Sunday, August 31, 2008

The FDA, Preemption, and Drug Safety

Two items came to my attention this past week that are worth pondering in tandem. Item #1 I might as well shamelessly lift from the Prescription Project 27 August weekly reader e-mail notice:

Label liability?

And now to Washington, where this week the FDA finalized a rule that will make it tougher to update a drug label to reflect warnings and side effects.

According to the BNA Health Care Daily Report:
“The final rule published in the Aug. 22 Federal Register (73 Fed. Reg. 49603) allows manufacturers to submit a supplemental application to amend the labeling for an approved product to reflect newly acquired information and to add or strengthen a contraindication, warning, precaution, or adverse reaction if there is sufficient evidence of a causal association with the product.

‘Expressly requiring that a CBE supplement reflect newly acquired information and be based on sufficient evidence of a causal association will help to ensure that scientifically accurate information appears in the approved labeling for such products,’ the FDA said.

Critics are saying that the rule adds up to immunity for drug makers, who would no longer have to warn consumers about drug risks or new side effects without proof of causation and newly acquired information. The American Association for Justice, which holds the new rule protects drug manufacturers, told the BNA the FDA’s decision “leaves the drug and device companies too much discretion in determining when to include safety hazards on warning labels."

Item #2 is the amicus brief filed by the editors of the New England Journal of Medicine in the case of Wyeth v. Diana Levine, opposing federal preemption of state law ( The issue is the pharmaceutical industry's claim before the U.S. Supreme Court that no one should be able to sue them for product liability in a state court, because the FDA law at the federal level preempts state jurisdiction, making drug safety a federal and not a state responsibility. The factual claim put forth by the industry is that the FDA does a splendid job of monitoring new drugs for safety; that no further consumer protection via tort law is needed; that a company that markets drugs in accord with the FDA label for that drug should be immune from tort lawsuits if the drugs later cause harm; and that permitting the current system in which consumers may sue the industry for damages presents a hazard to the industry's financial well-being and a threat to the future public health.

To all of the the NEJM says hogwash, and proceeds to offer a detailed look at several recent drug safety debacles, where the firm clearly connived to suppress data showing safety problems for profitable drugs, particuarly Redux, Vioxx, and Trasylol. The NEJM brief concludes that there is ample evidence that the current FDA review system is flawed and needs as much help as it can get from the possibility of a tort lawsuit (which, as noted on this blog as well as in HOOKED, has the additional virtue of forcing the company to cough up internal documents that otherwise would remain secret, and that are often our only way to see what the companies are really up to). There is no evidence at all that the industry cannot handle the risk of tort suits or that the public health is in danger from overzealous warning about drugs that really are safe. (Indeed, one of the strongest arguments against allowing tort lawsuits for product liability to continue, is that under the current system, these threatened suits obviously do very little to get the industry to shape up.)

The way I put these two items together is to note that one might think that just when the Supreme Court of the U.S. is about to rule on preemption, the pro-industry folks would not want to provide even more blatant evidence of the weakness of the FDA warning and labeling system. Yet as Item #1 shows, that seems to be exactly what is happening right now. I can only make sense of the timing if I suppose that the pro-industry people inside the FDA leadership, or the pro-industry people in the White House, or both, are in a hurry to be sure that industry friendly measures are enacted during the Bush watch--with the prediction that either a McCain or an Obama White House would be rather less industry-friendly.

Friday, August 22, 2008

The ADVANTAGE Revelations: Seeding Caught in the Act

Apologies to faithful readers for my slowness in posting the big news of the week (that darn day job again). The Annals of Internal Medicine made rather a big deal of their publication of Merck company documents showing that the ADVANTAGE trial of 2003, comparing gastrointestinal side effects in Vioxx (rofecoxib) vs. naproxen, was really a seeding trial. You might wonder why the big deal, given that the phenomenon of the seeding trial (a clinical trial whose real purpose is to stimulate many practitioners to prescribe a new drug, rather than to answer any scientifically pertinent question) has been widely described previously, including in HOOKED. Was it merely a mea culpa because Annals was hoodwinked into publishing ADVANTAGE in the first place? However, a closer look shows that it is indeed valuable to have the smoking gun laid out for inspection.

Merck did the usual sputtering when questioned by the media. According to Bloomberg (, Jonathan Edelman, Merck scientific affairs director, said: "As with all Merck clinical research, there is a commercial interest ... The documents included in this article include an example of the marketing use for the data. The allegation by the authors that the primary goal of the study was marketing is simply wrong.''

Let's see how the original documents brought to light in the Annals article (all resulting from the Vioxx litigation, and seen initially by the authors because of their role as paid consultants to the plaintiffs in that litigation) stack up against this Merck protest. A key memo dated 1/4/99 was a nomination of the designers of ADVANTAGE for the company's Best Physician Program Award. This is one of the marketing annual awards and the people nominated are all from the Marketing division. The memo goes on to justify the nomination by saying: "The trial was designed and executed in the spirit of the Merck marketing principles... The sales force nominated potential investigators and completed intake forms, allowing a very large number of sites to be evaluated and enrolled and ensuring equal distribution of investigators across the business groups. ... Finally, the results of the trial are being carefully tracked. An analysis performed at 6 months post launch demonstrated a significantly higher level of prescribing for VIOXX among primary care ADVANTAGE investigators compared to a control group..."

Okay, let's see if I've got it so far. The investigators for the trial were chosen by the sales force. The main goal was to insure that these investigators represented as broad as possible a selection from those to whom the company looked for its later profits. When the company set out to analyze the data from the trial, they did not look at the way Vioxx performed against naproxen in terms of stomach symptoms; they looked at how many Vioxx prescriptions the investigators wrote. So far no mention at all of anyone or anything related to the scientific trials division of Merck.

ADVANTAGE was designed so that each "investigator" enrolled around 6 subjects in the trial, meaning that 600 doctors were eventually recruited to involve 5557 patient/subjects. That might seem an inefficient way to run a scientific trial. But it's a great way to assure that more docs get used to writing prescriptions for Vioxx.

Mr. Edelman also insisted to Bloomberg that the study was conducted by the medical and scientific affairs unit, not the marketing unit. The next original document laid out for our inspection is a slide from a presentation that describes the role of Merck's Clinical Development Program, a part of the marketing division, in ADVANTAGE:
  • Design protocol and oversee execution of trial
  • Select investigator sites
  • Run investigator meetings
  • Choose and manage [contract research organization]
  • Perform data analysis
  • Prepare publications
All right, I give up. Exactly what is left over for the "scientific" division to do, after Marketing has done all of this? It walks like a seeding trial, it looks like a seeding trial, it quacks like a seeding trial...

The first author of ADVANTAGE was Dr. Jeffrey R. Lisse of the University of Arizona. Dr. Lisse had already felt heat (as explained in HOOKED) when it was shown several years ago that ADVANTAGE conveniently concealed a few cases of coronary disease that occurred among the Vioxx subjects. Dr. Lisse, contacted by the New York Times, was then forced to admit that he had had nothing to do with the data analysis or the writing of the first draft of the trial report, and that this was the first time he had heard about any cases suspicious for coronary disease. That is, he had to admit that the ADVANTAGE trial report was ghostwritten. When Bloomberg tried to contact Dr. Lisse for comments about these new seeding-trial revelations, they discovered that he was unavailable and on medical leave.

So in the end, the protestations of Merck seem pretty lame when laid aside the documents revealed. I have not checked out all the industry-friendly blogs, but I would imagine that the company's next line of attack will be to accuse the authors of an unacceptable conflict of interest (funny--sounds familiar) because they were paid by the plaintiff's attorneys who were suing Merck. That is indeed a problem (though the paper makes clear that a rigorous method was followed in analyzing the documents). The solution to the problem is for the drug industry to be more open and forthcoming with this sort of documentation. If they did not do such a good job of hiding these internal documents from scrutiny, then independent investigators who were not part of a lawsuit might someday get to see them.

Lisse JR, Perlman M, Johansson G, et al. ADVANTAGE Study Group. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med 139:539-46, 2003.

Hill KP, Ross JS, Egilman DS, Krumholz HM. The ADVANTAGE seeding trial: a review of internal documents. Ann Intern Med 149:521-58, 2008.

Sox HC, Rennie D. Seeding trials: just say "no." [editorial] Ann Intern Med 149:279-80, 2008.

Sunday, August 17, 2008

The Antidepressant Warning Affair: What Really Happened?

This tale unfolds in three chapters:

Chapter One. Critics of the pharmaceutical industry amass evidence that trials showing an excess risk of suicidal behavior among children and adolescents taking many serotonin-type (SSRI) antidepressants had been suppressed for many years. Responding, regulatory agencies in the US and Europe issue label warnings on SSRI drugs (except for fluoxetine or Prozac) for pediatric use.

Chapter Two. The prescriptions of SSRI's for children decline. Studies are then published by child psychiatrists claiming to show that the immediate result has been a worrying upsurge in suicides among young people. The authors claim that what has happened is typical of regulatory excess, and that while a few cases of suicidal behavior may have been caused by these drugs, their widespread use in kids clearly prevented a far greater number of suicides from occurring--prevention that has now ceased as physicians are scared off by label warnings from using these drugs even where they could save lives. The industry critics then note, first, that many of these rise-in-suicide studies are poorly designed (for instance, assuming a decline in prescriptions but actually having no data to prove that); and second, that many of the authors of these Chapter Two studies have financial ties to the industry.

Lineberry TW, Bostwick JM, Beebe TJ, Decker PA. Impact of the FDA black box warning on physician antidepressant prescribing and practice patterns: opening Pandora's suicide box. Mayo Clin Proc 82:518-20, 2007.

Gibbons RD, Brown CH, Hur K, Marcus SM, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 164:1356-63, 2007.

Chapter Three. More extensive and better designed studies appear from non-industry-funded sources. Olfson and Shaffer, for instance, note that the data Gibbons et al. relied on was a brief uptick in suicide rates at a single point in time, and that the best available data subsequently showed that this uptick had been a random event and not a sustained trend. In a more detailed study, Wheeler et al. looked at the UK situation, where the dropoff in SSRI pediatric prescriptions following the 2003 warning was much deeper than in the US, presumably creating a situation in which even more suicides would subsequently have occurred. On tracking long-term trends in both suicides and self-harm behavior, they found no effect of the abrupt change in prescribing of SSRIs on either.

Olfson M, Shaffer D. SSRI prescriptions and the rate of suicide. Am J Psychiatry 164:1907-8, 2007.

Wheeler BW, Gunnell D, Metcalfe C, Stephens P, Martin RM. The population impact on incidence of suicide and non-fatal self harm of regulatory action against the use of selective serotonin reuptake inhibitors in under 18s in the United Kingdom: ecological study. BMJ 336:542-5, 2008.

Comment: Anyone who had been following the literature on SSRIs generally knows that one of the major debates about pharmacologic treatment of depression in recent years is whether SSRI antidepressants as a group--quite apart from their risks--are demonstrably better than placebo in their average effectiveness. Given the difficulty in large-scale meta-analyses of demonstrating the effectiveness of this class of drugs, the claim that their widepread use was preventing many suicides, and the dropoff in their use led to a singificant increase in the suicide rate, was implausible on its face. As a family physician who prescribed many of these drugs (probably, in hindsight, far too many) for many years, I can testify to individual cases where the drugs appeared to be extremely effective. But here we are talking about population effects, not individual effects. The results of the more recent studies, showing no significant change in suicide rates, certainly appear overall to be more plausible, all things considered. And that, in turn, seems to suggest that the warnings regarding the increased risk of suicidal behavior among children and adolescents taking these drugs were prudent and evidence-based, and not the hysterical over-reaction that some industry-friendly physicians have alleged.

Wednesday, August 13, 2008

Massachusetts Gift Law: The Industry Took Notice

Thanks to our friends over at the Prescription Project, we learned of Gov. Patrick's signing the new law in Massachusetts requiring reporting of Pharma gifts and requiring the state to have standards at least as strict as the new PhRMA code of conduct (here's the AP coverage):

What is most notable for us about this was the huge lobbying effort put out by both Pharma and the biotech industry to pressure the Gov not to sign. The Prescription Project quoted:

“I have a lot of respect for the governor, and I am proud that he did not bend to the pressure,” state Sen. Mark C.W. Montigny (D-New Bedford) told the Standard-Times. “I have never seen lobbying this intense. They have been swarming the Statehouse for weeks.”

The industry took out a full page ad in the Boston Globe and the biotech people pulled out one of their standard chestnuts (as I personally got to hear a while ago in a Texas Senate committee hearing), the threat that if the law passed they'd take all their lucrative biotech jobs and move to a different state.

Unfortunately, given the way the industry plays so many of its cards so close to the vest, often the only way to get a pulse on what matters most is to see what the industry lobby fights hardest against. This is frankly a rare instance of the lobby not getting its way at the state level--which is not to say that Congress has historically had any more spine in standing up to them. With anti-Pharma hearings now a regular feature of Capitol Hill, we will have to wait to see if things are really changing.

Thursday, August 7, 2008

How Conflicts of Interest Poison the Academic Water Hole

Our colleague Barney Carroll over at the Health Care Renewal blog has been keeping up steady pressure on Stanford University and Dr. Alan Schatzberg, the president-elect of the American Psychiatric Association:

Briefly, Dr. Schatzberg is heavily invested in his commercial firm, Corcept, that has been doing research on a psychiatric application of the drug mifepristone--at the same time as he has been doing NIH-supported research on the drug and writing textbook chapters about it. Stanford intiially denied any problem but recently took the step of removing Dr. Schatzberg as Principal Investigator on his NIH grant, according to Dr. Carroll.

Dr. Carroll asserts in this present posting that there are serious questions of fraud in some of Dr. Schatzberg's writings about mifepristone. He has said flat out that the drug is effective when the actual data from the relevant trials do not demonstrate efficacy. I will not pass any judgment on the merits of Dr. Carroll's assertions; readers may decide for themselves.

The only point I wish to make here is that I believe that no one can read Dr. Carroll's post and not see that Dr. Schatzberg has created a huge problem by his multiple entanglements--with Stanford; with a private corporation; and with the NIH. Even if Dr. Schatzberg can sucessfully defend himself against every one of Dr. Carroll's individual assertions, it is very hard not to see the overall pattern as having cast a huge pall over his own credibility, that of Stanford, and that of the American Psychiatric Association, let alone whether any NIH rules were violated. Reasonably charitable folk would have to look at that overall pattern and scratch their heads about what they can believe about anything that Dr. Schatzberg has said regarding this drug. Was he giving his personal opinion as an academic psychiatrist? Was he speaking as a corporate official anxious to maintain the stock value of Corcept? Was he reflecting an official viewpoint on behalf of the APA? Was he upholding the standards of scientific accuracy and impartiality that Stanford claims to represent?

Some of Dr. Schatzberg's statements about mifepristone, however charitably viewed, sound like commercial shilling. Maybe he can prove that they are in fact backed up by hard evidence. But his extensive financial entanglements in Corcept suggest that he'd require superhuman powers of detachment not to allow his financial affairs to incluence his scientific judgment.

And this is what the ethical concern about conflicts of interest in academic science, ultimately, boils down to.

Tuesday, August 5, 2008

Saving the Medical Literature from Sponsorship Bias

Doucet and Sismondo, of the Philosophy Department of Queen's University in Ontario, recently wrote about the problem of sponsorship bias in the medical literature (; access requires subscription)

Doucet and Sismondo cite their fellow Canadian philosopher, Arthur Schafer, who wrote about his "sequestration thesis" in the same journal. In turn, I relied on Schafer's work to develop my own "divestment strategy" in HOOKED.

In summary, the present authors review the extensive evidence showing undue sponsorship bias, and the specific ways that medical journal reports of pharmaceutical trials may introduce inappropriate commercial bias. They then look at three commonly proposed solutions--increased financial disclosure; the CONSORT standards; and trial registries--and show precisely how each is able to address only a small portion of the different causes of inappropriate bias. They conclude that only radical changes, removing industry financing largely from drug trials, will be effective in the end (while acknowledging the political difficulty of implementing the radical changes).

Doucet M, Sismondo S. Evaluating solutions to sponsorship bias. J Med Ethics 34:627-30, 2008.

Friday, August 1, 2008

Thanks to Danny Carlat, Some Helpful News Updates

I can put up my feet and take the day off thanks to Dr. Danny Carlat and his blog focusing on psychiatry-related matters. First and most recent, Danny has commented on the bill that just passed both houses of the Mass. legislature on drug company gifts to physicians in the wake of the new PhRMA code of conduct:

Just before that Danny had blown the whistle on a particularly sneaky marketing ploy that Eli Lilly trotted out to try to maintain sales of its drug Zyprexa in the face of data showing a 3.5-fold increase in elevated blood sugar among patients taking it--funnel company money into a supposedly independent educational program, and have that program give "malpractice" seminars to psychiatrists reassuring them that they won't be sued if they keep on prescribing Zyprexa:

Incidentally, you might wonder what has made Dr. Carlat so energetic all of a sudden, and the secret is found when you scroll farther down into his blog. It seems he took a family vacation to the Jackson, Wyoming area-- and check out his helpful tips if you are planning to go there and see the Tetons.