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Rapid Responses: Rapid Responses published:
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Consider the influence of equipment manufacturers on the ‘evidence’ for palliative coronary intervention
- Michael R Chester (17 November 2007)
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Surprising Non-Finding, Predictable Criticism
- John H Noble Jr (17 December 2007)
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How valid were the assessments of concordance between results and conclusions?
- Adam Jacobs (15 February 2008)
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Michael R Chester, Consultant Cardiologist & Director of the National Refractory Angina Centre NRAC, RLBUHT, Thomas Drive, L14 3PE
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Yank and colleagues' recommendation that pharma sponsored drug trials should be interpreted with caution, is well made (1). If the authors’ analysis is correct, healthcare commissioners should be even more cautious when it comes to interpreting industry sponsored palliative coronary interventional studies and advice given by professional bodies who have close links with industry. Most percutaneous coronary intervention (PCI) procedures involve the implantation of a coronary stent. The majority of stent studies are funded by equipment manufacturers and are designed and conducted by researchers who believe in coronary intervention despite the lack of hard evidence of cost effectiveness or clinical superiority over optimal medical therapy (2,3). Therapists’ irrational faith in intuitive based practice adds an extra dimension to the ‘positive spin’ effect described in the paper. Given the paucity of independently funded coronary stent studies and the total lack of a placebo controlled study of this palliative therapy, healthcare commissioners have a hard time unravelling spin, especially when professional bodies weigh in with their spin on the evidence. The RITA 2 study showed that whilst palliative PCI was associated with a small and transient improvement in symptoms, it increased the incidence of MI/death by nearly 80% and was £2,684 more costly than medical therapy (4,5). It is worth remembering that the highly effective anti inflammatory agent Vioxx was withdrawn when a near identical excess incidence of MI/death was uncovered. Despite RITA 2’s worrying results the British Cardiovascular Intervention Society (BCIS) strongly lobbied for an expansion of PCI. What grounds did BCIS have for supporting the rapid expansion of palliative PCI despite the its poor showing in RITA 2? The present study suggests that it would be prudent to take account of the relationship between BCIS and industry when assessing BCIS’s recommendations. A search through UK professional bodies’ websites reveals that BCIS appears to be the only UK professional body to admit to having two industry representatives on council (6). References 1. Yank V et al. Financial ties and concordance between results and conclusions in meta-analyses: retrospective cohort study. BMJ, doi:10.1136/bmj.39376.447211.BE (published 16 November 2007) 2. Griffin et al. Cost effectiveness of clinically appropriate decisions on alternative treatments for angina pectoris: prospective observational study. BMJ 2007;334:624 (24 March) 3. Boden et al. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. N Engl J Med 2007; 356:1503-1516 4. RITA-2 Trial Participants. Coronary angioplasty versus medical therapy for angina: the second Randomised Intervention Treatment of Angina (RITA-2) trial. Lancet 1997;350:461–468 5. Sculpher et al. Coronary angioplasty versus medical therapy for angina. Eur Heart J 2002;23:1291-300. 6. http://www.bcis.org.uk/about/council Competing interests: Professor Chester provides advice to PCT/PBC Commissioners on patient centred angina service redesign |
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John H Noble Jr, Emeritus Professor, State University of New York at Buffalo 508 Rio Grande Loop, Georgetown, Texas, USA 78633
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The finding of no connection by Yank, Rennie and Bero1 between results in meta-analyses and financial ties is surprising, given the finding by Chan and Altman2 of “greater deficiencies for reporting of harm outcomes among trials that were solely funded by industry (median 56% per trial) compared with those that were not (27%).” Evidently the Oxman and Guyatt3 measure of scientific quality of research reviews used by Yank, Rennie and Berro in their study is not sensitive to the capture of primary research protocol-to-publication discrepancies and the selective reporting of outcomes, which Chan and Altman found to be prevalent in a large sample of PubMed-indexed randomized trial results. In context, three matters need emphasis. First, as indicated by Chan and Altman,4 “outcome reporting bias acts in addition to and in the same direction as publication bias of entire studies to produce inflated estimates of treatment effect.” Second, the antidote is to require registration of all trials and protocols in the public domain before study completion and to assure that they be made available along with any manuscript undergoing peer review for journal publication. Third, it is important to correct the mistaken belief that somehow the collected raw data are unaffected by the artifacts of research design, sampling, and measurement. Epstein’s5 dismissal of the importance of the Yank, Rennie and Bero1 findings, along with his strained argument to justify problematic drug and medical device industry practices, are based on such misunderstanding. Epstein’s5 assertion that “nothing in the work of Yank and colleagues suggests that the raw data from the drug sponsored studies were defective,” overlooks the authors’ use of the admittedly subjective Oxman-Guyatt3 measure of research quality as a statistical control variable. Meta-analysts, when combining the results of primary reports, are unlikely to run to the ground, as Chan and Altman2 did, research protocol-to-publication discrepancies and selective reporting of outcomes. Given the high stakes for the public health, Epstein’s5 choice between “fewer studies of presumably better quality” and “more studies whose quality may be more biased” in favor of the latter makes no sense except from the self-interested perspective of the drug and medical device industry. In biomedical as in all research, research quality is judged by (1) the importance of the question addressed and (2) the reliability of the answer. Indeed, Epstein’s argument that government intervention in the form of legal restrictions would be economically dysfunctional asserts the interests of industry. It is the argument of an unabashed industry apologist,6 who glosses over the fact that in welfare economics regulatory intervention is sometimes the solution for market failure.7 Widespread premeditated bias8 in published and unpublished reports of clinical trial results linked to industry sponsorship is certainly “smoking gun” evidence of market failure. 1 Yank V, Rennie D, Bero LA. Financial ties and concordance between results and conclusions in meta-analyses: retrospective cohort study. BMJ 2007; 335; 1202-1205. 2 Chan AW, Altman DG. Identifying outcome reporting bias in randomized trials on PubMed: review of publications and survey of authors. BMJ 2005; 330; 1-6, doi:10.1136/bmj.38356.424606.8F, available at http://bmj.bmjjournals.com/cgi/content/full/330/7494/753[accessed on September 7, 2006]. 3 Oxman AD, Guyatt GH. Validation of an index of the quality of review articles. J Clin Epidemiol 1991; 44; 1271-1278. 4 Chan, Altman, ‘Identifying outcome reporting bias’, op. cit, p. 5. 5 Epstein RA. Influence of pharmaceutical funding on the conclusions of meta-analyses. BMJ 2007; 335; 1167. 6 Epstein RA. Pharma furor: why two high-profile attacks on big drug companies flunk the test of basic economics. Legal Affairs 2005 (Jan/Feb), http://www.legalaffairs.org/issues/January-February- 2005/review_epstein_janfeb05.msp 7Market failure: http://en.wikipedia.org/wiki/Market_failure 8 Noble JH. Detecting bias in biomedical research: looking at study design and published findings is not enough. Monash Bioethics Rev 2007; 26; 24-45. Competing interests: None declared |
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Adam Jacobs, Director Dianthus Medical Limited
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Although the study by Yank et al appears for the most part to be carefully conducted, there is an important deficiency in their methods. I note that the information on whether results and conclusions were favourable or otherwise was assessed in an unblinded manner, mostly by a single rater. Given their a priori hypothesis that “financial ties to one drug company would be associated with favourable results and conclusions” and the subjective nature of assessing whether conclusions are “favourable”, there is a clear potential for bias in assessing outcomes. I do not find the moderate inter-rater agreement of 0.6 for assessment of conclusions reassuring in this respect. I therefore decided to look at a small number of the papers rated as having favourable conclusions in the absence of favourable results to see if those assessments appeared valid. The second such paper I found (Conlin et al, reference w18) was rated as having conclusions that were “In favour of study drug”. The drug first mentioned was losartan, which is also the drug marketed by the company with financial ties to the paper, and so I assume was considered the “study drug”. However, the conclusions of the paper do not in any way favour losartan. The discussion section of the paper begins “This comprehensive analysis shows the comparable efficacy of losartan, valsartan, irbesartan and candesartan”. Hardly “in favour of” losartan. The conclusions of Yank et al’s analysis depend on a valid and unbiased assessment of whether results and conclusions favoured the study drugs or not. The validity of those assessments appears open to question, which therefore calls into question the extent to which we can trust the conclusions. Competing interests: My company provides manuscript writing services to pharmaceutical companies. |
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