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Appendix D Systems for Rating the Strength of Evidence and Clinical Recommendations 231

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232 CLINICAL PRACTICE GUIDELINES WE CAN TRUST TABLE D-1 Selected Approaches to Rating Strength of Evidence and Clinical Recommendations Focus/ Systems for Rating System Audience Evidence Quality International Approaches Grading of Focus: Grades of evidence Recommendations Diagnosis and Randomized trial: High Assessment, therapy Observational study: Low Development, and Any other evidence: Very low Evaluation (GRADE) Audience: Working Group Decrease grade if limitations Guideline (2009) developers in study quality, important inconsistency of results, A voluntary, uncertainty about the directness international, of the evidence, imprecise or collaboration sparse data, and high risk of reporting bias. Increase grade if a very strong association, evidence of a dose– response gradient, presence of all plausible residual confounding would have reduced the observed effect.

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233 APPENDIX D System for Rating Clinical Recommendations’ Strength Strong: Desirable effects clearly outweigh the undesirable effects, or clearly do not. Quality of evidence is high and other considerations support a strong recommendation. Weak: Trade-offs are less certain—either because of low-quality evidence or because evidence suggests that desirable and undesirable effects are closely balanced. The quality of evidence is high and other considerations support a weak recommendation. Based on: • Quality of evidence. • ncertainty about the balance between desirable and undesirable effects. U • ncertainty or variability in values or preferences. U • ncertainty about whether the intervention represents a wise use of U resources. NOTE: Many organizations claim to use GRADE, but modify the system in the application of translating evidence into clinical recommendations or guidelines. continued

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234 CLINICAL PRACTICE GUIDELINES WE CAN TRUST TABLE D-1 Continued Focus/ Systems for Rating System Audience Evidence Quality Centre for Focus: CEBM is currently working on Evidence-Based Prevention, updating its level of evidence Medicine (CEBM) diagnosis, rankings and providing further (2009) prognosis, rationale for them, tentatively due therapy, to become available in January 2010. One of several UK differential centers with the aim of diagnosis/ This approach has different evidence promoting evidence- symptom rating system depending on the based health care prevalence, and type of healthcare intervention. For economic and example, the following rating decision system is used for therapy analyses interventions: Audience: Level 1a: Systematic review (SR) of Doctors, randomized controlled trials (RCTs) with homogeneity.a clinicians, teachers, and Level 1b: Individual RCT with others narrow confidence interval. Level 1c: All or none case series.b Level 2a: SR with homogeneity of cohort studies. Level 2b: Individual cohort studies (including quality RCT; e.g., <80% follow-up). Level 2c: Outcomes research, ecological studies.c Level 3a: SR with homogeneity of case control studies. Level 3b: Individual case control study. Level 4: Case series (and poor- quality cohort and case control studiesd). Level 5: Expert opinion without explicitly critical appraisal, or based on physiology, bench research, or “first principles.”

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235 APPENDIX D System for Rating Clinical Recommendations’ Strength A: Consistent level 1 studies. B: Consistent level 2 or 3 studies or extrapolationse from level 1 studies. C: Level 4 studies or extrapolations from level 2 or 3 studies. D: Level 5 evidence or troublingly inconsistent or inconclusive studies of any level. continued

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236 CLINICAL PRACTICE GUIDELINES WE CAN TRUST TABLE D-1 Continued Focus/ Systems for Rating System Audience Evidence Quality Scottish Levels of evidence Focus: All Intercollegiate 1++ High-quality meta-analyses, healthcare Guidelines Network systematic reviews of RCTs, or interventions (SIGN) (2009) RCTs with a very low risk of bias. Audience: 1+ Well-conducted meta-analyses, systematic reviews, or RCTs with a National Health low risk of bias. Service in 1– Meta-analyses, systematic reviews, Scotland or RCTs with a high risk of bias. 2++ High-quality systematic reviews of case control or cohort studies. ___ High-quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal. 2+ Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal. 2– Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal. 3 Non-analytic studies, such as case reports, case series. 4 Expert opinion. New Zealand Focus: The body of evidence is the sum Guidelines Group Screening, of the evidence of all the individual (NZGG) (2007) diagnosis, studies and the quality ratings of prognosis, and each study. Independent, therapy Good evidence: From studies of not-for-profit Audience: strong design for answering the Clinical question addressed. practitioners, Fair evidence: Reasonable policy makers, and consumers evidence, but there may be minimal inconsistency, or uncertainty. Expert opinion: For some outcomes, trials or studies cannot be or have not been performed and practice is informed only by expert opinion.

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237 APPENDIX D System for Rating Clinical Recommendations’ Strength Guidelines are developed based on judgment on the consistency, clinical relevance, and external validity of the whole body of evidence. A: At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results. B: A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+. C: A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++. D: Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+. Good practice points: Occasionally, guideline development groups find that there is an important practical point that they wish to emphasize, but for which there is not, nor is there likely to be, any research evidence. This typically will be where some aspect of treatment is regarded as such sound clinical practice that nobody is likely to question it. These are shown in the guideline as Good Practice Points, and are marked with a green check. The grade of the recommendation is based on consideration of • The design and quality of individual studies that have been identified. • uantity, consistency, applicability, and clinical impact of the body of Q evidence that is applicable to the guidelines question. • The consensus of a guideline development team. A: The recommendation is supported by GOOD evidence. B: The recommendation is supported by FAIR. C: The recommendation is supported by EXPERT opinion (published) only. I: Evidence to make a recommendation is INSUFFICIENT. continued

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238 CLINICAL PRACTICE GUIDELINES WE CAN TRUST TABLE D-1 Continued Focus/ Systems for Rating System Audience Evidence Quality The Canadian Focus: Uses flow charts to assess the Hypertension evidence according to study Diagnosis and Education Program methodology: therapy related (2007) to hypertension A: RCT with blinded assessment of Audience: A Canadian outcomes, intention-to-treat volunteer, non-profit Canadian analysis, adequate follow-up, and organization Diabetes sufficient sample size to detect a Association, clinically important difference with Canadian power >80%. Society of B: Adequate subgroup analysis: Nephrology, Canadian Analysis was a priori, performed Coalition for within an adequate RCT and one High Blood of only a few tested, and there Pressure was sufficient sample size within Prevention the examined subgroup to detect a and Control, clinically important difference. The College C: Systematic review or meta- of Family Physicians of analysis: Comparison arms are Canada, Heart derived from head-to-head and Stroke comparisons within the same RCT. Foundation of D: Observational study or Canada, and Public Health systematic review in which the Agency of comparison arms are derived from Canada different placebo-controlled RCTs and then extrapolations are made across RCTs.

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239 APPENDIX D System for Rating Clinical Recommendations’ Strength A: The recommendation is supported by a-, b-, or c-level evidence. Clinically important outcomes and the study population is representative of the population in the recommendation. B: The recommendation is supported by a-, b-, or c-level evidence. Clinically important or validated surrogate outcomes. C: The recommendation is supported by a-, b-, c-, or d-level evidence. For levels a, b, and c evidence, the outcome is an unvalidated surrogate for clinically important outcomes. For level d evidence, there must be a clinically important outcome and study population representative of the recommendation population, or an outcome-validated surrogate, or results that are extrapolated from study population to real population. D: Outcome is an unvalidated surrogate for clinically important population, or the applicability of the study is irrelevant. continued

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240 CLINICAL PRACTICE GUIDELINES WE CAN TRUST TABLE D-1 Continued Focus/ Systems for Rating System Audience Evidence Quality U.S. Approaches Institute for Clinical Focus: Primary reports of new data Systems Improvement collection: Prevention, (ICSI) (2003) A: RCT. diagnosis, or management B: Cohort study. Collaborative of 57 of a given medical groups in symptom, C: Nonrandomized trial with Minnesota disease, or condition for concurrent or historical controls, case individual control study, study of sensitivity patients and specificity of a diagnostic test, under normal population-based descriptive study. circumstances D: Cross-sectional study, case series, Audience: or case report. Minnesota healthcare providers and payers

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241 APPENDIX D System for Rating Clinical Recommendations’ Strength Grade I: Good evidence The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power. Grade II: Fair evidence The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of minor doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most. Grade III: Limited evidence The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusion because of inconsistencies among the results from different studies or because of serious doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed. Grade not assignable: No evidence is available that directly supports or refutes the conclusion. continued

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244 CLINICAL PRACTICE GUIDELINES WE CAN TRUST TABLE D-1 Continued Focus/ Systems for Rating System Audience Evidence Quality U.S. Preventive Focus: High: The available evidence usually Services Task Force Prevention includes consistent results from well- (USPSTF) designed, well-conducted studies (2008) Audience: in representative primary care Guideline populations. These studies assess developers and the effects of the preventive service users on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies. Moderate: The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the esti- mate is constrained by factors such as • he number, size, or quality of T individual studies. • nconsistency of findings across I individual studies. • imited generalizability of findings L to routine primary care practice. • ack of coherence in the chain of L evidence. As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. Low: The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of • he limited number or size of T studies. • mportant flaws in study design I or methods. • nconsistency of findings across I individual studies. • aps in the chain of evidence. G • indings not generalizable to F routine primary care practice. • ack of information on important L health outcomes. More information may allow estimation of effects on health outcomes.

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245 APPENDIX D System for Rating Clinical Recommendations’ Strength A: The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service. B: The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Offer or provide this service. C: The USPSTF recommends against routinely providing the service. There may be considerations that support providing the service in an individual patient. There is at least moderate certainty that the net benefit is small. Offer or provide this service only if other considerations support the offering or providing the service in an individual patient. D: The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Discourage the use of this service. I statement: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. Read the clinical considerations section of USPSTF Recommendation Statement. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms. continued

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246 CLINICAL PRACTICE GUIDELINES WE CAN TRUST TABLE D-1 Continued Focus/ Systems for Rating System Audience Evidence Quality Professional Societies American College Focus: A: Data derived from multiple of Cardiology Prevention, randomized clinical trials or meta- Foundation/American diagnosis, or analyses. Heart Association management of (ACCF/AHA) (2009) B: Data derived from a single heart diseases or conditions randomized trial, or non- randomized studies. Audience: C: Consensus opinion of experts, Healthcare providers case studies, or standard of care. American Focus: Pediatric A: Well-designed, randomized Academy of guidelines for controlled trials or diagnostic Pediatrics (AAP) all healthcare studies on relevant populations. (2004) interventions B: RCTs or diagnostics studies with Audience: minor limitations; overwhelmingly Guideline consistent evidence from developers, observational studies. implementers, C: Observational studies (case and users control and cohort design). D: Expert opinion, case reports, reasoning from principles. X: Exceptional situations where validating studies cannot be performed and there is a clear preponderance of benefit or harm.

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247 APPENDIX D System for Rating Clinical Recommendations’ Strength Any combination of classification of recommendation and level of evidence is possible. A recommendation can be Class I, based entirely on expert opinion (level C), or Class IIB, with level A evidence if based on multiple RCTs with divergent conclusions. Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective. Class 1 statements may read: should, is recommended, is indicated, or is useful/ effective/beneficial. Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. Class IIa statements may read: is reasonable, can be useful/effective/ beneficial, is probably recommended, is probably indicated. Class IIb: Usefulness/efficacy is less well established by evidence/ opinion. Class IIb statements may read: may/might be considered, may/ might be reasonable, usefulness/effectiveness is unknown/unclear/ uncertain/not well established. Class III: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful. Class III statements may read: is not recommended, is not indicated, should not, is not useful/effective/beneficial, may be harmful. Strong recommendation: The benefits of the recommended approach clearly exceed the harms (or in the case of a negative recommendation, the harms clearly exceed the benefits) and the quality of the evidence is either excellent or impossible to obtain (A, sometimes B, or X). Recommendation: The benefits exceed the harms or vice versa, but the quality of evidence is not as strong (sometimes B, C, or X). Option: The evidence quality that exists is suspect or not that well-designed; well-conducted studies have demonstrated little clear advantage of one approach versus another (A, B, C, or D). No recommendation: There is both lack of pertinent evidence and an unclear balance between benefits and harms (D). continued

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248 CLINICAL PRACTICE GUIDELINES WE CAN TRUST TABLE D-1 Continued Focus/ Systems for Rating System Audience Evidence Quality American Academy Focus: Screening, Similar ratings systems exist for of Neurology (AAN) diagnosis, diagnostic, prognostic, and screening (2004) prognosis, and interventions. Therapeutic therapy of interventions is one example: neurologic Class I: Prospective, RCT with disorders masked outcome assessment, in Audiences: a representative population. The Neurologists, following are required: (a) primary patients, payers, outcome(s) clearly defined, (b) federal agencies, exclusion/inclusion criteria clearly other healthcare defined, (c) adequate accounting providers, and for dropouts and crossovers with clinical numbers sufficiently low to have researchers minimal potential for bias, (d) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a through d above or an RCT in a representative population that lacks one criteria in a through d. Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement. Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion.

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249 APPENDIX D System for Rating Clinical Recommendations’ Strength A: Established as effective, ineffective, or harmful (or established as useful/ predictive or not useful/predictive) for the given condition in the specified population. Recommendation: Should be done or should not be done. Translation of evidence to recommendation: Requires at least two consistent Class I studies. B: Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. Recommendation: Should be considered or should not be considered. Translation of evidence to recommendation: Requires at least one Class I study or two consistent Class II studies. C: Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. Recommendation: May be considered or may not be considered. Translation of evidence to recommendation: Level C rating requires at least one Class II study or two consistent Class III studies. B: Data inadequate or conflicting. Given current knowledge, treatment (test, predictor) is unproven. Recommendation: None. Translation of evidence to recommendation: Studies not meeting criteria for Class I–Class III. continued

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250 CLINICAL PRACTICE GUIDELINES WE CAN TRUST TABLE D-1 Continued Focus/ Systems for Rating System Audience Evidence Quality American College of Focus: High: RCTs without important Chest Diagnosis and limitations or overwhelming evidence Physicians (ACCP) management of from observational studies. (2009) chest disease Moderate: RCTs with important Audience: Chest limitations (inconsistent results, physicians methodologic flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies. Low: Observational studies or case series. National Focus: High: High-powered randomized Comprehensive Prevention, clinical trials or meta-analysis. Cancer Network diagnosis, and (NCCN) (2008) Lower: Runs the gamut from phase II therapy related to cancer to large cohort studies to case series to individual practitioner experience. Audience: Oncologists and other healthcare providers

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251 APPENDIX D System for Rating Clinical Recommendations’ Strength 1A: Strong recommendation. High level of evidence. Benefits outweigh the risks/burdens, or the risks/burdens outweigh the benefits. 1B: Strong recommendation. Moderate evidence. Benefits outweigh the risks/burdens, or the risks/burdens outweigh the benefits. 1C: Strong recommendation. Low or very low evidence. Benefits outweigh the risks/burdens, or the risks/burdens outweigh the benefits. 2A: Weak recommendation. High evidence, and the risks/burdens are evenly balanced with the benefits. 2B: Weak recommendation. Moderate evidence, and the risks/burdens are evenly balanced with the benefits. 2C: Weak recommendation. Low or very low evidence, and the risks/ burdens are evenly balanced with the benefits. Or the balance of benefits to risks and burdens is uncertain. Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials), and there is uniform NCCN consensus. Category 2A: The recommendation is based on lower level evidence and there is uniform NCCN consensus. Category 2B: The recommendation is based on lower level evidence and there is non-uniform NCCN consensus (but no major disagreement). Category 3: The recommendation is based on any level of evidence, but reflects major disagreement. continued

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252 CLINICAL PRACTICE GUIDELINES WE CAN TRUST TABLE D-1 Continued Focus/ Systems for Rating System Audience Evidence Quality Infectious Diseases Focus: I: Evidence from >1 properly Society of America Healthcare randomized, controlled trial. (2001) interventions II: Evidence from >1 well-designed for infectious diseases clinical trial, without randomization; Audience: from cohort or case-controlled Infectious analytic studies (preferably from >1 disease center); from multiple time-series; or clinicians from dramatic results from uncontrolled experiments. III: Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. a Homogeneity refers to an SR that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. b Met when all patients died before the Rx became available, but some now survive on it, or when some patients died before the Rx became available, but none now die on it. cA member of CEBM stated that this ranking requires further analysis, as well as more detailed explanation of what is meant by ecological and outcomes research. d Poor-quality prognostic cohort study refers to one in which sampling is biased in fa- vor of patients who already had the target outcome, or the measurement of outcomes is accomplished in < 80 percent of study patients, or outcomes were determined in an unblinded, non-objective way, or there is no correction for confounding errors. e Extrapolations are where data are used in a situation that has potentially clinically important differences than the original study situation.

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253 APPENDIX D System for Rating Clinical Recommendations’ Strength A: Good evidence to support a recommendation for use. B: Moderate evidence to support a recommendation for use. C: Poor evidence to support a recommendation for use. f Clinicaldecision rules (CDRs) are tools designed to help clinicians make bedside di - agnostic and therapeutic decisions. The development of a CDR involves three stages: derivation, validation, and implementation. g Patient-oriented evidence measures outcomes that matter to patients: morbidity, mortality, symptom improvement, cost reduction, and quality of life. Disease-oriented evidence measures intermediate, physiologic, or surrogate end points that may or may not reflect improvements in patient outcomes (e.g., blood pressure, blood chem - istry, physiologic function, pathologic findings). SOURCES: AAN (2004); ACCF/AHA (2009); ACCP (2009); CEBM (2009); Ebell et al. (2004); GRADE Working Group (2009); ICSI (2003); Kish (2001); NCCN (2008); NZGG (2007); SIGN (2009); Steering Committee on Quality Improvement Management (2004); Tobe et al. (2007); USPSTF (2008).

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254 CLINICAL PRACTICE GUIDELINES WE CAN TRUST REFERENCES AAN (American Academy of Neurology). 2004. Clinical practice guidelines process manual. http://www.aan.com/globals/axon/assets/3749.pdf (accessed July 28, 2009). ACCF/AHA (American College of Cardiology Foundation/American Heart Associa- tion). 2009. Methodology manual for ACCF/AHA guideline writing committees. http://www.americanheart.org/downloadable/heart/12378388766452009Met hodologyManualACCF_AHAGuidelineWritingCommittees.pdf (accessed July 29, 2009). ACCP (American College of Chest Physicians). 2009. The ACCP grading system for guideline recommendations. http://www.chestnet.org/education/hsp/grading System.php (accessed July 28, 2009). CEBM (Centre for Evidence-Based Medicine). 2009. Oxford Centre for Evidence- based Medicine—Levels of Evidence (March 2009). http://www.cebm.net/ index.aspx?o=1025 (accessed July 28, 2009). Ebell, M. H., J. Siwek, B. D. Weiss, S. H. Woolf, J. Susman, B. Ewigman, and M. Bow - man. 2004. Strength of recommendation taxonomy (SORT): A patient-centered approach to grading evidence in medical literature. American Family Physician 69(3):548–556. GRADE Working Group (Grading of Recommendations Assessment, Development, and Evaluation Working Group). 2009. Grading the quality of evidence and the strength of recommendations http://www.gradeworkinggroup.org/intro.htm (accessed July 20, 2009). ICSI (Institute for Clinical Systems Improvement). 2003. Evidence grading system. http://www.icsi.org/evidence_grading_system_6/evidence_grading_system__ pdf_.html (accessed September 8, 2009). Kish, M. A. 2001. Guide to development of practice guidelines. Clinical Infectious Diseases 32(6):851–854. NCCN (National Comprehensive Cancer Network). 2008. About the NCCN clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_ gls/about.asp (accessed September 8, 2009). NZGG (New Zealand Guidelines Group). 2007. Handbook for the preparation of explicit evidence-based clinical practice guidelines. http://www.nzgg.org.nz/ download/files/nzgg_guideline_handbook.pdf (accessed September 4, 2009). SIGN (Scottish Intercollegiate Guidelines Network). 2009. SIGN 50: A guideline de - veloper’s handbook http://www.sign.ac.uk/guidelines/fulltext/50/index.html (accessed July 20, 2009). Steering Committee on Quality Improvement Management. 2004. Classifying recom - mendations for clinical practice guidelines. Pediatrics 114(3):874–877. Tobe, S. W., R. M. Touyz, and N. R. C. Campbell. 2007. The Canadian Hypertension Education Program—a unique Canadian knowledge translation program. Cana- dian Journal of Cardiology 23(7):551–555. USPSTF (U.S. Preventive Services Task Force). 2008. Grade definitions. http://www. ahrq.gov/clinic/uspstf/grades.htm (accessed July 28, 2009).