1. Holger Schünemann, MD, PhD Chair, Department of Clinical Epidemiology & Biostatistics Michael Gent Chair in Healthcare Research Professor of Clinical Epidemiology, Biostatistics and Medicine McMaster University, Hamilton, Canada Baltimore, May 5, 2009 1

2. Disclosure In the past three years, Dr. Schünemann received no personal payments for service from the pharmaceutical industry. During that time, his research group received research grants and - until April 2008 - fees and/or honoraria that were deposited into research accounts from Chiesi Foundation, Pfizer, UnitedBioSource and Lily, as lecture fees related to research methodology. He is documents editor for the American Thoracic Society. Institutions or organizations that he is affiliated with likely receive funding from for-profit sponsors that are supporting infrastructure and research that may serve his work. He is a GRADE Working Group Member

3. Content  Key principles of guidance documents  GRADE approach  Quality of evidence  Strength of recommendations

4. Case scenario 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. Interventions: antivirals, such as neuraminidase inhibitors oseltamivir and zanamivir

5. Relevant healthcare question? Clinical question: Population: Avian Flu/influenza A (H5N1) patients Intervention: Oseltamivir (or Zanamivir) Comparison: No pharmacological intervention Outcomes: Mortality, hospitalizations, resource use, adverse outcomes, antimicrobial resistance WHO Avian Influenza GL. Schunemann et al., The Lancet ID, 2007

6. Choosing outcomes  Every decision comes with desirable and undesirable consequences  Developing recommendations must include a consideration of desirable and undesirable consequences  desirable effects  lower mortality  improvement in quality of life, fewer hospitalizations  reduction in the burden of treatment  reduced resource expenditure  undesirable consequences  deleterious impact on morbidity, mortality or quality of life, increased resource expenditure

7. There are no RCTs!  Do you think that users of recommendations would like to be informed about the basis (explanation) for a recommendation if they were asked (by their patients)?  I suspect the answer is “yes”  If we need to provide the basis for recommendations, we need to say whether the evidence is good or not so good; in other words perhaps “no RCTs” 7

8. Confidence in evidence  There always is evidence  “When there is a question there is evidence”  Better research  greater confidence in the evidence and decisions

9. Hierarchy of evidence STUDY DESIGN Randomized Controlled Trials Cohort Studies and Case Control Studies Case Reports and Case Series, Non-systematic observations BIAS Expert Opinion

10. Can you explain the following?  Concealment of randomization  Blinding (who is blinded in a double blinded trial?)  Intention to treat analysis and its correct application  Why trials stopped early for benefit overestimate treatment effects?  P-values and confidence intervals

11. Hierarchy of evidence STUDY DESIGN Randomized Controlled Trials Cohort Studies and Case Control Studies Case Reports and Case Series, Non-systematic observations BIAS Expert Opinion

12. Which grading system? Evidence Recommendation  B Class I  A 1  IV C Organization  AHA  ACCP  SIGN Recommendation for use of oral anticoagulation in patients with atrial fibrillation and rheumatic mitral valve disease

13. Recommendations vs statements! 13

14. The GRADE approach Clear separation of 2 issues: 1) 4 categories of quality of evidence: very low, low, moderate, or high quality?  methodological quality of evidence  likelihood of bias  by outcome and across outcomes 2) Recommendation: 2 grades - weak or strong (for or against)?  Quality of evidence only one factor *www.GradeWorking-Group.org

15. G rades of R ecommendation A ssessment, D evelopment and E valuation CMAJ 2003, BMJ 2004, BMC 2004, BMC 2005, AJRCCM 2006, Chest 2006, BMJ 2008

16. About GRADE  Since 2000  Researchers/guideline developers with interest in methodology  Aim: to develop a common, transparent and sensible system for grading the quality of evidence and the strength of recommendations  Evaluation of existing systems

17. GRADE Uptake  World Health Organization  Allergic Rhinitis in Asthma Guidelines (ARIA)  American Thoracic Society  British Medical Journal  American College of Chest Physicians  UpToDate  American College of Physicians  Cochrane Collaboration  National Institute Clinical Excellence (NICE)  Infectious Disease Society of America  European Society of Thoracic Surgeons  Clinical Evidence  Agency for Health Care Research and Quality (AHRQ)  Over 20 major organizations

18. Limitations of existing systems  confuse quality of evidence with strength of recommendations  lack well-articulated conceptual framework  criteria not comprehensive or transparent  GRADE unique  breadth, intensity of development process  wide endorsement and use  conceptual framework  comprehensive, transparent criteria  Focus on all important outcomes related to a specific question and overall quality

19. GRADE Evidence Profiles

20. Determinants of quality  RCTs start high  observational studies start low  5 factors that can lower quality 1. limitations of detailed design and execution 2. inconsistency 3. indirectness 4. reporting bias 5. Imprecision  3 factors can increase quality 1. large magnitude of effect 2. all plausible confounding may be working to reduce the demonstrated effect or increase the effect if no effect was observed 3. dose-response gradient

21. 1. Design and Execution  limitations  Randomization  lack of concealment  intention to treat principle violated  inadequate blinding  loss to follow-up  early stopping for benefit The evidence for the effect of sublingual immunotherapy in children with allergic rhinitis on the development of asthma, comes from a single randomised trial with no description of randomisation, concealment of allocation, and type of analysis, no blinding, and 21% of children lost to follow-up. These very serious limitations would limit our confidence in the estimates of effect and likely lead to downgrading the quality of evidence.

22. 1. Design and Execution  From Cates, CDSR 2008 CDSR 2008

23. 1. Design and Execution Overall judgment required

24. 2. Consistency of results  Look for explanation for inconsistency  patients, intervention, comparator, outcome, methods  Judgment  variation in size of effect  overlap in confidence intervals  statistical significance of heterogeneity I2I2

25. 3. Directness of Evidence  indirect comparisons  interested in A versus B  have A versus C and B versus C  differences in  patients  interventions  outcomes

26. Directness of Evidence Table 5. Sources of likely indirectness of evidence Source of indirectnessQuestion of interestExample Indirect comparisonEarly emergency department systemic corticosteroids to treat acute exacerbations in patients with asthma Both oral and intravenous routes are effective but there is no direct comparison of these two routes of administration.

27. Directness of Evidence Table 5. Sources of likely indirectness of evidence Source of indirectnessQuestion of interestExample Indirect comparison Early emergency department systemic corticosteroids to treat acute exacerbations in patients with asthma Both oral and intravenous routes are effective but there is no direct comparison of these two routes of administration. Differences in populations Anti-leukotrienes plus inhaled glucocorticosteroids vs. inhaled glucocorticosteroids alone to prevent asthma exacerbations and nighttime symptoms in patients with chronic asthma and allergic rhinitis. Trials that measured asthma exacerbations and nighttime symptoms did not include patients with allergic rhinitis.

28. Directness of Evidence Table 5. Sources of likely indirectness of evidence Source of indirectnessQuestion of interestExample Indirect comparison Early emergency department systemic corticosteroids to treat acute exacerbations in patients with asthma Both oral and intravenous routes are effective but there is no direct comparison of these two routes of administration. Differences in populations Anti-leukotrienes plus inhaled glucocorticosteroids vs. inhaled glucocorticosteroids alone to prevent asthma exacerbations and nighttime symptoms in patients with chronic asthma and allergic rhinitis. Trials that measured asthma exacerbations and nighttime symptoms did not include patients with allergic rhinitis. Differences in intervention Avoidance of pet allergens in non-allergic infants or preschool children to prevent development of allergy. Available studies used multifaceted interventions directed at multiple potential risk factors in addition to pet avoidance.

29. Directness of Evidence Table 5. Sources of likely indirectness of evidence Source of indirectnessQuestion of interestExample Indirect comparison Early emergency department systemic corticosteroids to treat acute exacerbations in patients with asthma Both oral and intravenous routes are effective but there is no direct comparison of these two routes of administration. Differences in populations Anti-leukotrienes plus inhaled glucocorticosteroids vs. inhaled glucocorticosteroids alone to prevent asthma exacerbations and nighttime symptoms in patients with chronic asthma and allergic rhinitis. Trials that measured asthma exacerbations and nighttime symptoms did not include patients with allergic rhinitis. Differences in intervention Avoidance of pet allergens in non-allergic infants or preschool children to prevent development of allergy. Available studies used multifaceted interventions directed at multiple potential risk factors in addition to pet avoidance. Differences in outcomes of interest Intranasal glucocorticosteroids vs. oral H 1 -antihistamines in children with seasonal allergic rhinitis. In the available study parents were rating the symptoms and quality of life of their teenage children, instead the children themselves.

30. 4. Publication Bias  Publication bias  Cave! Only few small studies A systematic review of topical treatments for seasonal allergic conjunctivitis showed that patients using topical sodium cromoglycate were more likely to perceive benefit than those using placebo. However, only small trials reported clinically and statistically significant benefits of active treatment, while a larger trial showed a much smaller and a statistically not significant effect. These findings suggest that smaller studies demonstrating smaller effects might not have been published.

31. 5. Imprecision  small sample size  small number of events  wide confidence intervals  uncertainty about magnitude of effect Observational studies examining the impact of exclusive breastfeeding on development of allergic rhinitis in high risk infants showed a relative risk of 0.87 (95% CI: 0.48 to 1.58) that neither rules out important benefit nor important harm (Mimouni Bloch 2002).

32. What can raise quality? 3 Factors  large magnitude can upgrade one level  very large two levels  common criteria  everyone used to do badly  almost everyone does well  The parachute example: if we’d look at the observational evidence, we’d find a very large effect and the evidence probably would be high quality for preventing death  dose response relation (higher dose of brain radiation in childhood leukemia leads to greater risk of late malignancies)  Residual confounding unlikely to be responsible for observed effect

33. Quality assessment criteria

34. Strength of recommendation  “The strength of a recommendation reflects the extent to which we can, across the range of patients for whom the recommendations are intended, be confident that desirable effects of a management strategy outweigh undesirable effects.”  Strong or weak/conditional

35. Quality of evidence & strength of recommendation  Linked but no automatism  Other factors beyond the quality of evidence influence our confidence that adherence to a recommendation causes more benefit than harm  Systems/approaches failed to make this explicit  GRADE separates quality of evidence from strength of recommendation

36. Developing recommendations

37. Factors determining strength of recommendation

38. Judgments about the strength of a recommendation - oseltamivir for treatment of patients hospitalised with avian influenza (H5N1) FactorsComments Balance between desirable and undesirable effects “The benefits are uncertain, but potentially large.” Quality of the evidence“The quality of the evidence is very low.” Values and preferences“All patients and care providers would accept treatment for H5N1 disease.” No alternative Costs (resource use)“The cost is not high for treatment of sporadic cases.”

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

40. Recommendations vs statements! 40

41. Example: Oseltamivir for Avian Flu Recommendation: In patients with confirmed or strongly suspected infection with avian influenza A (H5N1) virus, clinicians should administer oseltamivir treatment as soon as possible (strong recommendation, very low quality evidence). Values and Preferences Remarks: 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

42. Conclusion  Clinicians need appropiate summaries  quality of evidence  strength of recommendations  explicit rules  transparent, informative  GRADE  four categories of quality of evidence  two grades for strength of recommendations  transparent, systematic by and across outcomes  wide adoption

43. 43

45. What can raise quality? 1. large magnitude can upgrade (RRR 50%)  very large two levels (RRR 80%)  common criteria  everyone used to do badly  almost everyone does well  oral anticoagulation for mechanical heart valves  insulin for diabetic ketoacidosis  hip replacement for severe osteoarthritis

46. What can raise quality? 2. dose response relation  (higher INR – increased bleeding)  childhood lymphoblastic leukemia  risk for CNS malignancies 15 years after cranial irradiation  no radiation: 1% (95% CI 0% to 2.1%)  12 Gy: 1.6% (95% CI 0% to 3.4%)  18 Gy: 3.3% (95% CI 0.9% to 5.6%) 3. all plausible confounding may be working to reduce the demonstrated effect or increase the effect if no effect was observed

47. All plausible confounding would result in an underestimate of the treatment effect  Higher death rates in private for-profit versus private not-for-profit hospitals  patients in the not-for-profit hospitals likely sicker than those in the for-profit hospitals  for-profit hospitals are likely to admit a larger proportion of well-insured patients than not-for- profit hospitals (and thus have more resources with a spill over effect)

48. All plausible biases would result in an overestimate of effect  Hypoglycaemic drug phenformin causes lactic acidosis  The related agent metformin is under suspicion for the same toxicity.  Large observational studies have failed to demonstrate an association  Clinicians would be more alert to lactic acidosis in the presence of the agent

49. Health Care Question (PICO) Systematic reviews Studies Outcomes Important outcomes Rate the quality of evidence for each outcome, across studies RCTs start high, observational studies start low (-) Study limitations Imprecision Inconsistency of results Indirectness of evidence Publication bias likely Final rating of quality for each outcome: high, moderate, low, or very low (+) Large magnitude of effect Dose response Plausible confounders would ↓ effect when an effect is present or ↑ effect if effect is absent Decide on the direction (for/against) and grade strength of the recommendation (strong/weak*) considering: Quality of the evidence Balance benefits/harms Values and preferences Decide if any revision of direction or strength is necessary considering: Resource use Rate overall quality of evidence (GRADE) (lowest quality among critical outcomes) S1S2S3S4 OC1OC2 OC3 OC4 OC1OC3 Critical outcomes OC4 Reevaluate estimate of effect for each outcome OC2 S5 *also labeled “conditional”

50. Implications of a strong recommendation  Patients: Most people in your situation would want the recommended course of action and only a small proportion would not  Clinicians: Most patients should receive the recommended course of action  Policy makers: The recommendation can be adapted as a policy in most situations

51. Implications of a weak/conditional recommendation  Patients: The majority of people in your situation would want the recommended course of action, but many would not  Clinicians: Be prepared to help patients to make a decision that is consistent with their own values  Policy makers: There is a need for substantial debate and involvement of stakeholders

52. Should oseltamivir be used for treatment of patients hospitalised with avian influenza (H5N1)?

53. What would you recommend?  Strong recommendation: the panel is confident that the desirable effects of adherence to a recommendation outweigh the undesirable effects.  Weak recommendation: the panel concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects, but is not confident.

54. Who would recommend oseltamivir for these patients (no other alternative)?  YES (green card)  No (pink card)

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

56. Example: Oseltamivir for Avian Flu Recommendation: In patients with confirmed or strongly suspected infection with avian influenza A (H5N1) virus, clinicians should administer oseltamivir treatment as soon as possible (strong recommendation, very low quality evidence). Values and Preferences Remarks: 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

57. Other explanations 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