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

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 HS from the Agency for Healthcare Research and Quality.

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

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

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 & 2008

6 Grading used in GI CPGs AASLD AGA ACGASGE I RCTs I RCTs, well designed, n↑ for suff. stat. power ISyst. review of RCTs A. Prospect. controlled trials II-1Controlled trials (no randomization) II1 large well- designed clinical trial (+/- rand.), cohort or case- control studies or well designed meta- analysis II-3Multiple time series, dramatic uncontr. experiments III Opinion of respected authorities, descrip. epidemiology II-2 Cohort or case- control analytical studies IIIClinical experience, descr. studies, expert comm. IVNot rated II1+ properly desig. RCT, n↑, clinical setting IIIPubl., well-desig. trials, pre-post, cohort, time series, case-control studies IV Non-exp. studies >1 center/group, opinion respected authorities, clinical evidence, descr. studies, expert consensus comm. B. Obser- vational studies C.Expert opinion

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

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

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

I B IIVIII Quality of evidence across studies Outcome #1 Outcome #2 Outcome #3 Quality: High Quality: Moderate Quality: Low

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?

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

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

Pagliaro L et al. Ann Intern Med 1992;117: Heterogeneity

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)

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

5. Reporting Bias (Publication Bias)  Reporting of studies  publication bias  number of small studies  Reporting of outcomes

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

BMJ 2003;327:1459–61 22

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

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

GRADE evidence profile

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”

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

Determinants of the strength of recommendation Factors that can weaken the strength of a recommendation Explanation  Lower quality evidenceThe higher the quality of evidence, the more likely is a strong recommendation.  Uncertainty about the balance of benefits versus harms and burdens 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 is a weak recommendation warranted.  Uncertainty or differences in values The greater the variability in values and preferences, or uncertainty in values and preferences, the more likely weak recommendation warranted.  Uncertainty about whether the net benefits are worth the costs The higher the costs of an intervention – that is, the more resources consumed – the less likely is a strong recommendation warranted.

Developing recommendations

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

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

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 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 GRADE

Systematic review Guideline development PICOPICO Outcome Formulate question Rate importance Critical Important Critical Not important Create evidence profile with GRADEpro Summary of findings & estimate of effect for each outcome Rate overall quality of evidence across outcomes based on lowest quality of critical outcomes RCT start high, obs. data start low 1.Risk of bias 2.Inconsistency 3.Indirectness 4.Imprecision 5.Publication bias Grade down Grade up 1.Large effect 2.Dose response 3.Confounders Rate quality of evidence for each outcome Select outcomes Very low Low Moderate High 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) “We recommend using…” “We suggest using…” “We recommend against using…” “We suggest against using…” Outcomes across studies

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