1. Holger Schünemann, MD, PhD Professor Utrecht, NL September 18 - 19, 2008 1

2. Disclosure In the past three years, Dr. Schünemann received no personal payments for service from the pharmaceutical industry. His research group received research grants and - until April 2008 - fees and/or honoraria that were deposited into research accounts from Chiesi Foundation 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.

3. Content  Background and rationale for revisiting guideline methodology  GRADE approach  Quality of evidence  Strength of recommendations

4. Content  Background and rationale for revisiting guideline methodology  GRADE approach  Quality of evidence  Strength of recommendations

5. Confidence in evidence  There always is evidence  “When there is a question there is evidence”  Evidence alone is never sufficient to make a clinical decision  Better research  greater confidence in the evidence and decisions

6. 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

7. 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

8. 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

9. Reasons for grading evidence?  People draw conclusions about the  quality of evidence and strength of recommendations  Systematic and explicit approaches can help  protect against errors, resolve disagreements  communicate information and fulfil needs  Change practitioner behavior  However, wide variation in approaches GRADE working group. BMJ. 2004 & 2008

10. 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

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12. A COPD guidelines 12

13. Another COPD guidelines 13

14. And another COPD guideline 14

15. What to do? 15

16. Content  Background and rationale for revisiting guideline methodology  GRADE approach  Quality of evidence  Strength of recommendations

17. 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

18. 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

19. GRADE Working Group  David Atkins, chief medical officer a  Dana Best, assistant professor b  Martin Eccles, professor d  Francoise Cluzeau, lecturer x  Yngve Falck-Ytter, associate director e  Signe Flottorp, researcher f  Gordon H Guyatt, professor g  Robin T Harbour, quality and information director h  Margaret C Haugh, methodologist i  David Henry, professor j  Suzanne Hill, senior lecturer j  Roman Jaeschke, clinical professor k  Regina Kunx, Associate Professor  Gillian Leng, guidelines programme director l  Alessandro Liberati, professor m  Nicola Magrini, director n  James Mason, professor d  Philippa Middleton, honorary research fellow o  Jacek Mrukowicz, executive director p  Dianne O ’ Connell, senior epidemiologist q  Andrew D Oxman, director f  Bob Phillips, associate fellow r  Holger J Sch ü nemann, professor g,s  Tessa Tan-Torres Edejer, medical officer t  David Tovey, Editor y  Jane Thomas, Lecturer, UK  Helena Varonen, associate editor u  Gunn E Vist, researcher f  John W Williams Jr, professor v  Stephanie Zaza, project director w  a) Agency for Healthcare Research and Quality, USA  b) Children's National Medical Center, USA  c) Centers for Disease Control and Prevention, USA  d) University of Newcastle upon Tyne, UK  e) German Cochrane Centre, Germany  f) Norwegian Centre for Health Services, Norway  g) McMaster University, Canada  h) Scottish Intercollegiate Guidelines Network, UK  i) F é d é ration Nationale des Centres de Lutte Contre le Cancer, France  j) University of Newcastle, Australia  k) McMaster University, Canada  l) National Institute for Clinical Excellence, UK  m) Universit à di Modena e Reggio Emilia, Italy  n) Centro per la Valutazione della Efficacia della Assistenza Sanitaria, Italy  o) Australasian Cochrane Centre, Australia  p) Polish Institute for Evidence Based Medicine, Poland  q) The Cancer Council, Australia  r) Centre for Evidence-based Medicine, UK  s) National Cancer Institute, Italy  t) World Health Organisation, Switzerland  u) Finnish Medical Society Duodecim, Finland  v) Duke University Medical Center, USA  w) Centers for Disease Control and Prevention, USA  x) University of London, UK  Y) BMJ Clinical Evidence, UK

20. GRADE Uptake  World Health Organization  Allergic Rhinitis in Asthma Guidelines (ARIA)  American Thoracic Society  British Medical Journal  Infectious Disease Society of America  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

21. 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 2) Recommendation: 2 grades - weak or strong (for or against)?  Quality of evidence only one factor *www.GradeWorkingGroup.org

22. GRADE Quality of Evidence “Extent to which confidence in estimate of effect adequate to support decision”  high: considerable confidence in estimate of effect.  moderate: further research likely to have impact on confidence in estimate, may change estimate.  low: further research is very likely to impact on confidence, likely to change the estimate.  very low: any estimate of effect is very uncertain

23. Determinants of quality  RCTs start high  observational studies start low  5 factors lower the quality of evidence  detailed design and execution  inconsistency  indirectness  reporting bias  Imprecision  3 factors can increase the quality of evidence

24. Quality assessment criteria

25. Example: Design and Execution  limitations  Randomization  lack of concealment  intention to treat principle violated  inadequate blinding  loss to follow-up  early stopping for benefit

26. Design and Execution  From Cates, CDSR 2008 CDSR 2008

27. Design and Execution Overall judgment required

28. 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  Epinephrin in allergic shock  dose response relation (higher INR – increased bleeding)  Residual confounding unlikely to be responsible for observed effect

29. Guideline development process Prioritise Problems, establish panel  Systematic Review  Evidence Profile  Relative importance of outcomes  Overall quality of evidence  Benefit – downside evaluation  Strength of recommendation  Implementation and evaluation of guidelines GRADE

30. Prioritise Problems, establish panel  Systematic Review  Evidence Profile  Relative importance of outcomes  Overall quality of evidence  Benefit – downside evaluation  Strength of recommendation  Implementation and evaluation of guidelines GRADE Summary of Findings Guideline development process

31. GRADE Profiles

32. Summary of Findings Tables

33. 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 Norris 9/11/08 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”

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35. The clinical scenario A 68 year old male long-term patient of yours. He suffers from COPD but is unable to stop smoking after over 30 years of tobacco use. He has been taking beta-carotene supplements for several months because someone in the “healthy food” store recommended it to prevent cancer. He wants to know whether this will prevent him from getting cancer and whether he should use beta-carotene.

36. 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.”

37. Desirable and undesirable effects  Desirable effects  Mortality  improvement in quality of life, fewer hospitalizations/infections  reduction in the burden of treatment  reduced resource expenditure  Undesirable effects deleterious impact on morbidity, mortality or quality of life, increased resource expenditure

38. Determinants of the strength of recommendation

39. Developing recommendations

40. Implications of a strong recommendation  Patients: Most people in this 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

41. Implications of a weak recommendation  Patients: The majority of people in this 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/decision aids and shared decision making  Policy makers: There is a need for substantial debate and involvement of stakeholders

42. A COPD guidelines 42

43. Another COPD guidelines 43

44. And another COPD guideline 44

45. The clinical question Population: In smokers with COPD Intervention: does beta-carotene suppl Comparison: compared to no suppl. Outcomes: reduce the risk of COPD symptoms, lung cancer and death and improve PFTs?

46. Two trials 1) The Alpha-Tocopherol Beta-Carotene (ATBC) trial randomly assigned 29,133 people to receive beta carotene, tocopherol, both, or placebo. Study participants averaged 57.2 years of age, 20.4 cigarettes per day, and 35.9 years of smoking. They were followed up for 5 to 8 years. RR for lung cancer = 1.16 (95% CI 1.02-1.33) Albanes et al, JNCI, 1996

47. Two trials 2) The Beta-Carotene and Retinol Efficacy Trial (CARET) evaluated high-risk current and former smokers with a 20–pack-year history of smoking (n = 14,254), ~ 60 years old. The participants were randomly assigned to receive either a combination of beta carotene and vitamin A or placebo. Mean length of follow up: 4 years. RR for lung cancer = 1.28 (95% CI 1.04-1.57)

48. Determinants of the strength of recommendation

50. Factors that can weaken the strength of a recommendation. Example: DecisionExplanation Lower quality evidence □ Yes □ No Uncertainty about the balance of benefits versus harms and burdens □ Yes □ No Uncertainty or differences in values □ Yes □ No Uncertainty about whether the net benefits are worth the costs □ Yes □ No Table. Decisions about the strength of a recommendation Frequent “yes” answers will increase the likelihood of a weak recommendation

51. Your recommendation  Team up in pairs of two or three or four and formulate your recommendation for the guideline on COPD  I will collect your answers

52. Your recommendation

53. Our recommendation In patients with COPD who continue to smoke, we recommend stopping beta-carotene supplementation. OR: In patients with COPD who continue to smoke, clinicians should stop beta-carotene supplementation.

54. Conclusions  GRADE is gaining acceptance as international standard  Criteria for evidence assessment across questions and outcomes  Criteria for moving from evidence to recommendations  Simple, transparent, systematic  four categories of quality of evidence  two grades for strength of recommendations  Transparency in decision making and judgments is key