectiveness Research). This is sponsored by the group, Partnership to Improve Patient Care ( No less a light than Sen. Max Baucus will be a keynote speaker.

This conference will bear close watching for reasons that I have previously posted about ( PIPC is funded in part with Pharma money and in part by medical specialty societies such as the American College of Cardiology, whose motto is, "Do all the CER you want so long as you don't take away any procedures that bring profits into the coffers of cardiologists." (The ACC's CEO is also one of the featured speakers at this conference.) Their clear agenda is to steer CER away from any research that would actually be used to save money in patient care, and hence cut into corporate or specialist profits. By pushing the language on CER that was in the Senate version of the health reform bill (instead of the House language which was more friendly to real cost containment and kept industry out of the CER picture) , Sen Baucus did a signal service to this "partnership," and will no doubt be appropriately thanked at the conference.

With these kinds of foxes watching over them, I am sure that the CER hens will sleep more comfortably at night.

Follow-up on the FDA Avandia Hearings: "GlaxoSmithKline...can't be trusted"

I have not been posting specifically on the FDA Avandia hearings of this past week, focusing rather on some important background that I believed the popular media were missing. The gap was very nicely filled by my esteemed colleague Roy Poses over at Health Care Renewal blog, whose comprehensive and thoughtful post I commend to your attention:

As to one of the main findings that came out of the hearings, the degree to which the manufacturer twisted and turned with the data to prevent bad news about Avandia from seeing daylight, one main bit of news coverage is by Gardiner Harris in the New York Times:

And the quote with which I began this post about "can't be trusted" is taken from a New York Times editorial:

Saturday, July 17, 2010

A Side Trip into Diabetes: Selling the Wrong Disease Model

This blog is about the ethics of the relationship between medicine and the pharmaceutical industry. Sometimes it seems that it is also about cholesterol and statin drugs. I've posted a lot on the latter subject because I think that the controversies over statins highlight a number of issues pertinent to the subtle effects of the drug marketing system on medical practice. Ditto for my occasional comments on why the serotonin model of depression is so widely believed even though research has thoroughly debunked it. Based on this and previous posts, I will now have to add Type 2 (adult) diabetes to my list of "regular side trips."

I have also had occasion in many previous posts to tip a hat to my friends Rick Bukata and Jerry Hoffman of Primary Care Medical Abstracts. (A footnote about them at the end.) For their June edition Rick and Jerry decided to go on vacation and turn their audiotaping over to two other good friends of mine, Gary Ferenchick (internal medicine) and Henry Barry (family medicine) at Michigan State. Most of the rest of this post is prompted by some of Gary and Henry's discussion.

One of the articles Gary and Henry reviewed was by a team out of Cardiff, Wales headed by Craig J. Currie, and interestingly enough including some people from Eli Lilly, in Lancet (subscription required). Basically the article addresses the fact that most diabetes treatment guidelines act as if lowering blood sugar--or lowering the hemoglobin A1C, which measures blood sugar trends over the long haul--is the be-all and end-all of Type 2 diabetes treatment, and the lower the A1c the better. Currie's team did a retrospective cohort study, which as such is unable to prove cause and effect. But its results jibe with many other controlled trials, all of which showed no outcomes benefit in Type 2 with tighter control of blood sugar, but an added risk when blood sugars are dropped too low by medication.

Currie's gang plotted all-cause mortality against A1C levels in nearly 50,000 older adults followed over a 20-year period. The graph they should have ended up with if the guidelines are correct would be a straight line downward toward the left, with fewer deaths the lower the A1C. What they actually found was a U-shaped plot, where the best overall A1C was about 7.5%, and death rates went up on either side. One scary feature of their diagram was that if you had a hemoglobin A1C of 6.5, generally considered "excellent blood sugar control," your death rate was actually higher than if you had a level of 9.5, which today would be viewed as rotten blood sugar control.

My pals Gary and Henry went on to chat at length about the new pay-for-performance systems whereby the amount of money docs get from insurance companies or Medicare depends on how well you meet various "quality indicators" set by current guidelines. A physician who practices according to what Gary, Henry, and I would consider to be the best available evidence on diabetes Type 2 would probably mostly ignore blood sugar anyway, and stress smoking cessation, lifestyle changes (especially exercise), and aggressive management of heart-disease risks (especially blood pressure control). If this evidence-based physician did pay attention to blood sugar, she would aim for a moderate A1C of around 7.5, as indicated by the Currie research. Many pay-for-performance programs, by contrast, would ding the doc for having patients above 7.0 and would pay a bonus only for patient who were below 7.0 A1C. So basically you have physicians being paid a bonus for putting their patients at higher health risk, all in the name of so-called "evidence-based" guidelines.

Two basic take home messages here. First, as we have been ragging about in the Avandia case, how did the basic disease model of "Type 2 diabetes = problems with high blood sugar" continue to gain such a powerful hold over the minds of physicians, biomedical scientists, and policymakers, when the best evidence today says rather that "Type 2 diabetes = increased cardiovascular risk, not necessarily made any better by tight sugar control"? Is it just a coincidence that the first model sells a lot more drugs than the second model? Is it just a coincidence that the marketing juggernaut of Big Pharma sides squarely with the first model and wants us not to hear about or think about the second?

The second take-home message is the unholy alliance between industry interests and the push to pay-for-performance. The P4P movement seems on the surface to be a no-brainer. Why pay docs for providing bad care when you could pay them only for providing good care? The devil-in-the-details of course is agreeing on what good care is and measuring it accurately in the real world. There, you create a drug marketer's paradise. In olden days the drug company could sell a drug like Avandia only by marketing individually and persuading (also known less delicately as "bribing") 800,000 free-range physicians in the U.S. Today, you can kiss off 799,00 of those guys and just focus on bribing 1000 docs--so long as you can get to the ones who write the P4P guidelines. Then you have the interesting coincidence that all the guidelines fly in the face of the most persuasive studies by still harping on blood sugar control; and that a majority of the writers of the guidelines happen to be paid speakers and consultants for the drug companies.

Thus we are back to Avandia, which as all readers no doubt know by now dodged the FDA advisory committee bullet this past week and will no doubt remain on the market. The stories in the media all say how Avandia was once the best selling diabetes drug and now has fallen on hard times due to fears of excess heart risks. None of the stories address the core question, How the heck did Avandia ever get to be the top-selling drug for Type 2 diabetes, when no study ever showed that it reduced any long-term cardiovascular risks from diabetes? The only way this could happen was for the industry first to"sell" medicine and the public a false model of the disease--which they seem to have done very well. They've done it so well that a doc who actually tries to practice evidence-based diabetes care will probably go broke under P4P, and will have his patients leave in droves because he won't recommend that they all get their free glucometers that are advertised all over daytime TV.

The footnote I promised is that Gary and Henry began their audiotape with a plea to Rick and Jerry that I would strongly second, even though I am sure it is futile. The three of us are all former faculty in the Primary Care Medical Abstracts CME courses. These courses were a lot of fun to teach, attempted to present evidence-based medicine, and were completely paid for by the attendees' registration--no drug company advertising of any sort. As you could guess, when all the competing CME courses were heavily subsidized by drug dollars, Rick and Jerry eventually had to quit offering these courses to primary care docs due to low enrollment. (As embarrassing for me as a primary care person to admit it, the ER docs still manage to pay for their own CME through the emergency medicine courses that Rick and Jerry continue to teach.)

Currie CJ, Peters JR, Tynan A, et al. Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. Lancet 375:481-89, Feb. 6, 2010.

Monday, July 5, 2010

Drug Safety Decisions--How Hard It Is to "Get It"

Here's a column by David Lazarus in the Los Angeles Times about Avandia:,0,1359952.column

Not being a regular reader of his column, I know little about Mr. Lazarus; but I assume from this specimen of his writing that he's a reasonably intelligent and perceptive individual. This makes it all the more discouraging how little he "gets it" with regard to what the real deal is about Avandia.

I'll discuss two assertions in his column. First, Lazarus seems to think it's a simple tradeoff of how much research you do pre-FDA-approval to discover potential adverse effects of drugs, vs. how much you hurt patients by delaying the approval of a potentially useful drug. That is, if you took long enough to do the pre-marketing research, you would find all major adverse reactions.

Experienced physicians know this ain't so, which is why there's the common folk wisdom among more conservative docs of waiting a year or two after a new drug is introduced before you start prescribing it for your own patients. Pre-marketing research always involves a limited number of patients compared to how many are exposed to a drug after it is being widely sold. A serious adverse effect that occurs 1 in 1000 times, for example, is very likely to be missed even in very intensive pre-approval research, yet once the drug is being sold, such a side effect might well be seen as fully sufficient reason to pull a drug off the market.

Even if the trade-off was as simple as Lazarus seems to think, he gets the politics all wrong. At the end of his column he advocates a policy shift that as soon as "credible" safety concerns are raised, the FDA should declare "an immediate moratorium on sales....If a drug becomes unavailable for a matter of months or even years, so be it."

Lazarus ignores the likelihood that neither the drug company nor patient advocacy groups (which in some cases will be joined at the hip financially) are likely to be in a "so be it" frame of mind. The industry will pull out all the stops to mobilize their "grass roots" to storm Congress and shriek that people are dying because this wonderful drug is suddenly unavailable. (As happened when new AIDS drugs were delayed in being released in the late 1980s, in that case by legitimate grass roots advocates and not by industry, which is why the FDA has its present policies in place that favor quick approvals.)

The other major issue that Lazarus doesn't get with regard to Avandia is why it is a bad drug and indeed could have been predicted to be a bad drug much sooner than it has been. Lazarus says that he's a Type 1 diabetic and so is not a candidate for Avandia in any case. That means he has a kind of diabetes where a drug that lowers your blood sugar provides positive health benefits. As I have tried to explain in numerous earlier posts, the main problem with Avandia is that it lowers your blood sugar but has never been shown to improve any other diabetes-related outcome. Type 2 diabetes has been now proven to the satisfaction of just about everyone except doctors who treat diabetes to be a disease whose outcomes are largely unaffected by tighter control of blood sugar levels. That means that blood sugar is what the evidence gurus call a "surrogate endpoint" and while a huge marketing tool for the drug company, ideally ought to be ignored by the medical community when deciding whether to recommend any new drug.

If a drug actually did something good for Type 2 diabetes, and as a downside it increased your risk of a heart attack by 43% (the figure Lazarus quotes for Avandia), then again you'd have a trade-off problem of the sort that Lazarus envisions. You'd have to decide if the benefit was worth the risk. The reason Avandia should have been yanked off the market the second there was even a whiff of a hint of increased heart risk was that in the face of no known (real patient-oriented) benefit, any risk is too high.

The short answer--the drug company bamboozled us twice about Avandia. First they conned us into thinking the drug was useful. Then they delayed us becoming aware of the downside risks of heart problems. Lazarus thinks he got un-bamboozled by figuring out the risk part of the equation. He's still bamboozled on the benefit side.

How would a person like Lazarus really figure it out with a complicated case like Avandia? Of the various books on the subject, the best I know on this particular matter is Jerry Avorn's Powerful Medicines. Avorn harps on how all judgments about pharmaceuticals necessarily hinge on judgments about benefits, risks, and costs, and all parts of the equation must be included. He also argues for a more flexible, sliding-scale FDA policy that can do a better job of approval than the simple "yes-no" the FDA now has as its only option. But, while Avorn's book is in fact quite correct and comprehensive, and while it offers a number of fine phrases here and there that I wish I had written, I have to say that overall it is a really tough slog. So you can see why even highly intelligent writers like Lazarus might not get it in the end.