Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol

Transcription

1 CADTH OPTIMAL USE REPORT Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol PROSPERO Registration Number: CRD Service Line: Optimal Use Issue: Volume 8, Issue 1a Publication Date: January 2018 Report Length: 62 Pages

2 Cite As: Optimal use of minimally invasive glaucoma surgery: a health technology assessment project protocol. Ottawa: CADTH; 2018 Jan. (CADTH optimal use report; vol.8, no.1a). ISSN: Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policymakers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH. CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials. This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the thirdparty website owners own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such thirdparty sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites. Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada s federal, provincial, or territorial governments or any third party supplier of information. This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user s own risk. This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada. The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors. About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system. Funding: CADTH receives funding from Canada s federal, provincial, and territorial governments, with the exception of Quebec. CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 2

3 Table of Contents Background and Rationale... 5 Policy Questions... 6 Objectives... 6 Research Questions... 7 Methods... 8 Clinical Review... 8 Literature Search Strategy... 8 Study Design... 9 Study Eligibility... 9 Literature Screening and Selection Data Extraction Quality Assessment: Individual Studies Data Analysis Reporting of Findings Economic Review Primary Economic Analysis Patient Perspectives and Experiences Review Overview Review Study Design Secondary Research Questions Literature Search Literature Selection Criteria Literature Screening and Selection Data Extraction Quality Assessment Data Analysis Techniques to Strengthen Methodological Rigour CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 3

4 Patient Engagement Ethics Analysis Inquiry Literature Search Analysis Implementation Issues Analysis Methods Descriptive Analysis Protocol Amendments References Appendix 1: MIGS Devices and Procedures of Interest Appendix 2: Analytical Framework Appendix 3: Literature Search Strategy Appendix 4: Screening Checklist Clinical Review Appendix 5: Clinical Review Data Extraction Form Appendix 6: Primary and Secondary Research Questions and Evidence Synthesis Patients and Caregivers and Clinical and Non-clinical Caregivers Perspectives and Experiences Review Appendix 7: Data Extraction Forms Patients and Clinical and Non-clinical Caregivers Perspectives and Experiences Review Appendix 8: Quality Appraisal Extraction Form Patients and Caregivers Perspectives and Experiences Review CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 4

5 Background and Rationale Glaucoma is an optic neuropathy characterized by progressive damage to the optic nerve that leads to visual impairment and potentially irreversible blindness. 1-3 Glaucoma is sometimes called the silent thief of sight because its symptoms are often not apparent until irreversible damage to the optic nerve fibres has been done. 4 It is estimated that glaucoma affects more than 400,000 Canadians, and the direct cost in Canada is estimated at $300 million per year. 5,6 Risk factors for primary glaucoma, which occurs without a known cause, include elevated intraocular pressure (IOP; i.e., pressure inside the eyes), increasing age, a family history of glaucoma, race, and comorbidities including diabetes, hypertension, and hypothyroidism. 3,4,7 Secondary glaucoma occurs when there is a known cause. 8,9 Glaucoma is a pressure-sensitive optic neuropathy with elevated IOP being the most important and only modifiable risk. 3,8 When IOP becomes elevated it can compress and damage the optic nerve; 1,10 for every 1 mm Hg increase in IOP, there is a 10% higher risk of both development and progression of glaucoma. 11 IOP can become elevated when the balance between production and drainage of fluid that nourishes the lens and cornea, known as aqueous humour, is disrupted. Open-angle glaucoma (OAG) occurs when the system responsible for draining fluid from the eye (i.e., Schlemm s canal, including trabecular meshwork [TM]) is anatomically open, but functioning suboptimally; angle-closure glaucoma occurs when the fluid draining system is anatomically blocked. 8 OAG represents the most common form of the condition. 4,12 In this regard, the most common treatment approach seeks to lower IOP, by either reducing the production of aqueous humour or enhancing its drainage, to delay the progression of glaucoma and prevent potential blindness. 8,13 Treatment can slow or halt the progression of the condition but cannot reverse damage that has already been done to the optic nerve. 4 The treatment spectrum for lowering IOP extends from pharmacotherapy (e.g., eye drops) or laser therapy as the first-line treatment to invasive filtration surgeries, such as trabeculectomy (i.e., removal of part of the TM and adjacent structures) and implantation of aqueous shunts. 14,15 Challenges associated with pharmacotherapy include ineffective use (e.g., under- or overdosing, incorrect timing, or administration), 16,17 local or systemic side effects (e.g., irritation) or toxicity, 18,19 and considerable lifetime costs. 20 Laser surgery may be less effective than pharmacotherapy, and can be associated with ocular discomfort, IOP spikes, and the need for repeat procedures. 21,22 Although filtration surgeries are well established and generally effective, 23 they carry the risk of potentially dangerous intraoperative and post-operative complications (such as hypotony [i.e., excessively low IOP], infection, inflammation, vision loss, cataract, and need for subsequent surgery), 4,14,24,25 have a long recovery period, 26 and, because of their invasive nature, may affect subsequent surgery due to scar tissue formation if required. 24 The filtration surgical options have typically been used in advanced glaucoma cases or when targeting a very low IOP as a treatment outcome because of the associated substantial risks. 24,27 Thus, there are strengths and limitations associated with existing treatment options. The advent of micro-invasive or minimally invasive glaucoma surgery (MIGS) devices and procedures presents a newer surgical option that may fill a previously existing gap between pharmacotherapy or laser therapy and the invasive filtration surgeries. 14,27-30 The FDA and the American Glaucoma Society (AGS) jointly proposed a working definition that describes MIGS as devices and procedures that intend to lower IOP by improving outflow of eye fluid CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 5

6 using either an ab interno (from inside the eye) or ab externo (from outside the eye) approach, with limited or no dissection of the sclera and minimal or no manipulation of the conjunctiva Other definitions 24,30 are generally consistent with the FDA-AGS definition, though they may differ in some aspects (e.g., inclusion of ab interno devices and procedures only). 24 Regardless, certain features and qualities are commonly associated with MIGS devices and procedures, including the following: They are expected to have a better safety profile and more rapid recovery than the traditional, invasive glaucoma surgeries. They are generally indicated for treatment of mild to moderate glaucoma cases. While they can be stand-alone surgeries, they are often performed in conjunction with cataract surgery to help maximize clinical effectiveness and cost efficiency and to reduce the risk of causing a cataract in a patient with phakic intraocular lenses. 13,14,20,24,27,28,33 Generally, MIGS devices and procedures are aimed at, and evaluated by, OAG patients. 27,29,34-36 While MIGS was initially positioned as filling a gap in the spectrum of treatment, the treatment paradigm is shifting and, if both clinically effective and costeffective, there is the potential for MIGS to become the first-line therapy for some patients. 23,37 The characteristics of patients for whom MIGS devices and procedures would be most clinically effective, cost-effective, and acceptable remain to be established. There are currently 10 MIGS devices and procedures approved for use in Canada (see Appendix 1). The MIGS options may be grouped according to the approach for reducing IOP: reducing aqueous production (i.e., endoscopic cyclophotocoagulation); increasing trabecular outflow by bypassing the TM using tissue ablation or removal (i.e., trabectome and Kahook Dual Blade), using a device (i.e., istent and istent Inject), or via 360º suture (i.e., gonioscopy-assisted transluminal trabeculotomy [GATT]); increasing uveoscleral outflow via suprachoroidal shunts (i.e., CyPass Micro-stent), or creating a subconjunctival pathway for filtration (i.e., XEN 45 Gel Stent, XEN 63 Gel Stent, and XEN 140 Gel Stent). As mentioned, MIGS may be performed alone or in conjunction with cataract surgery (i.e., phacoemulsification), which also independently lowers IOP. 32 In general, there is growing demand for and use of MIGS. 28,37 However, the cost of MIGS can be considerable, and coverage under the public health insurance plans is inconsistent across jurisdictions. 38 Therefore, there is a need to clarify current policy on access and reimbursement related to MIGS devices and procedures. Policy Questions What is the optimal use, including appropriate patient selection, of MIGS devices and procedures for adults with glaucoma? Should MIGS devices and procedures be funded by the public health care system? Objectives The purpose of this Health Technology Assessment (HTA) is to address the policy questions through an assessment of the clinical effectiveness and safety, cost-effectiveness, patient perspectives and experiences, ethical issues, and implementation issues of MIGS devices CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 6

7 and procedures for adults with glaucoma. An analytical framework can be found in Appendix 2. Research Questions The proposed HTA will address the following research questions: Clinical Review 1. What is the comparative clinical effectiveness of MIGS devices and procedures versus each other, pharmacotherapy, laser therapy, or filtration surgery, for the treatment of glaucoma in adults? 2. What is the comparative safety of MIGS devices and procedures versus each other, pharmacotherapy, laser therapy, or filtration surgery, for the treatment of glaucoma in adults? 3. What is the comparative clinical effectiveness of MIGS devices and procedures performed in combination with cataract surgery versus a different MIGS plus cataract surgery, filtration surgery plus cataract surgery, or cataract surgery alone for the treatment of glaucoma in adults? 4. What is the comparative safety of MIGS devices and procedures performed in combination with cataract surgery versus a different MIGS plus cataract surgery, filtration surgery plus cataract surgery, or cataract surgery alone for the treatment of glaucoma in adults? Economic Analysis 5. What is the cost-effectiveness of MIGS devices and procedures versus each other, pharmacotherapy, laser therapy, or filtration surgery, for the treatment of glaucoma in adults? Patient Perspectives and Experiences Review 6. What are the perspectives and experiences of patients with glaucoma regarding glaucoma and their treatment, and of their caregivers? Ethical Issues Analysis 7. What are the major ethical issues raised by the use of MIGS devices and procedures? 8. What are the broader legal, social, and cultural considerations? Implementation Issues Analysis 9. What are the challenges and enablers affecting the use of MIGS devices and procedures in Canada for the treatment of adult patients with glaucoma? CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 7

8 Methods This protocol was written a priori and will be followed throughout the study process. Any deviations from the protocol will be disclosed in the final report, and updates will be made to the PROSPERO submission accordingly (registration number: CRD ). Research questions 1 to 4 will be addressed by a de novo systematic review of published clinical evidence. Clinical Review The protocol for the clinical review has been developed in consideration of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) checklist 39 for guidance on clarity and completeness. The clinical review will address the following research questions: Research Question 1: What is the comparative clinical effectiveness of MIGS devices and procedures versus each other, pharmacotherapy, laser therapy, or filtration surgery, for the treatment of glaucoma in adults? Research Question 2: What is the comparative safety of MIGS devices and procedures versus each other, pharmacotherapy, laser therapy, or filtration surgery, for the treatment of glaucoma in adults? Research Question 3: What is the comparative clinical effectiveness of MIGS devices and procedures performed in combination with cataract surgery versus a different MIGS plus cataract surgery, filtration surgery plus cataract surgery, or cataract surgery alone for the treatment of glaucoma in adults? Research Question 4: What is the comparative safety of MIGS devices and procedures performed in combination with cataract surgery versus a different MIGS plus cataract surgery, filtration surgery plus cataract surgery, or cataract surgery alone for the treatment of glaucoma in adults? Literature Search Strategy The literature search will be performed by an information specialist using a using a peerreviewed search strategy. The clinical search strategy is presented in CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 8

9 Information will be identified by searching the following bibliographic databases: MEDLINE (1946 ) with in-process records and daily updates, Embase (1974 ), the Cochrane Central Register of Controlled Trials via Ovid; Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1981 ) via EBSCO, and PubMed. The search strategy will comprise both controlled vocabulary, such as the National Library of Medicine s MeSH (Medical Subject Headings), and keywords. The main search concepts will be glaucoma, minimally invasive glaucoma surgery, and minimally invasive glaucoma surgical devices. Retrieval will be limited to documents added to the databases since January 1, Conference abstracts will be excluded from the search results. The search will be limited to English- or French-language publications. The initial searches were completed by November Regular alerts will be established to update the searches until the publication of the final report. Regular search updates will be performed on databases that do not provide alert services. Studies meeting the selection criteria of the review and identified in the alerts prior to the completion of the stakeholder feedback period will be incorporated into the analysis of the final report. Any studies that are identified after the stakeholder feedback period will be described in the discussion, with a focus on comparing the results of these new studies with the results of the analysis conducted for this report. Grey literature (literature that is not commercially published) will be identified by searching the Grey Matters checklist ( which includes the websites of HTA agencies, clinical guideline repositories, systematic review (SR) repositories, economics-related resources, public perspective groups, and professional associations. Google and other Internet search engines will be used to search for additional Web-based materials. These searches will be supplemented by reviewing the bibliographies of key papers and through contacts with appropriate experts and industry. Study Design An informal scoping review of existing HTAs, SRs, primary clinical studies (including both randomized and non-randomized studies), and evidence-based guidelines, supported by a Rapid Response Reference List (i.e., a comprehensive list of relevant publications within the past five years), 40 was conducted to inform the preparation of this protocol. In this scoping review, although six recent SRs 1,29,31,34,41,42 were identified, they did not capture all of the most recent primary clinical studies or evidence for all of the MIGS that are approved for use in Canada. In addition, most SRs focused on a single MIGS procedure or device, and on a specific subgroup of patients with glaucoma (i.e., more narrow than the population of interest for the present clinical review). Therefore, to ensure inclusion of all relevant primary studies, and to enable examination of different subgroups of interest, it was decided that conducting a de novo SR of primary studies would be the most appropriate approach for CADTH to address the comparative clinical effectiveness and safety of MIGS for adults with glaucoma. Study Eligibility The eligibility criteria for the clinical research questions can be found in Table 1. CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 9

10 Table 1: Eligibility Criteria for Clinical Research Questions Population Adults (i.e., mean age of 18 years) with acquired glaucoma Exclusions: Adults with juvenile-onset/congenital glaucoma Adults with ocular hypertension but no evidence of optic nerve damage or formal diagnosis of glaucoma Animal or ex vivo populations Interventions Questions 1-2: The following MIGS a : o Approach: Reducing aqueous production ECP o Approach: Increasing trabecular outflow by bypassing the TM using tissue ablation/removal Trabectome Kahook Dual Blade o Approach: Increasing trabecular outflow by bypassing the TM using a device istent (first generation) istent Inject (second generation) o Approach: Increasing trabecular outflow by bypassing the TM via 360º suture GATT o Approach: Increasing uveoscleral outflow via suprachoroidal shunts CyPass Micro-Stent o Approach: Creating a subconjunctival pathway for filtration XEN 45 Gel Stent XEN 63 Gel Stent XEN 140 Gel Stent Questions 3-4: The above MIGS devices and procedures performed in combination with cataract surgery (i.e., phacoemulsification) Comparators Questions 1-2: A different b MIGS device or procedure Pharmacotherapy alone Laser therapy (e.g., excimer laser trabeculotomy or selective laser trabeculoplasty) Filtration surgery (e.g., trabeculectomy or aqueous shunt implantation) Questions 3-4: A different MIGS device or procedure performed in combination with cataract surgery (i.e., MIGS plus phacoemulsification) Filtration surgery performed in combination with cataract surgery (i.e., phacotrabeculectomy) Cataract surgery (i.e., phacoemulsification) alone Outcomes c Questions 1, 3 (Clinical Effectiveness): Primary: Health-related QoL Secondary: IOP (e.g., absolute level, reduction, or proportion of patients meeting target of 21 mm Hg) Number of glaucoma medications used Vision-related QoL Visual field loss, visual impairment, visual acuity Questions 2, 4 (Safety): Adverse events and complications (e.g., transient IOP fluctuation, infection, hyphema, hypotony, device occlusion or malposition, need for additional procedure(s), or cataract formation) CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 10

11 Study Design Comparative study designs: Randomized controlled trials Non-randomized controlled clinical trials Cohort studies d Case-control studies Exclusions: o Case reports o Case series o Review articles o Editorials, letters, and commentaries o Studies of any design published as conference abstracts, presentations, or thesis documents Time Frame 2000 to present ECP = endoscopic cyclophotocoagulation, or endocyclophotocoagulation; GATT = gonioscopy-assisted transluminal trabeculotomy; IOP = intraocular pressure; MIGS = minimally invasive glaucoma surgery; QoL = quality of life; TM = trabecular meshwork. a MIGS devices and procedures that are approved for use by Health Canada are eligible for inclusion. b A different MIGS means any MIGS device or procedure compared with any other MIGS device or procedure (i.e., MIGS compared with each other). c All outcomes are considered to be of critical importance 43 based on the informal scoping review that informed this project and on consultation with a clinical expert. d Cohort studies are defined as studies in which participants are sampled on the basis of exposure and in which outcomes are assessed in a follow-up. 44 This is distinct from case series studies, in which participants are sampled on the basis of the presence of an outcome, or of both an exposure and outcome, and from case-control studies in which there is a control group. 44 Only study designs providing comparative evidence are eligible for inclusion. Studies will be included if they are published in English or French and meet the selection criteria in Table 1. Studies with mixed populations, that is, comprising both individuals who meet and those who do not meet the eligibility criteria, will be included if the results pertaining to the population of interest are reported separately. If results for the population of interest are not reported separately, studies with a mixed population will be included if 80% or more of the population meet the inclusion criteria. The criteria used to assess glaucoma severity in the included studies will be clearly reported where possible. Regarding interventions specifically, devices not approved and indicated for MIGS according to the Medical Devices Active Licence Listing ]at the time of protocol development will be excluded. If there are multiple publications from the same study, the older publications will be excluded, unless they provide additional information on outcomes of interest. Literature Screening and Selection Two reviewers will independently screen titles and abstracts of all citations retrieved against eligibility criteria (see Table 1). Exclusion by both reviewers will be required for a record to be excluded at the title and abstract level. Full-text versions of all other articles will be retrieved for the second level of screening. The same reviewers will independently examine all full-text articles, and consensus will be required for inclusion in the review. Discrepancies between reviewers will be resolved by discussion between the reviewers or by a third reviewer if needed. Study selection will be conducted using DistillerSR using standardized screening forms (see Appendix 4 for a sample screening form). The list of included studies will be posted online for 10 business days, during which time stakeholders can submit additional publications for consideration. These publications will be CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 11

12 screened against the inclusion criteria by two independent reviewers following the previously described process. The study selection process will be presented in a PRISMA flowchart. 45 A list of excluded studies, with reasons for exclusion after full-text review, will be provided. Data Extraction Data extraction for included studies will be conducted in Microsoft Word using a standardized extraction form (Appendix 5). Relevant information will be extracted, including: Study characteristics (e.g., first author s name, publication year, publication title, country where the study was conducted, funding sources) Methodology (e.g., study design and objectives, Inclusion and exclusion criteria, recruitment method, primary and secondary outcomes, subgroup analyses of interest) Population (e.g., number of patients or eyes, age, sex/gender, race, type of glaucoma, glaucoma severity/stage, and baseline characteristics) Intervention (i.e., type and number of MIGS, and whether performed alone or in conjunction with cataract surgery) Comparator Results and conclusions regarding the outcomes and subgroups of interest To which research question(s) the study is relevant. Data extraction will be completed by one reviewer and checked for accuracy by a second reviewer. Data from figures will be extracted if explicit numerical data are reported. If relevant data are missing from included studies, attempts will be made to contact the corresponding authors of these studies to obtain missing information. Quality Assessment: Individual Studies The risk of bias in primary research studies will be systematically evaluated using the methods described in the Cochrane Risk of Bias assessment tool for randomized controlled trials 46 and the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for non-randomized interventions and observational studies. 47 The Cochrane Risk of Bias tool allows for the assessment of seven sources of bias. For each item, a judgment of low, high, or unclear will be assigned and used to indicate an overall judgment of risk of bias for each study. 46 The ROBINS-I tool allows for the assessment of risk of bias across 34 potential items in seven domains. Each item is answered as yes, probably yes, probably no, no, and no information, with yes signifying a judgment of low risk of bias and no indicating concern with risk of bias. Risk of bias for each domain in each study will be assessed as low, moderate, serious, critical, or no information, and will be used to assign an overall judgment to each study using the same classification scheme in accordance with ROBINS-I guidance. The risk of bias assessment will be conducted by two independent reviewers, with any disagreements resolved by discussion with a third reviewer if required. A narrative summary of the results of the risk of bias assessment for each included study will be provided. Specifically, tables will be developed to present the risk of bias judgments, along with a narrative description of the strengths and limitations of the included studies. CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 12

13 Quality Assessment: Overall Body of Evidence The quality of evidence for each outcome by each study design will be assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. 48 According to GRADE, evidence from randomized controlled trials (RCTs) begins with a rating of high quality, but can be rated down if there is risk of bias, 49 imprecision, 50, inconsistency, 51 indirectness, 52 or publication bias, 53 because these characteristics reduce the certainty in the estimated effect. Evidence from all other study designs begins with a low quality rating, but can be rated up if there is a large magnitude of effect, a dose-response gradient, or the presence of plausible confounders or biases that would decrease an apparent effect, 54 because these characteristics increase the confidence in the estimated effect. Quality assessments will be performed by one reviewer and verified by a second reviewer, and will be presented in GRADE evidence profile tables. 55 These assessments will be used to provide explicit judgments about the certainty in the evidence. Data Analysis Narrative Syntheses Narrative syntheses will be performed, including the presentation of study characteristics and findings within summary tables. The direction and size of any observed effects will be summarized across studies, including an assessment of the likelihood of clinical benefit (i.e., clinical effectiveness) or harm (i.e., safety). Meta-Analyses The results of the included studies will be pooled, using random effects meta-analyses, if data are sufficiently homogeneous in terms of clinical, methodological, and statistical characteristics. Clinical and methodological heterogeneity will be assessed in consultation with clinical experts, and will consider patient and study design factors that might be expected to affect the clinical effectiveness and/or safety of MIGS (e.g., severity or stage of disease and duration of medication washout period). Separate analyses will be conducted for randomized and non-randomized studies; results from randomized and non-randomized studies will not be pooled. When deemed appropriate, dichotomous outcomes (e.g., achievement of target IOP) will be pooled using relative risks and 95% confidence intervals (CIs) will be calculated. Continuous outcomes will be pooled using mean differences and corresponding 95% CIs. If adjusted effects measures are reported, the adjusted results will be used in the primary analysis, and differences between unadjusted and adjusted results will be discussed. If required measures of variance are not available, variances will be imputed where possible. 56 If non-parametric data (e.g., medians or quartiles) are reported, parametric data (e.g., means and standard deviations) will be estimated using the methods from Wan et al. 57 Forest plots will be created for individual summary estimates. Meta-analyses will be carried out using the Cochrane Review Manager software (version 5.3, or the most up-to-date version available at the time of analysis). Unit of Analysis The unit of analysis will be the participant. For each eligible study, whether randomization was at the level of the participant or the eye will be recorded. If both eyes from a single CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 13

14 participant were included in a trial, whether the analyses accounted for the intra-person correlation will be documented; if the trial did so, the paired analysis data will be used to maintain the participant as the unit of analysis. If the analyses did not account for the intraperson correlation, attempts to do so will be done using the methods in the Cochrane Handbook for Systematic Reviews of Interventions. 58 Heterogeneity and Subgroup or Meta-Regression Analyses Statistical heterogeneity will be assessed using graphical presentations (e.g., forest plots) and calculations of Cochran s chi-square test and the I 2 statistic, which quantifies the variability in the effect estimates due to heterogeneity rather than chance (i.e., sampling error). Heterogeneity will be interpreted according to the guidance in the Cochrane handbook, as follows: I 2 values < 40% might not be important, values of 30% to 60% may represent moderate heterogeneity, 50% to 90% may represent substantial heterogeneity, and 75% will be interpreted as considerable heterogeneity. 59 Heterogeneity will be considered statistically significant if the P value for Cochran s chi-square test is < If possible, depending on the amount of available data and the degree of observed statistical heterogeneity, reasons for heterogeneity will be explored using subgroup or meta-regression analyses. The subgroups of interest to be examined in exploratory analyses are: Treatment-naive versus treatment-experienced (e.g., previous laser therapy, previous MIGS, previous filtration surgery, or current/previous pharmacotherapy) Primary versus secondary glaucoma Open-angle versus angle-closure glaucoma Number of MIGS devices (e.g., one, two, or three istents) Severity or stage of glaucoma (e.g., early, moderate, or advanced) Phakic versus pseudophakic eyes. Sensitivity Analyses Sensitivity analyses may be considered to evaluate the robustness of findings by methodological and statistical factors, including the impact of different study designs (e.g., RCTs versus cohort studies), different population compositions (i.e., pure versus mixed samples with at least 80% of the included sample meeting the population inclusion criteria), varying study quality assessments, types of analysis (e.g., unadjusted versus adjusted; studies in which means were reported versus those in which means were estimated from medians), and effect measures (e.g., relative risks versus odds ratios). Recognizing that the surgical and/or clinical setting may change over time, sensitivity analyses by study publication date may also be considered. Publication Bias If there are 10 or more included studies of a given study design and a particular outcome, publication bias will be assessed visually using funnel plots and objectively using Egger s regression test and Begg s rank correlation test. 60 CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 14

15 Reporting of Findings The SR will be prepared in consideration of relevant reporting guidelines (i.e., PRISMA statement, 45 PRISMA harms, 61 and Meta-analysis Of Observational Studies in Epidemiology [MOOSE] reporting checklist 62 ) and will meet the criteria outlined in A Measurement Tool to Assess Systematic Reviews (AMSTAR) checklist. 63 CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 15

16 Economic Review A primary economic analysis will be conducted to evaluate the long-term cost-effectiveness of MIGS devices and procedures from a Canadian public payer perspective to address the following research question: Research Question 5: What is the cost-effectiveness of MIGS devices and procedures versus each other, pharmacotherapy, laser therapy, or filtration surgery, for the treatment of glaucoma in adults? Primary Economic Analysis A decision analytic model will be developed to assess the costs and health outcomes associated with MIGS to treat glaucoma in adults. The comparators considered will mirror those in the clinical review, including different MIGS, pharmacotherapy, laser therapy or invasive filtration surgeries. If data exist on MIGS procedures with cataract surgery, they will also be examined. Although the optimal sequence of therapy to treat glaucoma may be of interest, given that patients progress through the disease trajectory, there is unlikely to be clinical evidence to inform comparisons of sequences of treatment. Further attempts at considering this will exponentially increase the complexity of the economic model. As such, this analysis will evaluate single treatments as opposed to a sequence of treatment strategies. If available, the economic analysis will make specific considerations on different patient subgroups (e.g., severity of disease, treatment-naive or -experienced, previous surgical or medical treatment) to shed light on the relative cost-effectiveness of MIGS under these different patient subpopulations. Model Design The Markov cohort model will be based on published economic evaluations in glaucoma. 64,65 The model will evaluate, for different patient subgroups (e.g., treatment experience, disease severity), the cost-effectiveness of MIGS when compared with a set of clinically appropriate single interventions. Markov states will reflect health states relevant to the natural history of glaucoma and the nature of the treatments being evaluated. These will include different disease severities, transitions to blindness (unilateral or bilateral) and death as above. Medical complications, as well as surgical complications from each procedure, will be accounted for in the model. The clinical and economic importance of each complication will be assessed by the clinical expert; those that are clinically meaningful will be incorporated into the model. Preliminary data indicate that IOP is the most commonly reported outcome from available trials, and is a reasonable surrogate to indicate the likelihood of future vision-related outcomes, including loss of vision. As such, a cost-effectiveness analysis using IOP as the effectiveness metric will be used. Clinical experts and members of CADTH s Health Technology Expert Review Panel (HTERP) will be consulted as a means to ensure that the model structure reflects existing clinical literature and Canadian clinical practice. Checks on the internal and external validity of the model will be performed to assess for any logical discrepancies. The model will be created on TreeAge Pro Suite (Williamstown, Massachusetts). 66 CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 16

17 Perspective The primary perspective will be that of a publicly funded health care system (i.e., a provincial ministry of health). A secondary societal perspective will also be presented to account for patient-borne costs (e.g., lost productivity due to blindness, etc.). Resource Use and Cost Data The costs captured will reflect the perspectives of the analysis. All costs will be reported in Canadian dollars and will be inflated to 2017 costs using the general consumer price index in Canada. 67 The cost of each treatment strategy will be determined from focused literature searches and searches of Canadian cost sources (e.g., Canadian Institute for Health Information, National Ambulatory Care Reporting System, etc.), with preference given to Canadian data. If literature is lacking, other estimates of resource utilization will be sought from manufacturers of equipment and supplies; hospitals and clinics that deliver these treatment strategies; or from informed and guided expert opinion. Capital as well as ongoing costs will be accounted for; cost categories of interest include equipment, disposables, overhead, and labour. It will be assumed that treatment strategies will only be performed where there are reasonable economies of scale and volume-based analyses will not be conducted. A similar approach will be taken to estimate the cost of complications. Recognizing that these procedures may be conducted in the private or public health care system, actual cost versus charges will be assessed and actual cost to the public health care system will be used. Physician fees will also be incorporated, recognizing that there may be alternative current or proposed approaches to physician reimbursement. Alternative approaches to physician reimbursement (and their potential to act as an incentive or disincentive toward various procedures) will be discussed. Utilities Utilities associated with each health state and the disutility of complications will be obtained from a focused literature search, and expert opinion may be used if the data are not available. Canadian sources will be preferred where available. Clinical Parameters The natural history and disease trajectory of patients with glaucoma will be based on existing literature. The systematic review conducted to address the clinical research question will support parameterization of the effectiveness and safety of the treatments under consideration in the economic analysis. The clinical review will provide data on the relative risk of important events including IOP and glaucoma severity and blindness, as well as type and frequency of complications. Outcomes The expected costs and quality-adjusted life-years (QALYs) associated with different treatment strategies, over the model s time horizon, will be estimated. QALYs will represent the main clinical outcome modelled as this single measure is multi-dimensional and can CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 17

18 capture the effect of the disease and its treatment on patients morbidity and mortality. The primary economic outcome calculated will be the incremental cost-effectiveness ratios, measured in terms of the incremental costs per QALY gained. Time Horizon and Discounting As glaucoma is a progressive neuropathy that leads to irreversible loss of vision, a lifetime time horizon will be considered to account for all relevant clinical and cost consequences of treatment. Alternative time horizons may be assessed in the scenario analysis to evaluate the model s sensitivity to uncertainty from extrapolation. A discount rate of 1.5% will be applied to both costs and effects, with sensitivity analysis conducted across a range of discount rates (e.g., 0% and 5%). 68 Sensitivity Analysis All sources of uncertainty, as well as variability, will be identified and tested. The base-case analysis will represent the probabilistic findings, capturing the impact of parameter uncertainty on the cost-effectiveness results. If a cost-utility analysis is feasible, a costeffectiveness acceptability curve will be generated to present the treatment strategies that form the efficiency frontier (i.e., the set of treatment strategies that produces the highest health benefits across different willingness-to-pay thresholds). Uncertainty in the model will further be evaluated in a number of ways. Scenario and stratified subgroup probabilistic analysis will be performed to evaluate structural uncertainty and heterogeneity respectively. Potential subgroups of interest to the economic analysis that may be considered in stratified analyses include: Previous treatment experience: treatment-naive versus treatment-experienced Primary versus secondary glaucoma Open-angle versus angle-closure glaucoma Severity of glaucoma: early, moderate, advanced Number of eyes affected. Other sensitivity analyses may be conducted in response to the findings of the other sections of the review. Assumptions During the course of the development of the economic model, assumptions and limitations will be identified and acknowledged in the written report. Where possible, assumptions will be tested through the conduct of appropriate sensitivity analyses. CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 18

19 Patient Perspectives and Experiences Review Overview Patient perspectives and experiences of glaucoma and MIGS will be incorporated in this review through two activities: a systematic review and thematic synthesis of qualitative studies; and patient engagement. Review Study Design A systematic review and qualitative synthesis of primary qualitative research describing the perspectives and experiences of patients with glaucoma and of their caregivers will be conducted. The results of included studies will be synthesized using thematic synthesis, 69 an approach that draws on methods for analysis from grounded theory and metaethnography. 70 Thematic synthesis is an interpretive approach that facilitates the development of both descriptive and interpretive findings that address the policy question of this HTA. This protocol provides a general overview of the methods to be used at each stage of the study. Protocol refinement and amendment will be actively engaged at several stages as the review team responds to the set of eligible studies and available data for analysis. The potential for refinements and amendments are identified in each of the sections below. This iterative approach to protocol development and execution is not only consistent with the inductive principles of qualitative research, but also allows for further reflection on the relationship between the available qualitative studies and the decisions on study selection, data collection, extraction and analysis. Any subsequent refinements or amendments will be documented along with their rationale. The synthesis will be reported using Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) guidelines for reporting qualitative research syntheses. 71 The review team will comprise three researchers, two of whom have experience and training in conducting both primary and secondary qualitative research, and another with experience in systematic reviews of qualitative research. This review will address the following research question: Research Question 6: What are the perspectives and experiences of patients with glaucoma regarding glaucoma and its treatment, and what are those of their clinical and non-clinical caregivers? Secondary Research Questions Given the specificity of MIGS devices and procedures and their relatively new introduction into the course of care for patients with glaucoma, we expect to find few, if any, qualitative studies that report on the experiences and perceptions of patients who have had MIGS. To ensure the relevance of the analysis to the question of this review, a secondary set of research questions during data extraction and analysis will be explored: A. How do patients experience and perceive their glaucoma and their prognosis? B. How do patients experience and perceive treatment(s) for their glaucoma? C. What are the ways in which glaucoma and its treatment affect patients lives and the lives of their caregivers? CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 19

20 D. What do patients value or expect with regard to their treatment for glaucoma? E. Are there differences in perceptions and experiences relating to glaucoma and its treatment among patients, or between patients and clinical and non-clinical caregivers? F. What are health care providers experiences and perceptions of caring for patients with glaucoma? Appendix 6 (Figure 2) provides a visual mapping of the relationship between the primary and secondary questions. With the primary research question orienting the data selection, collection, and analysis toward patients and caregivers experiences and perceptions, the secondary research questions assist in interpreting findings to answer the question of this HTA. They have been crafted to reflect concepts relating to research questions from other sections of this HTA and will be used by the qualitative research team as sensitizing concepts (to orient the researchers observations), and will be further refined, with possible additional questions added, during data collection and analysis. Literature Search The literature search will be performed by an information specialist, using a peer-reviewed search strategy. The search strategy for the patient perspectives and experiences review is presented in Appendix 3. Information related to social dimensions will be identified by searching the following bibliographic databases: MEDLINE (1946 ) with in-process records and daily updates, CINAHL (1981 ) via EBSCO, PubMed, and Scopus. The search strategy will comprise both controlled vocabulary, such as the National Library of Medicine s MeSH (Medical Subject Headings), and keywords. The main search concepts will be glaucoma, minimally invasive glaucoma surgery, minimally invasive glaucoma surgical devices, and cataract removal surgery. Methodological filters will be applied to limit retrieval to qualitative studies, including surveys or questionnaires, or studies relevant to patient perspectives. No date or language limit will be applied. The initial searches will be completed in November Regular alerts will be established to update the searches until the publication of the final report. Regular search updates will be performed on databases that do not provide alert services. Studies meeting the selection criteria of the review and identified in the alerts prior to the completion of the stakeholder feedback period will be incorporated into the analysis of the final report. Any studies identified after the stakeholder feedback period will be described in the discussion, with a focus on comparing the results of these new studies to the results of the analysis conducted for this report. Grey literature (literature that is not commercially published) will be identified by searching the Grey Matters checklist ( which includes the websites of HTA agencies, clinical guideline repositories, SR repositories, and professional associations. Google and other Internet search engines will be used to search for additional Web-based materials. These searches will be supplemented by reviewing the bibliographies of key papers and through contacts with appropriate experts and industry. CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 20

21 Figure 1: Possible modifications to expand and focus search for relevant qualitative studies Reference lists of included studies and all qualitative syntheses retrieved (whether included or excluded) will be screened for any potential eligible studies. CADTH OPTIMAL USE Optimal Use of Minimally Invasive Glaucoma Surgery: A Health Technology Assessment Project Protocol 21