Showing posts with label Bristol-Myers-Squibb. Show all posts
Showing posts with label Bristol-Myers-Squibb. Show all posts
Tuesday, March 10, 2009
BLOGSCAN - An Example of Spinning Clinical Research Results
On the Clinical Psychology and Psychiatry blog, the anonymous blogger did a great job analyzing an article supported by pharmaceutical companies, and authored by in part pharmaceutical company employees, with the assistance of a medical education and communications company (MECC). The article ignored data about outcomes which were unfavorable to the companies' product, and dubbed a drug "well tolerated" even though a number of uncomfortable symptoms occurred two to four times as often on the drug as on placebo. This is a reminder of how often these days clinical research studies are spun in favor of the vested interests of their commercial sponsors.
Friday, March 6, 2009
Harvard Medical Students Against Marketing in the Guise of Medical Education
An article by Duff Wilson in the New York Times this week provided a new look at the pervasiveness of financial relationships among academic medicine and health care corporations, and the beginnings of resistance to them.
The Scope of the Relationships
Academic Medical Leaders' Defense of Their Relationships with Industry
So maybe it is not surprising that:
But,
Note that we discussed Dr Martin's directorship of Baxter on Health Care Renewal here in 2006, and that we also found that he was on the board of biotechnology company Cytyc. Note also that we have discussed how serving on the board of a health care corporation can produce particularly intense conflicts of interest for academic medical leaders, since such board service implies not just warm and fuzzy feelings for the company, but "unyielding loyalty" to the financial interests of the company and its stockholders (e.g., see this post).
Unsurprisingly, faculty who have their own lucrative relationships with industry are all for more of the same:
Note further that Dr Stossel may have even more financial relationships with industry than appeared in the NY Times article. When we analyzed some of the logical fallacies Dr Stossel employed in favor of industry payments to physicians in 2007, we cited Stossel's attck on the rigorous conflicts of interest rules re-imposed on the US National Institutes of Health (NIH) in which Stossel had to disclose "having received consulting fees from ZymeQuest, owning stock options in ZymeQuest and Biogen, and having pending and issued patents, owned by Brigham and Women's Hospital, some of which are licensed to ZymeQuest." [Stossel TP. Regulating academic-industrial research relationships - solving problems or stifling progress? N Engl J Med 2005; 353: 1060-1065.] In this paean to a laissez-faire approach to conflicts of interest, Stossel also disclosed that he "is a member of the Board of Directors of Zymequest Inc, and the Scientific Leadership Advisory Board of Merck & Co. The author is a founding scientist of Critical Biologics Corporation and a consultant to Boston Scientific, Inc., and Gerson-Lehrman, Inc." [Stossel TP. Regulation of financial conflicts of interest in medical practice and medical research. Perspect Biol Med 2007; 50: 54-71. ]
Another defender of the status quo also has her own major relationships with industry:
Note that Dr Glimcher now seems to view her role not as someone seeking to discover and disseminate the truth, but as someone seeking to develop commercial products. Again, maybe that is not surprising, since she is supposed to have an "unyielding loyalty" to the prominent pharmaceutical company on whose board she sits.
The NY Times article did not quote anybody in favor of financial relationships between academic medicine and industry who did not themselves have such relationships. I don't believe I have ever seen a defense of these relationships not authored by someone who was not already personally profiting from such relationships.
The Revolt of the Medical Students
While he documented how Harvard faculty who also lead huge pharmaceutical firms have no qualms about industry pouring money into medical academics, Mr Wilson found that medical students seem to have figured out the downside of being taught by pharmaceutical, biotechnology and device company employees:
Note that the example, while anecdotal, shows how financial relationships could lead to biased education. The students have made surprising progress:
Unfortunately, many academics of my generation have become so used to making some extra dollars by working part-time for companies selling health care goods or services that they cannot see how these relationships have distracted them from the academic mission and their professional ideals. Maybe the rising generation of students, now living in a time when the consequences of arrogance, greed, and corruption among our leaders has become so apparent, will put professionalism ahead of personal enrichment.
The Scope of the Relationships
Many individual Harvard Medical faculty members receive tens or even hundreds of thousands of dollars a year through industry consulting and speaking fees. Under the school’s disclosure rules, about 1,600 of 8,900 professors and lecturers have reported to the dean that they or a family member had a financial interest in a business related to their teaching, research or clinical care. The reports show 149 with financial ties to Pfizer and 130 with Merck.
The rules, though, do not require them to report specific amounts received for speaking or consulting, other than broad indications like 'more than $30,000.' Some faculty who conduct research have limits of $30,000 in stock and $20,000 a year in fees. But there are no limits on companies’ making outright gifts to faculty — free meals, tickets, trips or the like.
Other blandishments include industry-endowed chairs like the three Harvard created with $8 million from sleep research companies; faculty prizes like the $50,000 award named after Bristol-Myers Squibb, and sponsorships like Pfizer’s $1 million annual subsidy for 20 new M.D.’s in a two-year program to learn clinical investigation and pursue Harvard Master of Medical Science degrees, including classes taught by Pfizer scientists.
Academic Medical Leaders' Defense of Their Relationships with Industry
Dr. Flier, who became dean 17 months ago, previously received a $500,000 research grant from Bristol-Myers Squibb. He also consulted for three Cambridge biotechnology companies, but says that those relationships have ended and that he has accepted no new industry affiliations.
So maybe it is not surprising that:
Dr. Flier says that the Harvard Medical faculty may lead the nation in receiving money from industry, as well as government and charities, and he does not want to tighten the spigot. 'One entirely appropriate source, if done properly, is industrial funds,' Dr. Flier said in an interview.
But,
That is in contrast to his predecessor as dean, Dr. Joseph B. Martin. Harvard’s rules allowed Dr. Martin to sit on the board of the medical products company Baxter International for 5 of the 10 years he led the medical school, supplementing his university salary with up to $197,000 a year from Baxter, according to company filings.
Dr. Martin is still on the medical faculty and is founder and co-chairman of the Harvard NeuroDiscovery Center, which researches degenerative diseases, and actively solicits industry money to do so. Dr. Martin declined any comment.
Note that we discussed Dr Martin's directorship of Baxter on Health Care Renewal here in 2006, and that we also found that he was on the board of biotechnology company Cytyc. Note also that we have discussed how serving on the board of a health care corporation can produce particularly intense conflicts of interest for academic medical leaders, since such board service implies not just warm and fuzzy feelings for the company, but "unyielding loyalty" to the financial interests of the company and its stockholders (e.g., see this post).
Unsurprisingly, faculty who have their own lucrative relationships with industry are all for more of the same:
Encouraging them is Dr. Thomas P. Stossel, a Harvard Medical professor who has served on advisory boards for Merck, Biogen Idec and Dyax, and has written widely on academic-industry ties. 'I think if you look at it with intellectual honesty, you see industry interaction has produced far more good than harm,' Dr. Stossel said. 'Harvard absolutely could get more from industry but I think they’re very skittish. There’s a huge opportunity we ought to mine.'Note that Dr Stossel defended academic-industry "interaction," but did not explain why such interaction seems always to generate large money flows from industry to academic institutions and their individual faculty members. People can surely interact without paying each other.
Note further that Dr Stossel may have even more financial relationships with industry than appeared in the NY Times article. When we analyzed some of the logical fallacies Dr Stossel employed in favor of industry payments to physicians in 2007, we cited Stossel's attck on the rigorous conflicts of interest rules re-imposed on the US National Institutes of Health (NIH) in which Stossel had to disclose "having received consulting fees from ZymeQuest, owning stock options in ZymeQuest and Biogen, and having pending and issued patents, owned by Brigham and Women's Hospital, some of which are licensed to ZymeQuest." [Stossel TP. Regulating academic-industrial research relationships - solving problems or stifling progress? N Engl J Med 2005; 353: 1060-1065.] In this paean to a laissez-faire approach to conflicts of interest, Stossel also disclosed that he "is a member of the Board of Directors of Zymequest Inc, and the Scientific Leadership Advisory Board of Merck & Co. The author is a founding scientist of Critical Biologics Corporation and a consultant to Boston Scientific, Inc., and Gerson-Lehrman, Inc." [Stossel TP. Regulation of financial conflicts of interest in medical practice and medical research. Perspect Biol Med 2007; 50: 54-71. ]
Another defender of the status quo also has her own major relationships with industry:
Merck built a corporate research center in 2004 across the street from Harvard’s own big new medical research and class building. And Merck underwrites plenty of work on the Harvard campus, including the immunology lab run by Dr. Laurie H. Glimcher — a professor who also sits on the board of the drug maker Bristol-Myers Squibb, which paid her nearly $270,000 in 2007.
Dr. Glimcher says industry money is not only appropriate but necessary. 'Without the support of the private sector, we would not have been able to develop what I call our ‘bone team’ in our lab,' she said at a recent student and faculty forum to discuss industry relationships. Merck is counting on her team to help come up with a successor to Fosamax, the formerly $3 billion-a-year bone drug that went generic last year.
Note that Dr Glimcher now seems to view her role not as someone seeking to discover and disseminate the truth, but as someone seeking to develop commercial products. Again, maybe that is not surprising, since she is supposed to have an "unyielding loyalty" to the prominent pharmaceutical company on whose board she sits.
The NY Times article did not quote anybody in favor of financial relationships between academic medicine and industry who did not themselves have such relationships. I don't believe I have ever seen a defense of these relationships not authored by someone who was not already personally profiting from such relationships.
The Revolt of the Medical Students
While he documented how Harvard faculty who also lead huge pharmaceutical firms have no qualms about industry pouring money into medical academics, Mr Wilson found that medical students seem to have figured out the downside of being taught by pharmaceutical, biotechnology and device company employees:
In a first-year pharmacology class at Harvard Medical School, Matt Zerden grew wary as the professor promoted the benefits of cholesterol drugs and seemed to belittle a student who asked about side effects.
Mr. Zerden later discovered something by searching online that he began sharing with his classmates. The professor was not only a full-time member of the Harvard Medical faculty, but a paid consultant to 10 drug companies, including five makers of cholesterol treatments.
'I felt really violated,' Mr. Zerden, now a fourth-year student, recently recalled. 'Here we have 160 open minds trying to learn the basics in a protected space, and the information he was giving wasn’t as pure as I think it should be.'
Mr. Zerden’s minor stir four years ago has lately grown into a full-blown movement by more than 200 Harvard Medical School students and sympathetic faculty, intent on exposing and curtailing the industry influence in their classrooms and laboratories, as well as in Harvard’s 17 affiliated teaching hospitals and institutes.
They say they are concerned that the same money that helped build the school’s world-class status may in fact be hurting its reputation and affecting its teaching.
Note that the example, while anecdotal, shows how financial relationships could lead to biased education. The students have made surprising progress:
The Harvard students have already secured a requirement that all professors and lecturers disclose their industry ties in class — a blanket policy that has been adopted by no other leading medical school. (One Harvard professor’s disclosure in class listed 47 company affiliations.)
'Harvard needs to live up to its name,' said Kirsten Austad, 24, a first-year Harvard Medical student who is one of the movement’s leaders. 'We are really being indoctrinated into a field of medicine that is becoming more and more commercialized.'
David Tian, 24, a first-year Harvard Medical student, said: 'Before coming here, I had no idea how much influence companies had on medical education. And it’s something that’s purposely meant to be under the table, providing information under the guise of education when that information is also presented for marketing purposes.'
The students say they worry that pharmaceutical industry scandals in recent years — including some criminal convictions, billions of dollars in fines, proof of bias in research and publishing and false marketing claims — have cast a bad light on the medical profession. And they criticize Harvard as being less vigilant than other leading medical schools in monitoring potential financial conflicts by faculty members.
Unfortunately, many academics of my generation have become so used to making some extra dollars by working part-time for companies selling health care goods or services that they cannot see how these relationships have distracted them from the academic mission and their professional ideals. Maybe the rising generation of students, now living in a time when the consequences of arrogance, greed, and corruption among our leaders has become so apparent, will put professionalism ahead of personal enrichment.
Thursday, June 19, 2008
MEDSCAPE'S CME ETHICS, PART II
19 June 2008
MEDSCAPE’S CME ETHICS, PART II
A few days ago I discussed Medscape’s parasitic use of professional organizations to embellish its mediocre CME offerings – “highlights” of the closed 2007 ACNP annual meeting, for example. One of the responses to my post called attention to Dr. George D. Lundberg’s video editorial of 13 June 2008, denouncing attacks on commercially sponsored CME activities. Among other claims, Dr. Lundberg, a past editor-in-chief of JAMA, stated that Medscape “follow(s) rules that prevent bias and improper influence.” He went on to boast that Medscape is “the largest single source of CE for health professionals” and that “We are just going to keep doing what we are doing. It is good. We are clean. Our work is transparent…. We welcome analysis and criticism. We function in the best interests of patients …” These words were spoken before Daniel Carlat and I published our critiques of Medscape a few days later (see here and here and here).
There seems to be a right hand – left hand problem at Medscape. Though I take Dr. Lundberg at his word about his intentions, I invite him to defend the products that actually appear under his oversight as editor-in-chief. Let’s look at a case study of an “Expert Interview” published on-line June 9, 2008 under the tagline Medscape Perspectives on the American Psychiatric Association (APA) 161st Annual Meeting, May 3-8, 2008, Washington, DC. A boilerplate legal disclaimer noted, “This activity is not sanctioned by, nor a part of, the American Psychiatric Association. Conference news does not receive grant support and is produced independently.”
The “Expert Interview” for our case study is titled “Pharmacologic Options for Treatment-Resistant Depression…” The featured expert is Charles Nemeroff, chairman of Emory University’s department of psychiatry. Dr. Nemeroff is well known for ethical controversy. In 2003 the Nature Publishing Group revised their policies on disclosure of financial conflicts of interest in the wake of Dr. Nemeroff’s widely publicized nondisclosures. In 2006 Dr. Nemeroff resigned as editor of the journal Neuropsychopharmacology after he failed to disclose conflicts pertinent to a review article he co-authored and placed in his own journal. As is always true of case studies, the devil is in the details if we wish to understand just how sly and subtle was the spinning. Here are some of the issues that arise from Dr. Nemeroff’s Expert Interview on Medscape.
1. Internal contradiction. The legal disclaimer noted above states that there was no grant support and that the conference news items were produced independently. However, Dr. Nemeroff’s featured item prominently acknowledges an unrestricted educational grant from Bristol-Myers Squibb Company and Otsuka America Pharmaceutical, Inc. These two companies jointly market aripiprazole, a member of a drug class highlighted by Dr. Nemeroff in his Expert Interview.
2. Infomercial format. The Expert Interview by Dr. Nemeroff resembles nothing so much as Lindsay Wagner promoting the Select Comfort Sleep Number Bed in television advertisements. Promotional statements are made without scientific backup.
3. Disease mongering. In this interview, Dr. Nemeroff backed away from his earlier strict definition of treatment-resistant depression (TRD), proclaiming that in his current view 40% to 50% of depressed patients have treatment resistance. This sleight of hand naturally expands the market for the agents he later promotes as augmenting agents.
4. The primary care “hook.” Dr. Nemeroff introduced a professional “hook” to primary care physicians, emphasizing the association of depression with cardiovascular disease. This strategy is a component of disease mongering. Dr. Nemeroff’s discussion of this association had approximately zero educational value. Why did Medscape not insist on more substantive content?
5. Inappropriate drug recommendation. In discussing the switch strategy from one antidepressant class to another for resistant depression, Dr. Nemeroff included a recommendation for nefazodone. That drug was withdrawn by Bristol-Myers Squibb Company several years ago because of hepatic toxicity. What kind of “expert” makes such a recommendation? And what kind of editorial oversight by Medscape waves through such an incompetent statement?
6. Uncritical reliance on uncontrolled studies. In discussing switch of antidepressant drugs, Dr. Nemeroff noted that in phase II of the STAR*D trial 25% of patients switched from citalopram to sertraline responded. Dr. Nemeroff’s discussion of that result was inadequate. He invoked a dubiously relevant effect of sertraline on the dopamine transporter (when you are stuck for an answer, invoke neurochemical mythology) but he ignored the default hypothesis that 25% would have been the placebo response rate had STAR*D been designed to include placebo control groups. This default hypothesis assumes that all SSRI drugs are basically similar in terms of efficacy. For an educational item in Medscape or anywhere else, this aspect of the Expert Interview falls short of expected standards.
7. Pushing dangerous drugs. Dr. Nemeroff has been a leader in promoting use of second generation antipsychotic (SGA) drugs as augmenting agents for resistant depression. I have commented previously on his promotion of risperidone for this purpose, here and here. Others have raised serious questions about his reports. Overall, Dr. Nemeroff promotes these drugs by exaggerating their efficacy and glossing over their toxicity in resistant depression.
8. False statements. In this Expert Interview, Dr. Nemeroff leads off his discussion of SGA drugs for TRD with an endorsement of risperidone. The 2 published references to risperidone in TRD have major scientific flaws. Indeed, the study by Rapaport et al (reference 12 in this interview)was retracted. Nevertheless, Dr. Nemeroff still claims this study supports his position on SGA use in TRD. Does Dr. Nemeroff not read the retractions of his own publications (by his own “research team”)? How naïve are Medscape’s editors to be ignorant of these retractions?
9. Talking up the sponsor’s product. In reviewing the toxicity of SGA drugs for TRD, Dr. Nemeroff found something negative to say about the side effects of olanzapine, quetiapine, and risperidone. However, he made no mention of aripiprazole’s side effects, even though he emphasized its recent approval by the FDA for TRD. How convenient, as BMS-Otsuka sponsored his Medscape spot. Where were Medscape’s editors, described by George Lundberg as working to prevent bias and improper influence?
10. Glossing over weak efficacy. Though Dr. Nemeroff endorsed aripiprazole for TRD, he neglected to discuss the weak efficacy of this drug. The Number Needed to Treat for remission with aripiprazole in TRD is a disappointing 10. The studies cited by Dr. Nemeroff only compared aripiprazole against placebo. Dr. Nemeroff surely knows that just beating placebo does not qualify a drug as clinically useful. Dr. Nemeroff neglected to address the comparative efficacy of aripiprazole versus established treatments of TRD, such as lithium augmentation. The available evidence suggests that patients will do better on lithium and that aripiprazole would not be the first line choice, especially in primary care. Where were Medscape’s editors?
11. Reckless promotion of SGAs early in the course of TRD. Dr. Nemeroff emphatically stated he is not opposed to the early use of SGAs for TRD. Here especially he resembled Lindsay Wagner. A conscientious educator would weigh the risks and benefits of the early and broad use of SGA drugs in TRD. Dr. Nemeroff did no such thing. He simply opined. Why did Medscape’s editors allow him to get away with this reckless promotion? There does not appear to have been any effective editorial oversight of this publication.
12. For Dr. Nemeroff to promote early use of SGAs in TRD is reckless because of the serious toxicity associated with these drugs. Where is the discussion of akathisia (26% in the most recent study of aripiprazole in TRD)? Where is the discussion of emergent suicidality associated with akathisia in depression? Where is the discussion of tardive dyskinesia caused by aripiprazole (5% within 12 months in schizophrenia, and quite possibly higher in mood disordered patients)? Where is the discussion of neuroleptic malignant syndrome associated with SGAs like aripiprazole? Where is the discussion of weight gain with aripiprazole in TRD (significantly greater than with placebo)? Where is the overall analysis of risk versus benefit? Where were Medscape’s editors? Who at Medscape was looking out for “the best interests of patients”?
13. Incomplete disclosures. Dr. Nemeroff has a long history of recidivism concerning failure to disclose pertinent financial conflicts of interest. His record in this instance continues that sordid tradition. He failed to disclose that he is currently chairing a national series of CME meetings promoting aripiprazole for TRD, sponsored by, you guessed it, Bristol-Myers Squibb/Otsuka. Perhaps he thinks that because the money is laundered through a Medical Education Communications Company he doesn’t need to disclose it. Tell that to Joseph Biederman, who was called to task last week by Senator Grassley’s Senate Finance Committee for exactly that obfuscation. Dr. Nemeroff also failed to disclose his support from Janssen for studying risperidone in TRD. He failed to disclose his association with CeNeRx, that is developing MAO inhibitors, mentioned favorably in his interview. There is more, but these examples will suffice. Doesn’t Medscape know by now that Dr. Nemeroff cannot be relied on to report his conflicts appropriately? Does Medscape have knowledgeable professionals or ciphers in its editorial office?
So, this sleazy example illustrates many of the systemic problems that Medscape will need to correct if it hopes to remain credible. This documentation gives the lie to Dr. Lundberg’s claims that “We are clean. Our work is transparent.” One suggestion is for Medscape to abandon the degenerate form of scientific journalism exemplified by “Expert Interviews” and News items. In their present formats they cannot be truly educational and balanced items. They do not qualify for CME credit, as I verified with the company. They are simply vehicles for promoting sponsors’ products. And the Medscape staff seem to think their job is to ensure that the spin is firmly in place. Does George Lundberg really intend that?
MEDSCAPE’S CME ETHICS, PART II
A few days ago I discussed Medscape’s parasitic use of professional organizations to embellish its mediocre CME offerings – “highlights” of the closed 2007 ACNP annual meeting, for example. One of the responses to my post called attention to Dr. George D. Lundberg’s video editorial of 13 June 2008, denouncing attacks on commercially sponsored CME activities. Among other claims, Dr. Lundberg, a past editor-in-chief of JAMA, stated that Medscape “follow(s) rules that prevent bias and improper influence.” He went on to boast that Medscape is “the largest single source of CE for health professionals” and that “We are just going to keep doing what we are doing. It is good. We are clean. Our work is transparent…. We welcome analysis and criticism. We function in the best interests of patients …” These words were spoken before Daniel Carlat and I published our critiques of Medscape a few days later (see here and here and here).
There seems to be a right hand – left hand problem at Medscape. Though I take Dr. Lundberg at his word about his intentions, I invite him to defend the products that actually appear under his oversight as editor-in-chief. Let’s look at a case study of an “Expert Interview” published on-line June 9, 2008 under the tagline Medscape Perspectives on the American Psychiatric Association (APA) 161st Annual Meeting, May 3-8, 2008, Washington, DC. A boilerplate legal disclaimer noted, “This activity is not sanctioned by, nor a part of, the American Psychiatric Association. Conference news does not receive grant support and is produced independently.”
The “Expert Interview” for our case study is titled “Pharmacologic Options for Treatment-Resistant Depression…” The featured expert is Charles Nemeroff, chairman of Emory University’s department of psychiatry. Dr. Nemeroff is well known for ethical controversy. In 2003 the Nature Publishing Group revised their policies on disclosure of financial conflicts of interest in the wake of Dr. Nemeroff’s widely publicized nondisclosures. In 2006 Dr. Nemeroff resigned as editor of the journal Neuropsychopharmacology after he failed to disclose conflicts pertinent to a review article he co-authored and placed in his own journal. As is always true of case studies, the devil is in the details if we wish to understand just how sly and subtle was the spinning. Here are some of the issues that arise from Dr. Nemeroff’s Expert Interview on Medscape.
1. Internal contradiction. The legal disclaimer noted above states that there was no grant support and that the conference news items were produced independently. However, Dr. Nemeroff’s featured item prominently acknowledges an unrestricted educational grant from Bristol-Myers Squibb Company and Otsuka America Pharmaceutical, Inc. These two companies jointly market aripiprazole, a member of a drug class highlighted by Dr. Nemeroff in his Expert Interview.
2. Infomercial format. The Expert Interview by Dr. Nemeroff resembles nothing so much as Lindsay Wagner promoting the Select Comfort Sleep Number Bed in television advertisements. Promotional statements are made without scientific backup.
3. Disease mongering. In this interview, Dr. Nemeroff backed away from his earlier strict definition of treatment-resistant depression (TRD), proclaiming that in his current view 40% to 50% of depressed patients have treatment resistance. This sleight of hand naturally expands the market for the agents he later promotes as augmenting agents.
4. The primary care “hook.” Dr. Nemeroff introduced a professional “hook” to primary care physicians, emphasizing the association of depression with cardiovascular disease. This strategy is a component of disease mongering. Dr. Nemeroff’s discussion of this association had approximately zero educational value. Why did Medscape not insist on more substantive content?
5. Inappropriate drug recommendation. In discussing the switch strategy from one antidepressant class to another for resistant depression, Dr. Nemeroff included a recommendation for nefazodone. That drug was withdrawn by Bristol-Myers Squibb Company several years ago because of hepatic toxicity. What kind of “expert” makes such a recommendation? And what kind of editorial oversight by Medscape waves through such an incompetent statement?
6. Uncritical reliance on uncontrolled studies. In discussing switch of antidepressant drugs, Dr. Nemeroff noted that in phase II of the STAR*D trial 25% of patients switched from citalopram to sertraline responded. Dr. Nemeroff’s discussion of that result was inadequate. He invoked a dubiously relevant effect of sertraline on the dopamine transporter (when you are stuck for an answer, invoke neurochemical mythology) but he ignored the default hypothesis that 25% would have been the placebo response rate had STAR*D been designed to include placebo control groups. This default hypothesis assumes that all SSRI drugs are basically similar in terms of efficacy. For an educational item in Medscape or anywhere else, this aspect of the Expert Interview falls short of expected standards.
7. Pushing dangerous drugs. Dr. Nemeroff has been a leader in promoting use of second generation antipsychotic (SGA) drugs as augmenting agents for resistant depression. I have commented previously on his promotion of risperidone for this purpose, here and here. Others have raised serious questions about his reports. Overall, Dr. Nemeroff promotes these drugs by exaggerating their efficacy and glossing over their toxicity in resistant depression.
8. False statements. In this Expert Interview, Dr. Nemeroff leads off his discussion of SGA drugs for TRD with an endorsement of risperidone. The 2 published references to risperidone in TRD have major scientific flaws. Indeed, the study by Rapaport et al (reference 12 in this interview)was retracted. Nevertheless, Dr. Nemeroff still claims this study supports his position on SGA use in TRD. Does Dr. Nemeroff not read the retractions of his own publications (by his own “research team”)? How naïve are Medscape’s editors to be ignorant of these retractions?
9. Talking up the sponsor’s product. In reviewing the toxicity of SGA drugs for TRD, Dr. Nemeroff found something negative to say about the side effects of olanzapine, quetiapine, and risperidone. However, he made no mention of aripiprazole’s side effects, even though he emphasized its recent approval by the FDA for TRD. How convenient, as BMS-Otsuka sponsored his Medscape spot. Where were Medscape’s editors, described by George Lundberg as working to prevent bias and improper influence?
10. Glossing over weak efficacy. Though Dr. Nemeroff endorsed aripiprazole for TRD, he neglected to discuss the weak efficacy of this drug. The Number Needed to Treat for remission with aripiprazole in TRD is a disappointing 10. The studies cited by Dr. Nemeroff only compared aripiprazole against placebo. Dr. Nemeroff surely knows that just beating placebo does not qualify a drug as clinically useful. Dr. Nemeroff neglected to address the comparative efficacy of aripiprazole versus established treatments of TRD, such as lithium augmentation. The available evidence suggests that patients will do better on lithium and that aripiprazole would not be the first line choice, especially in primary care. Where were Medscape’s editors?
11. Reckless promotion of SGAs early in the course of TRD. Dr. Nemeroff emphatically stated he is not opposed to the early use of SGAs for TRD. Here especially he resembled Lindsay Wagner. A conscientious educator would weigh the risks and benefits of the early and broad use of SGA drugs in TRD. Dr. Nemeroff did no such thing. He simply opined. Why did Medscape’s editors allow him to get away with this reckless promotion? There does not appear to have been any effective editorial oversight of this publication.
12. For Dr. Nemeroff to promote early use of SGAs in TRD is reckless because of the serious toxicity associated with these drugs. Where is the discussion of akathisia (26% in the most recent study of aripiprazole in TRD)? Where is the discussion of emergent suicidality associated with akathisia in depression? Where is the discussion of tardive dyskinesia caused by aripiprazole (5% within 12 months in schizophrenia, and quite possibly higher in mood disordered patients)? Where is the discussion of neuroleptic malignant syndrome associated with SGAs like aripiprazole? Where is the discussion of weight gain with aripiprazole in TRD (significantly greater than with placebo)? Where is the overall analysis of risk versus benefit? Where were Medscape’s editors? Who at Medscape was looking out for “the best interests of patients”?
13. Incomplete disclosures. Dr. Nemeroff has a long history of recidivism concerning failure to disclose pertinent financial conflicts of interest. His record in this instance continues that sordid tradition. He failed to disclose that he is currently chairing a national series of CME meetings promoting aripiprazole for TRD, sponsored by, you guessed it, Bristol-Myers Squibb/Otsuka. Perhaps he thinks that because the money is laundered through a Medical Education Communications Company he doesn’t need to disclose it. Tell that to Joseph Biederman, who was called to task last week by Senator Grassley’s Senate Finance Committee for exactly that obfuscation. Dr. Nemeroff also failed to disclose his support from Janssen for studying risperidone in TRD. He failed to disclose his association with CeNeRx, that is developing MAO inhibitors, mentioned favorably in his interview. There is more, but these examples will suffice. Doesn’t Medscape know by now that Dr. Nemeroff cannot be relied on to report his conflicts appropriately? Does Medscape have knowledgeable professionals or ciphers in its editorial office?
So, this sleazy example illustrates many of the systemic problems that Medscape will need to correct if it hopes to remain credible. This documentation gives the lie to Dr. Lundberg’s claims that “We are clean. Our work is transparent.” One suggestion is for Medscape to abandon the degenerate form of scientific journalism exemplified by “Expert Interviews” and News items. In their present formats they cannot be truly educational and balanced items. They do not qualify for CME credit, as I verified with the company. They are simply vehicles for promoting sponsors’ products. And the Medscape staff seem to think their job is to ensure that the spin is firmly in place. Does George Lundberg really intend that?
Sunday, June 15, 2008
MEDSCAPE'S CME ETHICS
17 June 2008
MEDSCAPE’S CME ETHICS
Like global warming, the erosion of professional values and medical education by commerce shows no sign of slowing. The latest scandals involve Medscape. Medscape is a medical communications company that produces and distributes CME programs and other quasi-educational offerings, such as “Expert Interviews” and News items. A subsidiary of WebMD, Medscape is accredited by ACCME, and it relies on drug company money for its production costs. Medscape also displays multiple advertisements on every web page. Medscape uses salaried and contract medical writers to produce the “educational material.” The content is pedestrian, mainly because it makes no pretense of really educating – it is primarily a vehicle for promoting the sponsors’ products with varying degrees of slyness and subtlety, as Daniel Carlat has documented here http://carlatpsychiatry.blogspot.com/2008/06/medscapes-cme-corruption.html#links Some items are academic wallpaper, non-promotional pieces designed to create an appearance of commitment to education. For most featured items, Key Opinion Leaders (KOLs) are hired to push the material. These KOLs are paid for their roles, although Medscape never says so, much less discloses how much it pays. If they wish to be engaged regularly, the KOLs know they need to stay “on message.” These are standard arrangements in today’s amoral world of CME. Daniel Carlat recently published a fine exposé of Medscape’s corruption of CME standards (link above).
An especially distasteful practice is Medscape’s use of the names, reputations, and credibility of major professional societies to give its indifferent CME offerings and infomercials more pizzaz. Just to give two examples, Medscape web pages are currently hijacking the public images of both the American Psychiatric Association (APA) and the American College of Neuropsychopharmacology (ACNP), featuring highlights of these organizations’ annual meetings as CME and other items. These “highlights” from the APA and ACNP meetings are offered by Medscape FOR CME CREDIT!!! For us to call this presumptuous would be an understatement. For Medscape to dress it up with sanctimonious statements about avoiding conflict of interest is insufferable.
Both APA and ACNP annual meetings are closed events, so how does a commercial CME outfit like Medscape get its hands on these restricted materials? The most likely explanation is that venal KOLs accept Medscape payments for producing puff pieces with the organizational tagline (highlights of the APA/ACNP meeting!). In effect, these KOLs trade on their membership in professional organizations for personal gain in return for “authoring” Medscape-produced CME items, “Expert Interviews” and News pieces. How tacky is that? The KOLs who “authored” mini-manuscripts or provided “Expert Interviews” for Medscape’s “highlights” of the 2007 ACNP annual meeting, whether as infomercials or wallpaper, should know better. You can find them here and in the associated links: http://www.medscape.com/viewprogram/8683
Medscape is paid by Pharma to produce these items. The APA 2008 annual meeting highlights on Medscape’s website were supported by an “independent educational grant” from Shire and by an “unrestricted educational grant” from Bristol-Myers Squibb Company/Otsuka America Pharmaceuticals, Inc. It is a good bet that Medscape shares none of that revenue with the APA. Likewise, the ACNP 2007 annual meeting “highlights” were supported by an “independent educational grant” from Vanda Pharmaceuticals. We can be sure ACNP saw none of that revenue.
So what we have is Medscape profiting from Pharma sponsors while juicing up their mediocre CME offerings with tag lines to “highlights” of the APA and ACNP annual meetings. How tacky can you get? How tacky? This tacky: Here is the disclaimer published by Medscape’s lawyers regarding the ACNP meeting.
Legal Disclaimer
The materials presented here do not reflect the views of Medscape or the companies providing unrestricted educational grants. These materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. All readers or continuing education participants should verify all information and data before treating patients or employing any therapies described in this educational activity.
The materials presented here were prepared by independent authors under the editorial supervision of Medscape and do not represent a publication of the American College of Neuropsychopharmacology. These materials and the related activity are not sanctioned by the American College of Neuropsychopharmacology or the commercial supporter of the conference and do not constitute an official part of that conference.
Copyright © 2008 Medscape.
An additional disclaimer states, “This activity is not sanctioned by, nor a part of, the American College of Neuropsychopharmacology.” Well, fine. If it wasn’t sanctioned, why is Medscape splashing it over its web pages? I am confident ACNP gave Medscape no such authorization.
One hopes that APA and ACNP will publicly disown this corrupt use of their names and reputations for commerce by Medscape. The situation with APA is problematic because the incoming APA president, Alan Schatzberg, has been a frequent “Expert Interviewee” on Medscape. It remains to be seen whether his compromise and conflict will affect the organization’s response.
So, nobody at Medscape is accountable for the bias and bs in these items, even though they were written by Medscape staff and contractors. Medscape’s disclaimer tells us to go after the “independent authors.” That’s exactly what I intend to do in my next posting. Meanwhile, if Medscape wants credibility it will need to clean up its act. A good place to start would be to stop using these compromised KOLs who push infomercials and who provide soothing wallpaper. The real solution would be for Medscape to stop its skimming and money laundering activities altogether. Perhaps that is hoping for too much. Or they could just run naked advertising and they won’t need to bother with ACCME requirements. On the other hand, self-respecting health care professionals can just say no to Medscape’s kind of crap.
And what exactly does an “independent educational grant” mean, anyway? We will examine that trope in my next posting, which features the poster boy for compromised KOLs in psychiatry, Charles Nemeroff, MD from Emory University’s department of psychiatry. In that example, Medscape joins forces with Nemeroff to promote an entirely new level of sleaze. Stay tuned.
MEDSCAPE’S CME ETHICS
Like global warming, the erosion of professional values and medical education by commerce shows no sign of slowing. The latest scandals involve Medscape. Medscape is a medical communications company that produces and distributes CME programs and other quasi-educational offerings, such as “Expert Interviews” and News items. A subsidiary of WebMD, Medscape is accredited by ACCME, and it relies on drug company money for its production costs. Medscape also displays multiple advertisements on every web page. Medscape uses salaried and contract medical writers to produce the “educational material.” The content is pedestrian, mainly because it makes no pretense of really educating – it is primarily a vehicle for promoting the sponsors’ products with varying degrees of slyness and subtlety, as Daniel Carlat has documented here http://carlatpsychiatry.blogspot.com/2008/06/medscapes-cme-corruption.html#links Some items are academic wallpaper, non-promotional pieces designed to create an appearance of commitment to education. For most featured items, Key Opinion Leaders (KOLs) are hired to push the material. These KOLs are paid for their roles, although Medscape never says so, much less discloses how much it pays. If they wish to be engaged regularly, the KOLs know they need to stay “on message.” These are standard arrangements in today’s amoral world of CME. Daniel Carlat recently published a fine exposé of Medscape’s corruption of CME standards (link above).
An especially distasteful practice is Medscape’s use of the names, reputations, and credibility of major professional societies to give its indifferent CME offerings and infomercials more pizzaz. Just to give two examples, Medscape web pages are currently hijacking the public images of both the American Psychiatric Association (APA) and the American College of Neuropsychopharmacology (ACNP), featuring highlights of these organizations’ annual meetings as CME and other items. These “highlights” from the APA and ACNP meetings are offered by Medscape FOR CME CREDIT!!! For us to call this presumptuous would be an understatement. For Medscape to dress it up with sanctimonious statements about avoiding conflict of interest is insufferable.
Both APA and ACNP annual meetings are closed events, so how does a commercial CME outfit like Medscape get its hands on these restricted materials? The most likely explanation is that venal KOLs accept Medscape payments for producing puff pieces with the organizational tagline (highlights of the APA/ACNP meeting!). In effect, these KOLs trade on their membership in professional organizations for personal gain in return for “authoring” Medscape-produced CME items, “Expert Interviews” and News pieces. How tacky is that? The KOLs who “authored” mini-manuscripts or provided “Expert Interviews” for Medscape’s “highlights” of the 2007 ACNP annual meeting, whether as infomercials or wallpaper, should know better. You can find them here and in the associated links: http://www.medscape.com/viewprogram/8683
Medscape is paid by Pharma to produce these items. The APA 2008 annual meeting highlights on Medscape’s website were supported by an “independent educational grant” from Shire and by an “unrestricted educational grant” from Bristol-Myers Squibb Company/Otsuka America Pharmaceuticals, Inc. It is a good bet that Medscape shares none of that revenue with the APA. Likewise, the ACNP 2007 annual meeting “highlights” were supported by an “independent educational grant” from Vanda Pharmaceuticals. We can be sure ACNP saw none of that revenue.
So what we have is Medscape profiting from Pharma sponsors while juicing up their mediocre CME offerings with tag lines to “highlights” of the APA and ACNP annual meetings. How tacky can you get? How tacky? This tacky: Here is the disclaimer published by Medscape’s lawyers regarding the ACNP meeting.
Legal Disclaimer
The materials presented here do not reflect the views of Medscape or the companies providing unrestricted educational grants. These materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. All readers or continuing education participants should verify all information and data before treating patients or employing any therapies described in this educational activity.
The materials presented here were prepared by independent authors under the editorial supervision of Medscape and do not represent a publication of the American College of Neuropsychopharmacology. These materials and the related activity are not sanctioned by the American College of Neuropsychopharmacology or the commercial supporter of the conference and do not constitute an official part of that conference.
Copyright © 2008 Medscape.
An additional disclaimer states, “This activity is not sanctioned by, nor a part of, the American College of Neuropsychopharmacology.” Well, fine. If it wasn’t sanctioned, why is Medscape splashing it over its web pages? I am confident ACNP gave Medscape no such authorization.
One hopes that APA and ACNP will publicly disown this corrupt use of their names and reputations for commerce by Medscape. The situation with APA is problematic because the incoming APA president, Alan Schatzberg, has been a frequent “Expert Interviewee” on Medscape. It remains to be seen whether his compromise and conflict will affect the organization’s response.
So, nobody at Medscape is accountable for the bias and bs in these items, even though they were written by Medscape staff and contractors. Medscape’s disclaimer tells us to go after the “independent authors.” That’s exactly what I intend to do in my next posting. Meanwhile, if Medscape wants credibility it will need to clean up its act. A good place to start would be to stop using these compromised KOLs who push infomercials and who provide soothing wallpaper. The real solution would be for Medscape to stop its skimming and money laundering activities altogether. Perhaps that is hoping for too much. Or they could just run naked advertising and they won’t need to bother with ACCME requirements. On the other hand, self-respecting health care professionals can just say no to Medscape’s kind of crap.
And what exactly does an “independent educational grant” mean, anyway? We will examine that trope in my next posting, which features the poster boy for compromised KOLs in psychiatry, Charles Nemeroff, MD from Emory University’s department of psychiatry. In that example, Medscape joins forces with Nemeroff to promote an entirely new level of sleaze. Stay tuned.
Tuesday, March 25, 2008
BLOGSCAN - Imperial Pharmaceutical CEOs
On the PharmaLot blog, Ed Silverman has two posts about how pharmaceutical executives continue to rake in humongous compensation whose magnitude seems unrelated to their performance or the performance of their companies. The CEO of Cephalon got more than $15.8 million, including the value of stock options, while the company is dealing with an Federal Trade Commission lawsuit which contends the company blocked sales of a generic competitor, and despite settling a suit about off-label marketing (see post here.) The CEO of Bristol-Myers-Squibb got $13.5 million after the company's stock price fell, the company took a charge for losses on sub-prime mortgages, and several top financial officers left (see post here.) Again, as we noted earlier, imperial CEOs seem rampant in health care organizations.
Tuesday, January 22, 2008
Variations on a Theme of Sleaze
VARIATIONS ON A THEME OF SLEAZE
A few days ago I posted on corrupt reports in two medical journals, where key opinion leaders (KOLs) and corporate employees misrepresented the potential of Janssen’s atypical antipsychotic (AAP) drug risperidone for depression. One of these reports appeared in a general medical journal, Annals of Internal Medicine (AIM), which confirms the designs of the corporate marketers: by volume, treatment of depression now is centered in primary care. Considering the weak efficacy data, the dubious risk-benefit profile, and the inferiority of AAP drugs to other options, there is no justification for the broad and early adjunctive use of these agents for depression in primary care. The Eli Lilly Company, which markets the combination of olanzapine and fluoxetine in a single pill (Symbyax), has the same objective. Other companies are moving rapidly into this market space.
Combining AAP drugs with antidepressants takes us back to the bad old days of antidepressant-antipsychotic drug combinations like Triavil in the1960s and 1970s, when we learned that depressed patients are especially susceptible to a serious adverse event known as tardive dyskinesia (TD) caused by antipsychotic drugs. While the risk of TD is less than with the early antipsychotic agents, it is still unacceptably high with AAP drugs for patients who are unlikely to show meaningful clinical benefit, as I detailed earlier. In adult patients with schizophrenia the risk of TD with olanzapine treatment is about 2.5% at 1 year. In children and adolescents treated with AAP drugs for 6 months the risk is an alarming 6% (Wonodi I et al Movement Disorders 2007; 22: 1777). In patients with mood disorder, these figures are likely to be higher. And this is before one even begins to factor in the metabolic toxicity of AAP drugs (weight gain, obesity, insulin resistance, and Type II diabetes mellitus)! Patients are not well served when AAP drugs are pushed for treating depression in primary care.
Medical journals are not the only compromised medium. Continuing Medical Education (CME) is a second front in the campaign to expand the AAP drug market. The standard formula calls for corporate sponsorship channeled through an “unrestricted educational grant” to a medical education communications company (MECC). The MECC employs writers to prepare the “educational content,” and academic KOLs are recruited to deliver this content. The KOLs are chosen for their willingness to be “on message” for the corporate sponsor. If they go “off message” they know they will not be invited back. The talk of “unrestricted grants” is window dressing. The MECC also secures the imprimatur of a nationally accredited CME sponsor, typically an academic institution. The sponsor is paid to certify that the CME program meets the standards of the Accreditation Council on Continuing Medical Education (ACCME). Everybody turns a buck: the MECC and its staff are handsomely paid (CME is now a multi-billion dollar business); the KOLs are generously rewarded with honoraria and perquisites; the academic sponsor is well paid by the MECC; the ACCME receives dues from the academic sponsor; the audience obtains free CME credits rather than having to pay for these required educational experiences; and the corporate sponsor gets what it considers value for its marketing dollar.
ACCME standards include clear identification of off-label drug use; full and fair disclosure of clinical trial results, warts and all; and clinical guidance to the audience about risks, benefits, and treatment options. It is not an exaggeration to say that these standards are more often honored in the breach than in the observance. That is because CME events have been degraded to little more than thinly veiled advertising, built around promoting a product rather than around education. So corrupted has the process become that the Macy Foundation recently recommended that industry financing of CME be ended, “whether such support is provided directly or indirectly through subsidiary agencies.” See Daniel Carlat for more on this topic. Is this position alarmist? Consider the following examples of corruption in CME.
A widely advertised CME program appeared on-line 6 November 2007, titled Treatment-Refractory Depression: Is there a Role for Atypical Antipsychotics? Note the leading question and the product category focus. The program was developed by the MECC PeerView Institute for Medical Education, and it was sponsored by the Semel Institute for Neuroscience and Human Behavior at UCLA, which certified CME credits. Like the journal articles I discussed last week, this CME program is marked by a concatenation of deceits. The major messages were, augment earlier rather than later; AAP drugs are “an emerging therapeutic option” for augmentation (note the branding language); and AAP drugs are efficacious. None of these messages is based on credible evidence.
The first sleight of hand was the leadoff presentation, which featured the STAR*D study results concerning remission and response rates to adjunctive treatments or switching after various levels of treatment failure. The data naturally suggest unmet needs in treating depression (a favorite theme of marketers). The unspoken implication of this academic veneer is that the later studies described in the CME program were comparable to the STAR*D study in terms of case material, which is not so. Recruitment to STAR*D was explicitly different from recruitment to the usual experimercial sponsored by a drug company, where many cases come from contract research organizations, not from clinical referral streams. Moreover, STAR*D was a purely descriptive study that by design could not identify specific treatment effects.
Charles B. Nemeroff, MD, PhD from Emory University (yes, the same) discussed short term use of AAP drugs. His presentation is a model of being economical with the truth. Dr. Nemeroff has clearly mastered the art of accommodating his many corporate clients. He discussed 4 atypical antipsychotic drugs as augmenting agents for nonresponding depression. When discussing olanzapine he went beyond his short term remit to suggest that long term treatment is efficacious, yet he neglected to address the neurological or metabolic toxicity of long term olanzapine. When discussing risperidone he did not disclose that he was senior author of the major report he described and cited; he neglected to disclose the retractions he and Mark Rapaport from Cedars-Sinai Medical Center had been obliged to publish; he neglected to disclose that treatment with risperidone beyond 6 weeks was no more efficacious than placebo. That aspect was discussed by another speaker, who repeated Dr. Nemeroff’s now-retracted and discredited claims for significant long term preventive efficacy of risperidone in a subgroup of patients. Dr. Nemeroff made further claims about risperidone improving sexual function in patients receiving an SSRI antidepressant but he failed to disclose that beyond 6 weeks risperidone impaired sexual function in women who were receiving the SSRI; he backed up his claims about risperidone and sexual functioning by citing his publication in his own journal Neuropsychopharmacology that contained no data whatsoever on the matter; and he neglected to address the metabolic toxicity of risperidone that the corporation disclosed on ClinicalTrials.gov. He also falsely stated that the short term efficacy of risperidone in nonresponding depression was demonstrated in a controlled study, citing his own open-label study. These problems were called to the attention of the Semel Institute for Neuroscience and Human Behavior at UCLA. In response, the CME program was revised on January 11, 2008. Dr. Nemeroff’s material now contained a different citation that again contained no data concerning sexual side effects. They removed the claim that the short term efficacy of risperidone had been established in a controlled trial (although by then the problematic report of this very issue in AIM had been published for over 2 months). The inadequate discussion of the toxicity of risperidone in Dr. Nemeroff’s trial was unchanged, and another speaker continued to repeat the retracted and discredited claims of Dr. Nemeroff for significant long term preventive efficacy of risperidone in a subgroup of patients. No explanation of the changes made on January 11, 2008 in the on-line materials was provided by UCLA to CME readers who had studied the erroneous and biased material for more than 2 months. Other speakers made passing reference to the metabolic toxicity of AAP drugs but only in a perfunctory way that had no educational value, like what we see in direct-to-consumer advertising. Nobody mentioned the risk of TD.
As the Macy Foundation report makes clear, CME providers are expected to give learners guidance on the risk-benefit balance of new treatments. It is disingenuous of Dr. Nemeroff to talk up risperidone for short term treatment of these difficult depressions by exaggerating the benefit, downplaying the risks, avoiding comparison with alternative treatments, and glossing over the problem of longer term loss of efficacy. These are clear violations of ACCME principles.
When discussing aripiprazole for nonresponding depression, Dr. Nemeroff once again was economical with the truth. Note that Bristol-Myers Squibb, the marketer of aripiprazole, sponsored this PeerView/UCLA program. To document his claims about aripiprazole, Dr. Nemeroff cited one Abstract from the American Psychiatric Association meeting in May 2007. That does not meet ACCME standards of documentation for learners, most of whom would be unable to access the cited Abstract (not that it would tell them much even if they could). For some reason, Dr. Nemeroff did not inform learners that the complete report of the aripiprazole study had appeared in June 2007 (Berman RM et al. J Clin Psychiatry 2007;68: 843-853), fully 5 months before the CME event went on-line. From that readily available report it is clear that the Number Needed to Treat (NNT) for response with aripiprazole is 10, which compares unfavorably with a NNT of 4 for lithium, the best established augmenting option in placebo-controlled trials. A NNT of 10 means a clinician would need to treat 10 patients with aripiprazole before obtaining one remission that would not have occurred anyway with placebo. That does not constitute compelling clinical benefit. Dr. Nemeroff did not candidly discuss these troubling data. Dr Nemeroff provided his CME audience none of the remission or response data from the published aripiprazole study, though these data were readily available. These omissions of published, highly relevant information signify disrespect for his audience by Dr. Nemeroff, incompetence by the MECC, and failure of due diligence by the accrediting institution, UCLA, to ensure that accurate, balanced information and adequate documentation are provided. Likewise, no substantive risk-benefit analysis was provided to guide CME learners, and there was no meaningful discussion by Dr. Nemeroff of the metabolic toxicity of aripiprazole. The published report tells us that 7.1% of patients treated with aripiprazole gained more than 7% body weight, a very significant difference (p < 0.01) from the placebo treated patients (1.2%). Dr. Nemeroff did not share that information with the CME audience. Instead, he slyly minimized the appearance of the problem by showing a mean weight gain of only 2 kg with aripiprazole. In addition, the neuromotor toxicity of aripiprazole was remarkable (23.1% akathisia and 27.5% extrapyramidal symptoms). Dr. Nemeroff gave the CME audience no guidance about that problem or about its unblinding effect in the trial. Why do highly paid KOLs behave in this way? Do they think nobody will notice?
A final insult to CME learners in this program was the disclaimer that “The Semel Institute for Neuroscience and Human Behavior at UCLA is responsible for the selection of this report’s topics, the preparation of editorial content, and the distribution of this report” but “No responsibility is taken for errors or omissions in these reports.” Well, then, who is responsible? Why not UCLA, considering the ACCME standards and the fees UCLA received for sponsoring this CME activity through an “educational grant” from Bristol-Myers Squibb Company? Overall, it is difficult to avoid the impression that this so-called CME activity is a meretricious infomercial for Dr. Nemeroff’s corporate clients rather than a balanced educational event that aims to give practitioners considered guidance on a difficult clinical problem.
Will these revelations slow the marketing-inspired momentum for use of atypical antipsychotic drugs in depression? Not likely. Indeed, a new road show is right now getting under way, bringing the good news about atypical antipsychotic drugs in depression to CME audiences in Miami, San Francisco, Los Angeles, Chicago, Boston, and New York. Why now? Has some new insight been achieved that requires urgent communication to physicians? No. The road show has been launched now because aripiprazole was recently approved by the FDA for the secondary indication of adjunctive treatment in depression. It’s all about marketing. The faculty speakers are the usual suspects – KOLs and KOL wannabes who enjoy cozy or nepotistic relationships with the chairman. The funding is through another “educational grant” from the marketers of aripiprazole. The CME sponsor is an outfit in Texas that knows how the CME game is played. And the chairman of this new enterprise? Why, none other than the compromised Dr. Charles Nemeroff from Emory University. Why are we not surprised?
A few days ago I posted on corrupt reports in two medical journals, where key opinion leaders (KOLs) and corporate employees misrepresented the potential of Janssen’s atypical antipsychotic (AAP) drug risperidone for depression. One of these reports appeared in a general medical journal, Annals of Internal Medicine (AIM), which confirms the designs of the corporate marketers: by volume, treatment of depression now is centered in primary care. Considering the weak efficacy data, the dubious risk-benefit profile, and the inferiority of AAP drugs to other options, there is no justification for the broad and early adjunctive use of these agents for depression in primary care. The Eli Lilly Company, which markets the combination of olanzapine and fluoxetine in a single pill (Symbyax), has the same objective. Other companies are moving rapidly into this market space.
Combining AAP drugs with antidepressants takes us back to the bad old days of antidepressant-antipsychotic drug combinations like Triavil in the1960s and 1970s, when we learned that depressed patients are especially susceptible to a serious adverse event known as tardive dyskinesia (TD) caused by antipsychotic drugs. While the risk of TD is less than with the early antipsychotic agents, it is still unacceptably high with AAP drugs for patients who are unlikely to show meaningful clinical benefit, as I detailed earlier. In adult patients with schizophrenia the risk of TD with olanzapine treatment is about 2.5% at 1 year. In children and adolescents treated with AAP drugs for 6 months the risk is an alarming 6% (Wonodi I et al Movement Disorders 2007; 22: 1777). In patients with mood disorder, these figures are likely to be higher. And this is before one even begins to factor in the metabolic toxicity of AAP drugs (weight gain, obesity, insulin resistance, and Type II diabetes mellitus)! Patients are not well served when AAP drugs are pushed for treating depression in primary care.
Medical journals are not the only compromised medium. Continuing Medical Education (CME) is a second front in the campaign to expand the AAP drug market. The standard formula calls for corporate sponsorship channeled through an “unrestricted educational grant” to a medical education communications company (MECC). The MECC employs writers to prepare the “educational content,” and academic KOLs are recruited to deliver this content. The KOLs are chosen for their willingness to be “on message” for the corporate sponsor. If they go “off message” they know they will not be invited back. The talk of “unrestricted grants” is window dressing. The MECC also secures the imprimatur of a nationally accredited CME sponsor, typically an academic institution. The sponsor is paid to certify that the CME program meets the standards of the Accreditation Council on Continuing Medical Education (ACCME). Everybody turns a buck: the MECC and its staff are handsomely paid (CME is now a multi-billion dollar business); the KOLs are generously rewarded with honoraria and perquisites; the academic sponsor is well paid by the MECC; the ACCME receives dues from the academic sponsor; the audience obtains free CME credits rather than having to pay for these required educational experiences; and the corporate sponsor gets what it considers value for its marketing dollar.
ACCME standards include clear identification of off-label drug use; full and fair disclosure of clinical trial results, warts and all; and clinical guidance to the audience about risks, benefits, and treatment options. It is not an exaggeration to say that these standards are more often honored in the breach than in the observance. That is because CME events have been degraded to little more than thinly veiled advertising, built around promoting a product rather than around education. So corrupted has the process become that the Macy Foundation recently recommended that industry financing of CME be ended, “whether such support is provided directly or indirectly through subsidiary agencies.” See Daniel Carlat for more on this topic. Is this position alarmist? Consider the following examples of corruption in CME.
A widely advertised CME program appeared on-line 6 November 2007, titled Treatment-Refractory Depression: Is there a Role for Atypical Antipsychotics? Note the leading question and the product category focus. The program was developed by the MECC PeerView Institute for Medical Education, and it was sponsored by the Semel Institute for Neuroscience and Human Behavior at UCLA, which certified CME credits. Like the journal articles I discussed last week, this CME program is marked by a concatenation of deceits. The major messages were, augment earlier rather than later; AAP drugs are “an emerging therapeutic option” for augmentation (note the branding language); and AAP drugs are efficacious. None of these messages is based on credible evidence.
The first sleight of hand was the leadoff presentation, which featured the STAR*D study results concerning remission and response rates to adjunctive treatments or switching after various levels of treatment failure. The data naturally suggest unmet needs in treating depression (a favorite theme of marketers). The unspoken implication of this academic veneer is that the later studies described in the CME program were comparable to the STAR*D study in terms of case material, which is not so. Recruitment to STAR*D was explicitly different from recruitment to the usual experimercial sponsored by a drug company, where many cases come from contract research organizations, not from clinical referral streams. Moreover, STAR*D was a purely descriptive study that by design could not identify specific treatment effects.
Charles B. Nemeroff, MD, PhD from Emory University (yes, the same) discussed short term use of AAP drugs. His presentation is a model of being economical with the truth. Dr. Nemeroff has clearly mastered the art of accommodating his many corporate clients. He discussed 4 atypical antipsychotic drugs as augmenting agents for nonresponding depression. When discussing olanzapine he went beyond his short term remit to suggest that long term treatment is efficacious, yet he neglected to address the neurological or metabolic toxicity of long term olanzapine. When discussing risperidone he did not disclose that he was senior author of the major report he described and cited; he neglected to disclose the retractions he and Mark Rapaport from Cedars-Sinai Medical Center had been obliged to publish; he neglected to disclose that treatment with risperidone beyond 6 weeks was no more efficacious than placebo. That aspect was discussed by another speaker, who repeated Dr. Nemeroff’s now-retracted and discredited claims for significant long term preventive efficacy of risperidone in a subgroup of patients. Dr. Nemeroff made further claims about risperidone improving sexual function in patients receiving an SSRI antidepressant but he failed to disclose that beyond 6 weeks risperidone impaired sexual function in women who were receiving the SSRI; he backed up his claims about risperidone and sexual functioning by citing his publication in his own journal Neuropsychopharmacology that contained no data whatsoever on the matter; and he neglected to address the metabolic toxicity of risperidone that the corporation disclosed on ClinicalTrials.gov. He also falsely stated that the short term efficacy of risperidone in nonresponding depression was demonstrated in a controlled study, citing his own open-label study. These problems were called to the attention of the Semel Institute for Neuroscience and Human Behavior at UCLA. In response, the CME program was revised on January 11, 2008. Dr. Nemeroff’s material now contained a different citation that again contained no data concerning sexual side effects. They removed the claim that the short term efficacy of risperidone had been established in a controlled trial (although by then the problematic report of this very issue in AIM had been published for over 2 months). The inadequate discussion of the toxicity of risperidone in Dr. Nemeroff’s trial was unchanged, and another speaker continued to repeat the retracted and discredited claims of Dr. Nemeroff for significant long term preventive efficacy of risperidone in a subgroup of patients. No explanation of the changes made on January 11, 2008 in the on-line materials was provided by UCLA to CME readers who had studied the erroneous and biased material for more than 2 months. Other speakers made passing reference to the metabolic toxicity of AAP drugs but only in a perfunctory way that had no educational value, like what we see in direct-to-consumer advertising. Nobody mentioned the risk of TD.
As the Macy Foundation report makes clear, CME providers are expected to give learners guidance on the risk-benefit balance of new treatments. It is disingenuous of Dr. Nemeroff to talk up risperidone for short term treatment of these difficult depressions by exaggerating the benefit, downplaying the risks, avoiding comparison with alternative treatments, and glossing over the problem of longer term loss of efficacy. These are clear violations of ACCME principles.
When discussing aripiprazole for nonresponding depression, Dr. Nemeroff once again was economical with the truth. Note that Bristol-Myers Squibb, the marketer of aripiprazole, sponsored this PeerView/UCLA program. To document his claims about aripiprazole, Dr. Nemeroff cited one Abstract from the American Psychiatric Association meeting in May 2007. That does not meet ACCME standards of documentation for learners, most of whom would be unable to access the cited Abstract (not that it would tell them much even if they could). For some reason, Dr. Nemeroff did not inform learners that the complete report of the aripiprazole study had appeared in June 2007 (Berman RM et al. J Clin Psychiatry 2007;68: 843-853), fully 5 months before the CME event went on-line. From that readily available report it is clear that the Number Needed to Treat (NNT) for response with aripiprazole is 10, which compares unfavorably with a NNT of 4 for lithium, the best established augmenting option in placebo-controlled trials. A NNT of 10 means a clinician would need to treat 10 patients with aripiprazole before obtaining one remission that would not have occurred anyway with placebo. That does not constitute compelling clinical benefit. Dr. Nemeroff did not candidly discuss these troubling data. Dr Nemeroff provided his CME audience none of the remission or response data from the published aripiprazole study, though these data were readily available. These omissions of published, highly relevant information signify disrespect for his audience by Dr. Nemeroff, incompetence by the MECC, and failure of due diligence by the accrediting institution, UCLA, to ensure that accurate, balanced information and adequate documentation are provided. Likewise, no substantive risk-benefit analysis was provided to guide CME learners, and there was no meaningful discussion by Dr. Nemeroff of the metabolic toxicity of aripiprazole. The published report tells us that 7.1% of patients treated with aripiprazole gained more than 7% body weight, a very significant difference (p < 0.01) from the placebo treated patients (1.2%). Dr. Nemeroff did not share that information with the CME audience. Instead, he slyly minimized the appearance of the problem by showing a mean weight gain of only 2 kg with aripiprazole. In addition, the neuromotor toxicity of aripiprazole was remarkable (23.1% akathisia and 27.5% extrapyramidal symptoms). Dr. Nemeroff gave the CME audience no guidance about that problem or about its unblinding effect in the trial. Why do highly paid KOLs behave in this way? Do they think nobody will notice?
A final insult to CME learners in this program was the disclaimer that “The Semel Institute for Neuroscience and Human Behavior at UCLA is responsible for the selection of this report’s topics, the preparation of editorial content, and the distribution of this report” but “No responsibility is taken for errors or omissions in these reports.” Well, then, who is responsible? Why not UCLA, considering the ACCME standards and the fees UCLA received for sponsoring this CME activity through an “educational grant” from Bristol-Myers Squibb Company? Overall, it is difficult to avoid the impression that this so-called CME activity is a meretricious infomercial for Dr. Nemeroff’s corporate clients rather than a balanced educational event that aims to give practitioners considered guidance on a difficult clinical problem.
Will these revelations slow the marketing-inspired momentum for use of atypical antipsychotic drugs in depression? Not likely. Indeed, a new road show is right now getting under way, bringing the good news about atypical antipsychotic drugs in depression to CME audiences in Miami, San Francisco, Los Angeles, Chicago, Boston, and New York. Why now? Has some new insight been achieved that requires urgent communication to physicians? No. The road show has been launched now because aripiprazole was recently approved by the FDA for the secondary indication of adjunctive treatment in depression. It’s all about marketing. The faculty speakers are the usual suspects – KOLs and KOL wannabes who enjoy cozy or nepotistic relationships with the chairman. The funding is through another “educational grant” from the marketers of aripiprazole. The CME sponsor is an outfit in Texas that knows how the CME game is played. And the chairman of this new enterprise? Why, none other than the compromised Dr. Charles Nemeroff from Emory University. Why are we not surprised?
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