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Standards for Initiating a Systematic Review

Abstract: This chapter describes the initial steps in the systematic review (SR) process. The committee recommends eight standards for ensuring a focus on clinical and patient decision making and designing SRs that minimize bias: (1) establishing the review team; (2) ensuring user and stakeholder input; (3) managing bias and conflict of interest (COI) for both the research team and (4) the users and stakeholders participating in the review; (5) formulating the research topic; (6) writing the review protocol; (7) providing for peer review of the protocol; and (8) making the protocol publicly available. The team that will conduct the review should include individuals with appropriate expertise and perspectives. Creating a mechanism for users and stakeholders—consumers, clinicians, payers, and members of clinical practice guideline panels—to provide input into the SR process at multiple levels helps to ensure that the SR is focused on real-world healthcare decisions. However, a process should be in place to reduce the risk of bias and COI from user and stakeholder input and in the SR team. The importance of the review questions and analytic framework in guiding the entire review process demands a rigorous approach to formulating the research questions and analytic framework. Requiring a research protocol that prespecifies the research methods at the outset of the SR process helps prevent the effects of bias.



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2 Standards for Initiating a Systematic Review Abstract: This chapter describes the initial steps in the systematic review (SR) process. The committee recommends eight standards for ensuring a focus on clinical and patient decision making and designing SRs that minimize bias: (1) establishing the review team; (2) ensuring user and stakeholder input; (3) managing bias and conflict of interest (COI) for both the research team and (4) the users and stakeholders participating in the review; (5) formulating the research topic; (6) writing the review protocol; (7) provid- ing for peer review of the protocol; and (8) making the protocol publicly available. The team that will conduct the review should include individuals with appropriate expertise and perspectives. Creating a mechanism for users and stakeholders—consumers, clinicians, payers, and members of clinical practice guideline pan- els—to provide input into the SR process at multiple levels helps to ensure that the SR is focused on real-world healthcare decisions. However, a process should be in place to reduce the risk of bias and COI from user and stakeholder input and in the SR team. The importance of the review questions and analytic framework in guiding the entire review process demands a rigorous approach to formulating the research questions and analytic framework. Re- quiring a research protocol that prespecifies the research methods at the outset of the SR process helps prevent the effects of bias. 45

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46 FINDING WHAT WORKS IN HEALTH CARE The initial steps in the systematic review (SR) process define the focus of the complete review and influence its ultimate use in making clinical decisions. Because SRs are conducted under varying circumstances, the initial steps are expected to vary across differ- ent reviews, although in all cases a review team should be estab - lished, user and stakeholder input gathered, the topic refined, and the review protocol formulated. Current practice falls far short of recommended guidance1; well-designed, well-executed SRs are the exception. At a workshop organized by the committee, representa- tives from professional specialty societies, consumers, and payers testified that existing SRs often fail to address questions that are important for real-world healthcare decisions.2 In addition, many SRs fail to develop comprehensive plans and protocols at the out - set of the project, which may bias the reviews (Liberati et al., 2009; Moher et al., 2007). As a consequence, the value of many SRs to healthcare decisions makers is limited. The committee recommends eight standards for ensuring a focus on clinical and patient decision making and designing SRs that mini- mize bias. The standards pertain to: establishing the review team, ensuring user and stakeholder input, managing bias and conflict of interest (COI) for both the research team and users and stakeholders, formulating the research topic, writing the review protocol, provid- ing for peer review of the protocol, and making the protocol publicly available. Each standard includes a set of requirements composed of elements of performance (Box 2-1). A standard is a process, action, or procedure for performing SRs that is deemed essential to pro- ducing scientifically valid, transparent, and reproducible results. A standard may be supported by scientific evidence; by a reasonable expectation that the standard helps to achieve the anticipated level of quality in an SR; or by the broad acceptance of the practice in SRs. Each standard includes elements of performance that the committee deems essential. 1 Unless otherwise noted, expert guidance refers to the published methods of the Evidence-based Practice Centers in the Agency for Healthcare and Research Quality Effective Health Care Program, the Centre for Reviews and Dissemination (University of York, UK), and the Cochrane Collaboration. The committee also consulted experts at other organizations, including the Drug Effectiveness Review Project, the ECRI Institute, the National Institute for Health and Clinical Excellence (UK), and several Evidence-Based Practice Centers (with assistance from staff from the Agency for Healthcare Research and Quality). See Appendix D for guidance. 2 On January 14, 2010, the committee held a workshop that included four panels with representatives of organizations engaged in using and/or developing systematic reviews, including SR experts, professional specialty societies, payers, and consumer groups. See Appendix C for the complete workshop agenda.

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47 STANDARDS FOR INITIATING A SYSTEMATIC REVIEW ESTABLISHING THE REVIEW TEAM The review team is composed of the individuals who will man- age and conduct the review. The objective of organizing the review team is to pull together a group of researchers as well as key users and stakeholders who have the necessary skills and clinical content knowledge to produce a high-quality SR. Many tasks in the SR process should be performed by multiple individuals with a range of expertise (e.g., searching for studies, understanding primary study methods and SR methods, synthesizing findings, performing meta-analysis). Perceptions of the review team’s trustworthiness and knowledge of real-world decision making are also important for the final product to be used confidently by patients and clini- cians in healthcare decisions. The challenge is in identifying all of the required areas of expertise and selecting individuals with these skills who are neither conflicted nor biased and who are perceived as trustworthy by the public. This section of the chapter presents the committee’s recom- mended standards for organizing the review team. It begins with background on issues that are most salient to setting standards for establishing the review team: the importance of a multidisciplinary review team, the role of the team leader, and bias and COI. The ratio- nale for the recommended standards follows. Subsequent sections address standards for involving various users and stakeholders in the SR process, formulating the topic of the SR, and developing the SR protocol. The evidence base for these initial steps in the SR pro- cess is sparse. The committee developed the standards by reviewing existing expert guidance and weighing the alternatives according to the committee’s agreed-on criteria, especially the importance of improving the acceptability and patient-centeredness of publicly funded SRs (see Chapter 1 for a full discussion of the criteria). A Multidisciplinary Review Team The review team should be capable of defining the clinical ques- tion and performing the technical aspects of the review. It should be multidisciplinary, with experts in SR methodology, including risk of bias, study design, and data analysis; librarians or informa - tion specialists trained in searching bibliographic databases for SRs; and clinical content experts. Other relevant users and stakeholders should be included as feasible (CRD, 2009; Higgins and Green, 2008; Slutsky et al., 2010). A single member of the review team can have multiple areas of expertise (e.g., SR methodology and quantitative analysis). The size of the team will depend on the number and com-

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48 FINDING WHAT WORKS IN HEALTH CARE BOX 2-1 Recommended Standards for Initiating a Systematic Review Standard 2.1 Establish a team with appropriate expertise and experi- ence to conduct the systematic review Required elements: 2.1.1 Include expertise in the pertinent clinical content areas 2.1.2 Include expertise in systematic review methods 2.1.3 Include expertise in searching for relevant evidence 2.1.4 Include expertise in quantitative methods 2.1.5 Include other expertise as appropriate Standard 2.2 Manage bias and conflict of interest (COI) of the team conducting the systematic review Required elements: 2.2.1 Require each team member to disclose potential COI and professional or intellectual bias 2.2.2 Exclude individuals with a clear financial conflict 2.2.3 Exclude individuals whose professional or intellectual bias would diminish the credibility of the review in the eyes of the intended users Standard 2.3 Ensure user and stakeholder input as the review is de- signed and conducted Required element: 2.3.1 Protect the independence of the review team to make the final decisions about the design, analysis, and reporting of the review Standard 2.4 Manage bias and COI for individuals providing input into the systematic review Required elements: 2.4.1 Require individuals to disclose potential COI and profes- sional or intellectual bias 2.4.2 Exclude input from individuals whose COI or bias would di- minish the credibility of the review in the eyes of the intended users Standard 2.5 Formulate the topic for the systematic review Required elements: 2.5.1 Confirm the need for a new review plexity of the question(s) being addressed. The number of individu- als with a particular expertise needs to be carefully balanced so that one group of experts is not overly influential. For example, review teams that are too dominated by clinical content experts are more likely to hold preconceived opinions related to the topic of the SR,

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49 STANDARDS FOR INITIATING A SYSTEMATIC REVIEW 2.5.2 Develop an analytic framework that clearly lays out the chain of logic that links the health intervention to the outcomes of interest and defines the key clinical questions to be ad- dressed by the systematic review 2.5.3 Use a standard format to articulate each clinical question of interest 2.5.4 State the rationale for each clinical question 2.5.5 Refine each question based on user and stakeholder input Standard 2.6 Develop a systematic review protocol Required elements: 2.6.1 Describe the context and rationale for the review from both a decision-making and research perspective 2.6.2 Describe the study screening and selection criteria (inclu- sion/exclusion criteria) 2.6.3 Describe precisely which outcome measures, time points, interventions, and comparison groups will be addressed 2.6.4 Describe the search strategy for identifying relevant evidence 2.6.5 Describe the procedures for study selection 2.6.6 Describe the data extraction strategy 2.6.7 Describe the process for identifying and resolving disagree- ment between researchers in study selection and data ex- traction decisions 2.6.8 Describe the approach to critically appraising individual studies 2.6.9 Describe the method for evaluating the body of evidence, in- cluding the quantitative and qualitative synthesis strategies 2.6.10 Describe and justify any planned analyses of differen- tial treatment effects according to patient subgroups, how an intervention is delivered, or how an outcome is measured 2.6.11 Describe the proposed timetable for conducting the review Standard 2.7 Submit the protocol for peer review Required element: 2.7.1 Provide a public comment period for the protocol and pub- licly report on disposition of comments Standard 2.8 Make the final protocol publicly available, and add any amendments to the protocol in a timely fashion spend less time conducting the review, and produce lower quality SRs (Oxman and Guyatt, 1993). Research examining dynamics in clinical practice guideline (CPG) groups suggests that the use of multidisciplinary groups is likely to lead to more objective decision making (Fretheim et al.,

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50 FINDING WHAT WORKS IN HEALTH CARE 2006a; Hutchings and Raine, 2006; Murphy et al., 1998; Shrier et al., 2008). These studies are relevant to SR teams because both the guide- line development and the SR processes involve group dynamics and subjective judgments (Shrier et al., 2008). Murphy and colleagues (1998), for example, conducted an SR that compared judgments made by multi- versus single-disciplinary clinical guideline groups. They found that decision-making teams with diverse members con- sider a wider variety of alternatives and allow for more creative decision making compared with single disciplinary groups. In a 2006 update, Hutchings and Raine identified 22 studies examining the impact of group members’ specialty or profession on group deci- sion making and found similar results (Hutchings and Raine, 2006). Guideline groups dominated by medical specialists were more likely to recommend techniques that involve their specialty than groups with more diverse expertise. Fretheim and colleagues (2006a) iden - tified six additional studies that also indicated medical specialists have a lower threshold for recommending techniques that involve their specialty. Based on this research, a guideline team considering interventions to prevent hip fracture in the elderly, for example, should include family physicians, internists, orthopedists, social workers, and others likely to work with the patient population at risk. The Team Leader Minimal research and guidance have been done on the leader- ship of SR teams. The team leader’s most important qualifications are knowledge and experience in proper implementation of an SR protocol, and open-mindedness about the topics to be addressed in the review. The leader should also have a detailed understanding of the scope of work and be skilled at overseeing team discussions and meetings. SR teams rely on the team leader to act as the facilitator of group decision making (Fretheim et al., 2006b). The SR team leader needs to be skilled at eliciting meaningful involvement of all team members in the SR process. A well-balanced and effective multidisciplinary SR team is one where every team member contributes (Fretheim et al., 2006b). The Institute of Medi- cine (IOM) directs individuals serving on its committees to be open to new ideas and willing to learn from one another (IOM, 2005). The role of the leader as facilitator is particularly important because SR team members vary in professional roles and depth of knowledge (Murphy et al., 1998). Pagliari and Grimshaw (2002) observed a mul- tidisciplinary committee and found that the chair made the largest

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51 STANDARDS FOR INITIATING A SYSTEMATIC REVIEW contributions to group discussion and was pivotal in ensuring inclu- sion of the views of all parties. Team members with less specializa- tion, such as primary care physicians and nurses, tended to be less active in the group discussion compared with medical specialists. Bias and Conflicts of Interest Minimizing bias and COI in the review team is important to ensure the acceptability, credibility, and scientific rigor of the SR.3 A recent IOM report, Conflict of Interest in Medical Research, Education, and Practice, defined COI as “a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest” (IOM, 2009a, p. 46). Disclosure of individual financial, business, and professional interests is the established method of dealing with researchers’ COI (IOM, 2009a). A recent survey of high-impact medical journals found that 89 percent required authors to disclose COIs (Blum et al., 2009). The International Committee of Medical Journal Editors (ICMJE) recently created a universal disclosure form for all journals that are members of ICMJE to facilitate the disclosure process (Box 2-2) (Drazen et al., 2009, 2010; ICMJE, 2010). Leading guidance from pro- ducers of SRs also requires disclosure of competing interest (CRD, 2009; Higgins and Green, 2008; Whitlock et al., 2010). The premise of disclosure policies is that reporting transparency allows readers to judge whether these conflicts may have influenced the results of the research. However, many authors fail to fully disclose their COI despite these disclosure policies (Chimonas et al., 2011; McPartland, 2009; Roundtree et al., 2008). Many journals only require disclo- sure of financial conflicts, and do not require researchers to disclose intellectual and professional biases that may be similarly influential (Blum et al., 2009). Because of the importance of preventing bias from undermin- ing the integrity of biomedical research, a move has been made to strengthen COI policies. The National Institutes of Health (NIH), for example, recently announced it is revising its policy for manag- ing financial COI in biomedical research to improve compliance, strengthen oversight, and expand transparency in this area (Rockey and Collins, 2010). There is also a push toward defining COI to include potential biases beyond financial conflicts. The new ICMJE policy requires that authors disclose “any other relationships or 3 Elsewhere in this report, the term “bias” is used to refer to bias in reporting and publication (see Chapter 3).

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52 FINDING WHAT WORKS IN HEALTH CARE BOX 2-2 International Committee of Medical Journal Editors Types of Conflict-of-Interest Disclosures • Associations with commercial entities that provided support for the work reported in the submitted manuscript. Should include both resources received directly and indirectly (via your institution) that enabled the author to complete the work. • Associations with commercial entities that could be viewed as having an interest in the general area of the submitted manuscript. • Other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, what the author wrote in the submitted work. SOURCE: ICMJE (2010). activities that readers could perceive to influence, or that give the appearance of potentially influencing” the research, such as per- sonal, professional, political, institutional, religious, or other associa- tions (Drazen et al., 2009, 2010, p. 268). The Cochrane Collaboration also requires members of the review team to disclose “competing interests that they judge relevant” (The Cochrane Collaboration, 2006). Similarly, the Patient-Centered Outcomes Research Institute (PCORI), created by the 2010 Patient Protection and Affordable Care Act, will require individuals serving on the Board of Governors, the methodology committee, and expert advisory panels to disclose both financial and personal associations.4 Secondary interests, such as the pursuit of professional advance- ment, future funding opportunities, and recognition, and the desire to do favors for friends and colleagues, are also important potential conflicts (IOM, 2009a). Moreover, mere disclosure of a conflict does not resolve or eliminate it. Review teams should also evaluate and act on the disclosed information. Eliminating the relationship, fur- ther disclosure, or restricting the participation of a researcher with COI may be necessary. Bias and COI may also be minimized by creating review teams that are balanced across relevant expertise and perspectives as well as competing interests (IOM, 2009a). The Cochrane Collaboration, for example, requires that if a member of 4 The Patient Protection and Affordable Care Act, Public Law 111-148, 111th Cong., Subtitle D, § 6301 (March 23, 2010).

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53 STANDARDS FOR INITIATING A SYSTEMATIC REVIEW the review team is an author of a study that is potentially eligible for the SR, there must be other members of the review team who were not involved in that study. In addition, if an SR is conducted by individuals employed by a pharmaceutical or device company that relates to the products of that company, the review team must be multidisciplinary, with the majority of the members not employed by the relevant company. Individuals with a direct financial interest in an intervention may not be a member of the review team conduct- ing an SR of that intervention (The Cochrane Collaboration, 2006). Efforts to prevent COI in health research should focus on not only whether COI actually biased an individual, but also whether COI has the potential for bias or appearance of bias (IOM, 2009a). RECOMMENDED STANDARDS FOR ORGANIZING THE REVIEW TEAM The committee recommends two standards for organizing the review team: Standard 2.1—Establish a team with appropriate expertise and experience to conduct the systematic review Required elements: 2.1.1 Include expertise in pertinent clinical content areas 2.1.2 Include expertise in systematic review methods 2.1.3 Include expertise in searching for relevant evidence 2.1.4 Include expertise in quantitative methods 2.1.5 Include other expertise as appropriate Standard 2.2—Manage bias and conflict of interest (COI) of the team conducting the systematic review Required elements: 2.2.1 Require each team member to disclose potential COI and professional or intellectual bias 2.2.2 Exclude individuals with a clear financial conflict 2.2.3 Exclude individuals whose professional or intel- lectual bias would diminish the credibility of the review in the eyes of the intended users Rationale The team conducting the SR should include individuals skilled in group facilitation who can work effectively with a multidisciplinary review team, an information specialist, and individuals skilled in project management, writing, and editing (Fretheim et al., 2006a). In addition, at least one methodologist with formal training and

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54 FINDING WHAT WORKS IN HEALTH CARE experience in conducting SRs should be on the team. Performance of SRs, like any form of biomedical research, requires education and training, including hands-on training (IOM, 2008). Each of the steps in conducting an SR should be, as much as possible, evidence based. Methodologists (e.g., epidemiologists, biostatisticians, health services researchers) perform much of the research on the conduct of SRs and are likely to stay up-to-date with the literature on methods. Their expertise includes decisions about study design and potential for bias and influence on findings, methods to minimize bias in the SR, qualitative synthesis, quantitative methods, and issues related to data collection and data management. For SRs of comparative effectiveness research (CER), the team should include people with expertise in patient care and clinical decision making. In addition, as discussed in the following section, the team should have a clear and transparent process in place for obtaining input from consumers and other users and stakeholders to ensure that the review is relevant to patient concerns and useful for healthcare decisions. Single individuals might provide more than one area of required expertise. The exact composition of the review team should be determined by the clinical questions and context of the SR. The committee’s standard is consistent with guid- ance from the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC), the United Kingdom’s Centre for Reviews and Dissemination (CRD), and the Cochrane Collabora- tion (CRD, 2009; Higgins and Green, 2008; Slutsky et al., 2010). It is also integral to the committee’s criteria of scientific rigor by ensuring the review team has the skills necessary to conduct a high-quality SR. The committee believes that minimizing COI and bias is criti- cal to credibility and scientific rigor. Disclosure alone is insufficient. Individuals should be excluded from the review team if their partici- pation would diminish public perception of the independence and integrity of the review. Individuals should be excluded for financial conflicts as well as for professional or intellectual bias. This is not to say that knowledgeable experts cannot participate. For example, it may be possible to include individual orthopedists in reviews of the efficacy of back surgery depending on the individual’s specific employment, sources of income, publications, and public image. Other orthopedists may have to be excluded if they may benefit from the conclusions of the SR or may undermine the credibility of the SR. This is consistent with the recent IOM recommendations (IOM, 2009a). However, this standard is stricter than all of the major organizations’ guidance on this topic, which emphasize disclosure of professional or intellectual bias, rather than requiring the exclusion of

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55 STANDARDS FOR INITIATING A SYSTEMATIC REVIEW individuals with this type of competing interest (CRD, 2009; Higgins and Green, 2008; Slutsky et al., 2010). In addition, because SRs may take a year or more to produce, the SR team members should update their financial COI and personal biases at regular intervals. ENSURING USER AND STAKEHOLDER INPUT The target audience for SRs of CER include consumers, patients, and their caregivers; clinicians; payers; policy makers; private industry; organizations that develop quality indicators; SR spon - sors; guideline developers; and others involved in “deciding what medical therapies and practice are approved, marketed, promoted, reimbursed, rewarded, or chosen by patients” (Atkins, 2007, p. S16). The purpose of CER, including SRs of CER, is to “assist consum- ers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and populations levels” (IOM, 2009b, p. 41). Creating a clear and explicit mechanism for users and stakeholders to provide input into the SR process at multiple levels, beginning with formulating the research questions and analytic framework, is essential to achieving this pur- pose. A broad range of views should be considered in deciding on the scope of the SR. Often the organization(s) that nominate or sponsor an SR may be interested in specific populations, interven- tions, comparisons, and outcomes. Other users and stakeholders may bring a different perspective on the appropriate scope for a review. Research suggests that involving decision makers directly increases the relevance of SRs to decision making (Lavis et al., 2005; Schünemann et al., 2006). Some SR teams convene formal advisory panels with representa- tion from relevant user and stakeholder groups to obtain their input. Other SR teams include users and stakeholders on the review team, or use focus groups or conduct structured interviews with individu- als to elicit input. Whichever model is used, the review team must include a skilled facilitator who can work effectively with consum- ers and other users and stakeholders to develop the questions and scope for the review. Users and stakeholders may have conflicting interests or very different ideas about what outcomes are relevant, as may other members of the review team, to the point that reconciling all of the different perspectives might be very challenging. AHRQ has announced it will spend $10 million on establishing  a Community Forum for CER to engage users and stakeholders formally, and to expand and standardize public involvement in the entire Effective Health Care Program (AHRQ, 2010). Funds will be

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70 FINDING WHAT WORKS IN HEALTH CARE 1 2 Enteral supplement nutrition (type, dose, Geriatric Improved energy, Improved Healing Mortality etc.) patients supply to, and 4 nutritional of the with microcirculation status bedsore Quality of life bedsores 3 of the wound Diarrhea, other adverse effects FIGURE 2-1 Analytic framework for a new enteral supplement to heal Figure 2-1.eps bedsores. SOURCE: Helfand and Balshem (2010). and health outcomes (e.g., myocardial infarction and strokes). It can also help clarify the researchers’ implicit beliefs about the benefits of a healthcare intervention, such as quality of life, morbidity, and mortality (Helfand and Balshem, 2010). It increases the likelihood that all contributing elements in the causal chain will be examined and evaluated. However, the analytic framework diagram may need to evolve to accurately represent SRs of CER that compare alterna- tive treatments and interventions. Figure 2-1 shows an analytic framework for evaluating studies of a new enteral supplement to heal bedsores (Helfand and Balshem, 2010). On the left side of the analytic framework is the population of interest: geriatric patients with bedsores. Moving from left to right across the framework is the intervention (enteral supplement nutri- tion), intermediate outcomes (improved nutritional status, improved energy/blood supply to the wound, and healing of the bedsore), and final health outcomes of interest (reduction in mortality, quality of life). The lines with arrows represent the researchers’ questions that the evidence must answer at each phase of the review. The dotted lines indicate that the association between the intermediate outcomes and final health outcomes are unproven, and need to be linked by evaluating several bodies of evidence. The squiggly line denotes the question that addresses the harms of the intervention (e.g., diarrhea or other adverse effects). In this example, the lines and arrows represent the following key research questions:

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71 STANDARDS FOR INITIATING A SYSTEMATIC REVIEW Line 1 Does enteral supplementation improve mortality and quality of life? Line 2 Does enteral supplementation improve wound healing? Line 3 How frequent and severe are side effects such as diarrhea? Line 4 Is wound healing associated with improved survival and quality of life? Evidence that directly links the intervention to the final health outcome is the most influential (Arrow 1). Arrows 2 and 4 link the treatments to the final outcomes indirectly: from treatment to an intermediate outcome, and then, separately, from the intermediate outcome to the final health outcomes. The nutritional status and improved energy/blood supply to the wound are only important outcomes if they are in the causal pathway to improved healing, reduced mortality, and a better quality of life. The analytic frame - work does not have corresponding arrows to these intermediate outcomes because studies measuring these outcomes would only be included in the SR if they linked the intermediate outcome to heal- ing, mortality, or quality of life. RECOMMENDED STANDARDS FOR FORMULATING THE TOPIC The importance of the research questions and analytic frame- work in determining the entire review process demands a rigorous approach to topic formulation. The committee recommends the fol- lowing standard: Standard 2.5—Formulate the topic for the systematic review Required elements: 2.5.1 Confirm the need for a new review 2.5.2 Develop an analytic framework that clearly lays out the chain of logic that links the health inter- vention to the outcomes of interest and defines the key clinical questions to be addressed by the systematic review 2.5.3 Use a standard format to articulate each clinical question of interest 2.5.4 State the rationale for each clinical question 2.5.5 Refine each question based on user and stake- holder input

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72 FINDING WHAT WORKS IN HEALTH CARE Rationale SRs of CER should focus on specific research questions using a structured format (e.g., PICO[TS]), an analytic framework, and a clear rationale for the research question. Expert guidance recom- mends using the PICO(TS) acronym to articulate research ques- tions (CRD, 2009; Higgins and Green, 2008; Whitlock et al., 2010). Developing an analytic framework is required by the EPCs to illus - trate the chain of logic underlying the research questions (AHRQ, 2007; Helfand and Balshem, 2010; IOM, 2008). Using a structured approach and analytic framework also improves the scientific rigor and transparency of the review by requiring the review team to clearly articulate the clinical questions and basic assumptions in the SR. The AHRQ EPC program, CRD, and the Cochrane Collaboration all have mechanisms for ensuring that new reviews cover novel and important topics. AHRQ, for example, specifically requires that top- ics have strong potential for improving health outcomes (Whitlock et al., 2010). CRD recommends that researchers undertaking reviews first search for existing or ongoing reviews and evaluate the quality of any reviews on similar topics (CRD, 2009). The Cochrane Col- laboration review groups require approval by the “coordinating editor” (editor in chief) of the relevant review group for new SRs (Higgins and Green, 2008). Confirming the need for a new review is consistent with the committee’s criterion of efficiency because it prevents the burden and cost of conducting an unnecessary, duplica- tive SR (unless the “duplication” is considered necessary to improve on earlier efforts). If the SR registries now in development become fully operational, this requirement will become much easier for the review team to achieve in the near future (CRD, 2010; HHS, 2010; Joanna Briggs Institute, 2010; NPAF, 2011; PIPC, 2011). DEVELOPING THE SYSTEMATIC REVIEW PROTOCOL The SR protocol is a detailed description of the objectives and methods of the review (CRD, 2009; Higgins and Green, 2008; Liberati et al., 2009). The protocol should include information regarding the context and rationale for the review, primary outcomes of interest, search strategy, inclusion/exclusion criteria, data synthesis strategy, and other aspects of the research plan. The major challenge to writ - ing a comprehensive research protocol is accurately specifying the research questions and methods before the study begins. Develop- ing the protocol is an iterative process that requires communication with users and stakeholders, input from the general public, and a

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73 STANDARDS FOR INITIATING A SYSTEMATIC REVIEW preliminary review of the literature before all of the components of the protocol are finalized (CRD, 2009). Researchers’ decisions to undertake an SR may be influenced by prior knowledge of results of available studies. The inclusion of multiple perspectives on the review team and gathering user and stakeholder input helps pre- vent choices in the protocol that are based on such prior knowledge. The use of protocols in SRs is increasing, but is still not stan- dard practice. A survey of SRs indexed in MEDLINE in November, 2004 found that 46 percent of the reviews reported using a protocol (Moher et al., 2007), a significant rise from only 7 percent of reviews in an earlier survey (Sacks et al., 1987). Publication of the Protocol A protocol should be made publicly available at the start of an SR in order to prevent the effects of author bias, allow feedback at an early stage in the SR, and tell readers of the review about protocol changes that occur as the SR develops. It also gives the public the chance to examine how well the SR team has used input from con- sumers, clinicians, and other experts to develop the questions and PICO(TS) the review will address. In addition, a publicly available protocol has the benefit that other researchers can identify ongoing reviews, and thus avoids unnecessary duplication and encourages collaboration. This transparency may provide an opportunity for methodological and other research (see Chapter 6) (CRD, 2010). One of the most efficient ways to publish protocols is through an SR protocol electronic registration. However, more than 80 percent of SRs are conducted by organizations that do not have existing registries (CRD, 2010). The Cochrane Collaboration and AHRQ have created their own infrastructure for publishing protocols (Higgins and Green, 2008; Slutsky et al., 2010). Review teams conducting SRs funded through PCORI9 will also be required to post research proto- cols on a government website at the outset of the SR process. Several electronic registries under development intend to pub- lish all SR protocols, regardless of the funding source (CRD, 2010; Joanna Briggs Institute, 2010). CRD is developing an international registry of ongoing health-related SRs that will be open to all pro- spective registrations and will offer free public access for electronic searching. Each research protocol will be assigned a unique identifi- 9 The Patient Protection and Affordable Care Act, Public Law 111-148, 111th Cong., Subtitle D, § 6301 (March 23, 2010).

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74 FINDING WHAT WORKS IN HEALTH CARE cation number, and an audit trail of amendments will be part of each protocol’s record. The protocol records will also link to the resulting publication. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement reflects the growing rec- ognition of the importance of prospective registration of protocols, and requires that published SRs indicate whether a review protocol exists and if and where it can accessed (e.g., web address), and the registration information and number (Liberati et al., 2009). Amendments to the Protocol Often the review team needs to make amendments to a protocol after the start of the review that result from the researchers’ improved understanding of the research questions or the availability of pertinent evidence (CRD, 2009; Higgins and Green, 2008; Liberati et al., 2009). Common amendments include extending the period of the search to include older or newer studies, broadening eligibility criteria, and adding new analyses suggested by the primary analysis (Liberati et al., 2009). Researchers should document such amendments with an explanation for the change in the protocol and completed review (CRD, 2009; Higgins and Green, 2008; Liberati et al., 2009). In general, researchers should not modify the protocol based on knowledge of the results of analyses. This has the potential to bias the SR, for example, if the SR omits a prespecified comparison when the data indicate that an intervention is more or less effective than the retained comparisons. Similar problems occur when researchers modify the protocol by adding or deleting certain study designs or outcome measures, or change the search strategy based on prior knowledge of the data. Researchers may be motivated to delete an outcome when its results do not match the results of the other outcome measures (Silagy et al., 2002), or to add an outcome that had not been prespecified. Publishing the protocol and amendments allows readers to track the changes and judge whether an amend- ment has biased the review. The final SR report should also identify those analyses that were prespecified and those that were not, and any analyses requested by peer reviewers (see Chapter 5). RECOMMENDED STANDARDS FOR DEVELOPING THE SYSTEMATIC REVIEW PROTOCOL The committee recommends three standards related to the SR protocol:

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75 STANDARDS FOR INITIATING A SYSTEMATIC REVIEW Standard 2.6—Develop a systematic review protocol Required elements: 2.6.1 Describe the context and rationale for the re- view from both a decision-making and research perspective 2.6.2 Describe the study screening and selection criteria (inclusion/exclusion criteria) 2.6.3 Describe precisely which outcome measures, time points, interventions, and comparison groups will be addressed 2.6.4 Describe the search strategy for identifying rel- evant evidence 2.6.5 Describe the procedures for study selection 2.6.6 Describe the data extraction strategy 2.6.7 Describe the process for identifying and resolving disagreement between researchers in study selec- tion and data extraction decisions 2.6.8 Describe the approach to critically appraising individual studies 2.6.9 Describe the method for evaluating the body of evidence, including the quantitative and qualita- tive synthesis strategy 2.6.10 Describe and justify any planned analyses of dif- ferential treatment effects according to patient subgroups, how an intervention is delivered, or how an outcome is measured 2.6.11 Describe the proposed timetable for conducting the review Standard 2.7—Submit the protocol for peer review Required element: 2.7.1 Provide a public comment period for the protocol and publicly report on disposition of comments Standard 2.8—Make the final protocol publicly available, and add any amendments to the protocol in a timely fashion Rationale The majority of these required elements are consistent with leading guidance, and ensure that the protocol provides a detailed description of the objectives and methods of the review (AHRQ,

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76 FINDING WHAT WORKS IN HEALTH CARE 2009; CRD, 2009; Higgins and Green, 2008).10 The committee added the requirement to identify and justify planned subgroup analy- ses to examine whether treatment effects vary according to patient group, the method of providing the intervention, or the approach to measuring an outcome, because evidence on variability in treatment effects across subpopulations is key to directing interventions to the most appropriate populations. The legislation establishing PCORI requires that “research shall be designed, as appropriate, to take into account the potential for differences in the effectiveness of health- care treatments, services, and items as used with various subpopula- tions, such as racial and ethnic minorities, women, age, and groups of individuals with different comorbidities, genetic and molecular subtypes, or quality of life preferences.”11 The protocol should state a hypothesis that justifies the planned subgroup analyses, including the direction of the suspected subgroup effects, to reduce the pos- sibility of identifying false subgroup effects. The subgroup analyses should also be limited to a small number of hypothesized effects (Sun et al., 2010). The committee also added the requirement that the protocol include the proposed timetable for conducting the review because this improves the transparency, efficiency, and timeliness of publicly funded SRs. The draft protocol should be reviewed by clinical and method- ological experts as well as relevant users and stakeholders identified by the review team and sponsor. For publicly funded reviews, the public should also have the opportunity to comment on the protocol to improve the acceptability and transparency of the SR process. The review team should be responsive to peer reviewers and public com- ments and publicly report on the disposition of the comments. The review team need not provide a public response to every question; it can group questions into general topic areas for response. The period for peer review and public comment should be specified so that the review process does not delay the entire SR process. Cochrane requires peer review of protocols (Higgins and Green, 2008). The EPC program requires that the SR research questions and protocol be available for public comment (Whitlock et al., 2010).12 All of the leading guidance requires that the final protocol be pub- 10 The elements are all discussed in more detail in Chapters 3 through 5. 11 The Patient Protection and Affordable Care Act, Public Law 111-148, 111th Cong., Subtitle D, § 6301(d)(2)(D) (March 23, 2010). 12 Information on making the protocol public comes from Mark Helfand, Director, Oregon Evidence-Based Practice Center, Professor of Medicine and Medical Infor- matics and Clinical Epidemiology, Oregon Health and Science University, Portland, Oregon.

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