1. GRADE example application of Jan Brożek

2. My potential conflicts of interest GRADE working group Cochrane Collaboration

3. agenda

4. problem Q: what to do about it gather evidence what evidence says how believable is evidence summarise it balance good & bad individual preferences A: recommendation problem evidence solution O utline

5. question

6. problem

9. A 13 year old girl who lives in rural Indonesia presented with flu symptoms and developed severe respiratory distress over the course of the last 2 days. She required intubation. The history reveals that she shares her living quarters with her parents and her three siblings. At night the family’s chicken stock shares this room too and several chicken had died unexpectedly a few days before the girl fell sick. S cenario

10. At present, infection with influenza A(H5N1) virus is primarily a disease of birds. With the virus now reported in domestic or wild birds in >50 countries, sporadic human cases will almost certainly continue to occur. In many patients, the disease caused by the H5N1 virus follows an unusually aggressive clinical course, with rapid deterioration and high fatality rate. S cenario

12. What are the phenomena associated with the problem? What is frequency of the problem? What causes the problem? (aetiology) Does this person have the problem? (diagnosis) What if one gets the problem? (prognosis) What can we do about the problem? (treatment) … etc. Q uestions

13. Should oral oseltamivir be used for treatment of avian influenza (H5N1) in healthy individuals? Q uestion

14. avian flu A (H5N1) patients oseltamivir no antiviral mortality hospitalization adverse effects antimicrobial resistance resource use Q uestion P: I: C: O:

15. evidence

17. systematic review

18. cannot DO systematic review use EXISTING there is NO existing do PRAGMATIC search

22. how believable is evidence

23. limitations inconsistency indirectness imprecision publication bias large effect dose-response „antagonistic bias”

24. what is the evidence

25. no RCT of oseltamivir for H5N1 5 RCTs in seasonal influenza –hospitalization: OR 0.22 (0.02–2.16) –pneumonia: OR 0.15 (0.03–0.69) E vidence

27. solution

29. no RCT of oseltamivir for H5N1 5 RCTs in seasonal influenza –hospitalization: OR 0.22 (0.02–2.16) –pneumonia: OR 0.15 (0.03–0.69) 3 published case series many in vitro and animal studies no alternative more promising Cost: ~ €40 per course E vidence

30. no RCT of oseltamivir for treatment of H5N1 patients 4 systematic reviews and health technology assessments reporting 5 studies of oseltamivir in seasonal influenza –hospitalization: OR 0.22 (0.02–2.16) –pneumonia: OR 0.15 (0.03–0.69) 3 published case series many in vitro and animal studies no alternative more promising Cost: ~ €40 per course E vidence

31. quality of existing evidence balance of desirable and undesirable effects values and preferences cost (resource utilization) S trength Because I like it better that way!

32. Oseltamivir for Avian Flu Recommendation In patients with confirmed or strongly suspected infection with avian influenza A (H5N1) virus, clinicians should administer oseltamivir as soon as possible (? recommendation | very low quality evidence) Schunemann et al. The Lancet ID, 2007 strong ? weak

33. Oseltamivir for Avian Flu Recommendation In patients with confirmed or strongly suspected infection with avian influenza A (H5N1) virus, clinicians should administer oseltamivir as soon as possible (strong recommendation | very low quality evidence) Values and Preferences This recommendation places a high value on the prevention of death in an illness with a high case fatality. It places relatively low values on adverse reactions, the development of resistance and costs of treatment. Schunemann et al. The Lancet ID, 2007

34. Oseltamivir for Avian Flu Remarks Despite the lack of controlled treatment data for H5N1, this is a strong recommendation, in part, because there is a lack of known effective alternative pharmacological interventions at this time. The panel voted on whether this recommendation should be strong or weak and there was one abstention and one dissenting vote. Schunemann et al. The Lancet ID, 2007

35. quality of evidence strength of recommendation

37. Ask precise clinical question Decide on importance of outcomes Identify existing evidence Grade quality of existing evidence Construct evidence profiles Decide on balance of consequences Decide on strength Formulate recommendation 1 4 2 3 5 6 7 8 P rocess

38. questions Jan Brożek

39. No questions Jan Brożek

41. END

42. hypothesis more systematic observations observation experiment still a hypothesis law review of experiments theory leczenie lepsze kontrola lepsza 100,10,011

43. hypothesis more systematic observations observation experiment still a hypothesis law review of experiments theory leczenie lepsze kontrola lepsza 100,10,011

44. Factors that influence strength Comment Quality of the evidenceThe higher the quality of evidence, the more likely is a strong recommendation. Balance of desirable and undesirable effects The larger the difference between the desirable and undesirable consequences, the more likely a strong recommendation warranted. The smaller the net benefit and the lower certainty for that benefit, the more likely weak recommendation warranted. Values and preferencesThe greater the variability in values and preferences, or uncertainty in values and preferences, the more likely weak recommendation warranted. Cost (resource allocation) The higher the costs of an intervention – that is, the more resources consumed – the less likely is a strong recommendation warranted

46. 1