Rating quality of evidence and Strength of recommendations in GI using the GRADE Framework

1. Rating quality of evidence and Strength of recommendations in GI using the GRADE Framework AGA Clinical Practice & Quality Management Committee Teleconference 17 Oct 2008 Yngve Falck-Ytter, M.D. Assistant Professor of Medicine Case Western Reserve University, Cleveland Division of Gastroenterology, Case and VA Medical Center

2. Disclosure In the past 4 years, Dr. Falck-Ytter received no personal payments for services from industry. His research group received research grants from Valeant and Roche that were deposited into non-profit research accounts. He is a member of the GRADE working group which has received funding from various governmental entities in the US and Europe. Some of the GRADE work he has done is supported in part by grant # 1 R13 HS016880-01 from the Agency for Healthcare Research and Quality.

3. Content • Background and rationale for revisiting guideline methodology • The GRADE approach • Grading the quality of evidence and strength of recommendations in GI

4. 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 Expert Opinion Expert Opinion

5. 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 fulfill needs • Change practitioner behavior • However, wide variation in approaches GRADE working group. BMJ. 2004 & 2008

6. Grading used in GI CPGs AGA AASLD ACG ASGE I Syst. review of RCTs I RCTs A. Prospect. controlled trials I RCTs, well designed, n↑ for suff. stat. power II-1 Controlled trials(no randomization) II 1+ properly desig. RCT, n↑, clinical setting B. Obser-vational studies II 1 large well-designed clinical trial (+/- rand.), cohort or case-control studies or well designed meta-analysis II-2 Cohort or case-control analytical studies III Publ., well-desig. trials, pre-post, cohort, time series, case-control studies II-3 Multiple time series, dramatic uncontr. experiments IV Non-exp. studies >1 center/group, opinion respected authorities, clinical evidence, descr. studies, expert consensus comm. C. Expert opinion III Clinical experience, descr. studies, expert comm. III Opinion of respected authorities, descrip. epidemiology IV Not rated

7. 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

9. David Atkins, chief medical officera Dana Best, assistant professorb Martin Eccles, professord Francoise Cluzeau, lecturerx Yngve Falck-Ytter, associate directore Signe Flottorp, researcherf Gordon H Guyatt, professorg Robin T Harbour, quality and information director h Margaret C Haugh, methodologisti David Henry, professorj Suzanne Hill, senior lecturerj Roman Jaeschke, clinical professork Regina Kunx, Associate Professor Gillian Leng, guidelines programme directorl Alessandro Liberati, professorm Nicola Magrini, directorn James Mason, professord Philippa Middleton, honorary research fellowo Jacek Mrukowicz, executive directorp Dianne O’Connell, senior epidemiologistq Andrew D Oxman, directorf Bob Phillips, associate fellowr Holger J Schünemann, professorg,s Tessa Tan-Torres Edejer, medical officert David Tovey, Editory Jane Thomas, Lecturer, UK Helena Varonen, associate editoru Gunn E Vist, researcherf John W Williams Jr, professorv Stephanie Zaza, project directorw 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) Fédération 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) Università 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 GRADE Working Group

10. GRADE uptake

11. GRADE: Quality of evidence The extent to which our confidence in an estimate of the treatment effect is adequate to support particular recommendation. Although the degree of confidence is a continuum, we suggest using four categories: • High • Moderate • Low • Very low

12. Quality of evidence across studies Outcome #1 Quality: High Outcome #2 Quality: Moderate Outcome #3 Quality: Low I B II V III

13. Determinants of quality • RCTs start high • Observational studies start low • What lowers quality of evidence? 5 factors: • Detailed design and execution • Inconsistency of results • Indirectness of evidence • Imprecision • Publication bias

14. What is the study design?

15. 1. Design and execution • Study limitations (risk of bias) • Lack of allocation concealment • No true intention to treat principle • Inadequate blinding • Loss to follow-up • Early stopping for benefit

16. 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

17. Heterogeneity Pagliaro L et al. Ann Intern Med 1992;117:59-70

18. 3. Directness of Evidence • Indirect comparisons • Interested in head-to-head comparison • Drug A versus drug B • Infliximab versus adalimumab in Crohn’s disease • Differences in • patients (early cirrhosis vs end-stage cirrhosis) • interventions (CRC screening: flex. sig. vs colonoscopy) • outcomes (non-steroidal safety: ulcer on endoscopy vs symptomatic ulcer complications)

19. 4. Imprecision Small sample size • small number of events • wide confidence intervals • uncertainty about magnitude of effect

20. 5. Reporting Bias (Publication Bias) • Reporting of studies • publication bias • number of small studies • Reporting of outcomes

21. Quality assessment criteria Study design Lower if… Higher if… Quality of evidence Randomized trial Study limitations (design and execution) High (4) Moderate (3) Inconsistency What can raise the quality of evidence? Observational study Low (2) Indirectness Very low (1) Imprecision Publication bias

22. BMJ 2003;327:1459–61 22

23. Quality assessment criteria Lower if… Higher if… Quality of evidence Study design Study limitations Large effect (e.g., RR 0.5) Very large effect (e.g., RR 0.2) High (4) Randomized trial Moderate (3) Inconsistency Evidence of dose-response gradient Observational study Low (2) Indirectness All plausible confounding would reduce a demonstrated effect Very low (1) Imprecision Publication bias

24. Categories of quality High Further research is very unlikely to change our confidence in the estimate of effect Moderate Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Low Very low Any estimate of effect is very uncertain

25. Judgments about the overall quality of evidence • Most systems not explicit • Options: • Benefits • Primary outcome • Highest • Lowest • Beyond the scope of a systematic review • GRADE: Based on lowest of all the critical outcomes

26. GRADE evidence profile

27. 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.” Although the strength of recommendation is a continuum, we suggest using two categories : “Strong” and “Weak”

28. Desirable and undesirable effects • Desirable effects • Mortality reduction • 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

29. Determinants of the strength of recommendation

30. Developing recommendations

31. 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

32. 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

33. Where GRADE fits in Prioritize problems, establish panel Systematic review Searches, selection of studies, data collection and analysis Assess the relative importance of outcomes Prepare evidence profile: Quality of evidence for each outcome and summary of findings GRADE Assess overall quality of evidence Decide direction and strength of recommendation Draft guideline Consult with stakeholders and / or external peer reviewer Disseminate guideline Implement the guideline and evaluate

34. Create evidence profile with GRADEpro Summary of findings & estimate of effect for each outcome Guideline development Rate overall quality of evidence across outcomes based on lowest quality of critical outcomes Rate quality of evidence for each outcome Outcomes across studies Formulate question Rate importance Select outcomes RCT start high, obs. data start low Risk of bias Inconsistency Indirectness Imprecision Publication bias P I C O Outcome Critical High Outcome Critical Moderate Grade down Low Outcome Important Very low Outcome Not important Large effect Dose response Confounders Grade up Panel • Formulate recommendations: • For or against (direction) • Strong or weak (strength) • By considering: • Quality of evidence • Balance benefits/harms • Values and preferences • Revise if necessary by considering: • Resource use (cost) Systematic review • “We recommend using…” • “We suggest using…” • “We recommend against using…” • “We suggest against using…”

35. 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 • Transparency in decision making and judgments is key