Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
New JAMA rules make sense
- Jan P Vandenbroucke (10 December 2005)
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That which hurts, instructs!
- BM Hegde (10 December 2005)
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Imaginative solutions?
- John B Carlin (12 December 2005)
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Corrections and a Rebuttal to Vandenbroucke
- Kenneth J. Rothman, Stephen Evans (13 December 2005)
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Without new rules for industry-sponsored research, science will cease to exist
- Jan P Vandenbroucke (14 December 2005)
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Over scrutiny is better than selective under scrutiny
- Debasish Debnath (30 December 2005)
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Extra scrutiny is not enough
- Hugh JN Bethell (2 January 2006)
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Jan P Vandenbroucke, Professor of Clinical Epidemiology Leiden University Medical Center, 2300 RC Leiden
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The problem with Rothman and Evan’s dismissal of the new JAMA rules is the same as with Rothman’s earlier stand against declaring conflicts of interest (1): independent judgment of a piece of clinical research demands more knowledge than the average reader, or even the average reviewer, can have. Therefore, conflict of interest statements remain useful warning signs. Admittedly, the declaration of a conflict of interest does not guarantee anything, and more fundamental safeguards are necessary. The new proposals by JAMA seem to be directed at types of bias that cannot be seen from the published paper: JAMA want guarantees about the analysis by outsiders and indicates that data that should preferably be kept by non-industry investigators (2). In the same week as Rothman and Evans’s editorial, the NEJM published its “expression of concern” about an industry-funded trial – a further testimony of the problems (3). Earlier evidence has shown how manipulations before publication make the published record untrustworthy (4). Of course, any piece of research can have the same problem. In a certain sense all research and all data analyses are biased since they all start from preconceived notions. However, the fundamental problem is the pharmaceutical industry’s "de facto" monopoly of large clinical trials of its own products – so that counter-trials, with potential counter-biases, are impossible. Short of definitive solutions that break this monopoly, attempts at independent overseeing, as seems to be the spirit of JAMA’s proposals, have become a necessary step in the light of a consistent track record of prepublication biases. Denouncing the messenger of an argument as “biased” with past history as the only argument should happen sparingly. However, in rare circumstances it is defensible: when the track record of persistent bias is well- documented and incontrovertible (5). 1. Rothman KJ. Conflict of interest: the new McCarthyism in science. JAMA 1993;269: 2782-4. 2. Fontanarosa PB, Flanagin A, DeAngelis CD. Reporting conflicts of interest, financial aspects of research, and role of sponsors in funded studies. JAMA 2005;294; 110-1. 3. Curfman DG, Morrissey S, Drazen JM. Expression of concern: Bombardier et al., “Comparison of Upper Gastrointestinal toxicity of Rofecoxib and Naproxen in patients with Rheumatoid Arthritis,” N Engl J Med 2000;343:1520-8. 4. Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B. Evidence b(i)ased medicine--selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 2003;326:1171-3. 5. Walton D. One-sided arguments: a dialectical analysis of bias. New York: SUNY, 1999. Competing interests: None declared |
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BM Hegde, Retd. Vice Chancellor Manglore-575004.
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Dear Editor, I do not understand as to what bothers the authors about the new guidelines from JAMA? It is an open secret that the drug lobby tries to “doctor” the data that they get from their researchers. If the industry sponsored research is unbiased why should any one worry about the new guidelines? I can't understand the logic of comparing research coming from non- western sources with Drug Company sponsored research. Is there any philanthropic business? Business is for profit. Having sunk a lot of money to find a new molecule, except in the case of the "me- too" molecules, no business house would want to lose the prize catch. For the good of the patients, the journal editors must be extra vigilant in those situations, lest they should become an extended arm of the pharma lobby. The latter, I understand, is thrice as powerful and big as the oil lobby in Washington. When do we learn our lessons? Adverse drug reactions are a leading cause of death all over the world. Should we not be more vigilant in future? Medical science is only a statistical science and not a pure science in the first place. Medicine follows the wrong mathematical base of linear laws in a no-linear dynamic human body. Coupled with bad statistics and “sexed up” results of research the medical profession would be on top of the list of causes of death. We are not very far from that goal, anyway. Yours ever, bmhegde Further Reading. 1) Angell. M. The truth about drug companies. How they deceive us: what to do about it. Random House 2005. 2) Abramson J. Overdo$ed America. Harper Collins. 2005. Competing interests: None declared |
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John B Carlin, Director, Clinical Epidemiology & Biostatistics Unit, Royal Children's Hospital Melbourne, Australia 3052
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I agree with Rothman and Evans that the new JAMA guidelines are essentially absurd, despite the fact that I might qualify rather nicely for membership of the priesthood of "independent" statisticians that the guidelines apparently seek to create. (Indeed, if I were an entrepreneur I could probably make some money out of them!) However, it is disappointing that they have not proposed any more imaginative solutions, despite calling for such in their final sentences. In that regard, how about the idea of requiring investigators to lodge datasets in a secure repository where truly independent reviewers (including but not necessarily limited to card-carrying statisticians) could access the data and perform whatever independent re-analyses might be regarded as worthwhile? Suitable conditions might need to be placed on access to data, but managing such a system would appear to be a more worthwhile investment of journal editors' time than trying to manage a system of pseudo-independent statistical review. A final point of concern is the implication on JAMA's part that it is only at the stage of statistical analysis that industry pressures and biases may enter into the presentation of trial results. Not only must this be particularly insulting to statisticians who work in the pharmaceutical industry, but problems relating to commercial pressures are surely broader. These issues can only be addressed by comprehensive oversight and review of all aspects of trial presentation, not just the data analysis. Competing interests: None declared |
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Kenneth J. Rothman, RTI-Health Solutions Research Triangle Park, NC, USA, 27709-2194, Stephen Evans
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We would like to correct some errors and misconceptions in relation to our article. 1. Our original title ("The Brave New World of Journal Submission") was changed by an editor to "Extra Scrutiny for Industry Funded Trials" after we reviewed proofs. The new title unfortunately uses the word "trial" where study would have been more appropriate. JAMA's policy addresses all submissions from industry, not merely reports of trials, and we were writing about JAMA's policy, not industry trials. 2. In a cover editorial, Godlee (1) stated that "Kenneth Rothman and Stephen Evans come to the defence of drug industry trials. They say that JAMA's new policy requiring such trials to have independent statistical review is draconian and absurd." In fact we do not defend any industry study, whether it be a trial or not, in regards to methods or substance. We are not defending the conduct of industry in general. We simply offer our criticism of JAMA's review policy, which we consider unworkable and unfair, and would consider unfair whether its target was industry, government, academia, or any other subgroup of authors who wish to submit papers to JAMA. We consider the JAMA policy unfair largely because it is not uniform. 3. Vandenbroucke's Rapid Response rebuttal begins with a reference to a 12-year old paper (2) on conflict of interest, in which Vandenbroucke claims "The problem with Rothman and Evans' dismissal of the new JAMA rules is the same as with Rothman's earlier stand against declaring conflicts of interest: independent judgment of a piece of clinical research demands more knowledge than the average reader, or even the average reviewer, can have. Therefore, conflict of interest statements remain useful warning signs." No doubt few readers will bother to check the original paper; if they did they would learn that the paper said "I would not argue in favor of suppressing any of this information, or anything else that authors or editors wish to reveal. On the other hand, it seems unnecessary to have disclosures become a mandatory part of the review process." What Vandenbroucke does not acknowledge is that part of our argument in the editorial, although it did not use the phrase explicitly, is based on the problem of conflicts. If an academic is paid by industry, then this act itself will lead to a conflict of interest. In order to remain free of conflicts, then academic statisticians would have to do the work "pro bono" or be paid by the journal imposing the rules. Our point is that the JAMA policy does not allow for the practical difficulties associated with its implementation. In most instances it is good practice to have independent advice on all aspects of a study, its design, analysis and interpretation. One of us (SE) has been quoted in the British press recently arguing that a company should not conceal its data or analyses from outside investigators. The larger point is whether such openness should be a universal requirement in all studies. Unfairness is an issue of philosophy or law. Detention of suspects without trial for extended periods of time is justified by some politicians on the grounds of the threat of terrorism. Others argue that even in the face of such a threat it is unfair to deny basic rights. Our argument is that industry statisticians should not be painted as the villains. The JAMA policy will not solve the problems associated with industry studies, and furthermore violates basic principles of fairness. 1. Godlee F. Cure or care? BMJ 2005;331 (10 December) doi:10.1136/bmj.331.7529.0-f 2. Rothman KJ. Conflict of interest: the new McCarthyism in science. JAMA 1993;269: 2782-4. Competing interests: We are the authors of this article. See article for competing interests. |
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Jan P Vandenbroucke, Professor of Clinical Epidemiology Leiden University Medical Center, 2300 RC Leiden
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Rothman, Evans, Carlin and myself agree that there is a problem. I totally agree with them that the problem is not one of "villains". However, the problem is not only one of conflicts of interest. In all scientific debates all sides always have their own biases: we have no other way to look at data but to interpret them. However, in usual clinical or epidemiologic research, studies are repeated by others, in different settings and by different means, looking for biases, flaws, and ways of remedying them, endlessly arguing whether the biases are remedied or not. That is the essence of open scientific debate and criticism, which is the only guarantee for progress. That is no longer possible with pharmaceutical products because the monopoly of the pharmaceutical industry of studies of its own products leads to persistently one-sided studies that can no longer be questioned by studies from other sides. Moreover, the one-sidedness cannot be seen from the public record, that is the published papers. Without the possibility of open debate, science simply ceases to exist. That is why this is an exception which calls for other measures such as more overseeing for which a suitable mechanism should be found. Next to obligatory clinical trial registration, JAMA's proposal is a second. Rothman, Evans and Carlin's proposal to make all data public is another: e.g., all data submitted to drug regulatory authorities should become public because these data are different from the published papers. Even better would be independent funds for clinical research (1). These may lead to studies showing true equipoise in the long run: that new therapies in need of scrutiny have a 50-50 chance of being better than standard (2). (1) Remuzzi G, Schieppati A, Boissel JP, Garattini S, Horton R. Independent clinical research in Europe. Lancet. 2004;364:1723-6. (2) Kumar A, Soares H, Wells R, Clarke M, Hozo I, et al. Children's Oncology Group. Are experimental treatments for cancer in children superior to established treatments? Observational study of randomised controlled trials by the Children's Oncology Group. BMJ. 2005;331:1295-8. Competing interests: None declared |
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Debasish Debnath, Specialist Registrar North Middlesex Hospital, London, N18 1QX
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JAMA’s scepticism regarding industry-sponsored studies is understandable [1,2]. However its approach of using two different tools for assessing papers, depending upon their association with industries, may give rise to two-tier system. Perhaps a better solution will be to apply the stricter/ strictest criteria of assessment to all the papers uniformly, regardless of their association and origin. That could only ensure the very best quality of publication without any bias! References: [1] Henry D, Doran E, Kerridge I, Hill S, McNeill PM, Day R. Ties that bind: multiple relationships between clinical researchers and the pharmaceutical industry. Arch Intern Med 2005; 165(21): 2493-6. [2] Miller FG, Brody H. Viewpoint: professional integrity in industry- sponsored clinical trials. Acad Med 2005; 80(10): 899-904. Competing interests: None declared |
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Hugh JN Bethell, Part-time researcher The Cardiac Rehabilitation Centre, Chawton Park Road, Alton Hants GU34 5DY
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I could not disagree more with Drs Rothman and Evans. The problem with the JAMA requirement for extra scrutiny of pharmaceutical idustry- sponsored studies is that it does not go far enough. The influence of pharmaceutical companies on medical practice is all pervasive. One way in which their stranglehold on medical thinking and practice is maintained is by the funding and reporting of trials of their own products. The apparent effectiveness of their drugs can, as the authors acknowlege, be amplified by asking the right question. Once the trial is over there are legion ways to present the results to the greatest advantage for future sales. A solution to this problem might be the setting up of a trials commissioning body, staffed by academics with no competing interests and funded by the industry. If a company had a drug to test, it would present the known facts to the commissioning body which would design the trial based on the questions which needed answering - usually where the drug might fit into current treatment options. I realise that this idea is utopean - drug company interests and influence would give it no chance. And anyway where can one find doctors without competing interests? For instance, are there any doctors attending scientific meeting whose travel, accomodation, evening meals or all three have not been paid for by a drug company? Competing interests: I have received drug company sponsorship for travel, accomodation and evening meals when attending scientific meetings. |
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