Does Pharma Want its Researchers to Believe They Are Next to God?

In "Drug Maker Told Studies Would Aid It, Papers Say" (New York Times, Mar. 19, 2009), the Times discusses the case of psychiatrist Dr. Joseph Biederman. Dr. Biederman outlined plans to test Johnson & Johnson’s drugs including risperidone/Risperidal in presentations to company executives and seemed to guarantee positive outcomes for his studies of the drug, raising questions about his research.

Biederman has become a key witness in a series of lawsuits filed by state attorneys general claiming that makers of antipsychotic drugs defrauded state Medicaid programs by improperly marketing their medicines. His work helped fuel a rapid rise in the use of these medicines in children. Biederman earned at least $1.6 million in consulting fees from drug makers from 2000 to 2007 but failed to report all but about $200,000 of this income to university officials.

However, if a passage about Dr. Biederman's testimony in court is correct, I believe pharma should consider whether it wants to use someone who believes they are next to God in any capacity whatsoever.

There are certain damning statements that, once made by a person, cast a deep shadow over a person's character. I believe this one, if true, may rise to that level:

In a contentious Feb. 26 deposition between Dr. Biederman and lawyers for the states, he was asked what rank he held at Harvard. “Full professor,” he answered.

“What’s after that?” asked a lawyer, Fletch Trammell.

“God,” Dr. Biederman responded.

“Did you say God?” Mr. Trammell asked.

“Yeah,” Dr. Biederman said.

One does not usually joke in deposition.

I've been Yale faculty, and would never, ever have made anything even approaching such a comment, least of all in a deposition about drug issues affecting kids.

Let alone the the palm-greasing he was afforded, could Dr. Biederman's apparently hyperinflated ego have clouded his judgment and scientific objectivity?

In drug R&D, that is inherently an extremely dangerous proposition.

Where children are concerned, catastrophic might be a more apt term.

-- SS

What Me Worry? - Academic Leaders Blissfully Unaware of the Commercial Purposes of their Research Center

A few weeks ago, the Boston Globe published an investigative report on differences in reimbursements insurers and managed care organizations provide to different hospitals and hospital systems. One major bullet point was that the Partners HealthCare system, whose flagship hospitals include the Massachusetts General Hospital and the Brigham and Womens Hospital, received higher reimbursement rates than other well-known hospital and health care systems. A second was by some measures of quality, the major Partners teaching hospitals did not do better than other Boston hospitals.

In the resulting debate in the blogsphere (for example, see these posts and accompanying comments, on the Running a Hospital blog, and on the Movin' Meat blog,) some argued perhaps Partners really did deserve the extra payment. After all, the Massachusetts General Hospital and the Brigham and Womens Hospital are two of the most prestigious hospitals in the US, and indeed, the world. It is not implausible that this prestige arose from some real quality advantages. Furthermore, as we and others have argued, the available measures of quality, including those proposed to govern so-called "pay for performance" (P4P) in health care, are deeply flawed. For example, because of the Massachusetts General Hospital's reputation, it may attract the most difficult and complex patients, and these patients' severity and complexity of illness may have caused the hospital to have high mortality rates, despite the best of care.

Thus, at the time, the extra reimbursement going to Partners hospitals did not seem an issue for Health Care Renewal. But this week another series of stories came out about "Man's Best Hospital," (as it was called in "Samuel Shem's" House of God).... And they suggested that the Partners system may have quality problems of another kind.

Revelations about a research center at the Massachusetts General Hospital, and the renowned psychiatrist who ran it resulted from discovery legal proceedings. Lawsuits against several drug companies claimed that children were injured by atypical anti-psychotic drugs produced by several companies. The plaintiffs asserted that Dr Joseph Biederman's research was "crucial to the widespread acceptance of pediatric uses of antipsychotic medicines," (per Gardiner Harris reporting in the New York Times). The Massachusetts General Hospital's web-site notes that Dr Biederman is "Chief of the Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD at the Massachusetts General Hospital, and Professor of Psychiatry at the Harvard Medical School."

According to the NY Times article, Dr Biederman pressured Johnson & Johnson, the manufacturer of Risperdal (risperidone), an atypical antipsychotic drug, to finance a research center at Massachusetts General Hospital,

E-mail messages and internal documents from Johnson & Johnson made public in a court filing reveal that Dr. Biederman pushed the company to finance a research center at Massachusetts General Hospital, in Boston, with a goal to 'move forward the commercial goals of J.& J.'

Furthermore,

A series of documents described the goals behind establishing the Johnson & Johnson Center for the study of pediatric psychopathology, where Dr. Biederman serves as chief.

A 2002 annual report for the center said its research must satisfy three criteria: improve psychiatric care for children, have high standards and 'move forward the commercial goals of J.& J.,' court documents said.

A February 2002 e-mail message from Georges Gharabawi, a Johnson & Johnson executive, said Dr. Biederman approached the company 'multiple times to propose the creation' of the center. 'The rationale of this center,” the message stated, “is to generate and disseminate data supporting the use of risperidone in' children and adolescents.

Furthermore, David Armstrong, writing for the Wall Street Journal, noted

Internal J&J records that are part of the plaintiffs' filing indicate that Janssen (Johnson & Johnson subsidiary) paid, or was requested to make payments, of $500,000 to help start up the center in 2002, another $200,000 for operating funds in 2003 and an additional $250,000 for 2004 activities. Janssen declined to comment on those figures.

Dr. Biederman was receiving direct compensation from J&J during those years, according to records obtained by Sen. Charles Grassley, who has been investigating drug-company payments to the Harvard researcher at others at academic medical centers. In 2001, Dr. Biederman was paid $58,169 by J&J although he reported to Harvard that he was only paid $3,5000, according to Sen. Grassley. In all, Dr. Biederman received more than $1.6 million between 2000 and 2007 from drug companies while reporting to Harvard receiving only several hundred thousand, Sen. Grassley's documents show.

Also, per the WSJ,

The emails also suggest that the company's marketing staff were involved in creating the institute and that company officials helped to write and vet research work done by Dr. Biederman and his associates.

Officials from Massachusetts General Hospital denied that they knew what was really going on at the Center. Per an article in the Boston Globe,

Massachusetts General Hospital issued a statement yesterday saying that the center, the MGH-Johnson & Johnson Center for the Study of Pediatric Psychopathology, existed from 2002 to 2006 and gave many researchers 'the infrastructure necessary to complete projects related to the psychiatric care of children in an efficient, expeditious, and integrated manner.'

The hospital controlled the center's programs, it said, and, 'The grant agreements stated that the center was for scientific and educational purposes only and not for purposes of promoting, directly or indirectly, the products of Johnson & Johnson and its affiliates.'

The allegations in the Risperdal case 'have raised significant questions and concerns about the implementation of those agreements,' the statement said. 'The MGH takes these allegations very seriously and intends to investigate these issues thoroughly.'

Meanwhile, Harvard University denied any direct involvement. Per an article in Bloomberg News,

David Cameron, a spokesman for Boston-based Harvard Medical School, said Harvard isn’t involved with the J&J Center at Massachusetts General, a Harvard teaching hospital.

'Harvard Medical School does not ‘own’ any of its teaching hospitals,' Cameron said in an e-mail. 'While we are affiliated with them through academic appointments, all teaching hospitals are individually governed.'

A major theme of this blog has been how the leadership of ever larger and more dominant health care organization have forsaken their missions, and instead acted to threaten physicians' and other health professionals' core values. For example, a leader of academic medicine asserted that faculty were judged more for their ability to bring in money, to be "taxpayers," in his words, but not to teach, do research, or take care of patients. This occurred while health care organizations were increasingly run by people from the business world who had little experience in or knowledge of the care of patients, or of biomedical or clinical science.

The sorry tale of Dr Joseph Biederman now adds to the evidence that at even the most elite academic medical institutions commercial purposes may outweigh the academic or clinical mission. The remarkable feature of this story is that the leaders of the particular institutions involved seemed blissfully unaware of what was going on.

At best, the leaders of Massachusetts General Hospital did not seem to know what the purposes of their own so-called research units were. Although Harvard Medical School has long been identified with its prestigious teaching hospitals, and vica versa, now the Medical School says it was "not involved" in the hospitals' and its own faculty's research activities. It all has the smell of "plausible deniability." Maybe the leadership of ostensibly academic institutions no longer want to know too much about their institutions' academic activities, presumably as long as those activities brought in enough money to be good "taxpayers."

But if academic leaders claim to know nothing about and have no involvement in their organizations' academic activities, what sort of leaders are they, and what really are their missions?

Meanwhile, all too many medical academics cloak themselves in the mantles of their academic respectability while helping to hawk drugs and devices, while claiming to be perfectly uninfluenced by the tens or hundreds of thousands or more dollars they are making on the side, and uninfluenced by how the huge grants their sponsors hand to their institutions promote their careers, making their academic cloaks all the more showy.

For additional comment on this case, see this post in the Clinical Psychology and Psychiatry Blog, this one on the Alison Bass blog, and this one on the University Diaries blog.

ADDENDUM (1 December, 2008) - Also see this post on the Carlat Psychiatry Blog.

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?