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Independent medical research? Jos WM van der Meer Martijn B Katan Jan P Vandenbroucke Jos WM van der Meer Conflicts of interest • None Focus on pharmaceutical industry Industry & medical research Major journal editors: • Is academic medicine for sale? [NEJM,2000] • Western Medicine: a confidence trick, driven by the drug industry [BMJ,2002] • Journals have devolved into information laundering operations for pharmaceutical industry [Lancet 2004] • Medical journals are an extension of the marketing arm of the pharmaceutical industry [PLOS Medicine 2005] • Industry sponsored medical research: a broken system [JAMA 2008] Randomised controlled clinical trial (RCT) • Most objective kind of investigation regarding the effect of drugs • Double blinding • Chance determines who gets what • Requested for registration Pharma sponsoring: from 20-30% to 50-60% Ioannidis, BMJ 2006 Sponsored RCT • Trial design together with industry • Authors often consultant to industry • Recruiting physicians and patients, data retrieval and storage by industry or a dedicated bureau • Data analysis by industry • Manuscript written by/with industry ( or “ghost writing” Wall Street Journal 2005 ) • Warrantees: authors have access to data and agree on publication The “uncertainty principle” in RCT • RCT should be done under circumstances of uncertainty – It is unclear which arm is superior – The design should be such that both arms have a maximal chance of superiority. • The expectation is that results of RCT are 50 - 50 on average Is there 50 - 50 outcome? • Children’s Oncology Group (non-profit collaboration of US National Cancer Institute) compare new promising therapy with the best existing therapy • 40 years 126 trials average: 50% superiority Sponsored vs. Non-sponsored Djulbegovic, Lancet 2000 New drug superior Meta-analysis • Sponsored studies: the drug of the sponsor is 4x more often superior than the comparator drug! Lexchin, British Medical Journal 2003 Better performance of the sponsor’s product • Cardiovascular drugs Ridker and Torres, Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000-2005. JAMA. 2006;295:2270-4. • Nutritional intervention Lenard et al, Relationship between funding source and conclusion among nutrition-related scientific articles. PloS Medicine 2007 Jan;4(1):e5 How can we explain this skewing? Three levels of explanation 1. The comparator drug is a placebo (while an effective comparator is available) 2. The comparator drug is used in an unfavorable situation (suboptimal dose, selection of patients,...) 3. Selective publication Use of placebo Djulbegovic Lancet 2000 Suboptimal comparison Why drug A is better than drug B drug B better than drug C, and drug C better than drug A... (Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to- head comparison studies of second-generation antipsychotics. Heres et al. Am J Psychiatry 2006 ) Stand alone publication Submitted, significant Submitted, Non-significant Pooled publication What happens after publication? • The investigator as a vehiculum for promotional activities • Industrial influence on standards, protocols and guidelines – e.g. Surviving Sepsis Campaign – 87% of experts has (often undisclosed) ties with industry • Industrial influence on Ethical committees – 36% of members has ties with industry; disclosure often not asked for. Daily practice • Pharmaceutical industry often has more impact on prescribing behaviour than authorities and reliable literature. Beads & mirrors Are they devils? • No... • Their primary commitment is to create shareholder value,not to maintain an altruistic commitment to patients • Trials are driven by marketing [Brennan, JAMA 2007 Hill, Ann Int Med 2008] And the journals? • They gain from advertisements, reprints, sponsored special issues • Large trials raise the impact factor • They are biased towards positive studies ...and science? • Which role is left for the academic scientist? • How about the open scientific debate? • Can these large RCT’s ever be replicated? Solutions 1. No unnecessary placebo-controlled trials (optimal comparator drug) 2. Trial with the best possible design (investigator-driven; independent funding) 3. Clinical trial registration www.clinicaltrials.gov Further solutions • Code of conduct – Contract between sponsor and investigator at the start of the study ‘WETENSCHAP OP BESTELLING’ KNAW 2005* *www.knaw.nl Declaration of independence 1.The structure of the research shall not be geared towards producing the desired outcome for the client 2.The assignment and its objective shall preferably be formulated jointly by the client and the researcher 3.Remuneration and other tokens of appreciation shall never depend on the outcome or interpretation of the research 4.The results of the scientific research shall be published irrespective of whether they are favourable to the client 5.The scientist shall always be free to publish the findings of the research within a specified reasonable period of time, In this context 2 months can be regarded as a reasonable period, with 6 months generally the maximum (this period being calculated from the moment that the final results are submitted to the client). An exception should be made where there are issues of intellectual property in which case a period of no longer than 12 months would be acceptable. Declaration of independence(2) 6. The method of publication shall be stipulated in the contract. Publication in a scientific journal shall take place in consultation with the client, but the researcher shall have the final say on the contents, the authors, the form of publication and where the research will be published. 7. External financiers of research assignments and/or other sponsors shall be mentioned by name in publications and other forms of disclosure. 8. Relevant interests and/or advisory relations of the researcher(s) shall be cited in publications and other forms of disclosure. 9. The text of the contract shall be available for inspection in confidence by the National Council on Research Integrity Conclusions • Serious problem • Medical science, industry and journals are seriously entangled • Limited solutions – Study design – Conduct – Agreement – Funding – Publishing
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