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Elan and Wyeth announced "encouraging top-line results" from a randomized, dose-ranging phase 2 trial of bapineuzumab in 240 patients with mild-to-moderate Alzheimer's disease; although the monoclonal antibody was no better than placebo when assessing cognition or disability at 18 months, the primary endpoints. A press release from the companies contained the primary-endpoint data in the second paragraph.
Instead the companies chose to highlight results from the post-hoc analyses of subgroups, including patients who do not carry the high-risk apolipoprotein E4 allele (40%-70% of AD patients).* Data in this subgroup showed "statistically significant and clinically meaningful benefits" with bapineuzumab, per cognitive scales like the ADAS-cog. The treated subgroup also demonstrated relatively preserved brain volume on MRI, the press release reported.
Safety data in the phase 2 trial indicated that ApoE4 carriers may be especially prone to vasogenic edema with the agent. Consequently the dose of bapineuzumab, an anti-Aβ agent, is being modified for this subpopulation in phase 3 studies. According to ClinicalTrials.gov, two phase 3 studies of bapineuzumab in AD are currently recruiting subjects, and another two phase 3 studies are "active" but "not yet recruiting."
The Elan/Wyeth press release indicates that full details of the phase 2 study will be presented July 28 at the International Conference on Alzheimer's Disease in Chicago. Despite the mixed phase 2 results, the reaction of Wall Street was mostly optimistic, according to the WSJ Health Blog.
06/18/08 update: According to Forbes, analysts Leerink Swann and Davy Stockbrokers are talking up the study and the companies' prospects. For no particularly good reason, respective share prices of Elan and Wyeth shot up yesterday 10.6% and 4.8%.
Image: depiction of amyloid plaque from National Institute on Aging.
Aβ = amyloid beta.
*So, in this case, we may guess that approximately 12-20 patients per treatment group (4 for bapineuzumab; 4 for placebo) were noncarriers.
In an expected move, representatives of the primary voting blocks of the AMA House of Delegates—primary care doctors, state medical societies, and specialty medical societies—strongly objected to an AMA proposal to eliminate commercially supported CME, according to today's Medical Marketing & Media. The AMA's Council on Ethical and Judicial Affairs (CEJA) had recommended the phasing out of nearly all commercial support for CME, an issue which was debated at a committee hearing on Sunday, during the annual meeting of the AMA House of Delegates in Chicago.
John Kamp, executive director of the Coalition for Healthcare Communication, reported that the proposal "went down in flames," according to the paper. The CHC, along with the North American Association of Medical Education and Communication Companies (NAAMECC), objected to the CEJA proposal on the basis of 3 general arguments:
[T]he report ignores the dramatic difference between certified CME and other non-certified 'education' and thus overlooks the significant advances in the management and resolution of conflicts of interest mandated in the last several years by government, industry and the [ACCME].
[T]he report's conclusions are not based on current and scientifically relevant and rigorous evidence in the context of certified CME and do not respect dramatic progress in the past decade.
[T]he report lacks a plausible, detailed plan to ensure that the proposed elimination of $1 billion in certified CME funding would improve the quality of certified CME and patient care.
Given the objections voiced at the AMA meeting, the CEJA proposal is "referred back to the council, effectively tabling it for the year," wrote the paper.
The Public Broadcasting System is known for its high-quality cultural and investigative programming, like "Masterpiece," "Nova," and "Frontline." However, the station has also developed a disconcerting record for airing self-improvement claptrap (eg, Gary Null's "Mind Power"; Wayne Dyer's "Power of Intention"). The latest example comes in the form of psychiatrist Daniel Amen, whose infomercial, "Change Your Brain, Change Your Life," promotes the routine use of SPECT imaging to identify behavioral problems. The program aired on my local PBS channel last evening.
I lasted about 20 minutes: in part, because of Amen's simplistic nonsense about "prefrontal," "cingulate," and "limbic" personalities; in part, because of his promotion of diet, exercise, and his dubious proprietary supplements to alter these personalities; and in part, because of his annoying habit of constantly referring to some backroom prompter, a la Orson Welles in a Paul Masson wine ad.
In May, neurologist Robert Burton lasted a whole lot longer than I did while watching another installment of Amen's program, which promoted the prevention (yes, the prevention) of Alzheimer's disease. He provides a thoughtful critique at Slate.
The Boston Globe reports this afternoon that Senator Ted Kennedy has been diagnosed with a malignant glioma, following a brain biopsy at the Massachusetts General Hospital. The tumor is located in the "top left portion of his brain," according to the paper, and is the likely cause of a seizure he experienced last weekend, which led to his hospitalization. The glioma was implied to be high grade, according to a quote from a neurosurgeon at Boston's Children's Hospital. Therapy in this case is typically multimodal, incorporating radiation, systemic chemotherapy, intracranial chemotherapy, and/or experimental targeted therapies.
Photo: Biographical Directory of the United States Congress.
05/21/08 update: The Boston Herald reports this morning that Kennedy's glioma is located in his left parietal lobe.
Just when you thought it was safe to go back to reading mainstream pharma coverage, Forbes now questions the propriety of CEO Fred Hassan's $13-million bonus from Schering-Plough. Writers Matthew Herper and Michael Maiello imply today that the delay of the negative results of the ENHANCE study* directly benefited SP's leader by maintaining the company's stock price for as long as possible. The story was snapped up this morning by Sarah Rubenstein at the WSJ Health Blog and Ed Silverman at Pharmalot.
The results of the ENHANCE study were made public by SP in January of this year and presented in full by principal investigator John Kastelein at the annual meeting of the American College of Cardiology in March, after longstanding concerns of data quality. However, Kastelein believes that the study results could have been presented as early as March 2007 (but not November 2006), according to media reports, and Forbes argues that an earlier release would have cost Hassan at least $4 million in bonus money, given SP's sales requirements for generating bonuses.
SP's share price began dropping in October 2007 and took a preciptious plunge after the release of the ENHANCE results in January 2008, when highly critical reports of the study's data handling flooded pharma-related press outlets. For its part, the WSJ Health Blog doesn't blame itself or other media sources for fomenting the drop in SP stock—long before lower Vytorin sales could ever be reflected in the company's earnings.
*Which, if you've just come out of an extended coma (and congratulations, BTW), showed that the combination of ezetimibe and simvastatin (Vytorin) was no more effective for reducing carotid intima-media thickness than simvastatin alone. Data-quality issues in ENHANCE have been discussed previously at the Pathophilia blog (see here, here, here, here, here, here, here, here, and here, for instance).
Peter Libby, MD, now refuses pharma fees for his consulting services not because of impropriety, but because of the growing perception of impropriety. The chief cardiologist at Brigham and Women's Hospital in Boston told NPR's Madeline Brand last week that his decision was motivated by negative comments in the blogosphere after he appeared in a public-service documentary on PBS.
The documentary, "The Hidden Epidemic: Heart Disease in America," was a 4-year, unpaid labor for the doctor, according to a recent mini-profile in the NYT. However, shortly after the show's airing in October, Roy Poses, MD, at the Health Care Renewal blog raised conflict-of-interest (COI) issues, given that the show was funded by pacemaker-producer Medtronic and statin-maker AstraZeneca and that Libby, in particular, had an undisclosed relationship with AstraZeneca (although that relationship was not specified by Poses, other than in the form of grant support, consulting services, or participation on a speakers' bureau—which are important to distinguish [see below]).
Poses also discovered that another program participant, Douglas Zipes, MD, of Indiana University, had an undisclosed relationship with Medtronic. However, Poses did not identify particular instances in the documentary in which undue influence appeared to be exerted by the funding companies or by the participating experts themselves—other than to cite the unbranded claim that some cardiac arrhythmias are treated with implantable pacemakers (ho hum).
Yet despite the lack of specific examples suggesting commercial influence on the documentary's content, Pharmalot's Ed Silverman posted the story, arguably fomenting the unfounded perception that the program or its physician participants were biased, solely on the basis of their undefined relationships with the 2 supporting companies. Silverman (and Poses) also neglected to call out other documentary participants, including outspoken pharma critic Steven Nissen, MD, of the Cleveland Clinic.
In a moment of needed clarity, one Pharmalot commenter ("Reality") wrote:
Oh dear, another case of the COI vapors! Overall, I'd say this ranks around an 8 out of 10 on the conflict-of-interest overreaction scale...[F]rom what I've read, this was a simple, layman's educational series. No specific products were mentioned and what they reported in terms of treatments was straigh[t]forward and followed expert guidelines...
Should the advisors' ties to AZ and Medtronics...been noted? Probably. But I think the level of criticism here goes far beyond the seriousness of the infraction, or lack thereof. Look, there are some very real and very troubling COI issues out there, but to me, this is not one of them. This is a case of someone looking for a problem.
When Libby was asked by NPR last week if he could have been unconsciously* biased given his relationships with pharma, he denied influence. Because he has worked with "virtually every company that has produced, manufactured, sold, or even thought about producing, manufacturing, or selling" any cardiovascular product, he could claim no particular commercial allegiance.
Libby believes that academic investigators should be involved with pharma to ensure the integrity of clinical trials and, ultimately, the public good. Unfortunately Libby's decision to now refuse pharma money may confirm to a suspect crowd that his previous choice to do so was, somehow, improper.
N.B. In the 5-minute segment featuring Libby, NPR made a disingenuous, if not inaccurate, segue from the discussion of Robert Jarvik† appearing in Lipitor's DTC ads to physicians consulting for or receiving grant support from commercial interests. In doing so, NPR failed to make important distinctions among 1) the appearance of physicians in advertisements, 2) their participation in speakers' bureaus, 3) their participation in advisory boards, and 4) the receipt of grant support.
*Of course, consciously assessing unconscious influence is really difficult, given that the influence, by definition, hasn't bubbled up to consciousness. So it's a very difficult question to answer, other than to ensure that there are conditions (such as consulting for everybody) that make unconscious bias toward one company unlikely.
†NPR also falsely stated that Jarvik is not a medical doctor. Jarvik evidently earned his MD from the University of Utah; however, to my knowledge, he does not hold an active license to practice medicine.
The president of the American Medical Writers Association (to which I belong) has written to its members (below) regarding the practice of medical ghostwriting, and AMWA's response to the NYT article about Merck's use of guest authoring and ghostwriting has been printed. I agree with AMWA's assessment.
Hello, AMWA colleagues,
As many of you have been discussing, the articles in this week's JAMA about alleged misuse of medical writing resources by Merck in publications about Vioxx garnered a lot of press coverage. As is often the case, the JAMA articles and the associated press coverage tend to blur the distinction between "guest authorship" (putting an author's name on an article he/she did not help to write) and the unacknowledged use of medical writers (ghostwriting, a term AMWA tries to avoid). A number of people have asked whether AMWA should do something.
Several of us saw this as an opportunity to assert AMWA's leadership in promoting ethical practices in medical writing. Accordingly, we have submitted letters to the editors of the NY Times, Philadelphia Inquirer, and Chronicle of Higher Education, all of which carried stories about the JAMA articles. All letters are signed by me as AMWA president.
Key points in all the letters:
- While ghostwriting (the undisclosed contribution of a medical writer) is unethical in scientific publications, the use of professional medical writers may be appropriate and ethical.
- Using their skills in communicating complex data, professional writers help researchers report their findings effectively, making contributions comparable to those of professional statisticians who analyze data or artists who create illustrations.
- The 5500-member American Medical Writers Association promotes ethical practices in scientific publication, including acknowledgment of medical writers' roles, adherence to applicable guidelines (eg, authorship rules of the International Committee of Medical Journal Editors), and full disclosure of potential conflicts of interest, including financial support.
- Transparent disclosure of the roles of all contributors avoids ghostwriting and allows readers to evaluate the credibility of research reports.
We're also drafting a response to JAMA. We'll keep you posted to let you know if these letters are published. In addition, Lori Alexander will include an editorial in the summer issue of the [AMWA] Journal, bringing these issues to members' attention.
Best regards,
Sue Hudson
Despite all the press attention dedicated to the ENHANCE study results, which were finally presented at the ACC's annual meeting and printed in the NEJM yesterday, there's been little-to-no mention of the "missing" or "implausible" ultrasound data that were revealed originally in Schering-Plough's study timeline from January. The effect of these missing or implausible data on the validity of study has now been, in essence, inexplicably ignored. (See previous Pathophilia entries on the ENHANCE study here and here.)
The NEJM article devotes exactly one sentence to the subject:
The exclusion from the statistical analyses of patients with missing data or biologically implausible measures of the carotid-artery intima-media thickness (defined as a difference of >0.1 mm between visits) did not change the primary or secondary outcome results (data not shown).
Ok, the exclusion of these data, the volume of which is not provided, did not change the negative study outcomes. However, if the numbers of patients with missing or implausible data are considerable—and the S-P timeline suggests that they were*—they could very well undermine the validity and/or statistical power of the ENHANCE study and any subgroup analyses that might otherwise reveal significant treatment differences.
The authors do consider that the ultrasound measurement technique that was used to assess arterial intima-media thickness may not accurately reflect changes in atherosclerotic burden; but they dismiss this consideration on the basis of the precision of the measurements, "as exemplified by the high intraclass correlation coefficient and the small standard deviations." However, this explanation only addresses the use of arterial intima-media thickness as a surrogate marker for atherosclerotic burden; it is not relevant to the plausibility of the specific thickness measurements obtained by the ENHANCE study investigators and certainly doesn't address missing data.
In an accompanying NEJM editorial, Drazen et al write, "Only with the full data set and an independent analysis on the scientific record is it possible to properly interpret the trial and formulate follow-up studies to further pursue the intriguing but puzzling results." Amen. But neither of the 2 NEJM editorials that discuss the ENHANCE study mention the missing or implausible data and their potential effect on the trial's results.
Update: In its coverage of the ENHANCE study presentation, heartwire talked to Roger Blumenthal, MD, of Johns Hopkins, who said that 2 limitations "bias ENHANCE toward the null." One is that ENHANCE investigators did not consistently measure carotid intima-media thickness during cardiac contraction (ie, they did not use ECG gating), a method often employed to control the variability of images. The other limitation is that investigators "used single-frame technology instead of putting the images on a cine loop," which would have improved image quality. These comments imply that a sizeable percentage of the ENHANCE study images were, in fact, suboptimal and therefore undermined the validity of the study results.
*These are the data believed to have delayed the publication of the ENHANCE study results in the first place.
Photo: iStockPhoto
In a mildly curious case of media weirdness, the Bay Area's ABC news affiliate recently caught Scott Harkonen, the indicted former InterMune CEO, on tape offering his opinion about which Presidential candidate should receive California's vote. For what it's worth (and can that be much?), Harkonen* thinks pretty strongly that the CA vote should go to the candidate with the most delegates. Well, o-kay.
*If Harkonen's demeanor on camera is any indication, he's taking the indictment with equanimity.
Perhaps trying to justify how it spent the last 5 months, the AP follows up its throw-up-your-hands-to-the-skies "exposé" of trace-trace-trace pharmaceuticals in drinking water by reporting the reactions to its story. "Test it, study it, figure out how to clean it—but still drink it," is how the AP begins its follow-up. Did the AP—perhaps now substituting alcohol for all of its drinking water—expect that we would or should avoid consuming water on the basis of its arguably useless report?
"There is no wisdom in avoidance," advised one Washington-based environmental lawyer as quoted by the AP. No freekin' shit, Sherlock. Whatever risks may be posed by drinking infinitesimal amounts of pharmaceuticals—and nobody knows if there are any—lack of water will kill in no time. Trust me. They teach that stuff in medical school.
The AP water story reminds me of those ridiculous signs in
Next thing you know the AP's going to tell me that saliva causes cancer, but only if swallowed in small quantities over an extended period of time. No wait.
Photo: www.saturday-night-live.com
