1. Finding out what’s already known and what’s already happening before planning additional research Iain Chalmers on behalf of Mike Clarke, Sally Hopewell and Mona Nasser Evidence-Based Research Network Bergen, 3 December 2014

2. Mike Clarke Belfast Sally Hopewell Oxford/Paris Mona Nasser Plymouth

3. Embarking on research without reviewing systematically what is already known - particularly when the research involves people or animals - is unethical, unscientific, and wasteful.

4. JAMA 1992;268:240-248.

6. The human costs of failing to cumulate evidence from research scientifically “Advice on some life-saving therapies has been delayed for more than a decade, while other treatments have been recommended long after controlled research has shown them to be harmful.” Antman et al. JAMA 1992;268:240-8.

9. Data from Clarke and Hopewell, 2013, cited in Chalmers et al., 2014

10. 20 animal studies: “The results of this review did not show convincing evidence to substantiate the decision to perform trials with nimodipine in large numbers of patients. Stroke 2001;32:2433-8. STUDIES IN ANIMALS Horn J, Limburg M. Calcium antagonists for acute ischemic stroke. The Cochrane Database of Systematic Reviews, 2000 “46 trials were identified of which 28 were included (7521 patients). No effect of calcium antagonists on poor outcome at the end of follow- up (OR 1.07, 95% CI 0.97/1.18), or on death at end of follow-up (OR 1.10, 95% CI 0.98/1.24) was found.” STUDIES IN HUMANS

11. [4] [2] [24] [19] Findings

12. Some illustrative examples of waste from redundant research

13. Sena et al. 2010 Redundant animal research

14. Redundant clinical research…

15. …leaving key questions unaddressed

16. Cumulative odds ratios for front versus non-front sleeping position of sudden infant deaths versus controls. Gilbert et al. 2005. Redundant epidemiological research

17. “Systematic review of preventable risk factors for SIDS from 1970 would have led to earlier recognition of the risks of sleeping on the front and might have prevented over 10 000 infant deaths in the UK and at least 50 000 in Europe the USA and Australasia.” Consequences of failure to analyse epidemiological research cumulatively

18. What should research funders, research regulators, researchers and journals do to reduce this sometimes lethal waste?

19. Research funders

20. NIHR England Yes – Applications to fund primary research have to be supported with systematic reviews of existing evidence. For commissioned calls, this will have been done by the funder. NHMRC Australia No CIHR Canada Partially - Systematic reviews of prior clinical trials are encouraged but not required. There is a knowledge synthesis scheme but this does not seem to be related to funding for primary research. NIH USA No – A ‘check of literature’ is encouraged but there is no clear guidance covering all projects or clinical trials. MRC UK No, in general – Only the Global Health Clinical Trial Unit requires systematic reviews, but none of the other major grant opportunities. Do funders require applicants seeking support for primary research to refer to systematic reviews of existing evidence? (Mona Nasser, personal communication)

22. The Wellcome Trust 2013 2003

23. MS Society supports systematic reviews

24. http://www.nets.nihr.ac.uk/about/adding-value-in-research

25. Research regulators

26. Research ethics committees/IRBs

27. Inappropriate continued use of placebo controls in clinical trials assessing the effects on death of antibiotic prophylaxis for colorectal surgery

28. Health Research Authority

30. Researchers

34. ? First use of the term Evidence-Based Research Karen Robinson (2009). Use of prior research in the justification and interpretation of clinical trials. The Johns Hopkins University, ProQuest, UMI Dissertations Publishing, 2009. 3392375, p 123.

35. Conceptualising an Evidence-Based Research Network Tidsskrift for Den norske Legeforening, 29.11.2013, pp 2-3.

36. Lund H (2014). From evidenced-based practice to evidence- based research - Reaching research-worthy problems by applying an evidenced-based approach. Eur J Physioth 16:65-6. Announcement of An Evidence-Based Research Network

37. Journals

40. Low priority questions addressed Important outcomes not assessed Over 50% studies designed without reference to systematic reviews of existing evidence Questions relevant to users of research? Over 50% of studies fail to take adequate steps to reduce biases Studies with inadequate statistical power Inadequate replication of initial observations Appropriate research design, conduct and analysis? Over 50% of studies never published in full Biased under- reporting of studies with disappointing results Biased reporting of data within studies Accessible, full research reports? Over 30% of trial interventions not sufficiently described Over 50% of planned study outcomes not reported Most new research not interpreted in the context of systematic assessment of other relevant evidence Unbiased and usable reports? Research waste Increasing value and reducing waste in biomedical research. Lancet series, 8 Jan 2014 Hyper-regulation of research Inefficient delivery of research Poor re-use of data Failure to promote evaluative research as an integral element of good clinical practice Efficient research regulation and delivery?

41. www.researchwaste.net

42. Iain Chalmers, health services researcher Michael B Bracken, epidemiologist Benjamin Djulbegovic, oncologist, methodologist Silvio Garattini, clinical pharmacologist Jonathan Grant, science policy analyst Metin Gulmezoglu, clinical trialist David Howells, preclinical animal researcher John PA Ioannidis, methodologist, bibliometrician Sandy Oliver, social scientist

43. Issue 1 Issue 2 Issue 3

44. Recommendation 3

45. Recommendation 4

46. Chalmers I. Lancet 2000;356:774

47. BMJ 2010;340:456-7

48. Alessandro Liberati

49. Patients have suffered and died unnecessarily and resources for research have been wasted because the research community has failed to review existing evidence systematically when planning new research. Why should patients and the public trust us if we and our professional institutions fail to make systematic, efficient use of the results of the research that the public has funded?

50. 20062011

51. Promote research on the effects of treatments…

52. …but only if it meets scientific and ethical principles Promote research on the effects of treatments…

53. 53 “This is an important, scary and encouraging book.” “I think all doctors and medical students will benefit from this little book, which can be read in a few hours. It opens the eyes and gives medicine the critical foundation it needs.”

56. Editor: Kjetil Olsen

57. “Bad Science introduces the basic scientific principles to help everyone become a more effective bullshit detector.”

58. Embarking on research without reviewing systematically what is already known - particularly when the research involves people or animals - is unethical, unscientific, and wasteful.