Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Pharmaceutical companies need new financial incentives, not ever-more regulation
- Bruce G Charlton (8 July 2006)
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A more comprehensive and achievable alternative
- Peter R Mansfield (8 July 2006)
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Lack of balanced information available to regulatory bodies
- Raymond G Holder (9 July 2006)
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BMJ Rapid Response: are there any lessons to be learnt here ?
- J Malde (10 July 2006)
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The monster is free
- Anibal J. Morillo (10 July 2006)
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The continual surprise
- Lester A Firkins (10 July 2006)
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Re: BMJ Rapid Response: are there any lessons to be learnt here ?
- Tony Delamothe (12 July 2006)
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The sequestration thesis
- Arthur M. Schafer (14 July 2006)
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Regulation of drug companies
- Dominic C Horne (14 July 2006)
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From Mercky Waters to Greater Transparency
- Michael D E Goodyear (14 July 2006)
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Re: Re: BMJ Rapid Response: are there any lessons to be learnt here ?
- J Malde (14 July 2006)
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Independence From Conflicts of Interest Also Required
- Roy M Poses (22 July 2006)
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Taming Who?
- David T Healy (29 July 2006)
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Journals Must Exercise Their Authority as Gatekeepers
- Vera H. Sharav (19 September 2006)
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Bruce G Charlton, Editor-in-Chief Medical Hypotheses Newcastle University, UK, NE1 7RU
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It has been argued that the power and wealth of Big Pharma is an unintended consequence of ever-increasing government regulation since the Thalidomide disaster [1]. The escalating costs and risks of drug development have led to fewer but much larger corporations. If so, more regulation will probably make pharmaceutical companies even bigger, more powerful, and less open to competition. What is needed are new financial incentives, so that corporations are encouraged to develop and market a much larger number of agents - including those which are not currently patent-protected [2]. For example - fluoxetine was not the first SSRI-type drug. Nobel prizewinner Arvid Carlsson discovered in 1969 that the old antihistamines chlorpheniramine and diphenhydramine had serotonin-reuptake blocking properties, and would therefore probably make effective anti-depressants [3]. But his discovery was not exploited, because patents had expired - and the public had to wait another 15 years for the launch of fluoxetine (which was chemically modelled on diphenhydramine). Chlorpheniramine and diphenhydramine are available over-the-counter without prescription (for the treatment of conditions such as hay fever or cough), but there is currently no financial incentive to market them as safe alternative antidepressants or anti-anxiety agents for self-treatment [4]. Presumably there are many other unexploited yet probably-effective drugs languishing off-patent. It would be a useful step forward if regulators tried-out new forms of incentives (such as easier licencing and re-patenting) to make it possible for 'Small Pharma' to make money from optimal usage of those drugs we have already discovered [2]. 1. Healy D. The antidepressant era. Cambridge, MA, USA: Harvard University press. 2. Charlton BG. If 'atypical' neuroleptics did not exist, it wouldn't be necessary to invent them: perverse incentives in drug development, research, marketing and clinical practice. Medical Hypotheses. 2005; 6: 1005-9. 3. Hellbom E. Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter treatment. Medical Hypotheses 2006; 66: 689-90. 4. Charlton BG. Self-managment of psychiatric symptoms using over-the -counter (OTC) psychopharmacology: the S-DTM therapeutic model - self- diagnosis, self-treatment, self-monitoring. Medical Hypotheses 2005; 65: 823-828. Competing interests: None declared |
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Peter R Mansfield, Director, Healthy Skepticism Inc 34 Methodist St, Willunga SA 5172, Australia
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The Angell Spence Godlee proposal to ban pharmaceutical manufacturers from researching their products<1> has considerable merit. However, Healthy Skepticism Inc advocates a more comprehensive alternative that will also reduce the harm currently caused by misleading promotion, biased industry funding of education and high drug prices. Our alternative is also more politically achievable because implementation can be government revenue neutral whilst securing long term competitive return on investment for the pharmaceutical industry. Pharmaceutical companies currently have four main functions: manufacturing, research, promotion and education. Performance of those functions is currently distorted by incentive systems that reward only activities that increase sales of more expensive drugs regardless of the impact on health care. We recommend that the four functions be paid for separately by government agencies via iterative competitive public tender. This would allow the relevant divisions and subcontractors of pharmaceutical companies to compete with universities and non-profit non- government organisations (NGOs) for funding to provide each function separately. Incentives can then to be aligned to reward quality performance at each function separately. If a company performed poorly, eg research fraud or misleading promotion, then it would not get funding for that function in the next tender round. Drug prices would no longer include a premium for research, promotion and education. Consequently, drug companies would no longer fund those functions from drug sales. Lower prices would make drugs more cost-effective for larger numbers of people. Our recommendations can be implemented quickly or slowly by gradually reducing prices and transferring the savings to organisations that fund research (eg UK Medical Research Council) education (eg medical schools and royal colleges) and promotion (eg promotion provided by the Best Practice Advocacy Centre, New Zealand). We also recommend improving both regulation of the industry and education for health professionals about treatment decision making.<2,3,4,5> 1. Godlee F. Can we tame the monster? BMJ 2006 July 8;333(7558): 2. Sweet M. Doctors and drug companies are locked in 'vicious circle'. BMJ 2004 Oct 30;329(7473):998 http://bmj.bmjjournals.com/cgi/content/full/329/7473/998 2. Mansfield PR. Healthy Skepticism about drug promotion: Memorandum for the UK House of Commons Health Committee Inquiry: The Influence of the Pharmaceutical Industry. Healthy Skepticism International News 2004 Oct; 22(10-12)1 www.healthyskepticism.org/news/issue.php?id=6 3. Mansfield P, Rogers W, Jureidini J. Submission from Healthy Skepticism re RACP Ethical Guidelines. Healthy Skepticism International News 2005 Sep; 23(9)1 www.healthyskepticism.org/news/issue.php?id=15 4. Mansfield PR. Banning all drug promotion is the best option pending major reforms. J Bioethical Inquiry 2005;2(2):16-22 Competing interests: I have received funding from organisations that would benefit from implementation of our recommendations including the many universities, the Royal Australasian College of Physicians and the National Health and Medical Research Council (Australia). |
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Raymond G Holder, Retired engineer Not working BH9 3NF
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I have been amazed that the use of drugs such as statins is recommended by bodies such as NICE on the basis of biassed drug company financied studies and trials, with no real input from totally independent sources to add balance to their considerations. The parliamentary committee last year reported that three quarters of drug research funding came from drug companies, who will only fund research of which they approve, so research on such subjects as the cause of statin side effects, (depletion of the most important substance Coenzyme Q10 and consequent loss of other factors such as carnitine and the grave effects these have over the long term health of those taking them),is never made, except in a small number of independent establishments, and judgements are only based on statistics of studies and trials with no consideration of the scientific biological effects. Furthermore, books are appearing on the "myths" of the whole saturated fat, cholesterol and statin theories and studies, some of which I have examined myself and a layman can easily see those severe shortcomings. Some totally independent organisation should be there to check the validity and inclusion of all data gathered, and see how many impalatable results were swept under the carpet. Personally, I have little faith in much of the material, having come very near to losing my life to cholesterol lowering. The magnitude of suffering that statins in particular have inflicted on mankind can be seen by visiting the website www.spacedoc.net, where one can read about thousands of heartrending stories of victims who have been permanently damaged by this "preventive" medication, now in ever increasing long term use and at more harmful higher dosage. The tragedy is that insufficient regard to science has overlooked the apparent fact that homocysteine is a much more plausible cause of atherosclerosis than cholesterol level, only a chance side effect of statins reducing its production, heart deaths seem to occur at any cholesterol level, and are saved to a similar extent by statins at all levels, leading to the fallacious argument that they should be lower still. So much study has been clouded by including sufferers of the familial form, where there is a genetic inability to dispose of LDL cholesterol which accumulates in various parts of the body. Of course, this is not related to the fact that a simple three vitamin tablet which prevents homocysteine reaching a high level is not patentable, and costs about 20 pence each!!!! Similar problems are associated wih Beta blockers Those who sit in judgement on these matters, while not personally profiting from drug company funding, would probably not have a research department at all without that funding, which must bear upon their decisions, and the poor patient and his GP have to bear the consequences. Competing interests: None declared |
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J Malde, GP Woodlands, Poles Lane, Winchester, Hants, SO21 3ZQ
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Editor, I agree with your assertion that between the interests of safeguarding the public and the interests of drug companies stand the journal peer review process and that any journal with a reputation to protect should learn from the correction issued by the NEJM regarding its study on rofecoxib. The BMJ Rapid Response is a forum which I feel is an open invitation for drug companies to circumvent the peer review process as is evidenced by the recent publication of a Rapid Response by the Medical Director of Pfizer UK, on the subject of switching statins [1]. This particular response invloved some contentious points worthy of further scruitiny by the BMJ prior to its publication and its overemphasis on citing Pfizer sponsored studies of atorvastatin amounted to blatent advertising of this product. The Guidelines provided by the BMJ outlining the requirements for submitting a rapid response reinforce the validity of my concerns. These guidelines state that individial editors largely make a judgements on their own and that authors are responsible for the accuracy of what they say in their rapid responses. These guidelines also go on to state that the BMJ cannot check facts or references. The BMJ would do well to gets its house in order in its laudible aim of safeguarding the interests of the public and its readership. J Malde References: 1. BMJ 2006; 332: 1513 Competing interests: None declared |
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Anibal J. Morillo, Academic Coordinator Calle 119 No. 9-33,Dept of Diagnostic Imaging, Hospital Universitario Fundacion Santa Fe de Bogota
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Indeed, the solution must be in the same line of thought proposed by Godlee. External evaluations of pharmaceutical products should be imperative. The problem is that even the regulatory agencies come to fail in their goalkeeping, as was exemplified by the Faxon case reviewed in the BMJ by Tanne (1), where the FDA continued to sponsor research from a proven fraudulent investigator. The monster is free, but the tamers might not be valiant enough to stand aloof to this challenge. 1. Tanne, JH:FDA limits research of former AHA president for submitting false information BMJ, Dec 2002; 325: 1377 ; doi:10.1136/bmj.325.7377.1377/a Competing interests: None declared |
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Lester A Firkins, Lay person Malvern WR14 1GN
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Six years ago I was a Banker without a care in the world. Then my eldest son, Ellis, died from vCJD and by invitation from MRC (and Sir Iain Chalmers in particular) I became deeply involved as a professional amateur lay person on several projects. I am continualy surprised by articles such as this because what is suggested is such common sense that I am astounded it doesnt happen already. Imagine your Insurance Salesman being allowed to self regulate. It happened in the past and we are still paying the cost. I do not underestimate how challenging it is to "manage" the world of Health but there are some basic principles that should be embedded - and the editors suggestion is just one. Its not in the least bit radical - its obvious Competing interests: I am employed by DH and MRC as Co Chair of a clinical trial and am also Chair of the Development Group of james Lind Alliance |
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Tony Delamothe, editor-in-chief, bmj.com BMA House
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Regarding fact checking in responses We haven't got the resources to check that references cited in responses or articles elsewhere in the journal say what the authors claim they say. Nor can we ascertain whether the cited references are a fair representation of the literature or whether they're just those that suit the author's case. Our starting position is that authors are acting in good faith. (Nevertheless, we ask all authors to declare any competing interests, and we make these disclosures public.) Anyone who believes that an author isn't giving a fair representation of the issues is free to make this point - which we believe is one of the important functions of rapid responses. To be useful, however, such concerns would need to be expressed in more specific terms than "some contentious points worthy of further scrutiny." Competing interests: The author is editor-in-chief of bmj.com and partially responsible for its policies |
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Arthur M. Schafer, Director, Centre for Professional and Applied Ethics University of Manitoba, R3T 2M8
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An excellent article. Some dismiss proposals to isolate medical research and medical researchers from drug company money as "unrealistic". In my view, however, your sequestration proposal is feasible and deserves to be seriously considered, along with other alternatives designed to achieve the same end or goal. Such alternatives are outlined in a paper I published recently: “Biomedical Conflicts of Interest: a defence of the sequestration thesis”, Journal of Medical Ethics 2004; 30:8-24. Professor Arthur Schafer Director, Centre for Professional and Applied Ethics University of Manitoba Competing interests: None declared |
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Dominic C Horne, Salaried OOH GP GMED, Aberdeen, AB25 2ZP
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Yes it is the answer and yes it is feasible. I've been thinking the same thing for a long time now. It would guarantee the appearance of a lot more 'negative' results in the public domain, not necessarily fascinating reading but important nonetheless. Going one step further, I believe drug companies should not be allowed to promote their products directly but should again contribute to a central fund which would provide independent academic detailers. Of course, if a new drug is any good it will promote itself. Competing interests: None declared |
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Michael D E Goodyear, Assistant Professor Department of Medicine, Dalhousie University, Halifax, Nova Scotia, CANADA B3H 2Y9
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Dr Godlee has provided a good description of the problems that beset Evidence Based Medicine, namely a corrupt database, which is in danger of turning Archie Cochrane's admirable vision into a house of cards built on sand. Few have focussed on the role that medical journals have played in this crisis, but Godlee has now added her voice to the concerns about the role of journals in the murky waters of publication ethics. She refers to her predecessor, Richard Smith's proposals for radical restructuring of the way that results of research are more reliably, rapidly and more transparently disseminated and incorporated into clinical decision making. Godlee is also correct in urging a firewall between sponsors and the whole process of creating and disseminating knowledge and product regulation. Now Dr Smith has weighed in again as part of a series of articles in the Journal of the Royal Society of Medicine on restoring integrity to medical science. His current article (1) provides more detail on the entangled relations between Merck and the NEJM. Never afraid to call a spade a spade in the BMJ tradition, Smith writes "It fits with the argument that medical journals are an extension of the marketing arm of pharmaceutical companies and that the full data of trials should be published not in medical journals, where an incomplete story is advanced, but on the web" referring to his own startling essay in his current journal, last year (2). This joins a growing chorus of disillusionment in traditional publishing as a component of epistemiology (3-5). The reader may notice a pattern here, namely that former editors are almost unanimous in voicing concerns about the commercialisation of science and medicine. The encouraging factor is that Horton (Lancet) and Godlee (BMJ) are preaching from the pulpit, not the churchyard. It is time that the chorus was turned into definitive action. The Ottawa Statement (6) and the World Health Organization (WHO) statement on the new standard in clinical trial registration (7) enables this to now move forward with a comprehensive and systematic method for knowledge management independent of sponsors. However it is going to take organisations with the scope of WHO and the World Association of Medical Editors to build on all this groundwork and create a new system which fully exploits the technological resources that have already transformed publishing. There can be no turning back or excuses for further delay. References: 1. Smith R. Lapses at the New England Journal of Medicine JRSM 2006 vol 99 August http://www.rsmpress.co.uk/0607JRSMSmith.pdf 2. Smith R. Medical jourmnals are an extension of the marketing arm of pharmaceutical companies PLoS 2005 May 2:e138 2005 http://medicine.plosjournals.org/perlserv/?request=get- document&doi=10.1371/journal.pmed.0020138 3. Horton R. The dawn of McScience. New York Rev Books 2004 51(4): 7–9 4. Angell M. The truth about drug companies: How they deceive us and what to do about it. New York: Random House 2005. 336 p. 5. Kassirer JP. On the take: How medicine's complicity with big business can endanger your health. New York: Oxford University Press. 2004 251 p. 6. Ottawa Statement on Trial Registration. http://ottawagroup.ohri.ca/ 7. Sim I, Chan AW, Gülmezoglu AM, Evans T, Pang T Clinical trial registration: transparency is the watchword. Lancet 2006 May 20 367(923): 1631-1633 Competing interests: Have published on the need for greater integrity and transparency in science. |
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J Malde, GP Woodlands, Poles Lane, Winchester, Hants, SO21 3ZQ
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Editor-in-Chief, BMJ The basic point that I was seeking to make was that without the necessary checks and balances afforded by a robust editorial or peer review process, the BMJ Rapid Response format allows the publication of potentially misleading information by any party, notwithstanding the requirement to delcare any competing interests. To suggest that the BMJ starts from the point that the Authors are acting in good faith is to miss the point. Surely if there is anything to be learnt form the position in which the NEJM found itself is that reliance on the authors of any submission for factual accuracy and balance is not a sensible option. J Malde Competing interests: None declared |
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Roy M Poses, President Foundation for Integrity and Responsibility in Medicine, Warren, RI, 02885, USA
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I applaud your call for drugs (and presumably devices) to be evaluated independently. However, ensuring independent funding of trials may not be sufficient to ensure their independent implementation. The people who are most qualified to actually do drug (and device, for that matter) trials here in the US, and probably in many other countries, are academic physicians and researchers. The problem is that conflicts of interest that could threaten their trials' independence are pervasive in academic medicine. In the US, the most recent examples of the pervasiveness of such conflicts appeared in a series of investigative reports on Stanford University.(1,2) Furthermore, conflicts of interest may affect not only the academic physicians and researchers who might perform clinical trials, but also the administrators and executives to whom they report. We have presented numerous examples of such conflicts of interest on our blog, Health Care Renewal.(3) The most striking examples include deans of medical schools, and even the chief executives of universities to whom medical schools and academic medical centers report, who also sit on the boards of directors of large health care corporations. Such board memberships entail not only large salaries and grants of stock options, but fiduciary duties to those corporations and their stockholders. Some recent examples from the popular media were: the Chancellor of the University of California - San Diego, who is also on the boards of Boston Scientific and Pharmaceutical Product Development;(4) the Dean of the Medical School at Case-Western Reserve University, who was also briefly on the board of GlaxoSmithKline;(5) and the President of the University of Miami, who is also on the board of UnitedHealth Group.(6) To ensure independent evaluation of drugs (and devices), those performing clinical studies must not only get indendent funding, but also not have, or report to leaders with substantial conflicts of interest. References 1. Jacobs P. How profits, research mix at Stanford. San Jose Mercury News, July 9, 2006. 2. Jacobs P. Science critics make issue of financial ties. San Jose Mercury News, July 10, 2006. 3. http://hcrenewal.blogspot.com/ 4. Yang E. UCSD leader also serves as a director on 10 boards. San Diego Union-Tribune, January 28, 2006. 5. Irving R. GSK recruit helped in legal action against firm. (London) Times, January 18, 2006. 6. Staff Report. UM's Shalala named in shareholder suit. Miami Herald, May 23, 2006. Competing interests: I own 3200 shares of Elan Corp stock |
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David T Healy, Professor of Psychiatry Cardiff University LL57 2PW
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Dear Sir After approving SSRI antidepressants in the late 1980s and early 1990s, on the basis of slender evidence of efficacy, the Food and Drug Administration (FDA) in the United States (US) asserted there was “no credible evidence” that these drugs could cause violent and suicidal behaviour in some vulnerable individuals – despite what the evidence available from the late 1980s indicated. No warning was issued for prescribers or consumers. The new antidepressant market ballooned to a $20 billion dollar business. The US is the biggest profit centre for one of the richest industries in the world. But there remains for the drug companies a significant obstacle towards even greater profits: product liability awards. When drug companies fail to disclose important risks, US courts can award large sums, and in an effort to keep the risks and their concealment hidden, settlement costs are now a routine part of doing business on company ledger sheets. At someone’s behest – and this is the key point germane to Fiona Godlee’s question as to whether we can tame the monster (1) - FDA came to the aid of the pharmaceutical industry by including in a new rule amending an existing regulation regarding drug labelling, the argument that in the FDA's view, anyone suing a drug company for failing to disclose a risk should not be allowed to do so because such a lawsuit is pre-empted by federal law (2). The argument was that if a drug was sold, that meant it was approved by the FDA, and that all risks that should be known are in fact known and disclosed. In selecting a test case for this legislation, the FDA placed itself in a position of defending the drug companies against law-suits by people who claimed they had been harmed by undisclosed risks of antidepressants. In so doing, they have staked a position that it is illegal to warn patients about a risk of suicide from antidepressants. This position has become increasingly untenable as evidence accumulates so that even GlaxoSmithKline now acknowledges the risk to be present (3). But FDA dug in and continues to defend its claim even as its scientists protested the agency’s subjugation of science and public health to political aims (4). In 2003, the FDA first presented an analysis of suicide from clinical trials of antidepressants, most of which had been completed a decade previously (5). Analyses of suicides and suicide attempts in antidepressants trials had been published previously by others, each showing that antidepressants increased the risk of suicide. This result hid for years behind a statistical smokescreen with the claim that the increased risk of suicide with antidepressants should be disregarded because it was not “statistically” significant (6). But the FDA, with a database of more than 40,000 patients in trials from all of the antidepressant manufacturers, found an increased risk of suicide with antidepressants that was “statistically significant.” Instead of concluding that their analysis confirmed the increased risk, which would necessitate warnings on the drugs and admit the fallacy of their pre- emption argument (currently being defended in litigation with millions of dollars hanging in the balance), the FDA concluded that with a few clever statistical adjustments, all of the increased risk disappeared. This FDA claim is dubious because in short term randomised drug trials large amounts of bias sufficient to wipe out a doubling of risk are unprecedented (6). Indeed, if these trials were so biased, then it would mean that the studies that formed the scientific basis of FDA approval of these drugs were seriously flawed. The data present the FDA with a dilemma: was the FDA decision to approve antidepressants based on biased evidence, or were the trials valid, in which case so is the “unadjusted” analysis which shows that antidepressants cause suicide? On these data it would seem that FDA were faced with the prospect of admitting to a huge mistake - either the mistake of failing to warn against increased risk of suicidal behaviour or a mistake in approving antidepressants in the first place. Fortunately for FDA, this analysis only appeared as an abstract in a little read journal and their dilemma went unnoticed. In the meantime, an FDA employee created a scandal by finding that antidepressants increased suicidal behaviour in paediatric trials, and an advisory committee recommended a black box, the highest level of warning, indicating the increased risk for children to all antidepressants. And one manufacturer, GlaxoSmithKline, admitted that trials in adults showed an increased risk of suicidal behaviour too. But FDA continues on the path of denial. This year, they released the “full” publication of their analysis of suicidal behaviour in trials of antidepressants in adults (7). In their latest release, which fails to mention or cite their previous analysis, the FDA has claimed that the cases of suicide on the new antidepressants have mysteriously vanished, and with them the previously reported increased risk. In addition to all the unanswered questions raised previously, the FDA’s latest story only raises more embarrassing questions. What happened to the suicides? Why does the FDA now claim to be unaware of suicides that they previously analysed and of a risk that even manufacturers have admitted? (8). The FDA is in a shambles, and there is considerable evidence that Britain's Medicines and Healthcare Regulatory Agency (MHRA) is not in any better shape (9). The claims of these regulators in general are now no more credible than their claims that Vioxx was safe and effective. Given that these are the bodies that are supposed to tame the monster, the question posed by Fiona Godlee can only at present be answered in the negative – unless the answer is that our first step must be to radically reform these bodies. The key questions otherwise are first who’s bidding precisely are the regulators now following (are these politicians or businessmen or who are they?) and second what can we do about that? 1/ Godlee F (2006). Editorial: Can we tame the monster? BMJ 333 2/ Dept. of Health and Human Serv., Docket No. 2000N-1269, "Requirement of Content and Format of Labeling for Human Prescription Drug and Biological Products," p. 38 (Jan. 18, 2006). 3/ GlaxoSmithKline. Letter to healthcare professionals, May 2006. www.gsk.com/media/paroxetine/adult_hcp_letter.pdf (accessed 13/05/2006). 4/ Union of Concerned Scientists survey: http://www.ucsusa.org/scientific_integrity/interference/fda-scientist- survey.html). 5/ Hammad TA, Mosholder A, Boehm G, Racoosin JA, Laughren T. Incidence of suicides in randomized controlled trials of patients with major depressive disorder. Pharmacoepidemiol Drug Safety 2003;12(suppl 1):S156. 6/ Healy D (2006). Did regulators fail over selective serotonin reuptake inhibitors. BMJ 333, 92-95. 7/ Hammad TA, Laughren TP, Racoosin JA. Suicide rates in short term randomised controlled trials of newer antidepressants. J Clinical Psychopharmacology 2006; 26, 203-207. 8/ Healy D. bmjjournals.com/cgi/eletters/333/7558/92 9/ See correspondence on MHRA’s handling of trial suicide on www.socialaudit.org.uk/6060116.htm#FOI Competing interests: DH has links to all the major pharmaceutical companies and has been an expert witness in legal actions involving antidepressants and suicide |
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Vera H. Sharav, President, Alliance for Human Research Protection (AHRP) 142 West End Ave. New York, NY 10023
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The harm done by journals’ failure to protect the integrity of science can hardly be overstated. If physicians can’t rely on the unbiased objectivity of journal reports—they cannot practice evidence-based clinically responsible medicine. Changes are needed to restore credibility to the medical literature. December, 2005: an editor of The New England Journal of Medicine (NEJM) acknowledged under oath that although editors knew of three unreported Vioxx deaths in the VIGOR-Vioxx study, [1] but decided not to inform physicians. That acknowledgement, five years after publication, was reported by Forbes, [2] then The Wall Street Journal (WSJ) [3] sending shock waves—but did it change journal policies? May 2, 2006: The New York Times (NYT) reported: “Virtually every major scientific and medical journal has been humbled recently by publishing findings that are later discredited." [4] July 12: Just when Dr. Fiona Godlee’s editorial was posted, [6] the editor of the Journal of the American Medical Association (JAMA) acknowledged publishing two reports whose authors failed to disclose their financial ties to drug manufacturers. [7] [8] The reported findings provided a rationale for increased use of psychoactive drugs by women—even during pregnancy. Less than a week later, the FDA issued two public health advisories warning about evidence of additional lethal risks linked to antidepressant drugs: persistent pulmonary hypertension in newborn infants whose mothers took antidepressants during pregnancy, [9] http://www.fda.gov/cder/drug/advisory/SSRI_PPHN200607.htm and serotonin syndrome when taken with migraine medications. [10] http://www.fda.gov/cder/drug/advisory/SSRI_SS200607.htm These contradictions raise questions about the credibility of not only these two JAMA reports, but also the medical journals that clinicians rely on for guidance in their medical practice. JAMA editor, Dr. Catherine DeAngeles told the WSJ (which broke the news) that she was “misled.” [11] When questioned by the Chicago Tribune, she snapped: "I don't give people lie detector tests. I am not the FBI." [12] Do physician /authors and journals bear no moral, professional, or public responsibility when they publish misleading information resulting in preventable deaths? July 19: the WSJ exposed the “perfect storm,” involving coalescing conflicts of interest violations. [13] All eight prominent academic psychiatrists whose names are penned to a report in the official journal of the American College of Neuropsychopharmacolgy (ACNP), failed to disclose that they are paid members of the advisory board of Cyberonics, [14] the manufacturer of VNS (vagus nerve stimulation), an experimental surgically implanted device for the treatment of depression. The ninth author, an employee of the company, disclosed his company connection in the article. The report in Neuropsychopharmacology [15] purports to review the scientific evidence for the efficacy and safety of VNS. Its controversial approval “despite strong objection by FDA’s review team,” was severely criticized in a Congressional report. [16] The principle author, Dr. Charles B. Nemeroff, "one of the nation's most prominent psychiatrists" [13] is chairman of psychiatry at Emory University, a past president of ACNP, the editor-in-chief of Neuropsychopharmacology, and chairman of Cyberonics' Mechanism of Action Advisory Board. [14] An editorial in the NYT [17] described these industry ties as “particularly incestuous.” “It is hard to know whether to be more upset at the journal's failure to disclose these ties or at its decision to let such interested parties serve as authors in the first place.” The Times notes that “Early drafts of the article were prepared by a professional writer hired by the company.” In other words, the paper was crafted not by the authors but by a “professional writer” hired by the sponsor. Since the 1990s editors have known (or should have) that industry’s influence was penetrating journals not only directly (through advertising) but indirectly—by planting favorable reports often written by professional ghostwriters but “authored” by influential leaders in their field. [18] Academic scientists traded their influence for cash, penning their names to biased, ghostwritten reports of trials they did not conduct, and whose source data they did not analyze. [19] Others, constrained by contractual publication restriction agreements with the sponsoring company, published fraudulent reports based on partial data findings.[20] As two thirds of medical research is now sponsored by industry, [21] the most influential (“high impact”) medical journals have become accomplices, camouflaging the commercial nature of industry promotional reports. [22] Journals’ failure to take measures to stop this growing malaise provided a shield for corrupt practices that have undermined the integrity of science and the journals themselves. Dr. Richard Horton, editor of The Lancet, calls medical journals “information laundering operations.” [23] The magnitude of industry’s corrupting influence has put the credibility of the entire academic literature reporting the safety and efficacy of (psychotropic) drugs under a dark cloud. [24] June 2004: New York State Attorney General, Elliott Spitzer, charged GlaxoSmithKline with fraud for concealing negative data from its pediatric Paxil trials, [25] citing as evidence the dichotomy between published journal reports about and company documents refuting those claimed findings. [26] Only then did drug companies and their accomplices in academia wake up to the fact that their illegitimate practices constitute fraud and are subject to prosecution. May 2006: GlaxoSmithKline reversed years of denial, acknowledging a six-fold increased suicide risk in adults linked to its antidepressant, paroxetine (Paxil)—thereby discrediting the entire Paxil literature. [5] Writing about the SSRI antidepressants, Dr. Jonathan Leo observes: [27] “Doctors accepted these drugs and prescribed them so willingly not because they were given free pens, free dinners, or even free trips. They put their trust in the drugs because they were backed by papers that were: written by professors at the major academic medical centers; approved by peer reviewers; published in the major medical journals; cited in review articles; discussed at meetings; defended by the ACNP…You can hardly fault the average physician for putting faith in them.” A Danish review (2006) of head to head studies of so-called atypical antipsychotics found that in 90% (of 33 studies) outcomes favored the sponsor’s drug. “This pattern resulted in contradictory conclusions across studies when the findings of studies of the same drugs but with different sponsors were compared.” [28] Clearly major journals have not taken meaningful steps to protect the integrity of the scientific literature, or to cleanse it of discredited reports, or to ensure that biased findings are not published in the future. Academic medicine is tainted because its gatekeepers, the journals, not only turned a blind eye; they joined in the desecration of the scientific foundation of medicine for a 70% profit return from reprints of “favorable” industry-sponsored reports. The NEJM reportedly made $697,000 from VIGOR reprints. [3] Dr. Goldee’s call for a separation between drug producers and evaluators is both valid and justified, but journals must exercise their authority as gatekeepers if the integrity of science and safety in medicine is to be restored. A few suggestions: 1. Require authors to submit protocol and raw data to substantiate reported findings; 2. Post the protocols and data on a website so that independent analysis is possible; 3. Require authors’ to declare details of ties to the sponsor, indicating the nature of those ties (e.g., consultant, speaker, investment; stock option; advisory board, grant recipient); 4. Require detailed disclosure of author’s contribution to the report: specify who wrote the first draft, and whether any “professional writers” were involved; 5. Publish only reports by authors who have control over the data and control over what is published; 6. Enforce publication policy; adopt penalties for violators barring them for 3 years. Vera Hassner Sharav
References: 1. Bombardier C., Laine L., Burgos-Vargas R., Davis B., Day R., Ferraz M. B., Hawkey C. J., Hochberg M. C., Kvien T. K., Schnitzer T. J., Weaver A., Reicin A., Shapiro D. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520-1528. 2. Langreth, R and Herper, M. Merck’s Deleted Data, Forbes, December 8, 2005 http://www.forbes.com/home/sciencesandmedicine/2005/12/08/merck- vioxx-lawsuits_cx_mh_1208vioxx.html. 3. Amstrong, D. Bitter Pill: How the New England Journal Missed Warning Signs on Vioxx: Waited Years To Report Flaws in Article That Praised Pain Drug The Wall Street Journal, May 15, 2006; Page A1. http://online.wsj.com/article/SB114765430315252591.html 4. Altman, L. For Science's Gatekeepers, a Credibility Gap, The New York Times May 2, 2006. http://www.nytimes.com/2006/05/02/health/02docs.html? 5. See: GSK. Briefing. Paroxetine Adult Suicidality Analysis. April 5, 2006: http://www.gsk.com/media/paroxetine_adult.htm; GSK. Letter to healthcare professionals: “Clinical worsening and suicide risk” May 2006: http://www.gsk.com/media/paroxetine/mi_letter.pdf. 6. Godlee, F. Editor’s Choice: Can we tame the monster? BMJ 2006; 333: 7. Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006 Feb 1;295(5):499-507. 8. Kurth, T, Gaziano, MJ, Cook, NR, Logroscino, G, Diener, HC Buring,
JE. Migraine and Risk of Cardiovascular Disease in Women JAMA.
2006;296:283-291. 9. FDA advisory: Pulmonary Hypertensionion:
http://www.fda.gov/cder/drug/advisory/SSRI_PPHN200607.htm
10. FDA Advisory: Serotonin Syndrome:
http://www.fda.gov/cder/drug/advisory/SSRI_SS200607.htm
11. Armstrong, D, Drug Interactions: Financial Ties to Industry Cloud
Major Depression Study, WSJ. July 11, 2006; Page A1
http://online.wsj.com/article/SB115257995935002947.html
12. Japsen, B. and Dow Jones News Wires, Journal tightens rules for
authors: Doctors must disclose conflicts of interest, Chicago Tribune,
July 12, 2006, http://www.chicagotribune.com/business/chi-
0607120198jul12,1,1635801.story?coll=chi-business-hed
13. Armstrong, D Medical Reviews Face Criticism Over Lapses, WSJ.
July 19, 2006; B1 http://online.wsj.com/article/SB115322997681109756.html
14. Nemeroff, CB, Mayberg, HS, Krahl, SE, McNamara, J, Frazer, A,
Henry, TR, George, MS, Charney, DS, and Brannan, SK. VNS Therapy in
Treatment-Resistant Depression: Clinical Evidence and Putative
Neurobiological Mechanisms Neuropsychopharmacology (July, 2006)
31;1345–1355. Published online 19 April 2006.
http://www.nature.com/npp/journal/v31/n7/full/1301082a.html
15. Senator Charles Grassley. Review Of The FDA’s Approval Process
For The Vagus Nerve Stimulation Therapy System For Treatment-Resistant
Depression. Staff Report.
http://finance.senate.gov/press/Gpress/02_2006%20report.pdf
16. See: Cyberonics Press Release, August 13, 2003 at:
http://www.ahrp.org/cms/content/view/293/29
17. Our Conflicted Medical Journals, NYT, Editorial, July 23, 2006
http://www.nytimes.com/2006/07/23/opinion/23sun2.html?
18. Flanagin, A; Carey, LA, Fontanarosa, PB, Phillips, SG, Pace,
BP, Lundberg, GD, Rennie, D. Prevalence of Articles With Honorary Authors
and Ghost Authors in Peer-Reviewed Medical Journals. JAMA. 1998;280:222-
224.
19. Kaufman, A and Julien, A. Scientists helped industry to push
diet drug. Hartford Courant, April 10, 2000, p. A-1; A8; Peterson, M.
Madison Ave. Has Growing Role In the Business of Drug Research, NYT,
November 22, 2002, A-1.
20. Chan, AW, Hróbjartsson, A, Haahr, MT, Gøtzsche, PC, Altman, DG.
Empirical Evidence for Selective Reporting of Outcomes in Randomized
Trials, JAMA 2004;291:2457-2465; Gøtzsche, PC, Hróbjartsson, A, Johansen,
HK, Haahr, MT, Altman, DG, Chan, AW. Constraints on Publication Rights
in Industry-Initiated Clinical Trials, JAMA 2006;295:1645-1646.
21. Egger M, Bartlett C, Juni, P. Are randomised controlled trials in
the BMJ different? BMJ. 2001 Nov 24;323(7323):1253-4.
22. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical
industry sponsorship and research outcome and quality: systematic review.
BMJ 2003; 326: 1167-70.
23. Horton, R. “The Dawn of McScience,” New York Review of Books,
March 11, 2004;
Smith R. “Medical Journals an extension of the marketing arm of drug
companies,”
24. Healy, D and Cattell, D. Interface between authorship, industry
and science in the domain of therapeutics, British Journal of Psychiatry
(2003);183:22–27.
25. NYS Attorney General Press Release:
http://www.ahrp.org/infomail/04/06/02.php
26. GSK memo details concealment strategy, 1998:
http://www.ahrp.org/risks/SSRI0204/GSKpaxil/index.php
27. Leo, J. The SSRI Trials in Children: Disturbing Implications for
Academic Medicine Ethical Human Psychology and Psychiatry, Volume 8,
Number 1, Spring 2006
28. Heres S Davis J, Maino K, Jetzinger E, Kissling W, Leucht S. Why
olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine
beats olanzapine: an exploratory analysis of head-to-head comparison
studies of second-generation antipsychotics. Am J Psychiatry. 2006
Feb;163(2):185-94.
Competing interests:
None declared |
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