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?
Showing posts with label refractory depression. Show all posts
Showing posts with label refractory depression. Show all posts
Thursday, June 19, 2008
Wednesday, January 16, 2008
ANTIPSYCHOTIC DRUGS FOR DEPRESSION?
Readers concerned about commercial influence know that the Devil is in the details when it comes to recognizing and exposing distortions like spin, bias and shills in journal publications. One guiding observation is that “For private companies, publication and a positive press have cash value…” (E.W. Campion, New England Journal of Medicine, 2004).
With an eye to the sly details, this posting will describe a current campaign to promote the atypical antipsychotic (AAP) drug risperidone as an augmenting agent in nonresponding major depression. The campaign aims to shape a favorable climate of opinion for the drug through experimercials (commercially strategic clinical trials) and journal publications that are really infomercials. The stakeholders are some major corporations, “key opinion leaders” (KOLs), leading medical journals, and several million patients who suffer from nonresponsive depression in the US. The winners are the KOLs and the corporations, while the big losers are the patients.
We begin with the November 2006 report of an experimercial testing Janssen’s AAP drug risperidone for nonresponding depression, published in the journal Neuropsychopharmacology (NPP). This is the house journal of the American College of Neuropsychopharmacology (ACNP), which aspires to be the premier organization in its field. Bottom line: short term, open label, uncontrolled use of risperidone appeared to be helpful, but placebo-controlled continuation beyond 6 weeks was not effective in preventing relapse. The lead author was Mark H. Rapaport, MD from Cedars-Sinai Medical Center in Los Angeles. A co-author was the controversial Martin Keller, MD from Brown University, and the senior (last) author was Charles B. Nemeroff, MD, PhD from Emory University, who was also editor in chief of the journal.
Dr. Nemeroff’s is a long-time KOL for Janssen’s efforts to create a favorable climate of opinion for risperidone in depression. He fronted for the company in presentations of the risperidone infomercial at the ACNP meeting in 2004, in a Janssen-financed journal supplement in 2005, and in co-authoring the 2006 infomercial in his own journal, NPP. Readers will recall that Dr. Nemeroff ran into problems in 2003 for failing to disclose his financial conflicts of interest in a Nature publication, and again in 2006 for failing to disclose his commercial ties in a review article he co-authored favorable to the Cyberonics vagus nerve stimulation (VNS) device for depression (also published in the journal he edited). As a result of that episode, Dr. Nemeroff resigned as editor of NPP, but not before publishing the infomercial mentioned above on risperidone in depression. One wants to ask whether these publications that he co-authored went through a credible peer review in Dr. Nemeroff’s journal. One also wants to ask whether Dr. Nemeroff abused his position as editor to give product placement to his corporate clients Cyberonics and Janssen. And one wants to ask why the risperidone infomercial was published in NPP, given that the data had already been published by Dr. Nemeroff himself in another journal, in a special supplement financed by Janssen. This prior publication of the risperidone trial, that by journal policy should have precluded publication in NPP, was not revealed (cited) by Dr. Nemeroff and his co-authors. Did they think nobody would notice?
The main outcome of the risperidone trial reported in NPP was negative: long term use of risperidone did not prevent relapse. By assiduous secondary analyses and data mining, the authors found something positive to salvage their effort. They claimed by two analyses that risperidone was effective in preventing relapse in a subgroup of patients. In short order, however, they qualified the original report. First they belatedly disclosed the authors’ commercial ties to Janssen. A second Corrigendum retracted one of the claims of efficacy: by some process of Immaculate Conception, an “error” had occurred whereby a p value of 0.4 was transformed into a p value of 0.05, first in the text and again in the Abstract. This retraction occurred only because alert readers asked probing questions of the lead author, Dr. Rapaport. No author took responsibility for this compound misrepresentation in NPP. The “error” was so obvious that all authors and any conscientious reviewer should have seen it. You begin to see the picture: we have the appearance of editorial self-dealing, including product placement for a corporate client of the editor; an incompetent or possibly dishonest journal review process; and the appearance that somebody went out of his way in two places to insert a false claim of efficacy into the report of a negative clinical trial. Finally, we have reasonable cause to suspect that the KOLs did not actually read the article they were credited with authoring. For busy KOLs, tradecraft is a thing of the past.
Soon, more questions arose. In a letter to NPP published in 2007, I challenged the second claim of efficacy for risperidone in preventing relapse in a subgroup: the claim made in the journal and in two of Dr. Nemeroff’s prior publications did not match the corporation’s analysis reported on ClinicalTrials.gov. Rapaport, Keller and Nemeroff had “nudged” the statistical result of Janssen’s analysis from borderline to unqualified statistical significance. My letter also detailed how these KOLs downplayed the disturbing data on metabolic toxicity (weight gain): the raw data were stated but the unfavorable statistical analysis of those data that appeared on ClinicalTrials.gov was suppressed. The KOLs chose not to reveal that patients who received risperidone gained significantly more weight than those who received placebo. The appearance of bias and spin was unmistakable. In response to my letter, the lead author, Mark H. Rapaport, MD, who seemed to have been deserted by his KOL colleagues, abjectly disowned any claim of efficacy whatsoever for risperidone, while being nonresponsive to the charge that they had manipulated the risk-benefit profile of the drug. So now we have high profile academic KOL authors putting lipstick on the pig with both false and exaggerated claims of efficacy in a negative study, misstating the results of statistical analyses, and “burying” inconvenient toxicity analyses. Were the reviewers for NPP so incompetent that they could not see what any reader could see? One wants to ask whether this report, with the editor in chief as senior author, received any review at all.
So far so good: with Dr. Rapaport’s latest retraction, Janssen and its hired KOLs now disown any claim that risperidone is effective in long term prevention of relapse in nonresponding depression. What about short term treatment? The infomercial in NPP contained only uncontrolled, open label data on the short term efficacy of risperidone. That is the weakest level of evidence, even though it was touted by the KOLs with the message that many patients responded “rapidly and robustly.” Inconveniently, many of them relapsed even with continuation risperidone therapy. So much for robustness.
As luck would have it, Janssen reported a placebo-controlled short term study of risperidone in nonresponsive depression in the November 6, 2007 issue of Annals of Internal Medicine (AIM) (Mahmoud RA et al. Ann Intern Med 2007; 147: 593-602). The authors are Janssen employees who had been co-authors with Rapaport, Keller and Nemeroff on the now retracted NPP report. (Possibly in response to static over the earlier report, Nemeroff and Rapaport plus a few other KOLs were simply acknowledged as advisors instead of receiving co-author status on the AIM report).
The bottom line? Though there were some statistically significant differences favoring short term risperidone over inactive placebo by conventional rating scales, evidence of clinical utility was underwhelming. Once again, Janssen’s presentation of the results was biased: the authors used completer data for efficacy, which improved the appearance of benefit for risperidone, whereas they used Intent to Treat (ITT) data for toxicity, which minimized the apparent metabolic adverse effects of risperidone. Dr. Ralph Koek and I pointed out in an on-line response to the journal that when ITT data are used consistently the Number Needed to Treat (NNT) for remission was 15.6 at 4 weeks and 10.2 at 6 weeks. Those NNTs do not indicate compelling clinical benefit for risperidone: an NNT of 15 means one would need to treat 15 patients with risperidone to obtain 1 remission that would not have occurred anyway with placebo. Moreover, the metabolic toxicity of risperidone (weight gain) was significantly increased over placebo, but the authors downplayed that problem by keeping it out of the Abstract, and it did not appear in the “Summaries for Patients” posting by the journal. Once again, Janssen used questionable manipulations to maximize the appearance of efficacy while minimizing the apparent risk of risperidone in nonresponding depression. This is called “augmenting” the risk-benefit profile.
So now there is evidence from two controlled trials that risperidone confers little significant benefit and has a dubious risk-benefit profile either in short term use or in longer term use for nonresponsive depression. In light of this evidence it is difficult to justify the broad and early use of risperidone or, probably, any other atypical antipsychotic drug in such patients. Richard Shelton, MD from Vanderbilt and George Papakostas from MGH concur with this conclusion, in a thoughtful review article that has just appeared on-line in Acta Psychiatrica Scandinavica. These two investigators conducted several of the early trials of other AAP drugs in depression. They gave a timely warning about the late-appearing but often devastating side effect of tardive dyskinesia that can result from exposure of depressed patients to AAP drugs. Needless to say, that tissue was not addressed in either of the Janssen publications talking up risperidone for depression.
Studies of this issue routinely take the de minimis approach of testing AAP agents only against an inactive placebo, ignoring the problems of unblinding that occur when these sedating agents are used, and avoiding comparisons with other options. Quite possibly, any sedating or anxiolytic agent like off-patent trazodone would have effects indistinguishable from risperidone. The corporation’s goal is not to answer such important clinical questions, however, but only to clear the regulatory bars needed to expand the market for its drug. Patients lose out when an expensive atypical antipsychotic drug with an NNT of 10-15 is promoted while an inexpensive option like lithium augmentation, which has an NNT of 4, is ignored. But, as these experimercials are driven by marketing rather than by scientific or educational goals, the evidence that risperidone is inferior to lithium, the best established augmenting agent, is routinely ignored in the clinical trial reports.
So, here is the litany of sly tactics used by Janssen with the willing cooperation of KOLs like Nemeroff , Rapaport and Keller. Remember, these KOLs are paid directly or indirectly by Janssen for their association with the marketing campaign: design a clinical trial in which unblinding is guaranteed and ignore this confound which favors the drug; secure high profile product placement in a journal like NPP, with the cooperation of the editor; make false claims of efficacy in a negative trial report; when challenged, lamely try to pass off this compound misrepresentation as an “error” for which nobody accepts responsibility; take self-serving liberties with the results of statistical analyses so as to claim efficacy where none exists; suppress inconvenient statistical analyses of toxicity; manipulate the apparent risk-benefit profile of the drug; constructively plead nolo contendere to the charge of manipulating key data analyses; focus on the statistical significance of psychometric outcome measures while ignoring clinimetric measures of usefulness like NNT; bias the analysis of efficacy by using completer data; bias the analysis of toxicity by using ITT data; and ignore existing data that suggest the corporation’s drug is inferior to established alternatives.
Any one of these sly tactics might be viewed individually as an unfortunate slip, for which some will incline to give the authors the benefit of the doubt. The concatenation of deceits, however, speaks for itself. Readers ought never to underestimate the cunning and the venality of marketeers and their co-opted academic KOLs in corrupting the medical literature. In a future posting I will continue this sordid tale with illustrations from the equally compromised world of CME programs.
With an eye to the sly details, this posting will describe a current campaign to promote the atypical antipsychotic (AAP) drug risperidone as an augmenting agent in nonresponding major depression. The campaign aims to shape a favorable climate of opinion for the drug through experimercials (commercially strategic clinical trials) and journal publications that are really infomercials. The stakeholders are some major corporations, “key opinion leaders” (KOLs), leading medical journals, and several million patients who suffer from nonresponsive depression in the US. The winners are the KOLs and the corporations, while the big losers are the patients.
We begin with the November 2006 report of an experimercial testing Janssen’s AAP drug risperidone for nonresponding depression, published in the journal Neuropsychopharmacology (NPP). This is the house journal of the American College of Neuropsychopharmacology (ACNP), which aspires to be the premier organization in its field. Bottom line: short term, open label, uncontrolled use of risperidone appeared to be helpful, but placebo-controlled continuation beyond 6 weeks was not effective in preventing relapse. The lead author was Mark H. Rapaport, MD from Cedars-Sinai Medical Center in Los Angeles. A co-author was the controversial Martin Keller, MD from Brown University, and the senior (last) author was Charles B. Nemeroff, MD, PhD from Emory University, who was also editor in chief of the journal.
Dr. Nemeroff’s is a long-time KOL for Janssen’s efforts to create a favorable climate of opinion for risperidone in depression. He fronted for the company in presentations of the risperidone infomercial at the ACNP meeting in 2004, in a Janssen-financed journal supplement in 2005, and in co-authoring the 2006 infomercial in his own journal, NPP. Readers will recall that Dr. Nemeroff ran into problems in 2003 for failing to disclose his financial conflicts of interest in a Nature publication, and again in 2006 for failing to disclose his commercial ties in a review article he co-authored favorable to the Cyberonics vagus nerve stimulation (VNS) device for depression (also published in the journal he edited). As a result of that episode, Dr. Nemeroff resigned as editor of NPP, but not before publishing the infomercial mentioned above on risperidone in depression. One wants to ask whether these publications that he co-authored went through a credible peer review in Dr. Nemeroff’s journal. One also wants to ask whether Dr. Nemeroff abused his position as editor to give product placement to his corporate clients Cyberonics and Janssen. And one wants to ask why the risperidone infomercial was published in NPP, given that the data had already been published by Dr. Nemeroff himself in another journal, in a special supplement financed by Janssen. This prior publication of the risperidone trial, that by journal policy should have precluded publication in NPP, was not revealed (cited) by Dr. Nemeroff and his co-authors. Did they think nobody would notice?
The main outcome of the risperidone trial reported in NPP was negative: long term use of risperidone did not prevent relapse. By assiduous secondary analyses and data mining, the authors found something positive to salvage their effort. They claimed by two analyses that risperidone was effective in preventing relapse in a subgroup of patients. In short order, however, they qualified the original report. First they belatedly disclosed the authors’ commercial ties to Janssen. A second Corrigendum retracted one of the claims of efficacy: by some process of Immaculate Conception, an “error” had occurred whereby a p value of 0.4 was transformed into a p value of 0.05, first in the text and again in the Abstract. This retraction occurred only because alert readers asked probing questions of the lead author, Dr. Rapaport. No author took responsibility for this compound misrepresentation in NPP. The “error” was so obvious that all authors and any conscientious reviewer should have seen it. You begin to see the picture: we have the appearance of editorial self-dealing, including product placement for a corporate client of the editor; an incompetent or possibly dishonest journal review process; and the appearance that somebody went out of his way in two places to insert a false claim of efficacy into the report of a negative clinical trial. Finally, we have reasonable cause to suspect that the KOLs did not actually read the article they were credited with authoring. For busy KOLs, tradecraft is a thing of the past.
Soon, more questions arose. In a letter to NPP published in 2007, I challenged the second claim of efficacy for risperidone in preventing relapse in a subgroup: the claim made in the journal and in two of Dr. Nemeroff’s prior publications did not match the corporation’s analysis reported on ClinicalTrials.gov. Rapaport, Keller and Nemeroff had “nudged” the statistical result of Janssen’s analysis from borderline to unqualified statistical significance. My letter also detailed how these KOLs downplayed the disturbing data on metabolic toxicity (weight gain): the raw data were stated but the unfavorable statistical analysis of those data that appeared on ClinicalTrials.gov was suppressed. The KOLs chose not to reveal that patients who received risperidone gained significantly more weight than those who received placebo. The appearance of bias and spin was unmistakable. In response to my letter, the lead author, Mark H. Rapaport, MD, who seemed to have been deserted by his KOL colleagues, abjectly disowned any claim of efficacy whatsoever for risperidone, while being nonresponsive to the charge that they had manipulated the risk-benefit profile of the drug. So now we have high profile academic KOL authors putting lipstick on the pig with both false and exaggerated claims of efficacy in a negative study, misstating the results of statistical analyses, and “burying” inconvenient toxicity analyses. Were the reviewers for NPP so incompetent that they could not see what any reader could see? One wants to ask whether this report, with the editor in chief as senior author, received any review at all.
So far so good: with Dr. Rapaport’s latest retraction, Janssen and its hired KOLs now disown any claim that risperidone is effective in long term prevention of relapse in nonresponding depression. What about short term treatment? The infomercial in NPP contained only uncontrolled, open label data on the short term efficacy of risperidone. That is the weakest level of evidence, even though it was touted by the KOLs with the message that many patients responded “rapidly and robustly.” Inconveniently, many of them relapsed even with continuation risperidone therapy. So much for robustness.
As luck would have it, Janssen reported a placebo-controlled short term study of risperidone in nonresponsive depression in the November 6, 2007 issue of Annals of Internal Medicine (AIM) (Mahmoud RA et al. Ann Intern Med 2007; 147: 593-602). The authors are Janssen employees who had been co-authors with Rapaport, Keller and Nemeroff on the now retracted NPP report. (Possibly in response to static over the earlier report, Nemeroff and Rapaport plus a few other KOLs were simply acknowledged as advisors instead of receiving co-author status on the AIM report).
The bottom line? Though there were some statistically significant differences favoring short term risperidone over inactive placebo by conventional rating scales, evidence of clinical utility was underwhelming. Once again, Janssen’s presentation of the results was biased: the authors used completer data for efficacy, which improved the appearance of benefit for risperidone, whereas they used Intent to Treat (ITT) data for toxicity, which minimized the apparent metabolic adverse effects of risperidone. Dr. Ralph Koek and I pointed out in an on-line response to the journal that when ITT data are used consistently the Number Needed to Treat (NNT) for remission was 15.6 at 4 weeks and 10.2 at 6 weeks. Those NNTs do not indicate compelling clinical benefit for risperidone: an NNT of 15 means one would need to treat 15 patients with risperidone to obtain 1 remission that would not have occurred anyway with placebo. Moreover, the metabolic toxicity of risperidone (weight gain) was significantly increased over placebo, but the authors downplayed that problem by keeping it out of the Abstract, and it did not appear in the “Summaries for Patients” posting by the journal. Once again, Janssen used questionable manipulations to maximize the appearance of efficacy while minimizing the apparent risk of risperidone in nonresponding depression. This is called “augmenting” the risk-benefit profile.
So now there is evidence from two controlled trials that risperidone confers little significant benefit and has a dubious risk-benefit profile either in short term use or in longer term use for nonresponsive depression. In light of this evidence it is difficult to justify the broad and early use of risperidone or, probably, any other atypical antipsychotic drug in such patients. Richard Shelton, MD from Vanderbilt and George Papakostas from MGH concur with this conclusion, in a thoughtful review article that has just appeared on-line in Acta Psychiatrica Scandinavica. These two investigators conducted several of the early trials of other AAP drugs in depression. They gave a timely warning about the late-appearing but often devastating side effect of tardive dyskinesia that can result from exposure of depressed patients to AAP drugs. Needless to say, that tissue was not addressed in either of the Janssen publications talking up risperidone for depression.
Studies of this issue routinely take the de minimis approach of testing AAP agents only against an inactive placebo, ignoring the problems of unblinding that occur when these sedating agents are used, and avoiding comparisons with other options. Quite possibly, any sedating or anxiolytic agent like off-patent trazodone would have effects indistinguishable from risperidone. The corporation’s goal is not to answer such important clinical questions, however, but only to clear the regulatory bars needed to expand the market for its drug. Patients lose out when an expensive atypical antipsychotic drug with an NNT of 10-15 is promoted while an inexpensive option like lithium augmentation, which has an NNT of 4, is ignored. But, as these experimercials are driven by marketing rather than by scientific or educational goals, the evidence that risperidone is inferior to lithium, the best established augmenting agent, is routinely ignored in the clinical trial reports.
So, here is the litany of sly tactics used by Janssen with the willing cooperation of KOLs like Nemeroff , Rapaport and Keller. Remember, these KOLs are paid directly or indirectly by Janssen for their association with the marketing campaign: design a clinical trial in which unblinding is guaranteed and ignore this confound which favors the drug; secure high profile product placement in a journal like NPP, with the cooperation of the editor; make false claims of efficacy in a negative trial report; when challenged, lamely try to pass off this compound misrepresentation as an “error” for which nobody accepts responsibility; take self-serving liberties with the results of statistical analyses so as to claim efficacy where none exists; suppress inconvenient statistical analyses of toxicity; manipulate the apparent risk-benefit profile of the drug; constructively plead nolo contendere to the charge of manipulating key data analyses; focus on the statistical significance of psychometric outcome measures while ignoring clinimetric measures of usefulness like NNT; bias the analysis of efficacy by using completer data; bias the analysis of toxicity by using ITT data; and ignore existing data that suggest the corporation’s drug is inferior to established alternatives.
Any one of these sly tactics might be viewed individually as an unfortunate slip, for which some will incline to give the authors the benefit of the doubt. The concatenation of deceits, however, speaks for itself. Readers ought never to underestimate the cunning and the venality of marketeers and their co-opted academic KOLs in corrupting the medical literature. In a future posting I will continue this sordid tale with illustrations from the equally compromised world of CME programs.
Subscribe to:
Comments (Atom)