EUnetHTA Joint Action 3 WP4

Dec2015 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 1

EUnetHTA Joint Action 3 WP4

Version 1.0, 12/03/2020

Relative effectiveness assessment of pharmaceutical technologies

BROLUCIZUMAB FOR THE TREATMENT OF ADULTS WITH NEOVASCULAR

(WET) AGE-RELATED MACULAR DEGENERATION (AMD)

Project ID: PTJA09

PTJA09 - Brolucizumab for patients with neovascular (wet) AMD

March 2020 EUnetHTA Joint Action 3 WP4 1

DOCUMENT HISTORY AND CONTRIBUTORS

Version Date Description

V0.1 28/01/2020 First draft

V0.2 24/2/2020 Input from dedicated reviewers has been processed

V0.3 10/03/2020 Input from medical editor and manufacturer(s) has been processed

V1.0 12/03/2020 Final assessment report

Disclaimer

This Joint Assessment is part of the project / joint action ‘724130 / EUnetHTA JA3’ which has received funding from the European Union’s Health Programme (2014-2020). The content of this Assessment Report represents a consolidated view based on the consensus within the Authoring Team; it cannot be considered to reflect the views of the European Network for Health Technology Assessment (EUnetHTA), EUnetHTA’s participating institutions, the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.

Assessment team

Author(s) Finnish Medicines Agency (Fimea), Finland

Co-Author(s) Spanish Agency of Medicine and Sanitary Products (AEMPS), Spain

Andalusian Unit for Health Technology Assessment (AETSA), Spain

Dedicated Reviewer(s)

French National Authority for Health (HAS), France

Agency for Health Technology Assessment and Tariff System (AOTMiT), Poland

Regione Emilia-Romagna (RER), Italy

Association of Austrian Social Insurance Institutions (DVSV), Austria

Observer HTA Department/EC Ukraine, Ukraine



Further contributors

External experts

Prof. João Barbosa Breda Answer specific question during the assessment

Manufacturer(s) [v0.2]

Novartis Preparation of the submission dossier

Factual accuracy check

Medical editor [v0.2]

Compuscript Limited Responsible for medical editing of the report

Patient(s) / patient organisation(s) / citizens

Asociación Acción Visión España (Spain)

Društvo MDSS Kranj (Slovenia)

Fighting Blindness (Ireland)

Macula Retina (Spain)

Retina Bulgaria (Bulgaria)

Retina International (Ireland)

Retina Suisse (Swiss Confederation)

Provided input in response to the open call for patients

Input published on 20th May, 2019

Project Management

Zorginstituut Nederland (ZIN), Netherlands

Coordination between involved parties throughout the assessment

Other [v0.1]

EUnetHTA Senior Scientific Officer Giovanni Tafuri

Support for the systematic literature review

Conflict of interest

All authors and dedicated reviewers involved in the production of this assessment have declared they have no conflicts of interest in relation to the technology assessed according to the EUnetHTA Declaration of Interest and Confidentiality Agreement forms.

How to cite this assessment

Please cite this assessment as follows:

EUnetHTA PTJA09. Authoring Team. Relative Effectiveness Assessment of pharmaceutical technologies. Brolucizumab for the treatment of adults with neovascular (wet) age-related macular degeneration (AMD). Joint Assessment. Diemen (The Netherlands): EUnetHTA; 2020. [date of citation]. 124 pages. Report No.: PTJA09. Available from: https //www.eunethta.eu



TABLE OF CONTENTS

DOCUMENT HISTORY AND CONTRIBUTORS ............................................................................... 1

TABLE OF CONTENTS ................................................................................................................... 3

LIST OF TABLES AND FIGURES.................................................................................................... 5

LIST OF ABBREVIATIONS.............................................................................................................. 8

EXECUTIVE SUMMARY OF THE ASSESSMENT OF BROLUCIZUMAB ...................................... 10

INTRODUCTION ........................................................................................................................... 10 OBJECTIVE AND SCOPE................................................................................................................ 10 METHODS .................................................................................................................................. 10 RESULTS ................................................................................................................................... 11 DISCUSSION ............................................................................................................................... 14 CONCLUSIONS ............................................................................................................................ 15

1 BACKGROUND ....................................................................................................................... 16

1.1 OVERVIEW OF THE DISEASE OR HEALTH CONDITION .................................................................. 16 1.2 CURRENT CLINICAL PRACTICE................................................................................................. 17 1.3 FEATURES OF THE INTERVENTION ........................................................................................... 18

2 OBJECTIVE AND SCOPE ....................................................................................................... 21

2.1 DEVIATIONS FROM THE PROJECT PLAN ................................................................................... 21 3 METHODS ............................................................................................................................... 22

3.1 INFORMATION RETRIEVAL ....................................................................................................... 22 3.2 DATA EXTRACTION ................................................................................................................ 25 3.3 ROB ASSESSMENT ................................................................................................................ 25 3.4 EXTERNAL VALIDITY .............................................................................................................. 26 3.5 RESULTS AND ANALYSES FOR THE STUDIES INCLUDED ............................................................... 26 3.6 PATIENT INVOLVEMENT .......................................................................................................... 28

4 RESULTS ................................................................................................................................ 29

4.1 INFORMATION RETRIEVAL ....................................................................................................... 29 4.2 STUDIES INCLUDED IN THE ASSESSMENT .................................................................................. 31 4.3 EXCLUDED STUDIES .............................................................................................................. 35 4.4 CHARACTERISTICS OF THE STUDIES INCLUDED: DIRECT EVIDENCE .............................................. 35 4.5 OUTCOMES INCLUDED ........................................................................................................... 39 4.6 RISK OF BIAS ........................................................................................................................ 40 4.7 EXTERNAL VALIDITY .............................................................................................................. 41 4.8 DIRECT EVIDENCE: RESULTS FOR CLINICAL EFFICACY AND SAFETY .............................................. 42 4.9 DIRECT SUPPORTIVE EVIDENCE: BROLUCIZUMAB 3 MG .............................................................. 60 4.10 DIRECT SUPPORTIVE EVIDENCE: SUMMARY OF THE PHASE II OSPREY STUDY ...................... 61 4.11 INDIRECT EVIDENCE: NMA RESULTS ................................................................................ 62 4.12 LITERATURE REVIEW: EVIDENCE OF BEVACIZUMAB AS A TREATMENT OPTION IN NAMD .......... 67

5 PATIENT INVOLVEMENT ........................................................................................................ 74

6 DISCUSSION ........................................................................................................................... 75

6.1 DIRECT COMPARISONS .......................................................................................................... 75 6.2 INDIRECT COMPARISONS ........................................................................................................ 77 6.3 LITERATURE REVIEW OF BEVACIZUMAB .................................................................................... 77 6.4 PATIENT PERSPECTIVE .......................................................................................................... 77

7 CONCLUSIONS ....................................................................................................................... 78

8 REFERENCES ......................................................................................................................... 79



APPENDIX 1: GUIDELINES FOR MANAGEMENT OF AMD ......................................................... 86

APPENDIX 2: SEARCHES STRATEGIES FOR BEVACIZUMAB LITERATURE REVIEW ............. 89

STRATEGIES TO SELECT NMAS AND SRS ...................................................................................... 89 STRATEGIES TO UPDATE THE INCLUDED NMAS AND SRS ................................................................ 91

APPENDIX 3: SEARCHES PERFORMED BY THE INFORMATION SPECIALIST TO THE COMPLETENESS OF THE STUDY POOL ............................................................................... 93

SEARCH 1: SEARCH IN STUDY REGISTRIES FOR BROLUCIZUMAB ....................................................... 93 SEARCH 2: SEARCH IN STUDY REGISTRIES FOR RANIBIZUMAB, BEVACIZUMAB AND AFLIBERCEPT .......... 94 SEARCH 3: SEARCH FOCUSED IN PUBMED ..................................................................................... 95

APPENDIX 4: RESULTS FROM THE SCREENING OF THE SEARCHES OF BEVACIZUMAB..... 96

APPENDIX 5: STUDIES (SR OR NMA) THAT MET THE ELIGIBILITY CRITERIA FOR THE BEVACIZUMAB LITERATURE REVIEW ................................................................................. 97

APPENDIX 6: EXCLUDED ARTICLES FROM BEVACIZUMAB LITERATURE REVIEW ............. 110

APPENDIX 7: BASELINE CHARACTERISTICS OF HAWK AND HARRIER STUDY POPULATIONS...................................................................................................................... 114

APPENDIX 8: POOLED RESULTS OF HAWK AND HARRIER STUDIES ................................... 116

APPENDIX 9: CHECKLIST FOR CRITICAL APPRAISAL OF INDIRECT COMPARISONS – EVALUATION OF THE NMA PROVIDED BY MAH ................................................................ 117

APPENDIX 10: CRITICAL APPRAISAL FOR THE SYSTEMATIC REVIEWS SELECTED FROM THE SLR OF BEVACIZUMAB .................................................................................... 120

APPENDIX 11: PROTOCOL DEVIATIONS IN HAWK AND HARRIER STUDIES ........................ 123



LIST OF TABLES AND FIGURES

Tables

Table 0.1. Results for the change in BCVA from baseline to week 48: summary statistics and ANOVA (FAS-LOCF) ................................................................................................................. 12

Table 1.1. Features of the intervention and other treatment options ................................................. 19 Table 1.2. Administration and dosing of the technology and other treatment options ........................ 20 Table 2.1. Scope of the assessment ................................................................................................ 21 Table 3.1. Summary of information retrieval and study selection submitted by the MAH ................... 23 Table 3.2. PICO framework for the network meta-analysis ............................................................... 24 Table 3.3. Selection criteria for the literature searches regarding bevacizumab ................................ 25 Table 4.1. Study pool: list of relevant studies used for the assessment ............................................. 33 Table 4.2. Overview of trials included in the network meta-analysis .................................................. 34 Table 4.3. Characteristics of the studies included for direct comparison ........................................... 35 Table 4.4. Characterisation of the interventions and comparators..................................................... 36 Table 4.5. Trial populations used for analysis of outcomes in the HAWK and HARRIER studies ....... 36 Table 4.6. DAA criteria for the HAWK and HARRIER studies ........................................................... 38 Table 4.7. Risk of bias in the randomised HAWK and HARRIER studies .......................................... 40 Table 4.8. Risk of bias by outcome in the HAWK and HARRIER studies .......................................... 40 Table 4.9. Subject disposition in the HAWK and HARRIER studies .................................................. 42 Table 4.10. Change in BCVA from baseline to week 48: summary statistics and ANOVA (FAS-

LOCF, PPS-LOCF) .................................................................................................................... 44 Table 4.11. Selected secondary endpoints related to BCVA (LS mean estimates; proportion of

patients) at and up to week 48 and week 96 (FAS-LOCF) .......................................................... 45 Table 4.12. Change in CSFTns (μm) from baseline to week 48 for the study eye in HAWK and

HARRIER (FAS-LOCF).............................................................................................................. 46 Table 4.13. LSMD in CSFTtot (μm) from baseline to weeks 48 and 96 for the study eye in HAWK

and HARRIER (FAS-LOCF) ....................................................................................................... 48 Table 4.14. Proportion of subjects with IRF at week 16 and week 48 in HAWK and HARRIER

(FAS-LOCF) according to logistic regression.............................................................................. 49 Table 4.15. Proportion of subjects with SRF at week 16 and week 48 in HAWK and HARRIER

(FAS-LOCF) according to logistic regression.............................................................................. 50 Table 4.16. Number of injections from baseline to week 96 (SAF) .................................................... 53 Table 4.17. Mean change in VFQ-25 composite scores from baseline in HAWK and HARRIER

studies (FAS-observed) ............................................................................................................. 53 Table 4.18. Ocular adverse events up to week 96 (≥2% in any treatment group) for the study eye

(SAF)......................................................................................................................................... 54 Table 4.19. Serious ocular adverse events up to week 96 for the study eye (SAF) ........................... 55 Table 4.20. Non-ocular adverse events up to week 96 (≥2% in any treatment group) for the study

eye (SAF) .................................................................................................................................. 55 Table 4.21. Serious non-ocular adverse events up to week 96 (≥3 patients in any treatment group)

for the SAF ................................................................................................................................ 57 Table 4.22. Death, SAE or AE leading to permanent study treatment discontinuation up to week

96 (SAF) .................................................................................................................................... 58 Table 4.23. LSM estimates for the change in BCVA from baseline at weeks 12, 40 and 56 (FAS-

LOFC) ....................................................................................................................................... 61 Table 4.24. LSM estimates for the change in CSFT (µm) from baseline at weeks 12, 40 and 56

(FAS-LOFC) .............................................................................................................................. 62 Table 4.25. Summary of NMA results comparing MD in BCVA and OR of loss of at least 15 letters

(fixed effects). Results are presented as brolucizumab 6 mg Q8W/Q12W vs. each comparator. . 65 Table 4.26. Summary of NMA results comparing the MD in CRT and OR in gain of at least 15

letters (fixed effects). Results are presented as brolucizumab 6 mg Q8W/Q12W vs. each comparator. ............................................................................................................................... 66

Table 4.27. Treatment effect estimates: bevacizumab versus ranibizumab ....................................... 69 Table 4.28. AEs up to 1 year: bevacizumab versus ranibizumab ...................................................... 70 Table 4.29. Treatment effect estimates ............................................................................................ 72 Table 4.30. Adverse events: treatment versus comparator ............................................................... 73 Table 5.1. Summary of patient involvement...................................................................................... 74 Table A1. Overview of guidelines used for this assessment ............................................................. 86



Table A2. Information about the screening of the records from the searches of bevacizumab to include SRs and NMAs. ............................................................................................................. 96

Table A3. Information about the screening of the records from the searches to update included SRs and NMAs. ......................................................................................................................... 96

Table A4. Studies (SR or NMA) that met the eligibility criteria for the bevacizumab literature review . 97 Table A5. RCTs not included in the SR by Solomon 2019 which are considered in the other

references and reasons for exclusion in Solomon SR. .............................................................. 109 Table A6. Excluded articles, based on the full text, from the literature search regarding the relative

efficacy and safety of bevacizumab for nAMD. ......................................................................... 110 Table A7. Articles excluded, by title and abstract (full text not available), from the literature search

regarding the relative efficacy and safety of bevacizumab for nAMD. ....................................... 112 Table A8. Baseline characteristics of the study populations (FAS, excluding brolucizumab 3 mg

group in HAWK study) ............................................................................................................. 114 Table A9. Summary of direct comparison results (pooled results) for HAWK and HARRIER studies116 Table A10. Evaluation of the NMA provided by MAH ...................................................................... 117 Table A11. Critical appraisal for the SRs selected from the SLR of bevacizumab ........................... 120 Table A12. Protocol deviations by deviation category (RAN) in HAWK study - week 48 analysis .... 123 Table A13. Protocol deviations by deviation category (RAN) in HARRIER study - week 48 analysis 123



Figures

Figure 4.1. Flowchart of the selection process to identify systematic reviews and network meta-analyses. ................................................................................................................................... 30

Figure 4.2. Flowchart of the process to select randomised controlled trials to update the systematic reviews included. ...................................................................................................... 31

Figure 4.3. PRISMA diagram. .......................................................................................................... 32 Figure 4.4. HAWK and HARRIER trial design................................................................................... 37 Figure 4.5. LSM change in BCVA from baseline to week 96 (FAS-LOCF). ....................................... 45 Figure 4.6. LSM change in CSFTns (μm) from baseline by visit in HAWK (FAS-LOCF). ................... 47 Figure 4.7. LSM change in CSFTns (μm) from baseline by visit in HARRIER (FAS-LOCF). .............. 47 Figure 4.8. LSM change in CSFTtot (µm) from baseline by visit through to week 96 (FAS-LOCF). ... 48 Figure 4.9. Percentage of subjects with IRF by visit up to week 96 in HARRIER (FAS-LOCF). ......... 49 Figure 4.10. Percentage of subjects with IRF visit to week 96 in HAWK (FAS-LOCF). ...................... 49 Figure 4.11. Percentage of subjects with SRF by visit up to week 96 in HARRIER (FAS-LOCF). ...... 50 Figure 4.12. Percentage of subjects with SRF by visit up to week 96 in HAWK (FAS-LOCF). ........... 50 Figure 4.13. Proportion of patients with sub-RPE fluid at weeks 16, 48 and 96 in HAWK and

HARRIER (FAS-LOCF). ............................................................................................................. 51 Figure 4.14. Kaplan-Meier plot of time to first Q8W treatment needed for the brolucizumab group

in HAWK (FAS efficacy/safety approach). .................................................................................. 52 Figure 4.15. Kaplan-Meier plot of time to first Q8W treatment needed for the brolucizumab group

in HARRIER (FAS efficacy/safety approach). ............................................................................. 52 Figure 4.16. Forest plot of summary statistics and ANOVA for change in BCVA from baseline to

week 48 by subgroups of interest (FAS-LOCF) .......................................................................... 59 Figure 4.17. Proportion of patients maintained on Q12W dosing interval until week 48 (FAS). .......... 60 Figure 4.18. OSPREY trial design. ................................................................................................... 61 Figure 4.19. Quality assessment performed by the MAH for trials included in the NMA..................... 63 Figure 4.20. Network for mean change in BCVA from baseline to 1 year. ......................................... 64 Figure 4.21. RoB summary: judgements for each RoB item for each study comparing

bevacizumab versus ranibizumab included by Solomon et al. .................................................... 68 Figure 4.22. Cochrane RoB results for individual studies on nAMD included by Pham et al. ............. 68



LIST OF ABBREVIATIONS

AE Adverse event

AMD Age-related macular degeneration

ANOVA Analysis of variance

BCVA Best corrected visual acuity

CHMP Committee for Medicinal Products for Human Use

CI Confidence interval

CFT Central foveal thickness

CMT Central macular thickness

CNV Choroidal neovascularisation

CRD Centre for Reviews and Dissemination

CrI Credibility interval

CRT Central retinal thickness

CSFT Central subfield thickness

CSFTns Central subfield thickness of the neurosensory retina

CSFTtot Total central subfield thickness

CSR Clinical study report

DAA Disease activity assessment

DIC Deviance information criterion

EMA European Medicines Agency

EQ-5D European Quality of Life-5 Dimensions

ETDRS Early Treatment Diabetic Retinopathy Study

EUnetHTA European Network for Health Technology Assessment

EU-CTR European Clinical Trials Register

FAS Full analysis set

GRADE Grading of Recommendations, Assessment, Development and Evaluation

HR Hazard ratio

HRQoL Health-related quality of life

ICTRP International Clinical Trials Registry Platform

IRF Intraretinal fluid

ITT Intention to treat

IVT Intravitreal

LOCF Last observation carried forward

LP Loading phase

LS Least squares

LSM Least squares mean

LSMD Least squares mean difference

MA Marketing authorisation

MAH Marketing authorisation holder

MD Mean difference

MeSH Medical Subject Headings

nAMD Neovascular age-related macular degeneration

NA Not applicable

NEI VFQ-25 National Eye Institute Visual Function Questionnaire-25

NMA Network meta-analysis

NR Not reported

OR Odds ratio

QxW Every x weeks

QoL Quality of life

PCV Polypoidal choroidal vasculopathy



PDT Photodynamic therapy

PICO Patients, Intervention, Comparators, Outcomes instrument

PP Per protocol

PPS Per protocol set

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

PRN Pro re nata

PRNX Pro re nata and extend

RAN All randomised analysis set

RCT Randomised controlled trial

RD Risk difference

REA Relative effectiveness assessment

RoB Risk of bias

RPE Retinal pigment epithelium

RR Relative risk

SAE Serious adverse event

SAF Safety analysis set

SD Standard deviation

SE Standard error

SLR Systematic literature review

SPC Summary of product characteristics

SR Systematic review

SRF Subretinal fluid

Sub-RPE Subretinal pigment epithelium

TREX Treat and extend

VA Visual acuity

VEGF Vascular endothelial growth factor

wAMD Wet age-related macular degeneration



EXECUTIVE SUMMARY OF THE ASSESSMENT OF BROLUCIZUMAB

Introduction

Age-related macular degeneration (AMD) is a chronic eye disease characterised by progressive degeneration of the macula, the area of the retina responsible for sharp, central vision. The late stages of disease progression in AMD are further classified into two types: neovascular (nAMD) and atrophic AMD (1). nAMD is characterised by leaking of fluid due to the formation of abnormal blood vessels underneath the macula. This phenomenon, known as choroidal neovascularisation (CNV), is the defining feature in nAMD and occurs in response to abnormally high levels of vascular endothelial growth factor (VEGF).

Left untreated, AMD can lead to rapid, irreversible vision loss. nAMD is the leading cause of severe vision loss and legal blindness among individuals aged >65 years in Europe, North America, Australia and Asia (2, 3). Prevalence estimates suggest that nAMD affects approximately 1.7 million people in Europe (4, 5). The estimated incidence of late AMD in Europe in 2013 was between 2.9 and 3.7 per 1000 person-years (6). Since the introduction of anti-VEGF therapies, there has been a reduction in the incidence of blindness and visual impairment due to nAMD (7, 8).

The aim of nAMD treatment with drugs that are currently available is to resolve the accumulation of retinal fluid and subsequently recover and/or preserve visual function, while slowing disease progression. According to clinical guidelines, first-line treatment for nAMD is intravitreal (IVT) anti-VEGF agents (2, 9-15). Two authorised anti-VEFG treatment options for nAMD are currently available in Europe: aflibercept (Eylea®) (16) and ranibizumab (Lucentis®) (17). A third anti-VEGF product, bevacizumab (Avastin®) (18), is frequently used off-label for nAMD. In clinical trials, the anti-VEGF therapies currently in use maintain visual acuity (VA) in approximately 90% of patients over 2 years (19-22). The choice of agent and regimen should be individualised, taking into account clinical criteria, patient preferences and health care system characteristics.

Brolucizumab (Beovu®) is a humanised single-chain Fv inhibitor of VEGF-A (23). A single-chain Fv is an autonomous binding agent that comprises only the variable domains of the monoclonal antibody (joined by a short flexible linker peptide) that are responsible for binding to its receptor (24). Brolucizumab is indicated in adults for the treatment of nAMD. Treatment consists of a loading phase (LP) of three consecutive 6-mg injections every 4 weeks (Q4W), followed by a maintenance phase of injections Q8W or Q12W, depending on disease activity.

Objective and scope

The aim of this EUnetHTA Joint Relative Effectiveness Assessment (REA) is to compare the clinical effectiveness and safety of brolucizumab in the target patient population with relevant comparators. The target patient population and relevant comparators (based on the requirements of EUnetHTA Partners) are defined in the project scope. The project scope can be found in Table 2.1.

Methods

Direct evidence

The evidence base for the drug under assessment provided by the marketing authorisation holder (MAH) was reviewed by the information specialist on the authoring team. Search strategies were checked for appropriateness and the results of information retrieval included in the MAH’s submission dossier were checked for completeness against a search in study registries. Supplementary searches were conducted to check for possible incompleteness of the study pool.

Direct evidence used for assessment of the clinical effectiveness and safety was extracted from the submission dossier and verified against the clinical study reports (CSRs) or other original documentation provided in the submission dossier. The methods for data analysis applied by the MAH were checked against the requirements for the submission dossier and applicable EUnetHTA guidelines and assessed with regard to scientific validity. Assessment of the risk of bias (RoB; at both the study



level and outcome level) was conducted only for the randomised phase III studies using the Cochrane RoB tool, including relevant direct evidence on brolucizumab and aflibercept.

Indirect evidence

Direct evidence was available only for comparison between brolucizumab and aflibercept. The MAH performed a network meta-analysis (NMA) to assess the relative effectiveness of brolucizumab versus aflibercept and ranibizumab. Standard pairwise meta-analyses based on direct comparisons were carried out between pairs of treatments when possible when two treatments were compared in two or more clinical trials. The NMA was conducted using a Bayesian framework. Both fixed-effects and random-effects models were developed and the one associated with the lowest deviance information criterion (DIC) was selected, unless the absolute difference between the DIC values of the two models was less than three points, then the fixed-effect model was chosen. Several sensitivity analyses were conducted to test the assumptions adopted within the base-case NMA. The methods for data analysis and synthesis applied by the MAH were assessed with regard to scientific validity. The structured checklist developed by Ortega et al. (25) was used to critically appraise the indirect comparisons.

Information retrieval for bevacizumab

Bevacizumab was not included as a comparator in the NMA conducted by the MAH even though it had been identified as an important off-label comparator option through the Patients, Intervention, Comparators, Outcomes (PICO) survey and the authoring team had specifically requested its inclusion. Therefore, the authoring team (with support from the EUnetHTA Senior Scientific Officer) performed a systematic literature review (SLR) of bevacizumab in nAMD. The aim of this literature search was to find comprehensive systematic reviews (SRs) and NMAs of randomised controlled trials (RCTs). The quality of the SRs was assessed using the AMSTAR-2 checklist (26).

Patient involvement

At the start of this Joint Assessment, EUnetHTA conducted an open call for patient organisations. The information gathered from the open call was used to inform the scope of this assessment and in particular the outcomes to be considered.

Results

Direct evidence: results of direct comparison between brolucizumab and aflibercept

The clinical evidence is mainly based on two double-blind noninferiority RCTs: HAWK and HARRIER. In these trials brolucizumab 6 mg was compared with aflibercept 2 mg (HAWK also included a brolucizumab 3 mg arm). Results of HAWK and HARRIER studies are presented separately because pooled results were not available.

The study-level RoB was assessed as low for both the HAWK and HARRIER studies. At the outcome level, the RoB was low for most of the outcomes and unclear for some of the outcomes such as visual function–related QoL (measured using the National Eye Institute Visual Function Questionnaire-25 [NEI VFQ-25]) and some of the safety outcomes.

The following key results were observed during the assessment:

The change in best corrected VA (BCVA) from baseline to 48 weeks was noninferior with brolucizumab compared to aflibercept (Table 0.1). In addition, no differences in the change in BCVA from baseline to 96 weeks were observed between brolucizumab and aflibercept;

The mean change in the central subfield thickness of the neurosensory retina (CSFTns) from baseline to week 48 did not differ between the brolucizumab 6 mg and aflibercept 2 mg groups. The mean change in total central subfield thickness (CSFTtot) showed statistically significant difference between brolucizumab 6 mg compared to aflibercept 2 mg groups at weeks 16, 48 and 96. The absolute difference at the end of week 96 was 26 µm in HAWK and 43 µm in HARRIER, with lower mean measures in the brolucizumab groups. In general, lower CSFT measures potentially indicate better anatomical outcome;



In the HAWK and HARRIER studies, 56% and 51% of the patients, respectively, in the brolucizumab 6 mg arm remained on the Q12W regimen up to week 48;

Over 96 weeks, the mean number of injections was 10.2 for brolucizumab versus 11.3 for aflibercept in HAWK, and 10.9 for brolucizumab versus 12.1 for aflibercept in HARRIER study. The difference in the mean number of active injections administered in the brolucizumab and aflibercept treatment arms in HAWK and HARRIER was between 1 and 1.5. During the study, patients in the aflibercept 2 mg arm were treated at a fixed dose of Q8W and lengthening of the dosing interval was not allowed. In the brolucizumab arm, the dosing interval (Q8W or Q12W in the maintenance phase) was based on disease activity assessment (DAA). The slight difference in the mean number of injections might be driven by differences in the dosing intervals between the brolucizumab and aflibercept arms (protocol difference);

Both HAWK and HARRIER showed a similar change in visual function–related quality of life (VFQ-25 score) from baseline for both brolucizumab 6 mg and aflibercept 2 mg. No statistical comparisons were performed between the brolucizumab and aflibercept arms;

Serious adverse events (SAEs) were rare. Conjunctival haemorrhage and reduced VA were the most frequent ocular adverse events (AEs) across all treatment arms in HAWK and HARRIER. These AEs are known effects of anti-VEGF drugs administered via the IVT route. In comparison to aflibercept, the incidence of intraocular inflammation and retinal artery occlusive events was higher for brolucizumab. These safety concerns were also raised in the European public assessment report (27);

Results for subgroup analyses for the primary endpoint of change in BCVA from baseline to week 48 showed no difference between brolucizumab 6 mg and aflibercept 2 mg, irrespective of baseline disease characteristics or demographics. For the outcome of mean change in BCVA, the subgroup with poorer baseline VA (≤55 letters) experienced a greater change in the least squares (LS) mean change in BCVA (9.6 for brolucizumab 6 mg vs. 10.3 for aflibercept 2 mg) than the subgroups with better baseline VA (56–70 letters: change 7.1 vs. 7.0; ≥71 letters: change 2.4 vs. 2.4, respectively), but there was no difference between brolucizumab 6 mg and aflibercept 2 mg groups.

Table 0.1. Results for the change in BCVA from baseline to week 48: summary statistics and ANOVA (FAS-LOCF)

Trial name HAWK (NCT02307682) HARRIER (NCT02434328)

Brolucizumab 6 mg (n=360)

Aflibercept 2 mg (n=360)



Change in BCVA from baseline to week 48

Mean (SD) 6.4 (14.40) 7.0 (13.16) 6.9 (11.47) 7.6 (12.47)

Median (range) 7.5 (69, 52) 8.0 (57, 54) 8.0 (57, 38) 8.0 (37, 50)

95% CI for mean 4.9, 7.9 5.6, 8.3 5.8, 8.1 6.3, 8.9

Pairwise ANOVA (brolucizumab 6 mg vs. aflibercept 2 mg)

LSM (SE) 6.6 (0.71) 6.8 (0.71) 6.9 (0.61) 7.6 (0.61)

95% CI for LSM 5.2, 8.0 5.4, 8.2 5.7, 8.1 6.4, 8.8

LSMD (SE) 0.2 (1.00) 0.7 (0.86)

95% CI for LSMD 2.1, 1.8 2.4, 1.0

p-value for treatment difference (2-sided)

0.8695 0.4199

p-value for noninferiority (4-letter margin; 1-sided)

<0.0001 0.0001

Source: HAWK clinical study report, HARRIER clinical study report, Dugel et al. 2020 (28). Abbreviations: ANOVA=analysis of variance; BCVA=best corrected visual acuity; CI=confidence interval; FAS=full analysis

set; LOCF=Last observation carried forward; LSM=least squares mean; LSMD=least squares mean difference; SD=standard deviation; SE=standard error



Indirect evidence: NMA results

The quality of the NMA provided by the MAH was evaluated by the assessment team using the tool developed by Ortega et al (25). Quality assessment of the individual trials was perfomed by the MAH. The main limitation of the NMA is related to the external validity and applicability of the results and conclusions obtained, because one of the relevant comparators from the European perspective has not been considered.

In the base-case NMA, the main focus was comparison between brolucizumab 6 mg and different dosing schemes for aflibercept 2 mg and ranibizumab 0.5 mg. For the main outcome, mean change in BCVA, no differences were observed in any of the comparisons from baseline to year one or baseline to year two. For the following outcomes there were some differences favouring brolucizumab:

Patients losing at least 15 letters from baseline to 1 year: difference in one of the seven dosing schemes assessed for ranibizumab;

Patients gaining at least 15 letters from baseline to 1 year: difference in two of the seven dosing schemes assessed for ranibizumab;

Mean change in central retinal thickness from baseline to 1 year: difference in four of the four dosing schemes assessed for ranibizumab and two of the two dosing schemes assessed for aflibercept;

Mean change in central retinal thickness from baseline to 2 years: difference in three of the four dosing schemes assessed for ranibizumab and two of the three dosing schemes assessed for aflibercept.

There were no differences in the overall rate of treatment discontinuation. Indirect comparison of AEs was not provided.

Overall, the credibility and validity of NMA rest on a few key assumptions (homogeneity, transitivity and consistency assumptions) and have well-known limitations that should be taken into account in drawing conclusions from these results. In this NMA, some simplifying assumptions were made for practical reasons. These include assuming equivalence between the dosing regimens at year one and year two for the treatments in VIEW 1&2 studies. The other key assumptions were as follows: (1) central retinal thickness (CRT), central foveal thickness (CFT), CSFT and central macular thickness (CMT) were considered as the same measure; and (2) equivalence was assumed for assessment times between 48 and 52 weeks for 12-month outcomes, and between 96 and 104 weeks for 24-month outcomes. Furthermore, the NMA results are reported as mean differences only, and not as absolute values or absolute changes. Therefore, it is difficult to evaluate the clinical relevance of the NMA results. However, despite the above limitations the methodological approach and conduct of the NMA can be considered adequate.

Results for the bevacizumab literature search

Two applicaple SRs (29, 30) that included bevacizumab as a comparator in the treatment of nAMD were identified in the literature search. According to the AMSTAR-2 tool, the SR by Solomon et al. is a low quality review and the SR by Pham et al. a critically low quality review. However, the main limitations of the SRs are related to the level of details included in the methodology description of the SRs, and the authors of this REA consider that the results are robust enough to derive some conclusions on the effectiveness of bevacizumab in this setting.

Results for the meta-analysis by Solomon et al. showed that bevacizumab and ranibizumab were similar in terms of vision-related outcomes and numbers of AEs among participants followed for at least 1 year (30). Similarly, the SR by Pham et al. revealed no difference in vision related outcomes between bevacizumab and ranibizumab or between ranibizumab and aflibercept (29). The authors estimated that the mean difference between bevacizumab and aflibercept in terms of the change in BCVA suggests no difference between these tretments.



Results from patient involvement

Seven patient organisations completed the EUnetHTA patient survey. The key message was that patients with AMD often lose their autonomy and mobility and experience many difficulties in daily life. With current anti-VEGF treatments, regular hospital visits are a significant burden in terms of time, travel arrangements, financial issues, fear of injections and injection-related AEs. Patients expect new treatments to have long-lasting efficacy and less frequent injections. The availability of other modes of administration would also be appreciated (e.g., drops or tablets).

Discussion

The aim of this assessment was to compare the clinical effectiveness and safety of brolucizumab for the treatment of nAMD with relevant comparators. In the EUnetHTA PICO survey, aflibercept, ranibizumab and bevacizumab were identified as relevant comparators.

The efficacy and safety of brolucizumab were directly compared only with aflibercept in an RCT setting. Two phase III noninferiority RCTs demonstrated that brolucizumab was noninferior to aflibercept for the change in BCVA. The RoB for these studies was considered low.

The clinical trial data presented for brolucizumab did not raise previously undetected safety concerns regarding anti-VEGF treatments, at least for 2 years of use. In comparison to aflibercept, the incidence of intraocular inflammation and retinal artery occlusive events was higher for brolucizumab. These safety concerns were also raised in the European public assessment report (27). However, in real life most AMD patients need treatment for more than 2 years and some patients will need to be treated simultaneously for both eyes, so the safety of long-term use and systemic exposure needs to be monitored.

Direct comparisons to ranibizumab and bevacizumab are not available. Indirect comparisons based on NMA between brolucizumab and ranibizumab showed no differences for the main outcome (mean change in BCVA) or for most of the other outcomes. Differences between brolucizumab and bevacizumab remain unknown since indirect comparison between these two treatments was not formally conducted.

Regarding the direct evidence, the following key limitations were identified during the assessment:

In both the HAWK and HARRIER trials, the study eye for each patient had to be treatment-naïve for any anti-VEGF agents. The efficacy and safety of brolucizumab have not been studied as a second- or third-line treatment. The therapeutic indication for brolucizumab has no limitations in terms of prior anti-VEGF treatments;

The first three loading doses of brolucizumab are given Q4W. During maintenance treatment, the dosing interval is based on disease activity and injections are given Q12W or Q8W. At the start of the LP it is not possible to know which patients will be able to remain on Q12W dosing. It would be beneficial for both patients and hospitals if brolucizumab treatment could be targeted to patients who are able to remain on Q12W dosing;

In the HAWK and HARRIER trials the treatment duration and follow-up time were up to 96 weeks. Therefore, the long-term efficacy and safety of brolucizumab are not known. In clinical practice the treatment duration is often longer than 2 years;

Aflibercept was the only comparator in the HAWK and HARRIER trials. The MAH provided an NMA that included ranibizumab as a comparator. In many European countries bevacizumab is one of the primary treatment options for nAMD. However, brolucizumab has not been compared with bevacizumab either directly or indirectly;

Brolucizumab has been compared only to aflibercept 2 mg at fixed Q8W dosing and not to other dosing schemes (e.g., pro re nata [PRN] or treat and extend [TREX]) commonly used in clinical practice. Because the dosing schemes were different for brolucizumab and aflibercept in the HAWK and HARRIER trials, the trial design does not allow any conclusions to be drawn regarding the treatment burden (injection frequency) between these two regimens. Further investigations involving comparable treatment regimens would be needed;



Data on general health-related QoL (HRQoL; e.g., European Quality of Life-5 Dimensions [EQ-5D]) are not available. However, vision-related QoL (measured using NEI VFQ-25) was included.

Conclusions

Two pivotal phase III RCTs showed the noninferiority of brolucizumab in comparison to aflibercept in terms of visual function measured as BCVA in the treatment of patients with nAMD. Brolucizumab 6 mg Q8W or Q12W has only been compared to aflibercept 2 mg dosed at fixed intervals of Q8W and not to other dosing schemes commonly used in clinical practice. Because the dosing schemes were different for brolucizumab and aflibercept in the HAWK and HARRIER trials, the trial design does not allow any conclusions to be drawn about treatment burden (injection frequency) between these two drugs. Consequently, it is unknown how brolucizumab compares with existing flexible dose regimens, so no advantages related to treatment burden can be anticipated with available data. Further investigations involving comparable treatment regimens would be needed.

In comparison to aflibercept, the incidence of intraocular inflammation and retinal artery occlusive events were higher for brolucizumab. These safety concerns were raised also in European public assessment report and a close monitoring is requested in post-marketing setting to further investigate these events (27). The clinical trial data presented for brolucizumab did not raise previously undetected safety concerns for anti-VEGF treatments, at least up to 2 years of use. There are no safety data for brolucizumab beyond 2 years of treatment or in bilateral use.

Evidence of the efficacy and safety of brolucizumab is based only on data for anti-VEGF treatment– naïve patients. There is no evidence regarding the efficacy and safety of brolucizumab in patients with nAMD previously treated with an anti-VEGF agent.

Direct comparisons to ranibizumab and bevacizumab are not available. Indirect comparisons based on NMA between brolucizumab and ranibizumab showed no differences in the main outcome (mean change in BCVA) or most of the other outcomes. Differences between brolucizumab and bevacizumab remain unknown since direct comparisons are not available and indirect comparisons between these two treatments were not formally conducted.



1 BACKGROUND

1.1 Overview of the disease or health condition

AMD is a chronic eye disease characterised by progressive degeneration of the macula, the area of the retina responsible for sharp, central vision. Left untreated, AMD can lead to rapid, irreversible vision loss. Globally, 8.7% of all cases of blindness are attributed to AMD and it is the most common cause of blindness in developed countries (31, 32). Clinically, AMD is classified into early and late stages. The late stages of disease progression in AMD are further classified into two types: nAMD and atrophic AMD (1). Although nAMD represents only approximately 10% of all AMD cases, it accounted for approximately 90% of cases of severe vision loss due to AMD before the introduction of anti-VEGF therapies (33).

The risk of developing late AMD can be assessed using the risk scale derived from the Age-Related Eye Disease Study and based on a combination of retinal abnormalities. The risk of 5-year progression to late AMD is 0.5% for score 0 (normal ageing changes) to 50% for score 4 (34, 35). When one eye is affected, the risk of developing neovascularisation in the contralateral eye is 12.2% by 1 year and 26.8% by 4 years from initial diagnosis in the first eye (36).

1.1.1 Pathophysiology

nAMD is an acute and rapidly progressing disease characterised by leaking of fluid due to the formation of abnormal blood vessels underneath the macula. This phenomenon, known as CNV, is the defining feature in nAMD and occurs in response to abnormally high levels of VEGF (37). The newly formed blood vessels are fragile and leak fluid, and progressive exudation from the macula can lead to separation of Bruch’s membrane, retinal pigment epithelium (RPE) and the retina, as well as accumulation of sub-RPE, subretinal fluid (SRF) and/or intraretinal fluid (IRF). This leads to generalised thickening of the retina (central subfield thickness [CSFT]) and the generation of cystic spaces (2, 38). Unresolved fluid accumulation leads to disruption of the anatomic architecture of the retina and ultimately leads to progressive, severe and irreversible vision loss due to photoreceptor degeneration (39).

1.1.2 Prevalence and incidence

nAMD is the leading cause of severe vision loss and legal blindness among individuals aged >65 years in Europe, North America, Australia and Asia, and impacts an estimated 20–25 million people worldwide (2, 3). Prevalence reports have estimated that nAMD affects approximately 1.7 million people in Europe (4, 5). In developed nations, the estimated increase in population ageing is a contributing factor to the projected increase in nAMD prevalence, with the proportion of the population aged ≥60 years anticipated to increase and account for 35% of the population in Europe by 2050 (40). The estimated incidence of late AMD in Europe in 2013 was between 2.9 and 3.7 per 1000 person-years (6).

1.1.3 Symptoms and burden of the disease

The early and intermediate stages of AMD usually occur without symptoms, with minimal or no vision loss. As the disease progresses into late AMD, the symptoms of nAMD include reduced VA, blurred vision, reduced contrast sensitivity, metamorphopsia, scotoma, photopsia and difficulties in dark adaptation (1, 41-44).

nAMD is a debilitating, chronic disease that significantly impacts patients’ HRQoL, independence and functional ability. Several studies have shown that overall HRQoL is significantly associated with the degree of visual impairment suffered (45-47). Patients with nAMD commonly have difficulty in carrying out activities of daily living, increasing the likelihood that patients will require caregiver assistance; approximately 50% of patients with nAMD require caregiver support with instrumental daily activities (48). As a result, the nAMD-associated caregiver burden can be substantial. A study of nAMD patients found that the need for care increased with the level of visual impairment (49). The results showed that 35% and 37% of those with no visual impairment received formal and informal care, respectively, compared with 52% and 70% of those with moderate visual impairment and 56% and 89% of those with severe visual impairment.



1.2 Current clinical practice

The aim of nAMD treatment with currently available drugs is to resolve the accumulation of retinal fluid and subsequently recover and/or preserve visual function, while slowing disease progression. Early detection of disease onset, prompt therapeutic intervention and continuous follow-up to detect fluid accumulation are critical, as vision loss becomes irreversible with delayed diagnosis and treatment (2).

Identification of VEGF as a major pathogenic feature in the development of nAMD has positioned anti-VEGF therapies as the standard of care for most patients. Older therapies, such as laser photocoagulation therapy and verteporfin photodynamic therapy (PDT), remain a therapeutic option for selected patients in whom VEGF inhibition is not advisable (2).

Two authorised anti-VEGF treatment options for nAMD are currently available in Europe: aflibercept (Eylea®) (16) and ranibizumab (Lucentis®) (17). A third anti-VEGF product, bevacizumab (Avastin®) (18), is frequently used off-label for nAMD. At the moment, ranibizumab is considered the reference standard for treatment in the European Society of Retina Specialists guidelines (2). The efficacy of aflibercept was demonstrated in two phase III studies in a noninferiority setting against ranibizumab (17). Noninferiority trials comparing bevacizumab with ranibizumab showed similar effects for maintaining or improving VA for the same treatment regimen (monthly injections or PRN), while anatomic endpoints favoured ranibizumab. SRs (19-22) concluded that there are no significant differences between the two drugs after 2 years of follow-up.

According to national (9-15) and European (2) guidelines, nAMD should be treated with anti-VEGF agents. The choice of agent and regimen should be individualised, taking into account clinical criteria, patient preferences and health care system characteristics. Patients are monitored at regular intervals and, in addition to fixed regimens, individualised dosing schemes are used. Flexible treatment strategies based on imaging findings include TREX (the interval between injections is extended when no CNV activity is observed) and PRN regimens (treatment is stopped when no activity is observed, and restarted when necessary); PRN and extend (PRNX) combines both strategies. Bevacizumab for off-label ophthalmologic use is covered in several European national health care systems. Informed consent after discussing the benefits, risks and off-label use of the drug is mandatory before administration of the drug (11, 13, 14, 50, 51). An overview of the management of the disease from country-specific and European guidelines is presented in Appendix 1: Guidelines for management of AMD.

Since the introduction of anti-VEGF therapies there has been a reduction in the incidence of blindness and visual impairment due to nAMD (7, 8). In clinical trials, the anti-VEGF therapies currently in use maintained VA in approximately 90% of patients over 2 years (52-54). In real-world settings it has been shown that anti-VEGF therapies preserve vision during the first year of treatment, with a gradual decline over time (55). Real-world evidence demonstrates that visual outcomes with current anti-VEGF therapies are related to injection frequency. Clinical trial dosing regimens for currently available anti-VEGF therapies are difficult to achieve in clinical practice and thus injections are not commonly administered at the recommended frequency. As a result, real-world visual outcomes vary among countries and are often less favourable than clinical study results (56-58). The prevalence of nonresponsiveness to anti-VEGF therapy in treatment-naïve patients has been assessed in retrospective studies. A study evaluating treatment with ranibizumab or aflibercept found that 22.4% of patients did not respond to treatment and 12.7% developed early tachyphylaxis, with no correlation between the type of anti-VEGF agent and nonresponse to therapy (59). A second study found that the prevalence of initial nonresponders to ranibizumab was 10.1% (60).

There are significant differences in costs among anti-VEGF drugs. As a result, on the basis of cost-effectiveness considerations, bevacizumab is often used as a first-line treatment in countries where it is available as a treatment option for nAMD, while ranibizumab or aflibercept is offered as second-line treatment. In situations or countries where off-label bevacizumab is not considered an option, treatment with ranibizumab or aflibercept is recommended. Sequential administration of different anti-VEGF agents is usual in clinical practice when clinical outcomes are not achieved with the first selected agent. However, the optimal sequence of treatment has not been established through RCTs.



1.3 Features of the intervention

Brolucizumab (Beovu®) is a humanised single-chain Fv inhibitor of VEGF-A. A single-chain Fv is an autonomous binding agent that comprises only the variable domains of the monoclonal antibody (joined by a short flexible linker peptide) that are responsible for binding to its receptor (24). Features and administration of brolucizumab and other treatment options are presented in Table 1.1 and Table 1.2.



Table 1.1. Features of the intervention and other treatment options

Nonproprietary name (active substance)

Brolucizumab Aflibercept Ranibizumab Bevacizumab

Proprietary name Beovu® Eylea® Lucentis® Avastin®

Registered EMA indication

Brolucizumab is indicated in adults for the treatment of neovascular (wet) AMD

Aflibercept is indicated for adults for the treatment of neovascular (wet) AMD

Ranibizumab is indicated in adults for the treatment of neovascular (wet) AMD

Bevacizumab does not have an EU marketing authorisation for neovascular AMD

MAH Novartis Europharm Limited Bayer AG Novartis Europharm Limited Roche Registration GmbH

Contraindications Hypersensitivity to the active substance or to any of the excipients. Patients with active or suspected ocular or periocular infections. Patients with active intraocular inflammation.

Hypersensitivity to the active substance or to any of the excipients listed. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanised antibodies. Pregnancy.

Drug class Anti-VEGF

Pharmaceutical formulation(s)

120 mg/ml solution for injection in prefilled syringe. 120 mg/ml solution for injection

40 mg/ml solution for injection in prefilled syringe.

10 mg/ml solution for injection in prefilled syringe. 10 mg/ml solution for injection.

25 mg/ml solution for infusion. Injections for ophthalmic use are prepared by hospital pharmacies.

Anatomical therapeutic chemical code

S01LA06 S01LA05 S01LA04 L01xC07

Source: Summary of product characteristics for Beovu®, Eylea® and Lucentis®. Systematic reviews on anti-VEGF agents were consulted for the bevacizumab regimen (29, 30). Abbreviations: AMD=age-related macular degeneration; EMA=European Medicines Agency; VEGF=vascular endothelial growth factor.



Table 1.2. Administration and dosing of the technology and other treatment options

Active substance

Brolucizumab Aflibercept Ranibizumab Bevacizumab

Method of administration

Intravitreal injection

Doses 6 mg (0.05 ml) 2 mg (0.05 ml) 0.5 mg (0.05 ml) 1.25 mg (0.05 ml)

Dosing frequency

According to the SPC: Initial treatment: one injection every 4 weeks for the first three doses. A disease activity assessment is suggested 16 weeks after treatment initiation. In patients without disease activity, treatment every 12 weeks should be considered. In patients with disease activity, treatment every 8 weeks should be considered. Physicians may further individualise treatment intervals according to on disease activity.

According to the SPC: Initial treatment: one injection every 4 weeks for the first three doses. Fixed regimen: the treatment interval is extended to 2 months. Treat-and-extend: based on physician’s judgement of visual and/or anatomic outcomes, injection intervals may be increased in 2- or 4-weekly increments. Treatment intervals >4 months between injections have not been studied.

According to the SPC: Initial treatment: one injection every 4 weeks until maximum visual acuity is achieved and/or there are no signs of disease activity. Thereafter, monitoring and treatment intervals should be determined by the physician and should be based on disease activity, as assessed using visual acuity and/or anatomic parameters.

Dosing frequency according to available evidence is: Initial treatment: one injection every 4 weeks for the first 3 months. Fixed regimen: one injection every 4 weeks.

Standard length of a course of treatment

Treatment is continuous. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, it should be discontinued.

Dose adjustments

No dose adjustments are necessary.

Source: Summary of product characteristics for Beovu, Eylea and Lucentis. Systematic reviews on anti-VEGF agents were consulted for the bevacizumab regimen(29, 30). Abbreviations: SPC=summary of product characteristics.



2 OBJECTIVE AND SCOPE

The aim of this EUnetHTA joint REA is to compare the clinical effectiveness and safety of brolucizumab in the target patient population with relevant comparators. The target patient population and relevant comparators (based on the requirements of EUnetHTA partners) are defined in the project scope below.

Table 2.1. Scope of the assessment

Population Adults with neovascular (wet) age-related macular degeneration

Intervention Brolucizumab (Beovu®) as an intravitreal injection at a dosage strength of 6 mg/0.05 ml

Comparison Aflibercept (Eylea®) 2 mg/0.05 ml

Ranibizumab (Lucentis®) 0.5 mg/0.05 ml

Bevacizumab (Avastin®) 1.25 mg/0.05 ml1

Efficacy outcomes

Best corrected visual acuity (treated eye)2

Anatomic parameters of disease activity:

Central subfield thickness

Choroidal neovascularisation area

Subretinal fluid

Intraretinal fluid/intraretinal cyst

Subretinal pigment epithelium fluid

Neurosensory retinal thickness

Vision-related quality of life2

Health-related quality of life

Treatment frequency of brolucizumab in loading/maintenance phase (e.g., proportion of patients maintained on dosing every 12 weeks through to week 48)2

Safety outcomes

Adverse events due to treatment2

Any adverse events

Serious adverse events

Grade ≥3 adverse events

Death as a serious adverse event

Adverse events of special interest (e.g., ocular/non-ocular adverse events)

Rates of discontinuation2

All causes

Discontinuation due to adverse events

Percentage of patients who discontinued the treatment by reason for discontinuation

1 At the time of publication of the Joint Assessment (March 2020), bevacizumab did not have an EU marketing authorisation for the indication under assessment. Bevacizumab is included as a comparator because of its importance identified in the

EUnetHTA PICO survey; however its inclusion in the Joint Assessment should not be understood or quoted as a recommendation for its unlicensed use. 2 Outcomes related to issues particularly emphasised by patient organisations (please see patient involvement in Section

3.6 and Section 5).

2.1 Deviations from the Project Plan

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) method was not applied by either the MAH or the authors of this joint REA for rating the quality or certainty of the evidence (as high, moderate, low and very low certainty).



3 METHODS

The assessment is mainly based on the data and analyses included in the submission dossier prepared by the MAH, received on 12th November 2019. During the assessment, the completeness of the data and analyses in the submission dossier was verified. Furthermore, the methods for data analysis and synthesis applied by the MAH were checked against the requirements for the submission dossier and applicable EUnetHTA guidelines and assessed with regard to scientific validity.

In addition, during the scoping phase the MAH indicated that no information about the off-label comparator bevacizumab would be included in the submission dossier. Since bevacizumab was identified as an important off-label comparator option for nAMD in several European countries in the PICO survey, the authoring team decided to perform an SLR with the support of the EUnetHTA Senior Scientific Officer.

3.1 Information retrieval

3.1.1 Information retrieval submitted by the MAH

The evidence base with regard to the drug under assessment provided by the MAH was reviewed by the information specialist on the authoring team. Search strategies were checked for appropriateness and the results of information retrieval included in the MAH submission dossier were checked for completeness against a search in study registries and against the studies included in the regulatory assessment report. Supplementary searches were conducted to check for possible incompleteness of the study pool.

The MAH provided an SLR to identify relevant evidence of the efficacy and safety of brolucizumab versus authorised comparator therapies for the treatment of nAMD. The following electronic databases were included: EMBASE, MEDLINE, Medline-in-Process and the Cochrane Library. In addition to the searches of electronic databases, manual searches were also conducted for congress proceedings and clinical trials registries (US National Library of Medicine and EU Clinical Trials Register [EU-CTR]). An original search was conducted on 10th September 2018, with an update conducted on 13th June 2019. The manual searches covered the period between 2015 and 2019. Detailed search strategies for each electronic database and the search terms used for the manual searches are available in the appendices in the MAH submission dossier. Complete details of the search are available in Table 3.1.

The PICO selected for the SLR (Table 3.1) differed from the PICO proposed in the Project Plan (Table 2.1). Most notably, the PICO for SLR provided by MAH did not include bevacizumab as a comparator. In addition, PDT with verteporfin, laser photocoagulation therapy and macular surgeries were included as comparators; these were not selected in the Project Plan and are thus not considered relevant for this assessment.



Table 3.1. Summary of information retrieval and study selection submitted by the MAH

Element Details

Inclusion criteria

Population: Patients aged ≥18 years with neovascular age-related macular degeneration

Intervention: Brolucizumab

Comparators:

Ranibizumab

Aflibercept

Photodynamic therapy with verteporfin

Laser photocoagulation therapy

Macular surgeries

Outcomes:

Visual acuity

Other measures of visual acuity (blindness and gain/loss of ≥15 letters)

Central retinal thickness


Severe ocular and systemic adverse events

Treatment discontinuation

Injection and monitoring frequencies

Study type:

RCTs or crossover RCTs (if data presented at the time of crossover) of 44 weeks or longer

Open-label extension studies of RCTs

Publication type: peer reviewed published in journals or retrieved via hand searches on relevant websites

Language: English

Exclusion criteria

Population: Polypoidal choroidal vasculopathy (if >10% of population)

Intervention/comparators: intervention or comparator of interest not included in any arm of the trial

Outcomes: outcomes that do not measure efficacy, safety or HRQoL

Study type: SLRs, observational or real-world evidence studies, single-arm trials, nonrandomised trials, post hoc analyses, case studies, reviews

Publication type: letters, editorials and conference abstracts

Language: languages other than English

Source: Submission dossier.

Abbreviations: RCT=randomised controlled trial; SLR=systematic literature review.

3.1.2 Information retrieval for the NMA submitted by the MAH

Following the identification of relevant studies from the clinical SLR, a feasibility assessment was conducted to assess the possibility of performing an NMA and of conducting baseline pooling analysis to estimate the absolute treatment effect for treatment regimens with more than one trial. The eligibility criteria for the NMA were based on the PICO criteria presented in Table 3.2.



Table 3.2. PICO framework for the network meta-analysis

Topic Description

Population Patients aged ≥18 years with neovascular age-related macular degenerationa

Intervention Brolucizumab

Comparators Ranibizumab (Lucentis®)

Aflibercept (Eylea®)

Outcomes Mean change in best corrected visual acuity

Mean change in central retinal thickness

Proportion of patients gaining at least 15 letters on the ETDRS test

Proportion of patients losing at least 15 letters on the ETDRS test

Overall discontinuation

Injection frequenciesb

Adverse eventsb

Study type and duration

RCTs of 44 weeks or longer, crossover RCTs (if data presented at the time of crossover)

Open-label extension studies of RCTs


Abbreviations: ETDRS=Early Treatment Diabetic Retinopathy Study; RCT=randomised controlled trial. aStudies that enrolled patients with uncommon manifestations of neovascular age-related macular degeneration, including polypoidal choroidal vasculopathy, were excluded if these subtypes comprised >10% of the total population. bThese outcomes were evaluated through baseline pooling analysis only.

Only studies investigating therapies and doses licensed in the EU were included in the NMA. On the basis of these criteria, the treatments and doses considered in the NMA base-case analysis were brolucizumab 6 mg (and 3 mg) as the intervention of interest, and ranibizumab 0.5 mg and aflibercept 2 mg as comparators.

Different treatment regimens were also taken into account in the NMA using an attribute-based approach (e.g., PRN, TREX). Each treatment was evaluated separately by its treatment regimen, including whether an LP was used.

Regimen-based pooling was conducted for the mean change in BCVA, patients gaining at least 15 letters, patients losing at least 15 letters, injection frequency and AEs. Molecule-based pooling was conducted for discontinuation as well as AEs. The outcomes were analysed at both 1 and 2 years.

3.1.3 Information retrieval for bevacizumab

Bevacizumab was not included as a comparator either in the SLR or in the NMA searches performed by the MAH, even though it had been identified as an important off-label comparator option in the PICO survey and the authoring team had specifically requested its inclusion.

Therefore, an exhaustive literature search was conducted for clinical review of bevacizumab in nAMD, which was developed by the information specialist with input from the authoring team. The selection criteria are presented in Table 3.3.

As the first step, the following bibliographic databases were searched (through the OVID interface): MEDLINE, Embase, the Cochrane Database of Systematic Reviews and the Centre for Reviews and Dissemination (CRD) database. The aim of these searches was to find comprehensive and high-quality SRs and NMAs of RCTs.

The literature search was performed on 24th October 2019 to identify studies meeting the predefined eligibility criteria in Table 3.3. The searches did not include language or publication year restrictions.



Table 3.3. Selection criteria for the literature searches regarding bevacizumab

Topic Description

Population Adults with neovascular (wet) age-related macular degeneration

Intervention Bevacizumab

Comparators Brolucizumab, aflibercept, ranibizumab

Outcomes Efficacy

Best corrected visual acuity

Anatomical parameters of disease activity

Vision-related quality of life


Safety

Adverse events due to treatment

Any adverse events

Serious adverse events

Grade ≥3 adverse events

Death as a serious adverse event

Adverse events of special interest (e.g., ocular/non-ocular adverse events)

Rates of discontinuation

All causes

Discontinuation due to adverse events

Percentage of patients who discontinued treatment by reason for discontinuation

Design Systematic reviews or network meta-analyses that include RCTs

Abbreviations: RCT=randomised controlled trial.

In a second step and to identify primary studies (RCTs), a systematic search of the OVID interface in MEDLINE and Embase was conducted to update the SRs or NMAs selected in the first step, taking into account the date of the search strategies in those reports until 19th November 2019.

Controlled vocabulary and keywords used in the search included terms for nAMD and the drugs of interest. Methodological filters were applied to limit retrieval to meta-analyses and SRs and to clinical controlled trials. The detailed search strategies are presented in Appendix 2: Searches strategies for bevacizumab Literature ReVIEW.

Once the search results were obtained, two researchers independently performed initial screening of the records (titles and abstracts) using the predefined inclusion and exclusion criteria. Conflicts regarding screening decisions between the two researchers were resolved via discussion and consensus.

The full-text articles of the records considered potentially relevant by title and abstract by both researchers were obtained and were reviewed independently to classify each record as “included” or “excluded”. Any discrepancies were resolved via discussion.

3.2 Data extraction

Information used for assessment of the clinical effectiveness and safety was extracted from the submission dossier and verified against the CSRs or other original documentation provided in the submission dossier. Information about the off-label comparator bevacizumab was extracted from the literature review conducted by the authoring team with support from the EUnetHTA Senior Scientific Officer.

3.3 RoB assessment

In accordance with EUnetHTA guideline recommendations (61), the quality rating tool developed by the Cochrane Collaboration (version 5.1.0) (62) was used to assess the RoB in randomised trials.

RoB at the study level was assessed for six different domains:



The method used to generate the sequence for randomisation (random sequence generation);

The method used to mask the sequence for allocation to treatment (allocation concealment);

The measures used to ensure the blindness of the study with respect to treatment assignment (blinding of participants, medical personnel and outcome assessors);

The completeness of the data for each outcome considered (incomplete outcome data);

The selective description of the results (selective outcome reporting);

Other sources of bias (e.g., bias due to early interruption of the study because of the benefits without an appropriate stopping rule, use of a nonvalidated measurement instrument, incorrect statistical analysis).

For each domain, two independent assessors judged the RoB (low risk, high risk or unclear) on the basis of the information retrieved from the full-text publications, the protocols and the submission dossier. RoB assessment (at both the study level and outcome level) was conducted only for the randomised phase III studies that included relevant direct evidence on brolucizumab and comparators.

Studies included in the NMA conducted by MAH were not individually assesed for RoB by the authoring team, but the MAH provided quality assessment for each trial.

The individual studies included in the SRs on bevacizumab were not assessed separately for RoB by the authors of this joint REA, as the RoB of the RCTs described in the SRs was already assessed for by the authors of the selected SRs. In addition, the quality of the SRs was assessed using the AMSTAR-2 checklist (26). The AMSTAR-2 critical domains are as follows:

The protocol registered before commencement of the review;

The adequacy of the literature search;

The justification for excluding individual studies;

The RoB for individual studies included in the review;

The appropriateness of the meta-analytical methods;

The consideration of RoB when interpreting the results of the review;

The assessment of presence and likely impact of publication bias.

The critical appraisal of key issues in indirect comparisons, including comments for assessing the consequences of application to drug evaluation, was evaluated using a structured checklist developed by Ortega et al. (25). The checklist has two parts. The first consists of three eliminatory key questions while the second includes 17 items: five regarding quality, five regarding clinical issues and seven dealing with the methodology and statistics.

3.4 External validity

The external validity of the trials included was assessed using EUnetHTA guidelines on the applicability of evidence in the context of an REA of pharmaceuticals considering the following elements: population, intervention, comparator, outcomes, and setting (63, 64).

3.5 Results and analyses for the studies included

The information in the submission dossier on the study design, study methods, populations, endpoints (patient relevance, validity and operationalisation) and study results was evaluated. The results including direct evidence from phase III trials comparing brolucizumab and aflibercept form the basis for the results and assessment. The results of the two relevant reviews (including bevacizumab) identified in the literature review conducted by the authoring team are presented and summarised separately. Finally, the results from the NMA conducted by the MAH are presented and assessed as applicable.



3.5.1 Meta-analysis and indirect evidence

In the absence of head-to-head data for brolucizumab versus ranibizumab, an NMA was performed by the MAH to assess the relative effectiveness of brolucizumab versus aflibercept and ranibizumab.

Standard pairwise meta-analyses based on direct comparisons were carried out between pairs of treatments when possible for cases in which two treatments were compared in two or more clinical trials. Direct pairwise comparisons were conducted to assess the heterogeneity between studies when there was more than one study comparing the same treatments.

The NMA was conducted using a Bayesian framework that preserved the randomisation of each trial. The relative goodness of fit of the models was assessed using the deviance information criterion. Both fixed-effects and random-effects models were developed and the one associated with the lowest deviance information criterion (DIC) was selected, unless the absolute difference between the DIC values of the two models was less than three points, then the fixed-effect model was chosen.

The base-case NMA included studies with treatment-naïve patients (naïve to any anti-VEGF treatment) and mixed populations (treatment-naïve and previously treated with an anti-VEGF agent). All trials that were connected via common comparators to brolucizumab were included in the analyses. Outcomes included in the NMA are reported in Table 3.2.

During the assessment, the methods applied for the meta-analyses presented in the submission dossier and, if applicable, the justification for deviations from the procedures described above were evaluated.

Potential sources of heterogeneity in the studies included in the NMA were investigated and discussed with clinicians on the basis of the descriptive statistics. Analyses to determine the inconsistency of the assessment results were conducted.

Several sensitivity analyses were conducted to test the assumptions adopted in the base-case NMA. Sensitivity analyses were related to the networks of evidence, the time of assessment and the methodological choices made.

Networks of evidence

A sensitivity analysis was conducted for trials that reported only the median change in BCVA and retinal thickness.

In addition, the following two sensitivity analyses were conducted on the basis of clinical expert opinion:

The RIVAL study was excluded from VA outcomes (mean change in BCVA and patients gaining or losing at least 15 letters) as patients in RIVAL had the highest mean BCVA at baseline and the results from this study appeared to be outlier values;

The PIER and MARINA studies were excluded, as these two trials compared an active treatment to sham IVT, which could have introduced bias into the relative efficacy results versus results from studies comparing anti-VEGF treatments.

Time of assessment

A sensitivity analysis was performed in which results before 52 weeks and 104 weeks were extrapolated. Given that time equivalence was assumed between 48 and 52 weeks for 1-year results and between 96 and 104 weeks for 2-year results, this analysis made it possible to identify if the results are highly influenced by this assumption.



Methodological analyses

The following methodological sensitivity analyses were run to test the effects of the model specifications chosen:

A sensitivity analysis was conducted regarding trials with imputed standard error from the baseline and final value: rather than correlation of 0.5, correlation of 0.7 between the baseline and the final value was assumed;

Two sensitivity analyses were conducted regarding trials with an imputed standard error from the mean standard deviation of the other trials:

o The minimum standard deviation instead of the mean;

o The maximum standard deviation instead of the mean.

3.5.2 Subgroup analyses and other effect modifiers

The following subgroups considered relevant for the analysis were: age category; sex (male and female); baseline BCVA categories; baseline CSFT category; baseline lesion type (predominantly classic, minimally classic, occult); baseline CNV lesion size; baseline lesion size by lesion type; and baseline fluid status (IRF, SRF, sub-RPE fluid).

During the assessment, the subgroup analyses examining potential effect modifiers presented in the submission dossier and the corresponding methods applied were evaluated.

3.6 Patient involvement

At the start of this joint REA, EUnetHTA conducted an open call for patient organisations. General questions were asked to elicit patients’ views on living with the disease, important outcomes to be considered in this assessment and expectations about the drug under assessment. The key questions and a summary of the answers are presented in Section 5.

European and national patient organisations were asked to provide an organisational perspective on the questions in English. In all parts of the open call, the term patient refers to anyone living with, or who has lived with, the condition for which the new medicine is indicated.

Seven patient organisations completed the survey: Asociación Acción Visión España (Spain); Društvo MDSS Kranj (Slovenia); Fighting Blindness (Ireland); Macula Retina (Spain); Retina Bulgaria (Bulgaria); Retina International (Ireland); and Retina Suisse (Swiss Confederation).

The information gathered from the open call was used to inform the scope of this assessment and in particular the outcomes to be considered. In Table 2.1, the outcomes related to issues particularly emphasised by patient organisation are identified.



4 RESULTS

4.1 Information retrieval

4.1.1 Check for completeness of the literature search submitted by the MAH

Overall, the authors considered that the search followed EUnetHTA guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

The study pool for the assessment was compiled on the basis of the following information sources reported by the MAH in the submission dossier:

Bibliographic databases (last search on 12th–13th June 2019);

Study registries (the date when the search was run was not reported);

A manual search (date when the search was carried out is not reported).

In general, the scope described by the MAH in the submission dossier presents one significant difference from the scope defined in the Project Plan: the MAH does not include bevacizumab as a comparator. In addition, CRT was the only outcome related to anatomic parameters of disease activity considered by the MAH.

The main concerns regarding the searches are as follows:

Firstly, the searches are not up to date (more than 3 months old) and do not meet the requirements from the Project Plan; therefore, newer evidence could be missing;

Secondly, regarding clinical trial registries, the search syntax in the submission dossier includes the same strategy for both registries, and the two interfaces do not allow running the searches in the same way. Results for the search in all the study registries are not reported; therefore, this could not be checked.

Besides these main overall issues, other shortcomings were noted:

The flow chart results do not match with the hits shown in the search history appendix;

Synonyms for the target intervention are missing;

There are misspellings in the search strategies and search fields are missing in some strategy lines.

Overall, the information specialist questioned the completeness of the study pool. Thus, a search in study registries was performed to check the completeness of the study pool for RCTs with brolucizumab.

Check for completeness of the study pool for direct comparisons

A search in study registries for brolucizumab (ClinicalTrials.gov, EU-CTR, ICTRP Search Portal, last search on 20th December 2019) was carried out (Appendix 3: Searches performed by the Information specialist to the completeness of the study pool).

The check did not identify any additional relevant study.

Check of completeness of the study pool for indirect comparisons with a common comparator

A search in study registries (ClinicalTrials.gov, EU-CTR, ICTRP Search Portal, last search on 20th December 2019) was carried out (Appendix 3: Searches performed by the Information specialist to the completeness of the study pool).

A focused search (simple Boolean search as well as the “Similar articles” function in PubMed) was not possible because of inconsistencies on the platform on days when the information retrieval was checked



for the first time (16th–20th December 2019); this is why a focused search was run on 7th February 2020. The check did not identify any additional RCTs.

4.1.2 Results for the bevacizumab literature search

In the first step of the literature search (conducted in October 2019) to identify SRs/NMAs regarding the relative efficacy and safety of treatment with bevacizumab in nAMD, 371 records were retrieved among the four databases (212 from MEDLINE, 22 from Embase, 12 from the Cochrane Database of Systematic Reviews and 125 from CRD). A flowchart of the selection process to identify SRs/NMAs is shown in Figure 4.1. The screening results with reasons for exclusion based on title and abstract are in Appendix 4: Results from the screening of the searches of bevacizumab. Fifty-six records were selected for full-text review. Thirty-five of those documents met the inclusion criteria. They are briefly described in Appendix 5: Studies (SR or NMA) that met the eligibility criteria for the bevacizumab literature review. There was consensus between the two researchers in the selection of studies. The reasons for exclusion by full-text report are described in Appendix 6: Excluded articles from bevacizumab literature review.

Figure 4.1. Flowchart of the selection process to identify systematic reviews and network meta-analyses.

The second step to update the SRs or NMAs identified in the first step searched for RCTs: 110 records were retrieved from the searches conducted in November 2019 (87 from MEDLINE and 23 from Embase). There were two duplicates. All the records were excluded by title or abstract. The flowchart of the selection process to identify RCTs is shown in Figure 4.2. The screening results with the reasons for exclusion based on title and abstract are in Appendix 4: Results from the screening of the searches of bevacizumab. No records were reviewed by full text, nor included from the searches in both databases.

Records identified in the searches

n=371

Records after deleting duplicates n=300

Articles excluded based on title and abstract

n=244

Articles excluded by full text

n=14

Relevant articles included n=35

Potentially relevant articles retrieved for more detailed evaluation

n=56

Full text not available, articles excluded based on abstract

n=7



Figure 4.2. Flowchart of the process to select randomised controlled trials to update the systematic reviews included.

4.2 Studies included in the assessment

4.2.1 Studies included from the literature search submitted by the MAH

In literature search submitted by MAH, a total of 48 publications reporting on 38 RCTs were included in the SLR, as shown in the PRISMA diagram in Figure 4.3, extracted for four treatments: ranibizumab, aflibercept, brolucizumab and PDT. Three of these RCTs compared brolucizumab to a relevant comparator: HAWK (NCT02307682), HARRIER (NCT02434328) and OSPREY (NCT01796964).

Citations identified in the searches

n=110

Articles excluded by full text n=0

Relevant articles included n=0

Citations after deleting duplicates n=108

Articles excluded based on title and abstract n=108



Figure 4.3. PRISMA diagram.


HAWK and HARRIER are phase III trials and OSPREY is a phase II trial. In all three studies the efficacy and safety of brolucizumab were compared to aflibercept.

The studies listed in Table 4.1 were included in the assessment. The OSPREY study was a phase II study and in the REA it has been handled as supportive evidence, as well as in the EMA market authorisation process and the REA submission dossier. It has a different primary outcome to HAWK and HARRIER. Thus, results from the OSPREY study are presented separately as supportive evidence in Section 4.10.

It is worth mentioning that in addition to the brolucizumab 6 mg dose, the HAWK study included a brolucizumab arm with a dose of 3 mg. The EMA has approved brolucizumab 6 mg for this indication and for this reason the scope for this assessment (Table 2.1) focuses on the brolucizumab 6 mg dose. Results from the brolucizumab 3 mg arm are described in brief as supportive evidence in Section 4.9.



Table 4.1. Study pool: list of relevant studies used for the assessment

Study Study category

Study for marketing authorisation of the technology under assessment

Sponsored or third-party

Available documentation

HAWK (NCT02307682)

Yes Sponsored HAWK CSR Dugel et al. 2020 (28) CHMP Assessment Report

HARRIER (NCT02434328) Yes Sponsored HARRIER CSR Dugel et al. 2020 (28) CHMP Assessment Report

OSPREY (NCT01796964) Yes Sponsored OSPREY CSR

Dugel et al. 2017 (65) CHMP Assessment Report

Abbreviations: CSR=clinical study report; CHMP=Committee for Medicinal Products for Human Use.

4.2.2 Studies included from the NMA literature search submitted by the MAH

Given the data availability and homogeneous populations in the trials identified, an NMA was determined to be feasible and was conducted on all outcomes of interest considered in the MAH’s PICO. The trials included in the base case are summarised in Table 4.2.

Overall, the studies were considered largely homogeneous, and representative of the target population and treatments. Potential sources of heterogeneity identified by the MAH were as follows:

Outcome measures: For continuous measures, only mean changes were included in the analyses, following a conservative approach. This led to exclusion of one trial (RABIMO);

Previous treatment use: Among the trials included in the base case, most were conducted among treatment-naïve patients according to the inclusion criteria (defined as patients who are naïve to other anti-VEGF agents). Two studies did not report prior therapies but, since pegaptanib was the only authorised treatment at the time, it was considered that patients in the study were predominantly anti-VEGF–naïve and the studies were included in the analysis.

Heterogeneity in the relative treatment effects was assessed for each pairwise comparison using Cochran’s Q test and the I2 statistic. The significance for Cochran’s Q test was set at a level of 10%, or I2 >50%. Forest plots were generated for each comparison to illustrate heterogeneity.

Consistency between direct and indirect comparisons in the NMA was assessed.

The RCTs included in the NMA were qualitatively assessed using the CDR for assessing RoB in randomised trials. Overall, the evidence was of moderate to high quality. The greatest RoB was due to insufficient information identified in the publication during the quality assessment. The majority of studies did not have unexpected imbalances in drop-outs between groups.

Overall, the studies included in the NMA were considered largely homogeneous and representative of the target population and treatments. There was homogeneity among the trials included in the NMAs for the following baseline characteristics:

Age;

Sex (proportion of males);

VA (ETDRS);

Retinal thickness (CRT, CMT, CSFT, CFT);

CNV lesion size in disc areas and mm2;

CNV lesion type (predominantly classic, minimally classic and occult).



Table 4.2. Overview of trials included in the network meta-analysis

Author, year Assessment

time (months) Trial name

Sample size

Phase Blinding status

Intervention Comparator

Dugel 2017 12 OSPREY 90 II Double-blind LP → Bro 6 mg Q8W → Q12W LP → Afli 2 mg Q8W

Dugel 2020 96 weeks HARRIER 739 III Double-blind LP → Bro 6 mg Q12W/Q8W LP → Afli 2 mg Q8W

Dugel 2020 96 weeks HAWK 1078 III Double-blind LP → Bro 6 mg Q12W/Q8W LP → Bro 3 mg Q12W/Q8W

LP → Afli 2 mg Q8W

Martin 2011/ Martin 2012

12/24 CATT 1143 NR Single-blind Rani 0.5 mg Q4W Rani 0.5 mg PRN

Bev 1.25 mg Q4W Bev1.25 mg PRN

Eldem 2015 12 SALUTE 77 IV Open-label LP → Rani 0.5 mg PRNX LP → Rani 0.5 mg PRN

Feltgen 2017 12 RABIMO 40 IV Open-label LP→ Rani 0.5 mg Q8W LP → Rani 0.5 mg PRN

Heier 2012/Yuzawa 2015/ Schmidt-Erfurth 2014

12/96 weeks VIEW 1 & 2/ VIEW 1 & 2/ Pooled

1217 III Double-blind Afli 0.5 mg Q4W → PRN Afli 2 mg Q4W → PRN LP → Afli 2 mg Q8W → PRN

Rani 0.5 mg Q4W → PRN

Ho 2014 24 HARBOR 1089 III Double-blind Rani 0.5 mg Q4W Rani 2 mg Q4W

LP → Rani 0.5 mg PRN LP → Rani 2 mg PRN

Gillies 2019/ Hunyor 2018

12/24 RIVAL 278 III Double-blind LP → Rani 0.5 mg TREX LP → Afli 2 mg TREX

Kertes 2019 24 CAN-TREAT 580 NR Open-label LP → Rani 0.5 mg TREX Rani 0.5 mg Q4W

Regillo 2008 12 PIER 184 IIIb Double-blind LP → Rani 0.5 mg Q12W LP → Rani 0.3 mg Q12W

Sham IVT

Rosenfeld 2006/ Chang 2007

24 MARINA 716 III Double-blind Rani 0.5 mg Q4W Rani 0.3 mg Q4W

Sham IVT

Silva 2017 12 TREND 650 IIIb Single-blind LP → Rani 0.5 mg TREX Rani 0.5 mg Q4W

Wykoff 2015/2017 12/24 TREX-AMD 60 IIIb Open-label LP → Rani 0.5 mg TREX Rani 0.5 mg Q4W


Abbreviations: Aflib=aflibercept; Bro=brolucizumab; IVT=intravitreal; LP=loading phase of three initial monthly injections; NR=not reported; PRN=pro re nata dosing regimen; PRNX=PRN and extend dosing regimen; QXW=one injection every X weeks; Rani=ranibizumab; TREX=treat and extend dosing regimen.



4.2.3 Studies included from the bevacizumab literature search

Two SRs were described as relevant reviews used for assessment of bevacizumab, by Solomon et al. (30) (literature search up to January 2018) and Pham et al. (29) (literature search up to August 2017). This latter SR was considered because Solomon et al. did not include aflibercept among the drugs assessed.

Of the 35 articles included that met the eligibility criteria for the bevacizumab literature review, 33 were not further described in detail in the SR of the relative efficacy and safety of bevacizumab in patients with nAMD as the RCTs considered in those reviews are included in the most up-to-date and complete SR by Solomon et al. (30).

Appendix 6: Excluded articles from bevacizumab literature review includes a table that lists RCTs not included in the SR by Solomon et al. that were included in the other references and reasons for exclusion in the SR by Solomon et al. (30). The main reasons for not including the RCTs in the SR performed by Solomon et al. were follow-up of <1 year, dosing studies and studies with combination therapy. The exclusion of those studies is not considered to impact the applicability to our PICO.

A description of the two SRs included and a summary of their results are presented in Section 4.12.

4.3 Excluded studies

None of the studies in the literature search provided by the MAH was excluded for this assessment. The studies excluded from the SLR on bevacizumab and the reasons for their exclusion are described in Section 4.2.

4.4 Characteristics of the studies included: direct evidence

Table 4.3 and Table 4.4 describe the studies used for the assessment. HAWK and HARRIER are phase III multicentre RCTs comparing the efficacy and safety of brolucizumab versus aflibercept 2 mg in a noninferiority setting. Definitions for the analysis populations are provided in Table 4.5.

Table 4.3. Characteristics of the studies included for direct comparison

Study Study design

Patient population

Brolucizumab (patients randomised)

Aflibercept (patients randomised)

Study duration

Primary outcome

HAWK (NCT02307682)

Randomised, double-masked, multicentre, three-arm phase III study (212 study centres across 11 countries)

Treatment naïve patients aged ≥50 years; active CNV lesions secondary to AMD affecting the central subfield in the study eye; IRF and/or SRF affecting the central subfield of the study eye; BCVA between 78 and 23 letters, inclusive, in the study eye at baseline using ETDRS testing

Group 1: 3 mg (N=360) Group 2: 6 mg (N=361)

Group 3: 2 mg (N=361)

96 weeks follow-up


HARRIER (NCT02434328)

Randomised, double-masked, multicentre, two-arm phase III study (147 study centres across 29 countries)

6 mg (N=372) 2 mg (N=371)

96 weeks follow-up


Source: European Medicines Agency public assessment report, submission dossier. Abbreviations: AMD=age-related macular degeneration; BCVA=best corrected visual acuity; CNV=choroidal

neovascularisation; ETDRS=Early Treatment Diabetic Retinopathy Study; IRF=intraretinal fluid; SRF=subretinal fluid.



Table 4.4. Characterisation of the interventions and comparators

Study Brolucizumab Aflibercept Treatment characteristics

HAWK (NCT02307682)

Group 1: 3 mg Group 2: 6 mg

Group 3: 2 mg Loading: Monthly injections for the first 3 months (day 0, week 4 and week 8) across all groups. Maintenance: Q8W injections in aflibercept arm. In both brolucizumab arms the dosing frequency was either Q8W or Q12W, according to the patient’s disease activity. Once patients were adjusted to a Q8W interval, they remained on that interval until the end of the study (week 96/exit)

HARRIER (NCT02434328)

6 mg 2 mg Loading: Monthly injections for the first 3 months (day 0, week 4 and week 8) across all groups. Maintenance: Q8W injections in aflibercept arm. In brolucizumab arm the dosing frequency was either Q8W or Q12W, according to the patient’s disease activity. Once patients were adjusted to a Q8W interval, they remained on that interval until the end of the study (week 96/exit)

Source: Submission dossier. Abbreviations: Q8W=every 8 weeks; Q12W=every 12 weeks.

Table 4.5. Trial populations used for analysis of outcomes in the HAWK and HARRIER studies

Analysis set Description

All enrolled analysis set

All patients who signed informed consent and were assigned a subject number. This analysis set was used to summarise subject disposition and pretreatment AEs.

All randomised analysis set (RAN)

All patients who were randomised in the interactive response technology. This analysis set was used to summarise protocol deviations, analysis restrictions, medical history and prior medications.

Full analysis set (FAS)

All randomised patients who received at least one IVT injection of the study treatment. The FAS served as the primary analysis set for all efficacy analyses, with LOCF imputation of missing/censored (after start of alternative anti-VEGF treatment) BCVA values. The FAS represented the analysis set that was as close as possible to the intent-to-treat principle of including all randomised patients.

Safety analysis set (SAF)

All patients who received at least one IVT injection.

Per protocol analysis set (PPS)

Subset of the FAS that excluded patients with protocol deviations and violations of analysis requirements that were expected to have a major effect on the validity of the assessment of efficacy at week 48.

Source: Submission dossier. Abbreviations: AE=adverse event; BCVA=best-corrected visual acuity; IVT=intravitreal; LOCF=last observation carried

forward; VEGF=vascular endothelial growth factor.

4.4.1 Trial design

A schematic of the study design for the HAWK and HARRIER trials is presented in Figure 4.4. Both trials primarily followed the same study design, with the following differences:

Dosing of brolucizumab (in addition to brolucizumab 6 mg, HAWK also included a brolucizumab dose of 3 mg);

Number of scheduled DAA visits;

Potential dosing interval adjustments (from week 20, DAAs were conducted every 12 weeks in both trials; in HARRIER, additional DAAs occurred at weeks 28, 40, 52, 64, 76 and 88).

Both studies included screening visits (2–14 days before baseline) and a baseline visit (day 0), followed by monthly post-baseline study visits from week 4 until week 96. After confirmation of eligibility at baseline, patients were randomised to receive either brolucizumab 3 mg, brolucizumab 6 mg or aflibercept 2 mg via IVT injection in a 1:1:1 ratio in HAWK, and randomised to receive either



brolucizumab 6 mg or aflibercept 2 mg via IVT injection in a 1:1 ratio in HARRIER. Monthly loading dose injections were given for the first 3 months (day 0, week 4 and week 8) across all arms of both trials, followed by maintenance dosing.

Figure 4.4. HAWK and HARRIER trial design.

Randomisation was 1:1:1 in HAWK and 1:1 in HARRIER. Source: Dugel et al. 2020 (28). Supplementary material. Appendix 3. aHAWK only. bDisease activity assessments were conducted at prespecified visits by a masked investigator. Guidance for

assessing disease activity (based on dynamic functional and anatomical characteristics) was given in the protocol; however, the final decision was made by the investigator. Abbreviations: q8w=every 8 weeks; q12w=every 12 weeks.

Maintenance dosing for aflibercept in both trials was administered at fixed 8-week intervals (Q8W). This was in line with the marketing authorisation for aflibercept for this indication at the time when the HAWK and HARRIER trials were designed. However, individualised aflibercept regimens were included in the SPC indication when the pivotal studies were ongoing. The aflibercept SPC allows further individualised dosing schedules and these regimens are commonly used in clinical practice (16).

Maintenance dosing for brolucizumab in both trials was Q12W/Q8W, where the treatment interval could be adjusted according to the patient’s individual treatment need from 12- to 8-week intervals on the basis of DAA. DAAs were performed by masked investigators at prespecified visits. At the week 16 visit, DAA was based on the decrease in BCVA and anatomic parameters (CSRT, IRF, intraretinal cysts). After week 16, DAA was based on the decrease in BCVA only. More detailed information on the DAA criteria is provided in Table 4.6. If disease activity was identified by the investigator at either of these DAAs, the dosing interval was adjusted to Q8W. Once patients were adjusted to a Q8W interval, they remained on that interval until the end of the study (week 96/exit) and could not return to a Q12W interval.

In both HAWK and HARRIER studies, sham injections were administered to establish an identical monthly injection schedule across treatment arms to maintain the masking and data integrity. Sham was administered by mimicking an IVT injection and using an injection syringe without a needle. (HAWK CSR, HARRIER CSR)



Table 4.6. DAA criteria for the HAWK and HARRIER studies

Study weeks DAA criteriaa

Week 16 Decrease in BCVA of ≥5 letters compared with baseline

Decrease in BCVA of ≥3 letters and CSFT increase ≥75 μm compared with week 12

Decrease in BCVA of ≥5 letters due to wAMD disease activity compared with week 12

New or worse IRF/intraretinal cysts compared with Week 12

Weeks 20, 28b, 32, 40

b and 44 Decrease in BCVA of ≥5 letters due to wAMD disease activity compared

with week 12

Weeks 52b, 56, 64

b, 68, 76

b,

80, 88b and 92

Decrease in BCVA of ≥5 letters due to wAMD disease activity compared with week 48

Source: Submission dossier. a

DAA criteria used to assign brolucizumab every 12 or 8 weeks dosing were developed based on findings from predictive data modelling combined with clinically meaningful vision and anatomic parameters of disease activity. Dynamic criteria

identified in analyses of the PIER, EXCITE and CATT studies support DAA at week 16 for early determination of patients suited to dosing every 8 weeks and to minimise patient reassignment at later time points. Subsequent DAA visits coincide with every 12 weeks dosing visits to allow reassignment to every 8 weeks dosing if patients experience a BCVA decline due

to wAMD at these time points. b

Additional DAA visits were included in the HARRIER study owing to a health authority request. Abbreviations: BCVA=best-corrected visual acuity; CSFT=central subfield thickness; DAA=disease activity assessment; IRF=intraretinal fluid; wAMD=wet age-related macular degeneration.

4.4.2 Statistical methods for primary analyses of the HAWK and HARRIER studies

The objectives were as follows:

The primary hypothesis was noninferiority in terms of the mean change in BCVA from baseline to week 48 (margin of 4 letters) with fewer injections;

The first key secondary efficacy endpoint was the average change in BVCA from baseline over the period from week 36 to week 48;

The statistical hypotheses for the primary and first key secondary efficacy endpoints were intended to demonstrate the noninferiority of brolucizumab to aflibercept.

Noninferiority was demonstrated (i.e., the null hypothesis was rejected) if the lower limit of the two-sided 95% CI for the corresponding treatment difference (brolucizumab [6 mg or 3 mg] vs. aflibercept 2 mg)

was greater than 4 ETDRS letters.

In calculating the study power, a sample size of 297 patients per treatment arm was considered sufficient to demonstrate noninferiority (margin of 4 letters) of brolucizumab 3 mg/6 mg versus

aflibercept 2 mg with respect to the change in BCVA from baseline to week 48 at a two-sided level of 0.05 with a power of approximately 90%, assuming equal efficacy and a common SD of 15 letters.

Power of at least 90% was expected for the first key secondary efficacy endpoint, assuming that averaging over the four time points would not lead to an increase in SD.

To account for a dropout rate of 10%, a total of 330 patients was planned for randomisation to each treatment arm (total of 990 randomised patients in HAWK and 660 in HARRIER).

In HARRIER study, hypothesis testing for secondary endpoints lack management of type one error and consequently multiplicity is not controlled for. Consequently, nominal statistical significances for superiority for these outcomes cannot be considered as confirmatory evidence.

In HAWK study, the analysis plan included additional hypotheses testing for superiority of brolucizumab versus aflibercept related to CSFT, retinal fluid, and disease activity. Correspondingly, the analysis plan

also pre-specified a proper management of the global level in relation to the resulting multiple testing. As these hypotheses were derived from an independent source (HARRIER study) and were pre-



specified prior to unmasking of this study all related statistical significances for superiority provide confirmatory evidence. (27)

More details on confirmatory testing related to additional secondary endpoints in HAWK study are described in appendix 5 of Dugel et al. 2020 (28).

4.4.3 Follow-up duration and discontinuations

The planned follow-up duration was 96 weeks in both HAWK and HARRIER. In the HAWK study, 10.5% of the patients (31 in the brolucizumab 3 mg arm, 37 in the brolucizumab 6 mg arm and 46 in the aflibercept arm) discontinued the study before week 48 when the primary outcome analysis was performed. In the HARRIER study, 6.6% of the patients (25 in the brolucizumab arm and 24 in the aflibercept arm) discontinued before week 48.

Overall, 171 subjects (15.8%) discontinued the study and 211 (19.5%) discontinued the study treatment before week 96 in HAWK. Withdrawal by subject was the most frequent reason for study (9.4% brolucizumab 6 mg arm, 6.4% aflibercept) or treatment (10.0% brolucizumab, 6.4% aflibercept) discontinuation. AEs were the second most frequent reason for study (2.2% brolucizumab, 3.3% aflibercept) or study treatment (3.6% brolucizumab, 3.9% aflibercept) discontinuation.

Similarly, 72 subjects (9.7%) discontinued the study and 95 (12.8%) discontinued the study treatment overall before week 96 in HARRIER. Withdrawal by subject was also the main reason for study (3.2% brolucizumab, 5.7% aflibercept) or study treatment (2.7% brolucizumab, 5.4% aflibercept) discontinuation. Adverse events were also the second most frequent reason for study (2.4% brolucizumab, 1.1% aflibercept) or study treatment (5.4% brolucizumab, 2.4% aflibercept) discontinuation.

In week 96 analysis, twelve patients (1.1 %) were lost to follow-up in HAWK and seven patients (0.9%) in HARRIER (HAWK CSR, HARRIER CSR). More details on subject disposition are presented in Table 4.9, in Section 4.8.

4.4.4 Baseline characteristics of the study populations

Baseline characteristics of the patients in the HAWK and HARRIER studies are presented in Appendix 7: Baseline characteristics of HAWK and HARRIER study populations. The demographic and disease characteristics of patients were similar between the treatment arms in both trials. The mean age of patients included was 76.5 years (range 50–97 years) in HAWK and 75.1 years (range 50–95 years) in HARRIER, with the majority aged ≥75 years (HAWK 60.9%; HARRIER 56.4%) at the time of study entry. A greater percentage of the patients were female than male (HAWK 56.5%; HARRIER 57.1%) and the patients were predominantly white (HAWK 81.1%; HARRIER 92.2%). In the HAWK trial, 14.3% of patients were of Japanese ancestry. The majority of the patients had unilateral nAMD (HAWK 75.0%; HARRIER 70.8%) with occult CNV lesions (HAWK 57.7%; HARRIER 50.3%) at baseline.

Approximately 25%–31% of patients in each study arm had nAMD in both eyes. According to the HAWK and HARRIER study protocols, patients could received another anti-VEGF drug for the non-study eye. Therefore, the authoring team asked the MAH to provide information about this subgroup in the scoping document request. The MAH did not provide the requested information.

4.5 Outcomes included

The following outcomes were included in both pivotal RCTs (HAWK and HARRIER):

Change in BCVA baseline to week 48 and week 96;

Proportion of patients maintaining Q12W dosing in the brolucizumab arms through to week 48;

Treatment frequency (number of IVT injections in each treatment arm);

Anatomic parameters of disease activity;

Visual function–related QoL, assessed using NEI VFQ-25;

Safety and tolerability of brolucizumab relative to aflibercept.



In relation to the scope of the assessment (Table 2.1), data were available for all outcomes except HRQoL and grade ≥3 AEs.

4.6 Risk of bias

Table 4.7 and Table 4.8 describe the RoB in HAWK and HARRIER at the study level and for the relevant outcomes. At the study level, RoB was low in both HAWK and HARRIER. At the outcome level, RoB was low for most of the outcomes. There was some uncertainty related to three outcomes in both studies: visual function–related QoL, AEs due to treatment and rates of discontinuation. Explanations for these uncertainties are given in the footnotes to Table 4.8.

Table 4.7. Risk of bias in the randomised HAWK and HARRIER studies

Study

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HAWK L L L L L L L L L

HARRIER L L L L L L L L L aFor self-reported outcomes including pain, function and global assessment bFor assessor-reported outcomes.

Abbreviations: H=high risk; L=low risk; U=unclear risk.

Table 4.8. Risk of bias by outcome in the HAWK and HARRIER studies

Trial

Bli

nd

ing

of

ou

tco

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assessm

en

t (d

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e level

Change in BCVA baseline to week 48 and week 96

HAWK L L L L L

HARRIER L L L L L

Proportion of patients maintaining Q12W dosing in the brolucizumab arms through to week 48

HAWK L L L L L

HARRIER L L L L L

Anatomic parameters of disease activitya

HAWK L L L L L

HARRIER L L L L L

Visual function–related QoL assessed using NEI VFQ-25

HAWK L Ud L L L/Ud

HARRIER L Ud L L L/Ud

Health-related QoL*

HAWK - - - - -

HARRIER - - - - -

Safety: AEs due to treatmentb

HAWK L L L Ue L / Ue

HARRIER L L L Ue L / Ue

Safety: rates of discontinuationc

HAWK L L L Uf L / Uf

HARRIER L L L Uf L / Uf



*Data not available. aThis includes the following parameters: central subfield thickness, choroidal neovascularisation area, subretinal fluid,

intraretinal fluid/intraretinal cyst, subretinal pigment epithelium fluid and neurosensory retinal thickness. Risk of bias was similar for all of these parameters and therefore they are reported as one group: “anatomic parameters of disease activity”. bThis includes the following outcomes: any AEs, serious AEs, grade ≥3 AEs, death as serious AE and AE of special interest

(e.g., ocular/non-ocular AEs). cThis includes the following outcomes: rates of discontinuation for any reason, rates of discontinuation due to AEs and percentage of patients who discontinued the treatment by reason for discontinuation. dIt was unclear whether ITT principle was appropriately implemented. It was unclear how the missing values for the outcome were dealt with in the analysis. eIt was unclear whether there were some other potential sources of bias. AEs were not reported by grade categories (e.g.,

grade ≥3 AEs). This could be a minor shortcoming but the authoring team was unable to determine whether this was important or not. fIt was unclear whether there were some other potential sources of bias. Rates of discontinuation for any reason were not

reported clearly, especially for discontinuations between weeks 48 and 96. In addition, the percentages of patients who discontinued the treatment by reason for discontinuation were not reported clearly. Abbreviations: H=high risk; L=low risk; U=unclear risk; AE=adverse event; BCVA=best corrected visual acuity;

ITT=intention to treat; NEI VFQ-25=National Eye Institute Visual Function Questionnaire-25; Q12W=every 12 weeks; QoL=quality of life.

4.7 External validity

The external validity and evidence gaps for the HAWK and HARRIER studies were assessed in relation to the population, intervention, comparators and outcomes of this joint REA (Table 2.1).

Population

In both HAWK and HARRIER, the study eye for each patient had to be treatment-naïve for any anti-VEGF agents. In clinical practice some patients do not experience a treatment response or their treatment response declines in the long run. The efficacy and safety of brolucizumab have not been studied as a second- or third-line treatment. The therapeutic indication for brolucizumab has no limitations in terms of prior anti-VEGF treatments. This means that brolucizumab can also be used as second- or third-line treatment even without clinical evidence.

Intervention

The first three loading doses of brolucizumab are given every 4 weeks. During maintenance treatment the dosing interval is based on disease activity and injections are given every 12 or every 8 weeks. At the start of the loading treatment it is not possible to know which patients will be able to remain on Q12W dosing. There is a need to recognise baseline patient characteristics predicting Q8W treatment need. It would be beneficial for both patients and hospitals if brolucizumab treatment could be targeted to patients who will be able to remain on Q12W dosing.

In the HAWK and HARRIER trials the treatment duration and follow-up time were only up to 96 weeks. Therefore, the long-term efficacy and safety of brolucizumab are not known. In clinical practice the treatment duration is often longer than 2 years. Because the data are limited to 2 years, the average duration of response to brolucizumab treatment is not known. From other anti-VEGF treatments we know that in some patients the treatment effect declines in the long run.

Comparators

Aflibercept was the only comparator in the HAWK and HARRIER trials. The MAH provided an NMA that included ranibizumab as a comparator. In many European countries bevacizumab is one of the primary treatment options for nAMD. However, brolucizumab has not been compared with bevacizumab either directly or indirectly.

In clinical practice different anti-VEGF dosing schemes are often used, such as PRN and TREX. In the HAWK and HARRIER trials aflibercept was given as a fixed dose every 8 weeks, whereas the dosing frequency for brolucizumab was based on disease activity during the maintenance phase. According to the MAH, brolucizumab is expected to have long-lasting efficacy and a lower frequency of injections compared to other currently available anti-VEGF treatments. However, the trial design does not allow any conclusions to be drawn regarding the treatment burden (injection frequency) between brolucizumab and aflibercept.



Outcomes

Outcomes from the HAWK and HARRIER trials are reasonable. Regarding patient-reported outcomes, vision-related QoL is included (measured by NEI VFQ-25 tool). The only outcome that is missing in relation to the PICO for this assessment (Table 2.1) is HRQoL measured using a generic tool.

4.8 Direct evidence: results for clinical efficacy and safety

Only the 6 mg dose of brolucizumab was submitted for a marketing authorisation and received approval, so the intervention of interest in this REA is brolucizumab 6 mg. Therefore, study results for brolucizumab 3 mg are only presented in brief as supportive evidence in Section 4.9. The comparators of interest defined in PICO were aflibercept, ranibizumab and bevacizumab. The submission included two applicable studies for direct comparisons, HARRIER and HAWK. The OSPREY study has supportive evidence and is presented in Section 4.10. Thus, this section only presents direct comparisons between brolucizumab 6 mg and aflibercept 2 mg from the HAWK and HARRIER studies. The primary objective in HAWK and HARRIER was to demonstrate that the efficacy of brolucizumab 6 mg is not inferior to aflibercept 2 mg, one of the medications used for nAMD treatment.

This section presents results from the HAWK and HARRIER studies separately. The authoring team asked the MAH to provide pooled results for the HAWK and HARRIER studies. In response, the MAH stated that pooled results are not available. However, as part of the NMA, the MAH provided some pooled results for key outcomes. These included only mean differences for fixed- and random-effects models, which are presented in Appendix 8: Pooled results of HAWK and HARRIER studies.

The number of patients analysed is presented in Table 4.9. The full analysis (FAS) set includes all patients randomised to treatment who received at least one dose of the assigned treatment. The ITT population consists of all randomised subjects who received at least one dose of the study drug and underwent at least one follow-up visit, regardless of the dose actually received or the visits completed. The per-protocol (PP) population consists of all ITT subjects without any significant violation of the protocol, such as missing a critical number of planned treatments. More information on protocol deviations is available in Appendix 11: Protocol deviations in HAWK and HARRIER studies.

Table 4.9. Subject disposition in the HAWK and HARRIER studies

HAWK study HARRIER study

Brolucizumab 6 mg

Aflibercept 2 mg

Brolucizumab 6 mg

Aflibercept 2 mg

Number randomised 361 361 372 371

Full analysis set 360 (99.7%) 360 (99.7%) 370 (99.5%) 369 (99.5%)

Per protocol set 328 (90.9%) 312 (86.4%) 351 (94.4%) 341 (91.9%)

Completed week 48 333 (92.2%) 327 (90.6%) 354 (95.2%) 352 (94.9%)

Completed week 96 304 (84.2%) 297 (82.3%) 342 (91.9%) 329 (88.7%)

Subjects with at least one protocol deviation

46 (12.7%) 52 (14.4%) 43 (11.6%) 43 (11.6%)

Source: European Medicines Agency public assessment report (27).



4.8.1 Primary endpoint: change in BCVA from baseline to week 48

According to the primary analysis, HAWK and HARRIER demonstrated in both the FAS and PPS the noninferiority of brolucizumab 6 mg in comparison to aflibercept 2 mg. To demonstrate noninferiority,

the lower bound of the 95% CI had to be greater than 4 letters in this outcome. Analyses in the FAS and PPS were consistent.

In the HAWK study, the LS mean change in BCVA from baseline to week 48 was 6.6 letters (95% CI 5.2–8.0) for brolucizumab 6 mg and 6.8 letters (95% CI 5.4–8.2) for aflibercept 2 mg for the FAS population. Pairwise ANOVA demonstrated the noninferiority (4-letter margin) of brolucizumab 6 mg

compared to aflibercept 2 mg, with an LSMD of 0.2 (95% CI 2.1 to 1.8; p<0.0001). Results for the PPS population are presented in Table 4.10.

In the HARRIER study, the LS mean change in BCVA from baseline to week 48 was 6.9 letters (95% CI 5.7–8.1) for brolucizumab 6 mg and 7.6 letters (95% CI 6.4–8.8) for aflibercept 2 mg in the FAS population. Pairwise ANOVA demonstrated the noninferiority (4-letter margin) of brolucizumab 6 mg

compared to aflibercept 2 mg, with an LSMD of 0.7 (95% CI 2.4 to 1.0; p=0.0001). Results for the PPS population are presented in Table 4.10.



Table 4.10. Change in BCVA from baseline to week 48: summary statistics and ANOVA (FAS-LOCF, PPS-LOCF)

HAWK trial HARRIER trial

FAS population Brolucizumab 6 mg (n=360)





Mean (SD) 6.4 (14.40) 7.0 (13.16) 6.9 (11.47) 7.6 (12.47)

Median (range) 7.5 (69, 52) 8.0 (57, 54) 8.0 (57, 38) 8.0 (37, 50)

95% CI for mean 4.9, 7.9 5.6, 8.3 5.8, 8.1 6.3, 8.9


LSM (SE) 6.6 (0.71) 6.8 (0.71) 6.9 (0.61) 7.6 (0.61)

95% CI for LSM 5.2, 8.0 5.4, 8.2 5.7, 8.1 6.4, 8.8

LSMD (SE) 0.2 (1.00) 0.7 (0.86)

95% CI for LSMD 2.1, 1.8 2.4, 1.0

p-value for treatment difference (2-sided) 0.8695 0.4199

p-value for noninferiority (4-letter margin; 1-sided) <0.0001 0.0001

PPS population Brolucizumab 6 mg (n=328)





Mean (SD) 6.6 (14.68) 7.4 (12.71) 7.0 (11.24) 7.8 (12.49)

Median (range) 8.0 (69, 52) 8.0 (57, 51) 8.0 (57, 38) 8.0 (35, 50)

95% CI for mean 5.0, 8.2 6.0, 8.8 5.8, 8.2 6.5, 9.1


LSM (SE) 6.9 (0.74) 7.1 (0.76) 7.0 (0.62) 7.8 (0.63)

95% CI for LSM 5.4, 8.3 5.7, 8.6 5.8, 8.2 6.6, 9.0

LSMD (SE) 0.3 (1.06) 0.8 (0.88)

95% CI 2.4, 1.8 2.5, 1.0


p-value for noninferiority (4-letter margin; 1-sided) 0.0003 0.0001

Source: HAWK clinical study report, HARRIER clinical study report, Dugel et al. 2020 (28).

Abbreviations: ANOVA=analysis of variance; BCVA=best corrected visual acuity; CI=confidence interval; FAS=full analysis set; LOCF=last observation carried forward; LSM=least squares mean; LSMD=least squares mean difference; PPS=per protocol set; SD=standard deviation; SE=standard error.



4.8.2 Secondary endpoints


Results for the change in BCVA from baseline to week 96, did not show difference between

brolucizumab and aflibercept (Figure 4.5). The difference in mean change was 0.5 (95% CI 1.6 to 2.7)

in the HAWK study and 0.4 (95% CI 2.5 to 1.6) in HARRIER.

Figure 4.5. LSM change in BCVA from baseline to week 96 (FAS-LOCF).


Abbreviations: BCVA=best corrected visual acuity; ETDRS= Early Treatment Diabetic Retinopathy Study; FAS=full analysis set; LOCF=last observation carried forward; LSM=least squares mean; SE=standard error.

Selected secondary endpoints related to BCVA

Selected secondary endpoints are presented in Table 4.11. A loss or gain of three lines (15 letters) is commonly used as an outcome in clinical trials in nAMD. The MAH was asked to present these outcomes as individual measures, but data for the outcome of a gain of at least 15 letters from baseline at week 48/week 96 were not available separately.

Table 4.11. Selected secondary endpoints related to BCVA (LS mean estimates; proportion of patients) at and up to week 48 and week 96 (FAS-LOCF)

Trial HAWK HARRIER

Secondary BCVA endpoint

Brolucizumab 6 mg

Aflibercept 2 mg

LSMD (95% CI) p-value

Brolucizumab 6 mg

Aflibercept 2 mg

LSMD (95% CI)

p-value

Analysis at week 48a

≥15 letters gained from baseline/ BCVA of ≥84 letters at week 48

33.6 25.4 8.2 (2.2,15.0), p=0.0136

29.3 29.9 0.6

(7.1,5.8), p=0.8600

≥15 letters lost from baseline at week 48

6.4 5.5 0.9

(2.7,4.3), p=0.6198

3.8 4.8 1.0

(3.9, 2.2), p=0.5079

BCVA of ≥73 letters at week 48

49.5 51.9 2.4

(8.6, 3.6), p=0.4442

50.7 50.3 0.4

(5.4,6.1), p=0.8922



Trial HAWK HARRIER

Secondary BCVA endpoint

Brolucizumab 6 mg

Aflibercept 2 mg

LSMD (95% CI) p-value

Brolucizumab 6 mg

Aflibercept 2 mg

LSMD (95% CI)

p-value

Analysis at week 96a

≥15 letters gained from baseline/ BCVA of ≥84 letters at week 96

34.2 27.0 7.2 (1.4,13.8), p=0.0313

29.1 31.5 2.4

(8.8, 4.1), p=0.4765

≥15 letters lost from baseline at week 96

8.1 7.4 0.7

(3.6,4.6), p=0.7210

7.1 7.5 0.4

(3.8, 3.3), p=0.8377

BCVA of ≥73 letters at week 96

48.6 46.3 2.3

(3.8,9.0), p=0.4820

47.6 49.6 2.0

(8.1 to 4.1), p=0.5295

Source: HAWK clinical study report, HARRIER clinical study report, Khanani et al. [52]. aAnalysis of variance (for continuous variables) and logistic regression (for categorical variables) models with baseline

BCVA categories (55, 56–70, 71 letters), age categories (<75, 75 years) and treatment as fixed-effect factors were used. Abbreviations: BCVA=best-corrected visual acuity; CI=confidence interval; FAS=full analysis set; LOCF=last observation carried forward; LSMD=least squares mean difference.

Additional secondary endpoints: anatomic outcomes

CSFTns CSFTns was defined as the retina thickness measured from the apical outer segment tip to the inner limiting membrane (HARRIER CSR). The mean change in CSFTns from baseline to week 48 did not differ between brolucizumab 6 mg and aflibercept 2 mg (Table 4.12). Overall, the reduction in CSFTns observed at the end of the first year of treatment was maintained through to week 96 (Figure 4.6 and Figure 4.7) in both studies and for both treatments.

Table 4.12. Change in CSFTns (μm) from baseline to week 48 for the study eye in HAWK and HARRIER (FAS-LOCF)

Trial HAWK HARRIER

FAS populationa Brolucizumab 6 mg (n=360)




Mean change (SD) 66.6 (98.72) 64.5 (92.74) 56.2 (100.12) 42.9 (92.89)

SE 5.20 4.89 5.20 4.84

Median change (range) 38.0 (681 to 159)

33.5 (485 to 91)

-21.5 (-552, 99) 16.0 (434 to

344)

95% CI for mean (76.8 to 56.3) (74.1 to 54.9) (-66.4, -46.0) (52.4 to 33.3)


LSM (SE) 65.8 (4.18) 65.3 (4.18) 53.0 (3.79) 46.0 (3.79)

95% CI for LSM (74.0 to 57.6) (73.5 to 57.1) (60.4 to 45.6) (53.5 to 38.6)

LSM difference (SE) 0.5 (5.92) - 7.0 (5.36) -

95% CI for treatment difference

(12.1 to 11.1) - (17.5 to 3.6) -


0.9318 - 0.1945 -

Source: HAWK clinical study report, HARRIER clinical study report. an is the number of subjects with data used in the model. The 95% CIs for the mean are based on a t-distribution. Analysed using an ANOVA model with baseline CSFTns categories (<250, ≥250 μm), age categories (<75, ≥75 years) and treatment

as fixed-effect factors. CSFT assessments after the start of an alternative anti–vascular endothelial growth factor treatment in the study eye are censored and imputed using the last value before initiation of this alternative treatment. Abbreviations: ANOVA=analysis of variance; CI=confidence interval; CSFTns=central subfield thickness of the

neurosensory retina; FAS=full analysis set; LOCF=last observation carried forward; LSM=least squares mean; SD=standard deviation; SE=standard error.



Figure 4.6. LSM change in CSFTns (μm) from baseline by visit in HAWK (FAS-LOCF).

LSM (±SE) estimates are based on an ANOVA model with baseline CSFTns categories (<250, ≥250 μm) age categories (<75, ≥75 years) and treatment as fixed-effect factors. Source: HAWK clinical study report.

Abbreviations: CSFTns=central subfield thickness of the neurosensory retina; FAS=full analysis set; LOCF=last observation carried forward; LSM=least mean squares; SE=standard error.

Figure 4.7. LSM change in CSFTns (μm) from baseline by visit in HARRIER (FAS-LOCF).

LSM (±SE) estimates are based on an ANOVA model with baseline CSFT-neurosensory retina categories (<250, ≥250 μm) age

categories (<75, ≥75 years) and treatment as fixed effect factors. Source: HARRIER clinical study report. Abbreviations: CSFTns=central subfield thickness of the neurosensory retina; FAS=full analysis set; LOCF=last observation

carried forward; LSM=least mean squares; SE=standard error.

CSFTtot In addition to CSFTns, CSFTtot was reported. At week 96, absolute changes in CSFTtot from baseline

were 175 µm for brolucizumab 6 mg versus 149 µm for aflibercept 2 mg in HAWK, and 198 µm

versus 155 µm in HARRIER, respectively. Absolute differences at the end of week 96 were 26 µm in HAWK and 43 µm in HARRIER. CSFTtot showed statistically significant difference between the groups at weeks 16, 48 and 96 (Table 4.13 and Figure 4.8).



Table 4.13. LSMD in CSFTtot (μm) from baseline to weeks 48 and 96 for the study eye in HAWK and HARRIER (FAS-LOCF)

Trial name HAWK HARRIER

FAS population Brolucizumab 6 mg (n=360)




Week 48

LSM 172.8 143.7 193.8 143.9

LSM difference (95% CI) -29.0 (-47.6,-10.4)) 49.9 (68.9 to 30.9)


0.0023 <0.001

week 96

LS Mean 174.8 148.7 197.7 155.1

LSM difference (95%CI) 26.0 (46.2 to 5.9) 42.6 (62.0 to 23.3)


Not reported <0.0001

Source: HAWK and HARRIER clinical study reports. aANOVA models with baseline CSFTns categories ( <400, ≥400 µm), age categories (<75, ≥75 years) and treatment as fixed-effect factors were used. CSFT assessments after the start of an alternative anti–vascular epithelial growth factor

treatment in the study eye were censored and imputed using the last value before initiation of this alternative treatment. Abbreviations: ANOVA=analysis of variance; CI=confidence interval; CSFTns=central subfield thickness of the neurosensory retina; FAS=full analysis set; LOCF=last observation carried forward; LSM=least mean squares; SE=standard

error.

Figure 4.8. LSM change in CSFTtot (µm) from baseline by visit through to week 96 (FAS-LOCF).

The p-values are one-sided for HARRIER; two-sided p-values at week 96. The p-values are descriptive.

Source: Submission dossier. Abbreviations: CSFTtot=total central subfield thickness; FAS=full analysis set; LOCF=last observation carried forward; LSM=least mean squares; SE=standard error.



Proportion of patients with IRF The proportions of patients with IRF are presented in Figure 4.9 and Figure 4.10 and in Table 4.14. There was no difference in the proportion of subjects with IRF at week 16 and week 48 in either study.

Figure 4.9. Percentage of subjects with IRF by visit up to week 96 in HARRIER (FAS-LOCF).

Source: HARRIER clinical study report. Abbreviations: FAS=full analysis set; IRF=intraretinal fluid; LOCF=last observation carried forward.

Figure 4.10. Percentage of subjects with IRF visit to week 96 in HAWK (FAS-LOCF).

Source: HAWK clinical study report. Abbreviations: FAS=full analysis set; IRF=intraretinal fluid; LOCF=last observation carried forward

Table 4.14. Proportion of subjects with IRF at week 16 and week 48 in HAWK and HARRIER (FAS-LOCF) according to logistic regression


Brolucizumab

6 mg Aflibercept

2 mg Brolucizumab

6 mg Aflibercept

2 mg

Proportion with IRF at week 16 20.3 24.7 12.4 12.3

Difference (95% CI) 4.3 (10.0 to 1.9) 0.1 (4.5 to 4.4)


Proportion with IRF at week 48 21,4 22.2 10.8 12.8



Source: HAWK clinical study report, HARRIER clinical study report. Abbreviations: CI=confidence interval; FAS=full analysis set; IRF=intraretinal fluid; LOCF=last observation carried forward.



Proportion of patients with SRF Figure 4.11 and Figure 4.12 show the proportion of patients with SRF from baseline to week 96. The proportions were higher in the aflibercept groups and the difference was statistically significant (Table 4.15).

Figure 4.11. Percentage of subjects with SRF by visit up to week 96 in HARRIER (FAS-LOCF).

Source: HARRIER clinical study report. Abbreviations: FAS=full analysis set; LOCF=last observation carried forward; SRF=subretinal fluid.

Figure 4.12. Percentage of subjects with SRF by visit up to week 96 in HAWK (FAS-LOCF).

Source: HAWK clinical study report. Abbreviations: FAS=full analysis set; LOCF=last observation carried forward; SRF=subretinal fluid.

Table 4.15. Proportion of subjects with SRF at week 16 and week 48 in HAWK and HARRIER (FAS-LOCF) according to logistic regression.


Brolucizumab

6 mg Aflibercept

2 mg Brolucizumab

6 mg Aflibercept

2 mg

Proportion with SRF at week 16 17.0 36.6 21.2 35.4


p-value for treatment difference (2-sided) <0.0001 <0.0001

Proportion with SRF at week 48 14.4 30.0 17.7 33.6


p-value for treatment difference (2-sided) <0.0001 <0.0001

Source: HAWK clinical study report, HARRIER clinical study report.

Abbreviations: CI=confidence interval; FAS=full analysis set; LOCF=last observation carried forward; SRF=subretinal fluid.



Proportion of patients with sub-RPE fluid The proportion of participants with sub-RPE fluid at weeks 16, 48 and 96 is reported in Figure 4.13. These proportions were lower in the brolucizumab 6 mg group, and the difference was statistically significant for weeks 16 and 48 in HAWK and for weeks 16, 48 and 96 in HARRIER.

Figure 4.13. Proportion of patients with sub-RPE fluid at weeks 16, 48 and 96 in HAWK and HARRIER (FAS-LOCF).

Source: Submission dossier. Abbreviations: FAS=full analysis set; LOCF=last observation carried forward; RPE=retinal pigment epithelium; SRF=subretinal

fluid.

Change in CNV

The mean change in CNV lesion size from baseline to week 48 was 4.0 mm2 versus 3.5 mm2 in

HAWK, and 2.3 mm2 versus 2.5 mm2 in HARRIER. This difference between the brolucizumab 6 mg and aflibercept 2 mg arms had a p-value of 0.0344 for HAWK and 0.1207 for HARRIER. From baseline

to week 96, the mean change in CNV lesion size was 4.1 mm2 versus 3.5 mm2 in HAWK, and 2.5

mm2 versus 2.7 mm2 in HARRIER. This difference between the brolucizumab 6 mg and aflibercept 2 mg arms had a p-value of 0.0022 in HAWK and 0.0366 in HARRIER.

Other additional secondary endpoints

Proportion of patients maintained on Q12W dosing through week 48 The proportion of subjects maintained on the Q12W regimen up to the DAA at week 44 in the brolucizumab 6 mg arm was 55.6% (95% CI 50.1%–60.7%) in HAWK and 51.0% (95% CI 45.6%–56.1%) in HARRIER (Figure 4.14 and Figure 4.15). Thus, only approximately half of the patients could remain on the Q12W regimen through the first year.



Figure 4.14. Kaplan-Meier plot of time to first Q8W treatment needed for the brolucizumab group in HAWK (FAS efficacy/safety approach).

Source: HAWK clinical study report.

Abbreviations: FAS=full analysis set; QxW=every x weeks.

Figure 4.15. Kaplan-Meier plot of time to first Q8W treatment needed for the brolucizumab group in HARRIER (FAS efficacy/safety approach).

Source: HARRIER clinical study report.

Abbreviations: FAS=full analysis set; QxW=every x weeks.

Treatment frequency (number of IVT injections) Over 96 weeks, the mean number of injections was 10.2 for brolucizumab versus 11.3 for aflibercept in HAWK, and 10.9 versus 12.1 in HARRIER, respectively. The difference in the mean number of active injections administered in the brolucizumab and aflibercept treatment arms of HAWK and HARRIER was 1.1 and 1.2, respectively.

Descriptive statistics for the number of active injections administered overall from baseline to week 96 are presented in Table 4.16. In HAWK, the majority of the brolucizumab 6 mg group (39.2%) received ten active injections and the majority of the aflibercept 2 mg group (67.5%) received 13 active injections during the study. In HARRIER, in the brolucizumab 6 mg arm approximately one-third of the subjects (34.1%) received 13 injections and one-third (34.3%) received ten active injections; the majority of the aflibercept 2 mg group (78.6%) received 13 active injections during the study. However, patients in the aflibercept group were not permitted to extend the interval between injections from fixed Q8W to Q12W.



The differences in the number of active injections between the brolucizumab 6 mg and aflibercept 2 mg arms might be driven by differences in the dosing intervals (protocol difference).

Table 4.16. Number of injections from baseline to week 96 (SAF)


Brolucizumab 6 mg (N=360)

Aflibercept 2 mg (N=360)

Brolucizumab 6 mg (N=370)

Aflibercept 2 mg (N=369)

Mean (SD) 10.2 (2.74) 11.3 (3.21) 10.9 (2.38) 12.1 (2.32)

Median 10.0 13.0 11.0 13.0

Range 1–13 1–13 1–13 1–14

Source: Submission dossier. Abbreviations: SAF=safety analysis set (including all patients who received at least 1 intravitreal injection); SD=standard deviation.

Patient-reported outcomes

In the PICO, HRQoL was defined as a patient-relevant outcome in conjunction with vision-related QoL. Data on HRQoL were requested from MAH, but the response stated that HRQoL data measured using a generic tool were not available. Only vision-related QoL data using the NEI VFQ-25 instrument were presented. The mean changes in score are presented in Table 4.17. Separate presentations for the number of patients and vision-related QoL results for patients who received treatment for the first-affected eye and second-affected eye were requested, but the MAH did not provide these separately.

VFQ-25 is a patient-reported instrument widely used to measure vision-related QoL in nAMD. A positive change in VFQ-25 score indicates a benefit. Both HAWK and HARRIER showed a similar change in VFQ-25 score from baseline for both brolucizumab 6 mg and aflibercept 2 mg.

Table 4.17. Mean change in VFQ-25 composite scores from baseline in HAWK and HARRIER studies (FAS-observed)

Trial name

HAWK HARRIER

Time point

Brolucizumab 6 mg Aflibercept 2 mg Brolucizumab 6 mg Aflibercept 2 mg

Week 24 4.0 (n=341) 3.5 (n=333) 3.9 (n=354) 3.5 (n=355)

Week 48 4.1 (n=324) 4.5 (n=317) 4.8 (n=347) 3.6 (n=346)

Week 72 3.9 (n=303) 4.0 (n=298) 5.0 (n=342) 3.2 (n=334)

Week 96 3.8 (n=301) 2.8 (n=296) 3.8 (n=338) 2.6 (n=329)

Source: Submission dossier. Abbreviations: FAS=full analysis set; VFQ-25=visual Function Questionnaire-25

4.8.3 Safety outcomes

Safety outcomes of interest are listed in Table 2.1. Data were available for all of those outcomes except grade ≥3 AEs. Statistical comparisons between study arms were not available for any of the safety outcomes.

Frequencies of ocular AEs and serious ocular AEs in the study eye are presented in Table 4.18 and 4.19. At week 96, the number of patients with at least one AE in the study eye was similar across treatment arms and higher in HAWK (brolucizumab 6 mg: 220 [61.1%]; aflibercept 2 mg: 201 [55.8%]) than in HARRIER (brolucizumab 6 mg: 174 [47.0%]; aflibercept 2 mg: 176 [47.7%]; Table 4.18). Conjunctival haemorrhage and reduced VA were the most frequent ocular AEs across all treatment arms in both studies. These AEs are known effects of anti-VEGF drugs administered via the IVT route. The majority of ocular AEs were of mild or moderate severity in HAWK (96.1%) and HARRIER (94.9%).



Table 4.18. Ocular adverse events up to week 96 (≥2% in any treatment group) for the study eye (SAF)

Event Patients experiencing an event, n (%)

HAWK HARRIER

Brolucizumab 6 mg

(N=360)

Aflibercept 2 mg

(N=360)

Brolucizumab 6 mg

(N=370)

Aflibercept 2 mg

(N=369)

Patients with at least one event 220 (61.1) 201 (55.8) 174 (47.0) 176 (47.7)

Conjunctival haemorrhage 29 (8.1) 32 (8.9) 17 (4.6) 19 (5.1)

VA reduced 22 (6.1) 29 (8.1) 32 (8.6) 26 (7.0)

Vitreous floaters 22 (6.1) 16 (4.4) 15 (4.1) 5 (1.4)

Retinal haemorrhage 21 (5.8) 20 (5.6) 12 (3.2) 4 (1.1)

Cataract 20 (5.6) 13 (3.6) 11 (3.0) 43 (11.7)

Vitreous detachment 19 (5.3) 19 (5.3) 10 (2.7) 8 (2.2)

Dry eye 19 (5.3) 26 (7.2) 10 (2.7) 11 (3.0)

Eye pain 18 (5.0) 21 (5.8) 13 (3.5) 19 (5.1)

Posterior capsule opacification 14 (3.9) 11 (3.1) – –

Intraocular pressure increased 13 (3.6) 15 (4.2) 14 (3.8) 15 (4.1)

Blepharitis 13 (3.6) 12 (3.3) 13 (3.5) 5 (1.4)

Retinal pigment epithelial tear 12 (3.3) 4 (1.1) 8 (2.2) 5 (1.4)

Vision blurred 11 (3.1) 10 (2.8) – –

Visual impairment 10 (2.8) 14 (3.9) – –

Eye irritation 10 (2.8) 11 (3.1) – –

Punctate keratitis 9 (2.5) 10 (2.8) – –

Conjunctivitis 9 (2.5) 3 (0.8) 15 (4.1) 8 (2.2)

Iritis 9 (2.5) 1 (0.3) 0 (0.0) 1 (0.3)

Uveitis 8 (2.2) 1 (0.3) 3 (0.8) 0 (0.0)

Visual field defect 7 (1.9) 5 (1.4) – –

Corneal abrasion 7 (1.9) 10 (2.8) – –

Macular fibrosis 5 (1.4) 4 (1.1) – –

Dry AMD 5 (1.4) 3 (0.8) – –

Foreign body sensation in eyes 4 (1.1) 9 (2.5) – –

Lacrimation increased 4 (1.1) 5 (1.4) – –

Lenticular opacities 1 (0.3) 4 (1.1) 13 (3.5) 12 (3.3)

Source: Submission dossier. Abbreviations: AMD=age-related macular degeneration; SAF=safety analysis set (includes all subjects who received at least one injection of the study drug).

Serious ocular AEs were rare. The number of patients with at least one serious ocular AEs was twelve (3.3%) in the brolucizumab 6 mg and five (1.4%) in the aflibercept 2 mg group in HAWK; the corresponding rates in HARRIER study were 13 (3.5%) and six (1.6%). Intraocular inflammation (endophthalmitis, uveitis, vitritis and anterior chamber inflammation) was more frequent in the brolucizumab 6 mg groups (6 [1.7%] in HAWK and 5 [1.4%] in HARRIER) than in the aflibercept 2 mg groups (0 [0%] and 1 [0.3%], respectively). Retinal arterial occlusive events (retinal artery thrombosis, retinal artery occlusion, retinal artery embolism) were more frequent in brolucizumab 6 mg (1 [0.3%] in HAWK and 3 [0.9%] in HARRIER) than in aflibercept 2 mg groups (0 [0%] in HAWK and 1 [0.3%] in HARRIER).



Table 4.19. Serious ocular adverse events up to week 96 for the study eye (SAF)


HAWK HARRIER

Brolucizumab 6 mg

(N=360)

Aflibercept 2 mg

(N=360)

Brolucizumab 6 mg

(N=370)

Aflibercept 2 mg

(N=369)


Endophthalmitis 3 (0.8) 0 (0.0) 1 (0.3) 1 (0.3)

Uveitis 2 (0.6) 0 (0.0) 3 (0.8) 0 (0.0)

Retinal detachment 1 (0.3) 1 (0.3) 1 (0.3) 1 (0.3)

VA reduced 1 (0.3) 2 (0.6) 1 (0.3) 1 (0.3)

Macular hole 1 (0.3) 1 (0.3) – –

Cataract 1 (0.3) 0 (0.0) – –

Retinal artery thrombosis 1 (0.3) 0 (0.0) 1 (0.3) 0 (0.0)

Retinal depigmentation 1 (0.3) 0 (0.0) – –

Retinopathy proliferative 1 (0.3) 0 (0.0) – –

Vitritis 1 (0.3) 0 (0.0) – –

Retinal artery occlusion 0 (0.0) 0 (0.0) 1 (0.3) 1 (0.3)

Glaucoma 0 (0.0) 0 (0.0) – –

Cataract subscapular 0 (0.0) 1 (0.3) – –

Retinal tear – – 2 (0.5) 1 (0.3)

Retinal pigment epithelial tear – – 2 (0.5) 0 (0.0)

Anterior chamber inflammation – – 1 (0.3) 0 (0.0)

Blindness – – 1 (0.3) 0 (0.0)

Cataract traumatic – – 1 (0.3) 0 (0.0)

Dacryocystitis – – 1 (0.3) 0 (0.0)

Retinal artery embolism – – 1 (0.3) 0 (0.0)

Dry AMD – – 0 (0.0) 1 (0.3)


Abbreviations: AMD=age-related macular degeneration; SAF=safety analysis set (includes all subjects who received at least one injection of the study drug).

Table 4.20. Non-ocular adverse events up to week 96 (≥2% in any treatment group) for the study eye (SAF)


HAWK HARRIER

Brolucizumab 6 mg

(N=360)

Aflibercept 2 mg

(N=360)

Brolucizumab 6 mg

(N=370)

Aflibercept 2 mg

(N=369)


Nasopharyngitis 38 (10.6) 44 (12.2) 43 (11.6) 31 (8.4)

Pneumonia 32(8.9) 20 (5.6) 7 (1.9) 13 (3.5)

Urinary tract infection 27 (7.5) 41 (11.4) 16 (4.3) 19 (5.1)

Hypertension 25 (6.9) 24 (6.7) 28 (7.6) 25 (6.8)

Upper respiratory tract infection 18 (5.0) 16 (4.4) 6 (1.6) 14 (3.8)

Influenza 17 (4.7) 20 (5.6) 24 (6.5) 27 (7.3)

Arthralgia 15 (4.2) 21 (5.8) 14 (3.8) 13 (3.5)

Pain in extremity 15 (4.2) 10 (2.8) 9 (2.4) 4 (1.1)

Back pain 14 (3.9) 17 (4.7) 16 (4.3) 28 (7.6)

Diarrhoea 14 (3.9) 13 (3.6) 10 (2.7) 6 (1.6)

Cough 13 (3.6) 17 (4.7) 12 (3.2) 8 (2.2)

Bronchitis 13 (3.6) 22 (6.1) 23 (6.2) 21 (5.7)




HAWK HARRIER

Brolucizumab 6 mg

(N=360)

Aflibercept 2 mg

(N=360)

Brolucizumab 6 mg

(N=370)

Aflibercept 2 mg

(N=369)

Constipation 13 (3.6) 13 (3.6) – –

Nausea 12 (3.3) 12 (3.3) – –

Headache 12 (3.3) 13 (3.6) 12 (3.2) 8 (2.2)

Contusion 12 (3.3) 12 (3.3) – –

Chronic obstructive pulmonary disease

12 (3.3) 12 (3.3) – –

Arthritis 12 (3.3) 13 (3.6) – –

Sinusitis 11 (3.1) 14 (3.9) – –

Fall 10 (2.8) 7 (1.9) – –

Musculoskeletal pain 10 (2.8) 4 (1.1) – –

Seasonal allergy 10 (2.8) 9 (2.5) – –

Osteoarthritis 9 (2.5) 11 (3.1) 19 (5.1) 7 (1.9)

Blood pressure increased 9 (2.5) 9 (2.5) 2 (0.5) 11 (3.0)

Cardiac failure congestive 9 (2.5) 6 (1.7) – –

Atrial fibrillation 8 (2.2) 15 (4.2) 5 (1.4) 10 (2.7)

Dizziness 8 (2.2) 6 (1.7) 5 (1.4) 9 (2.4)

Gamma-glutamyltransferase increased

8 (2.2) 7 (1.9) – –

Herpes zoster 8 (2.2) 8 (2.2) – –

Dental caries 8 (2.2) 7 (1.9) – –

Basal cell carcinoma 8 (2.2) 6 (1.7) – –

Neck pain 8 (2.2) 3 (0.8) – –

Anaemia 7 (1.9) 15 (4.2) 5 (1.4) 8 (2.2)

Gastroesophageal reflux disease

7 (1.9) 3 (0.8) – –

Oedema peripheral 7 (1.9) 8 (2.2) – –

Dyspnoea 6 (1.7) 8 (2.2) – –

Vomiting 6 (1.7) 5 (1.4) – –

Anxiety 5 (1.4) 10 (2.8) – –

Insomnia 5 (1.4) 10 (2.8) – –

Laceration 5 (1.4) 6 (1.7) – –

Cystitis 5 (1.4) 4 (1.1) 17 (4.6) 5 (1.4)

Benign prostatic hyperplasia 5 (1.4) 5 (1.4) – –

Depression 5 (1.4) 7 (1.9) – –

Blood uric acid increased 4 (1.1) 4 (1.1) – –

Dehydration 4 (1.1) 8 (2.2) – –

Coronary artery disease 3 (0.8) 3 (0.8) – –

Asthenia 3 (0.8) 2 (0.6) – –

Blood urea increased 2 (0.6) 5 (1.4) – –

Haematoma 2 (0.6) 4 (1.1) – –

Muscle strain 1 (0.3) 10 (2.8) – –

Hypercholesterolaemia – – 13 (3.5) 8 (2.2)

Sciatica – – 9 (2.4) 8 (2.2)

Pharyngitis – – 2 (0.5) 12 (3.3)

Syncope – – 8 (2.2) 8 (2.2)

Source: Submission dossier. Abbreviations: SAF=safety analysis set (includes all subjects who received at least one injection of the study drug).



Table 4.21. Serious non-ocular adverse events up to week 96 (≥3 patients in any treatment group) for the SAF


HAWK HARRIER

Brolucizumab 6 mg

(N=360)

Aflibercept 2 mg

(N=360)

Brolucizumab 6 mg

(N=370)

Aflibercept 2 mg

(N=369)


Pneumonia 10 (2.8) 9 (2.5) 2 (0.5) 8 (2.2)

Cardiac failure congestive 6 (1.7) 4 (1.1) – –

Chronic obstructive pulmonary disease

6 (1.7) 4 (1.1) 2 (0.5) 1 (0.3)

Atrial fibrillation 4 (1.1) 2 (0.6) – –

Cerebrovascular accident 4 (1.1) 3 (0.8) 0 (0.0) 4 (1.1)

Sepsis 4 (1.1) 1 (0.3) – –

Septic shock 3 (0.8) 0 (0.0) – –

Urinary tract infection 2 (0.6) 2 (0.6) – –

Hyponatraemia 2 (0.6) 1 (0.3) – –

Syncope 2 (0.6) 3 (0.8) 3 (0.8) 2 (0.5)

Myocardial infarction 2 (0.6) 3 (0.8) 2 (0.5) 0 (0.0)

Femur fracture 2 (0.6) 4 (1.1) 2 (0.5) 0 (0.0)

Coronary artery disease 1 (0.3) 3 (0.8) – –

Cholelithiasis 1 (0.3) 2 (0.6) 2 (0.5) 0 (0.0)

Transient ischaemic attack 1 (0.3) 2 (0.6) 1 (0.3) 2 (0.5)

Noncardiac chest pain 1 (0.3) 3 (0.8) – –

Subdural haematoma 1 (0.3) 3 (0.8) – –

Influenza 0 (0.0) 1 (0.3) – –

Intestinal obstruction 0 (0.0) 3 (0.8) – –

Lower limb fracture – – 3 (0.8) 0 (0.0)

Cardiac failure – – 2 (0.5) 2 (0.5)

Ischaemic stroke – – 2 (0.5) 1 (0.3)

Prostate cancer – – 2 (0.5) 1 (0.3)

Rectal haemorrhage – – 2 (0.5) 1 (0.3)

Benign prostatic hyperplasia – – 2 (0.5) 0 (0.0)

Cholecystitis acute – – 2 (0.5) 0 (0.0)

Gastroenteritis – – 2 (0.5) 0 (0.0)

Inguinal hernia – – 2 (0.5) 0 (0.0)

Joint dislocation – – 2 (0.5) 0 (0.0)

Pulmonary oedema – – 2 (0.5) 0 (0.0)

Bronchitis – – 1 (0.3) 2 (0.5)

Femoral neck fracture – – 1 (0.3) 2 (0.5)

Osteoarthritis – – 1 (0.3) 2 (0.5)

Pulmonary embolism – – 1 (0.3) 2 (0.5)

Death – – 0 (0.0) 3 (0.8)

Arrhythmia – – 0 (0.0) 2 (0.5)

Cerebrovascular disorder – – 0 (0.0) 2 (0.5)

Fall – – 0 (0.0) 2 (0.5)

Humerus fracture – – 0 (0.0) 2 (0.5)

Source: Submission dossier. Abbreviations: SAF=safety analysis set (includes all subjects who received at least one injection of the study drug).



Rates for study discontinuation due to death, SAEs or AEs are presented in Table 4.22. At week 96, 20 patients had died in HAWK (brolucizumab 6 mg: 8 patients [2.2%]; aflibercept 2 mg: 12 patients [3.3%]) and 11 in HARRIER (brolucizumab 6 mg: 4 patients [1.1%]; aflibercept 2 mg: 7 patients [1.9%]). Deaths were not suspected to be related to study treatment by the investigator in HAWK and HARRIER in brolucizumab 6 mg and aflibercept 2 mg arms. Discontinuations due to SAE were more frequently related to non-ocular SAE, while AEs leading to discontinuation were related to ocular AEs.

Table 4.22. Death, SAE or AE leading to permanent study treatment discontinuation up to week 96 (SAF)

Event Patients with serious or significant AE, n (%)

HAWK HARRIER

Brolucizumab 6 mg

(N=360)

Aflibercept 2 mg

(N=360)

Brolucizumab 6 mg

(N=370)

Aflibercept 2 mg

(N=369)

Death 8 (2.2) 12 (3.3) 4 (1.1) 7 (1.9)

SAEs 95 (26.4) 114 (31.7) 79 (21.4) 89 (24.1)

Study eye 12 (3.3) 5 (1.4) 13 (3.5) 6 (1.6)

Other eye 4 (1.1) 1 (0.3) 0 (0.0) 0 (0.0)

Non-ocular 85 (23.6) 110 (30.6) 69 (18.6) 85 (23.0)

AE leading to permanent study treatment discontinuation

16 (4.4) 22 (6.1) 20 (5.4) 9 (2.4)

Study eye 11 (3.1) 12 (3.3) 13 (3.5) 6 (1.6)

Other eye 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Non-ocular 5 (1.4) 10 (2.8) 8 (2.2) 3 (0.8)

Source: Submission dossier. Abbreviations: AE=adverse event; SAE=serious AE; SAF=safety analysis set.

4.8.4 Subgroup analyses


The results for subgroup analyses for the primary endpoint of change in BCVA from baseline to week 48 showed no difference between brolucizumab 6 mg and aflibercept 2 mg, irrespective of baseline disease characteristics or demographics (Figure 4.16). For the outcome of mean change in BCVA, the subgroups with poorer baseline VA (≤55 letters) showed a greater LSM change in BCVA (brolucizumab 6 mg 9.6 vs. aflibercept 2 mg 10.3) than those with better baseline VA (56–70 letters: 7.1 vs. 7.0; ≥71 letters: 2.4 vs. 2.4 respectively), but there was no difference between brolucizumab 6 mg and aflibercept 2 mg (Figure 4.16).



Figure 4.16. Forest plot of summary statistics and ANOVA for change in BCVA from baseline to week 48 by subgroups of interest (FAS-LOCF)


Abbreviations: ANOVA=analysis of variance; BCVA=best corrected visual acuity; CI=confidence interval; CNV=choroidal neovascularisation; CSFTtot=total central subfield thickness; FAS=full analysis set; LOCF=last observation carried forward; LSM=least squares mean; SRF=subretinal fluid.

Proportion of patients maintained on Q12W dosing until week 48 by baseline characteristics

Subgroup analyses for Q12W treatment status at week 48 suggested that, irrespective of subgroup parameters, >40% of patients qualified for Q12W in all subgroups in the brolucizumab arms of both HAWK and HARRIER.

Baseline characteristics were not predictive for patients able to remain on a Q12W dosing interval until week 48. The most discriminative parameter in both trials influencing the potential to remain on the Q12W regimen was baseline CSFT status (Figure 4.17). Patients with CSFT <400 µm are potentially more likely to be able to remain on the Q12W dosing interval.



Figure 4.17. Proportion of patients maintained on Q12W dosing interval until week 48 (FAS).

Predefined subgroup analysis for the efficacy/safety population. The numbers are based on estimated percentages from Kaplan-Meier analysis.

Source: Monés et al. 2018 (66). Abbreviations: BCVA=best corrected visual acuity; CST=central subfield thickness; Q12W=every 12 weeks; RPE=retinal pigment epithelium.

4.9 Direct supportive evidence: brolucizumab 3 mg

Following scientific advice from the EMA, the MAH included a brolucizumab 3 mg arm in the HAWK study. Nevertheless, the MAH only applied for a 6 mg dose, which is the dose finally approved for MA (27). In the HAWK study, treatment with brolucizumab 3 mg was noninferior to aflibercept in the primary outcome (change in BCVA from baseline to week 48), with an LS-mean estimate of 6.1 letters (in the aflibercept 2 mg arm 6.8 letters (95% CI 5.4–8.2)) giving a p-value of 0.0003 for noninferiority (4-letter margin, 1-sided) on ANOVA. The comparison between brolucizumab 3 mg and brolucizumab 6 mg was not presented. However, differences between the 3 mg and 6 mg doses across primary and secondary endpoints were numerically limited.

The brolucizumab 6 mg arm had a slightly higher proportion of patients maintained on a Q12W regimen compared to the brolucizumab 3 mg arm across all subgroups. The estimated proportion of patients remaining on the Q12W dosing interval up to week 48 was 49.4% in the brolucizumab 3 mg arm (HAWK), and 55.6% (HAWK) and 51.0% (HARRIER) in the brolucizumab 6 mg arms.

There was no significant difference in CSFT between brolucizumab 3 mg and aflibercept 2 mg; the

mean difference on ANOVA (LSMD) was 1.3 (SE 5.75; 95% CI 10.0 to 12.6) with p-value of 0.8228.

According to EMA benefit-risk balance is positive for 3 mg dose as well. However, the 6 mg dose could be accepted by EMA based on limited numerical differences in efficacy and the similarity of the safety profile in unilateral administration between the doses of 3 mg and 6 mg (27).



4.10 Direct supportive evidence: summary of the phase II OSPREY study

The phase II OSPREY study was a prospective multicentre RCT. It compared the efficacy and safety of brolucizumab 6 mg (n=44) with aflibercept 2 mg (n=45). Study subjects were followed for up to 56 weeks. The trial design is presented in Figure 4.18. In brief, the LP (weeks 0–8) and the period from 12 to 40 weeks were similar in both arms. In the LP, the study drugs were administered in weeks 0, 4 and 8. In the following period, both regimens were dosed in Q8W cycles (weeks 16, 24 and 32) up to week 40. Thereafter, the brolucizumab 6 mg group received one injection at week 44 (on Q12W cycle) and were followed up to week 56. The aflibercept group remained on the Q8W cycle up to week 56.

Figure 4.18. OSPREY trial design.

Source: Submission dossier Abbreviations: q12w=every 12 weeks.

4.10.1 Clinical efficacy outcomes

The primary outcome was the change in BCVA from baseline at week 12. The statistical hypothesis for the primary outcome was that brolucizumab is noninferior to aflibercept, using a margin of 5 letters and

one-sided of 0.1 (27). The change in BCVA at week 16 and by visit were defined as secondary endpoints. Data for the outcomes of ≥15 letters gained or lost from baseline were not presented in the submission dossier. The change in CSFT from baseline by visit was a secondary outcome. Clinically relevant outcomes of change in VA (BCVA) and retinal thickness (CSFT) are presented in Table 4.23 and Table 4.24. Week 40 was chosen for presentation here because of the similar protocols in each arm.

Table 4.23. LSM estimates for the change in BCVA from baseline at weeks 12, 40 and 56 (FAS-LOFC)

Time point Brolucizumab 6 mg (n=44) Aflibercept 2 mg (n=45)

Week 12

LSM (SE) 5.75 (1.68) 6.89 (1.67)

LSMD (80% CI) 1.13 (4.19 to 1.93)

p-value 0.6335

Week 40

LSM (SE) 6.25 (2.14) 5.75 (2.12)

LSMD (80% CI) 0.50 (3.39 to 4.39)

p-value 0.8685

Week 56

LSM (SE) 4.84 (2.37) 7.33 (2.34)

LSMD (80% CI) 2.49 (6.80 to 1.82)

p-value 0.4579


Abbreviations: CI=confidence interval; FAS=full analysis set; LOCF=last observation carrier forward; LSM=least squares mean; LSMD=LSM difference; SE=standard error.



Table 4.24. LSM estimates for the change in CSFT (µm) from baseline at weeks 12, 40 and 56 (FAS-LOFC)

Time point Brolucizumab 6 mg (n=44) Aflibercept 2 mg (n=45)

Week 12

LSM (SE) 196.57 (14.95) 189.00 (14.79)

LSMD (80% CI) 7.57 (34.74, 19.60)

p-value 0.7200

Week 40

LSM (SE) 197.46 (16.89) 178.29 (16.70)

LSMD (80% CI) 19.17 (-49.86, 11.52)

p-value 0.4221

Week 56

LSM (SE) 193.72 (16.04) 183.40 (15.86)

LSMD (80% CI) 10.32 (39.47 to 18.82)

p-value 0.6486

Source: OSPREY trial clinical study report.

Abbreviations: CI=confidence interval; CSFT=central subfield thickness; FAS=full analysis set; LOCF=last observation carrier forward; LSM=least squares mean; LSMD=LSM difference; SE=standard error.

4.10.2 Safety outcomes

The most common ocular AE for the study eye was conjunctival haemorrhage, which was reported by five patients (11.4%) in the brolucizumab 6 mg and seven (15.6%) in the aflibercept 2 mg arm. Other common ocular AEs in the study eye included vitreous floaters (11.4% vs. 8.9%), reduced VA (9.15% vs. 8.9%) and vitreous detachment (6.8% vs. 6.7%). Commonly reported non-ocular AEs were upper respiratory tract infection (11.4% vs. 6.7%) and urinary tract infection (4.5% vs. 8.9%). Serious AEs and deaths were rare. One 80-year-old subject in the brolucizumab 6 mg arm died of myocardial ischaemia. A total of 19 patients experienced nonfatal SAEs (10 in the brolucizumab 6 mg and 9 in the aflibercept 2 mg arm) with only one patient in the aflibercept 2 mg arm experiencing a treatment-related SAE. One patient discontinued because of an SAE of pancreatic carcinoma and another patient discontinued because of an SAE of retinal detachment in the study eye in the brolucizumab 6 mg and aflibercept 2 mg arms, respectively; neither event was considered to be treatment-related. No other nonfatal events led to study discontinuation.

More detailed information on clinical efficacy and safety outcomes in OSPREY is presented in Appendix 7.4 of the submission dossier.

4.11 Indirect evidence: NMA results

4.11.1 Quality assessment of the NMA

The quality of the NMA provided by the MAH was evaluated using the tool developed by Ortega et al. [25]. The detailed evaluation is available in Appendix 9: Checklist for critical appraisal of indirect comparisons – Evaluation of the NMA provided by MAH. The quality assessment performed by the MAH of the trials included in the assessment is shown in Figure 4.19. The main limitation identified by the REA authors is related to the external validity and applicability of the results and the conclusions obtained, as one of the relevant comparators from the European perspective was not considered.

Additional limitations identified in the submission dossier include the assumption of time equivalence for 1-year and 2-year outcomes. In order to include all the available evidence for the treatments of interest, equivalence was assumed between 48 and 52 weeks for 1-year outcomes and between 96 and 104 weeks for 2-year outcomes. The MAH stated that no publication was found to validate this hypothesis, but the results from HAWK and HARRIER at week 52 were similar to those at week 48. The results from sensitivity analyses indicate that there was no impact on the results of the equivalence assumption used.



In addition, the MAH stated that in order to connect the networks, an assumption was made for the VIEW 1&2 studies. While patients in VIEW 1&2 began a PRN treatment regimen at 52 weeks, these

patients were still considered as remaining on continuous treatment arms (i.e. LP aflibercept 2 mg Q8W, aflibercept 2 mg Q4W and ranibizumab 0.5 mg Q4W) to connect to the brolucizumab treatments. To assess the impact of this assumption, heterogeneity for ranibizumab 0.5 mg Q4W was assessed for each endpoint at 2 years and was only found for injection frequency. Since only baseline pooling was conducted for injection frequency, this switch to a PRN regimen was considered in these analyses. Furthermore, CNV lesion size was considered as a treatment effect modifier in nAMD following feedback from a leading clinical expert who indicated that VIEW 1&2 seemed to be the biggest outlier. However, this trial was needed to connect the network and therefore this represents a limitation of the analysis.

Another limitation of the NMA was that ranibizumab 0.5 mg Q4W versus LP ranibizumab 0.5 mg

TREX and LP brolucizumab 6 mg Q12/Q8W versus LP aflibercept 2 mg Q8W were the only comparisons for which multiple studies were included (as VIEW 1&2 were pooled in the analyses). The other comparisons were all connected by one trial only, making these arms of the network less robust.

Lastly, the NMA was performed by the MAH of brolucizumab, so we cannot exclude the possibility that conflicts of interest could have influenced the results. However, despite the above limitations, the methodological approach and conduct of the NMA can be considered as adequate.

Figure 4.19. Quality assessment performed by the MAH for trials included in the NMA.

Source: Submission dossier. Abbreviations: MAH=marketing authorisation holder; NMA=network meta-analysis.

4.11.2 NMA results

A brief summary of indirect comparisons is presented for the key outcomes in Table 4.25 and Table 4.26, followed by information on other outcomes such as injection frequency, treatment discontinuation and safety outcomes.

The network for the primary outcome (mean change in BCVA from baseline to 1 year) is presented in Figure 4.20. A total of 13 studies were included in the analysis. More detailed results are available in the submission dossier. Results are presented for cases with brolucizumab 6 mg (LP of three initial monthly injections and maintenance dosing either Q8W or Q12W) comparisons with each comparator (Table 4.25).

Sensitivity analyses and the results are presented in the submission dossier in detail. The sensitivity analyses performed showed that the results of the NMA were not significantly affected by the assumptions made.



Mean change in BCVA (baseline to 1 year and baseline to 2 years)

There was no difference between brolucizumab 6 mg and ranibizumab, aflibercept or brolucizumab 3 mg for the mean change in BCVA from baseline to 1 year or from baseline to 2 years. There was a difference observed between brolucizumab and sham for mean change in BCVA at both 1 and 2 years (MD 16.87, 95% credibility interval (CrI) 13.37–20.41 at 1 year, and 21.21, 95% CrI 17.46–24.99 at 2 years).

Figure 4.20. Network for mean change in BCVA from baseline to 1 year.

Source: Submission dossier Abbreviations: BCVA=best corrected visual acuity; Afli=aflibercept; Bro=brolucizumab; IVT=intravitreal; LP=loading phase;

Rani=ranibizumab; PRN= pro re nata dosing regimen; PRNX=pro re nata and extend dosing regimen; qXw=every X weeks; TREX= treat-and-extend dosing regimen.

Patients losing at least 15 letters (baseline to 1 year)

There was no difference between brolucizumab 6 mg and aflibercept, brolucizumab 3 mg and most of the ranibizumab dosing schemes for loss of at least 15 letters from baseline to 1 year. Brolucizumab had lower odds for loss of at least 15 letters only compared to sham IVT (odds ratio [OR] 0.07, 95% CrI

0.03–0.18) and the ranibizumab dosing scheme LP 0.5 mg PRN (OR 0.29, 95% CrI 0.08–0.95).

Patients losing at least 15 letters (baseline to 2 years)

There was no difference between brolucizumab 6 mg and aflibercept, ranibizumab or brolucizumab 3 mg for loss of at least 15 letters from baseline to 2 years. Brolucizumab had lower odds for loss of at least 15 letters only compared to sham IVT (OR 0.11, 95% CrI 0.05–0.23).



Table 4.25. Summary of NMA results comparing MD in BCVA and OR of loss of at least 15 letters (fixed effects). Results are presented as brolucizumab 6 mg Q8W/Q12W vs. each comparator.

Comparator arm MD in BCVA (95% CrI)a OR for loss of ≥15 letters (95% CrI)b

Baseline to 1 year Baseline to 2 years

Baseline to 1 year

Baseline to 2 years

Rani 0.5 mg Q4W 0.72

(2.68, 1.23)

0.29

(2.45, 1.88)

0.79 (0.38, 1.62)

0.90 (0.50, 1.60)

LPAfli 2 mg Q8W 0.43

(1.72, 0.86)

0.01

(1.48, 1.49)

0.96 (0.60, 1.54)

1.0 (0.68, 1.48)

LPRani 0.5 mg PRN 1.18

(1.77, 4.13)

0.91

(2.39, 4.2)

0.29** (0.08, 0.95)

0.55 (0.23, 1.31)

LPRani 0.5 mg Q12W

0.77

(6.69, 8.29)

– 0.73 (0.19, 2.98)

–

LPRani 0.5 mg Q8W – – 0.11 (0.2, 2.09)

–

Afli 2 mg Q4W 1.33

(3.28, 0.62)

0

(2.15, 2.16)

0.96 (0.46, 2.0)

0.97 (0.54, 1.72)

LPRani 0.5 mg TREX

0.89

(3.29, 1.52)

3.4

(4.57, 11.54)

0.70 (0.28, 1.75)

0.08 (0.0, 1.3)

Rani 0.5 mg PRN 0.97

(1.99, 3.95)

1.8

(2.03, 5.68)

0.99 (0.35, 2.84)

0.82 (0.29, 2.19)

LPBro 6 mg Q8W Q12W

0.78

(5.55, 7.08)

– – –

LPBro 3 mg Q12/8W 0.38

(1.41, 2.17)

0.01

(2.01, 2.04)

1.01 (0.56, 1.85)

0.89 (0.54, 1.48)

Sham IVT 16.87* (13.37, 20.41)

21.21* (17.46, 24.99)

0.07** (0.03, 0.18)

0.11** (0.05, 0.23)

LPRani 0.5 mg PRNX

3.29

(12.13, 5.59)

– 0.28 (0.04, 2.0)

–

LPAfli 2 mg TREX 1.53

(1.89, 4.9)

5.39

(3.02, 14.09)

0.42 (0.08, 2.11)

–

Source: Modified from the submission dossier (Figures 27, 29, 31 and 33). aMD >1 favours brolucizumab. bOR <1 favours brolucizumab. *The lower bound of the 95% CrI interval is >0. **The upper bound of the 95% CrI is <1.

Abbreviations: Afli=aflibercept; BCVA=best corrected visual acuity; Bro=brolucizumab; CrI=credibility interval; IVT=intravitreal; MD=mean difference; OR=odds ratio; LP=loading phase; Rani=ranibizumab; PRN= pro re nata dosing regimen; PRNX=pro re nata and extend dosing regimen; qXw=one injection every X weeks; TREX= treat-and-extend dosing

regimen.

Patients gaining at least 15 letters (baseline to 1 year)

There was no difference between brolucizumab and aflibercept and most of the ranibizumab dosing schemes for a gain of at least 15 letters from baseline to 1 year. However, compared to the following treatment options, brolucizumab had greater odds of gaining at least 15 letters:

Sham IVT (odds ratio 10.99, 95% CrI 5.47–23.43);

Ranibizumab: dosing scheme LP 0,5 mg Q12W (OR 7.57, 95 % CrI 1.89–30.06);

Ranibizumab: dosing scheme 0,5 mg PRN (OR 1.74, 95% CrI 1.07–2.84);

Brolucizumab LP 3 mg Q12W/Q8W (OR 1.37, 95% CrI 1.01–1.86).



Patients gaining at least 15 letters (baseline to two years)

There was no difference between brolucizumab 6 mg and aflibercept, ranibizumab or brolucizumab 3 mg for gain of at least 15 letters from baseline to 2 years. Brolucizumab had greater odds for a gain of at least 15 letters only compared to sham IVT (OR 16.06, 95% CrI 7.47–37.99).

Mean change in CRT (baseline to 1 year)

There was a difference observed between brolucizumab 6 mg and aflibercept as well as brolucizumab 6 mg and ranibizumab for mean change in retinal thickness at one year (Table 4.26). No differences were observed in comparisons to brolucizumab 3 mg and brolucizumab 6 mg dosing scheme LP Q8W Q12W (Table 4.26).

Mean change in CRT (baseline to 2 years)

There was a difference observed between brolucizumab 6 mg and nearly all comparators for mean change in CRT at 2 years. No difference was observed for the following comparator arms: ranibizumab

dosing scheme LP 0.5 mg TREX, aflibercept dosing scheme LP 2 mg TREX and brolucizumab 3 mg (Table 4.26).

Table 4.26. Summary of NMA results comparing the MD in CRT and OR in gain of at least 15 letters (fixed effects). Results are presented as brolucizumab 6 mg Q8W/Q12W vs. each comparator.

Comparator arm OR for gain of ≥15 letters (95% CrI)a MD in CRT (95% CrI)b

Baseline to 1 year Baseline to 2 years Baseline to 1 year Baseline to 2 years

Rani 0.5 mg Q4W 1.11 (0.8, 1.54)

1.21 (0.87, 1.70)

50.49*

(71.63, 29.7)

49.57*

(70.22,-29.29)

LPAfli 2 mg Q8W 1.19 (0.95, 1.49)

1.11 (0.89, 1.39)

39.66*

(53.02, 26.44)

35.01*

(48.94,-21.23)

LPRani 0.5 mg PRN 1.36 (0.84, 2.2)

1.29 (0.80, 2.11)

59.79*

(91.68, 28.13)

58.98*

(89.59,-28.75)

LPRani 0.5 mg Q12W 7.57** (1.89, 30.06)

– – –

LPRani 0.5 mg Q8W 2.18 (0.52, 9.32)

– – –

Afli 2 mg Q4W 1.06 (0.77, 1.48)

1.24 (0.9, 1.72)

40.26*

(61.45, 19.66)

39.78*

(60.22, 19.23)

LPRani 0.5 mg TREX 0.95 (0.62, 1.45)

0.67 (0.15, 2.47)

57.86*

(89.88, 25.87)

16.81

(83.06, 53.94)

Rani 0.5 mg PRN 1.74** (1.07, 2.84)

1.34 (0.77, 2.35)

75.79*

(111.7, 39.55)

68.53*

(110.54, 27.11)

LPBro 6 mg Q8W

Q12W

– – 22.68

(77.62, 31.8)

–

LPBro 3 mg Q12/8W 1.37** (1.01, 1.86)

0.96 (0.72, 1.30)

10.42

(28.26, 7.18)

0.44

(18.05, 18,72)

Sham IVT 10.99** (5.47, 23.43)

16.06** (7.47, 37.99)

– –

LPRani 0.5 mg PRNX 0.77 (0.24, 2.38)

– – –

LPAfli 2 mg TREX 1.03 (0.49, 2.17)

– – 4.77

(72.68, 68,31)

Rani 0.5 mg TREX – – – –

Source: Modified from the submission dossier (Figures 35, 37, 40 and 42). aOR >1 favours brolucizumab. bMD <1 favours brolucizumab. *The upper bound of the 95% CrI is <0.

**The lower bound of the 95% CrI is >1. Abbreviations: Afli=aflibercept; Bro=brolucizumab; CrI=credibility interval; CRT=central retinal thickness; IVT=intravitreal; MD=mean difference; OR=odds ratio; LP=loading phase; Rani=ranibizumab; PRN= pro re nata dosing regimen; PRNX=pro re

nata and extend dosing regimen; qXw=one injection every X weeks; TREX= treat-and-extend dosing regimen.



Injection frequency

The MAH presented arm-based pooling of the injection frequency for each comparator from baseline to 1 year and baseline to 2 years (Tables 48 and 49 in the submission dossier). However, different dosing schemes cannot be compared with each other in terms of injection frequency.

Overall rate of treatment discontinuation (baseline to 1 year and baseline to 2 years)

There was no difference between brolucizumab 6 mg and ranibizumab, aflibercept or brolucizumab 3 mg for the odds of discontinuation from baseline to 1 year and baseline to 2 years.

AEs

The MAH presented molecule-based pooling and regimen-based pooling for SAEs (Tables 54–61 and 63–69 in the submission dossier). Indirect comparisons of AEs were not presented.

4.12 Literature review: evidence of bevacizumab as a treatment option in nAMD

4.12.1 Quality assessment of the SRs included in the assessment

The systematic literature search (see Sections 3.1, 4.1 and 4.2) performed to identify relevant SRs and/or NMAs in which bevacizumab was evaluated as a treatment for nAMD resulted in selection of two SRs by Solomon et al. (30) and Pham et al. (29). The results from the screening of the searches, information on the studies that met eligibility criteria, and excluded articles are available in Appendiced 4-6.

The SR by Solomon et al. (30) only included RCTs. The inclusion and exclusion criteria, and the RCTs included are available in Appendix 6: Excluded articles from bevacizumab literature review. The trials included patients with nAMD as defined by the study investigators, and compared anti-VEGF treatment to another treatment, sham treatment or no treatment. In the SR, 16 RCTs that had enrolled a total of 6347 participants with nAMD were selected and one potentially relevant ongoing trial was identified. Six trials compared anti-VEGF treatment (pegaptanib, ranibizumab or bevacizumab) to a control, and 10 trials compared bevacizumab versus ranibizumab; a total of 3657 participants were included in direct comparisons between bevacizumab and ranibizumab in those trials.

The RoB summary for the ten trials that compared bevacizumab and ranibizumab is presented in Figure 4.21. Pharmaceutical companies conducted or sponsored four trials but funded none of the studies that evaluated bevacizumab. Researchers conducted these trials at various centres across five continents (North and South America, Europe, Asia and Australia). The overall certainty of the evidence was moderate to high, and most trials had an overall low RoB. All but one trial had been registered prospectively.



Figure 4.21. RoB summary: judgements for each RoB item for each study comparing bevacizumab versus ranibizumab included by Solomon et al.

Legend: low risk of bias; unclear risk of bias; high risk of bias. Source: Solomon et al. (30).

Abbreviations: RoB=risk of bias.

The SR by Pham et al. (29) included RCTs evaluating treatment for several retinal conditions. A total of twelve trials evaluating treatment of nAMD were included. The judgment of the SR authors on the RoB of the studies is detailed in Figure 4.22.

Figure 4.22. Cochrane RoB results for individual studies on nAMD included by Pham et al.

Legend: low risk of bias; unclear risk of bias; high risk of bias. Source: Pham et al. (29). Abbreviations: RoB=risk of bias; nAMD=neovascular age-related neovascularisation.



The REA authors applied the AMSTAR-2 tool to both SRs. Details of the evaluation are available in Appendix 10: Critical appraisal for the systematic reviews selected from the SLR of bevacizumab. According to the tool, the SR by Solomon et al. is a low-quality review. The main limitations of the SR are related to the level of detail of some aspects of the study selection methodology, such as the reasons for selecting RCTs only and not describing the meta-analysis techniques in sufficient detail. Despite these limitations, the REA authors consider that the results of the SR by Solomon et al. are robust enough to derive some conclusions on effectiveness of bevacizumab compared to other nAMD treatments.

Using the AMSTAR-2 tool, the REA authors considered the SR by Pham et al. a critically low-quality review. The main limitations are related to the lack of detailed information in the SR protocol, failure to explain the reasons for selecting only RCTs and detailed information on some aspects of the study selection, such as detailed justification of the trials excluded and the predetermined follow-up timeframe in the search strategy. Moreover, even if RoB and heterogeneity were assessed as detailed in the method section of the SR by Pham et al., the impact on the results is not thoroughly detailed in their discussion section. Even with the limitations described, the REA authors consider that the review provides some useful data for indirect comparisons of aflibercept not included in the SR by Solomon et al.

4.12.2 Results from the SRs

In both SRs, meta-analysis was used to gather evidence from different studies. In the SR by Solomon et al. the authors concluded that bevacizumab and ranibizumab were similar in terms of vision-related outcomes among participants followed for at least 1 year (30). More detailed meta-analysis results for the mean change in BCVA (number of letters) are presented in Table 4.27; there was no difference

between the groups (MD 0.52, 95% CI 1.49 to 0.45). For the outcome of gain of ≥15 letters in VA, comparison of bevacizumab to ranibizumab revealed RR of 0.95 (95% CI 0.81–1.12) at 1 year and 0.84 (95% CI 0.64–1.11) at 2 years. Nine of ten trials reported the mean change in CRT at 1 year; the MD

was 11.6 (95% CI 21.55 to 1.66). There were no differences between bevacizumab and ranibizumab in ocular or non-ocular AEs (Table 4.28).

Table 4.27. Treatment effect estimates: bevacizumab versus ranibizumab

Outcomea Number of participants Results of evidence synthesis

Bevacizumab Ranibizumab

Mean VA change in 1 year (letters)

1562 1628 MD, random: 0.52 (95% CI 1.49 to 0,45)

Gain of ≥15 letters in VA 1542 1602 RR 0.95 (95% CI 0.81–1.21)

Gain of ≥15 letters in VA at 2 years

751 796 RR 0.84 (95% CI 0.64–1.11]

Reduction in central retinal thickness at 1 year

1317 1376 MD, random: 11.61 (95% CI 21.55 to

1.66)

Reduction in central retinal thickness at 2 years

592 607 MD, random: 12.4 (95% CI 33.83 to 9.04)

Source: Modified from Solomon et al.(30) (studies included: CATT 2011; IVAN 201; BISWAS 2011; GEFAL 2013; MANTA

2013; SUBRAMANIAN 2010; BRAMD 2016; LUCAS 2015; SCHOLLER 2014). aOutcomes are for bevacizumab versus ranibizumab. There were no direct comparisons for bevacizumab versus pegaptanib.

Abbreviations: AE=adverse event; CI=confidence interval; MD=mean difference; RR=relative risk for bevacizumab vs. ranibizumab; VA=visual acuity.



Table 4.28. AEs up to 1 year: bevacizumab versus ranibizumab

Patients, n (%) RR (95% CI) Studies reporting AEs

Bevacizumab Ranibizumab

With AE Total With AE Total

Serious ocular AEs

Endophthalmitis 5 (<1%) 1052 3 (< 1%) 1059 1.68 (0.40 to 7.00) CATT 2011; GEFAL 2013; LUCAS 2015

Retinal detachment 3 (<1%) 832 0 838 7.05 (0.36–136.28) CATT 2011; GEFAL 2013

Retinal pigment epithelial tear 4 (<1%) 1102 3 (< 1%) 1134 1.37 (0.31–6.12) CATT 2011; IVAN 2013; LUCAS 2015

Traumatic cataract 1 (<1%) 1128 2 (< 1%) 1152 0.51 (0.05–5.62) CATT 2011; GEFAL 2013; IVAN 2013

Severe uveitis 4 (<1%) 882 1 (< 1%) 913 4.14 (0.46–36.97) CATT 2011; IVAN 2013

Non-ocular SAEs

At least 1 SAE 298 (18%) 1663 265 (16%) 1702 1.15 (0.99–1.34) BRAMD 2016; CATT 2011;GEFAL 2013; IVAN 2013; LU-CAS 2015; MANTA 2013

Death 30 (2%) 1663 28 (2%) 1702 1.10 (0.66–1.83) BRAMD 2016; CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015; MANTA 2013

Myocardial infarction 8 (<1%) 1502 16 (1%) 1536 0.51 (0.22–1.19) CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015; MANTA 2013

Stroke or cerebral infarction 7 (<1%) 1502 11 (< 1%) 1536 0.65 (0.25–1.67) CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015; MANTA 2013

Transient ischaemic attack 6 (<1%) 1348 4 (< 1%) 1373 1.53 (0.43–5.40) CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015

Cardiac disorders 46 (3%) 1663 56 (3%) 1702 0.84 (0.57–1.23) BRAMD 2016; CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015; MANTA 2013

Venous thrombotic event 8 (<1%) 1348 4 (< 1%) 1373 2.04 (0.61–6.75) CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015

Source: Modified from Solomon et al. (30). Abbreviations: AE=adverse event; CI=confidence interval; RR=relative risk for bevacizumab vs. ranibizumab.



The SR by Pham et al. only included RCTs. There were twelve RCTs for which the population matched our PICO, namely nAMD (Appendix 5: Studies (SR or NMA) that met the eligibility criteria for the bevacizumab literature review). The SR included studies in which the interventions were anti-VEGF drugs in use in Canada (ranibizumab, IVT bevacizumab and aflibercept) and the comparators were placebo, ranibizumab, IVT bevacizumab or aflibercept. In this SR, meta-analysis was used to perform evidence synthesis from direct comparisons performed in different studies.

The evidence synthesis results show no difference between bevacizumab and ranibizumab in terms of vision-related outcomes or numbers of AEs among participants followed for at least 1 year (Table 4.29 and Table 4.30). Meta-analysis results for the mean change in BCVA (number of letters) are presented in Table 4.29. The average change in the number of letters read was seven versus six, with no difference between the groups (Table 4.29). Comparison of bevacizumab to ranibizumab for the outcome of gain of ≥15 letters in VA at 1 year also revealed no difference.

Two studies comparing ranibizumab and aflibercept directly were found in the SR by Pham et al. In terms of the gain and mean change in VA, no differences were found between ranibizumab and aflibercept. Other outcomes are presented in Table 4.29. Vision-related function was evaluated using the NEI VFQ-25 questionnaire in both studies comparing ranibizumab and aflibercept, with similar changes in NEI VFQ-25 scores observed.

RCTs with direct comparisons between bevacizumab and aflibercept were not found in the SR by Pham

et al. While the MD in BCVA change was 0.03 (95% CI 1.08 to 1.02) between bevacizumab and

ranibizumab and 0.05 (95% CI 2.5 to 2.4) between aflibercept and ranibizumab, the MD estimate

between bevacizumab and aflibercept was 0.02 (95% CI 2.60 to 2.64). Moreover, for vision gain, the RR estimate was 0.96 (95% CI 0.75–1.22) for bevacizumab versus aflibercept, 0.95 (95% CI 0.84–1.07) for bevacizumab versus ranibizumab and 0.99 (95% CI 0.81–1.22) for aflibercept versus ranibizumab (29).

The mean change in CRT was not reported for bevacizumab versus ranibizumab or ranibizumab versus aflibercept. There were no differences between bevacizumab and ranibizumab or between ranibizumab and aflibercept in ocular or non-ocular AEs (Table 4.30).



Table 4.29. Treatment effect estimates

Direct comparisons

Participants Mean estimated effect (range) RR (95% CI) RD (95% CI) I2

Treatment Comparator (%)

Bevacizumab versus ranibizumab

Vision gain in BCVA of ≥15 ETDRS letters 9 3245 0.22 (0.12–0.33) 0.23 (0.14–0.29) 0.95 (0.84–1.08) 1.62 (4.86 to 1.62) 0

Vision loss in BCVA of ≥15 ETDRS letters 10 3302 0.06 (0–0.11) 0.07 (0.04–0.14) 1.1 (0.84–1.43) 0.39 (1.46 to 2.23) 4

Mean change in BCVA (MD in letters) 8 3064 7.24 (4.1–15.2) 5.85 (0.6–11.43) NA 0.03 (1.02 to 1.08) 0

Vision-related function NR NR NR NR NR NR NR

Aflibercept versus ranibizumab

Vision gain in BCVA of ≥15 ETDRS letters 2 1815 0.32 (0.3–0.34) 0.32 (0.31–0.34) 0.99 (0.81–1.22) 0.21 (6.82 to 6.4) 52

Vision loss in BCVA of ≥15 ETDRS letters 2 1815 0.05 (0.05–0.05) 0.06 (0.05–0.06) 0.9 (0.6–1.35) 0.51 (2.75 to 1.72) 0

Mean change in BCVA (MD in letters) 2 1793 8.83 (8.25–9.41) 8.75 (8.1–9.4) NA 0.05 (2.36 to 2.46) 66

Vision related function 2 1632 5.32±14.46 5.60±14.40 NA 2.23 (5.07 to 0.61) 73

Bevacizumab versus aflibercept

None

Source: Modified from Pham et al. (29) (studies included: BRAMD 2016; LUCAS 2015; Scholler 2014; IVAN 2013; GEFAL 2013; MANTA 2013; Biswas 2011 a & b; CATT 2011; Subramanian

2010, VIEW1 2012; VIEW2 2012). Abbreviations: AE=adverse event; BCVA=best corrected visual acuity; ETDRS=Early Treatment Diabetic Retinopathy Study; MD=mean difference; NA=not applicable; NR=not reported; RD=risk difference; RR=relative risk.



Table 4.30. Adverse events: treatment versus comparator

Direct Participants Mean estimated effect (range) RR (95% CI) RD (95% CI)

comparisons Treatment Comparator

Bevacizumab versus ranibizumab

Blindness 3 1823 0.04 (0–0.12) 0.02 (0–0.06) 2.04 (0.32–12.5) 0.11 (0.25 to 0.47)

Mortality 6 2941 0.04 (0.01–0.12) 0.03 (0.01–0.06) 1.14 (0.72–1.79) 0.31 (0.74 to 0.36)

Serious AEs 5 3026 0.19 (0.12–0.28) 0.18 (0.09–0.28) 1.09 (0.93–1.27) 0.02 (0.01 to 0.05)

Arterial thromboembolic events 4 2033 0.03 (0–0.05) 0.04 (0–0.08) 0.86 (0.51–1.47) 0.03 (0.97 to 0.9)

Venous thromboembolic events 3 2135 0 (0–0.01) 0 (0–0.01) 1.59 (0.42–5.88) 0.18 (0.43 to 0.79)

Bacterial endophthalmitis 3 2011 0 (0–0.01) 0 (0–0) 1.75 (0.44–6.67) 0.18 (0.40 to 0.77)

Retinal detachment 2 1526 0.01 (0.01–0.01) 0 (0–0.01) 2.33 (0.31–16.67) 0.38 (0.2 to 0.96)

Aflibercept versus ranibizumab

Blindness NR NR NR NR NR NR

Mortality NR NR NR NR NR NR

Serious AEs NR NR NR NR NR NR

Arterial thromboembolic events 2 1818 0.02 (0.01–0.02) 0.02 (0.02–0.02) 0.96 (0.45–2.04) 0.07 (1.32 to 1.18)

Venous thromboembolic events 1 913 0.0033 0 00.25 (0.01–7.69) 0.25 (0.93 to 0.44)

Bacterial endophthalmitis NR NR NR NR NR NR

Retinal detachment NR NR NR NR NR NR

Bevacizumab versus aflibercept

None

Source: Modified from Pham et al. (29). Abbreviations: AE=adverse event; NR=not reported; RD=risk difference; RR=relative risk.



5 PATIENT INVOLVEMENT

A summary of patient involvement is presented in Table 5.1. The key message is that reduced VA means that patients with AMD often lose their autonomy and mobility. They have difficulties in daily life such as reading, driving and recognising people’s faces. Some patients experience depression, anxiety and other mental health issues.

With current anti-VEGF treatments, regular hospital visits are a significant burden in terms of time, travel arrangements, financial issues, fear of injections and injection-related AEs. Patients expect new treatments to have long-lasting efficacy and less frequent injections. They would also appreciate other modes of administration (e.g., drops or tablets).

Table 5.1. Summary of patient involvement

Question Summary of the responses

How does AMD affect patients’ quality of life?

AMD has a significant impact on quality of life. As their visual acuity declines, patients often lose their autonomy and mobility. They are unable to read, drive, watch TV or recognise faces. They also feel social exclusion.

How does AMD affect carers/unpaid care-givers?

Family members often have to take responsibility for duties previously carried out by the person with AMD, such as household duties and driving. Caregivers may also have financial or time pressures (time away from work, time away from the rest of the family). They often feel guilty that they are not taking enough care of the patient. They also feel sadness observing the patient decline over time.

How well are adult patients managing neovascular (wet) AMD with currently available therapies?

Anti-VEGF injections cause feelings of fear and anxiety for some patients. Some patients also feel pain or disturbed vision after injection. For patients who live far away from urban centres, a lot of effort is required to travel for injections (transportation time and cost, caregiver’s time). However, the majority of patients receiving anti-VEGF injections feel that they are very beneficial. Benefits include retaining the ability to read and drive, employment and the ability to take care of him/herself and of family members when needed. Some answers also indicated that for many patients current treatment is not effective or if it is effective, at some point patient become refractory to the treatment and the disease continues to progress.

What are the expectations and requirements for a new medicine for adult patients with neovascular (wet) AMD?

Possibility to maintain current vision and even restore vision that has already been lost Lower frequency of injections or no need for regular injections No side effects or fewer side effects Improvement in quality of life Other methods of administration, such as drops or tablets

Please include any additional information you believe would be helpful to the EUnetHTA Joint Assessment Team (e.g., ethical or social issues)

The number of AMD patients is increasing. New treatment options are needed that are more effective and less expensive for the patient. European protocols for AMD treatment were also suggested. AMD impacts elderly people who often have other significant health problems. If AMD is effectively treated, it may have positive effects on many other areas of the health service and society. For example, effective AMD treatment could reduce the risk of falls, depression and the need to move to a nursing home. In addition to medical treatment, more attention should be paid to rehabilitation such as better lighting conditions and the possibility of using a white cane.

Abbreviations: AMD=age-related macular degeneration; VEGF=vascular endothelial growth factor.



6 DISCUSSION

The aim of this assessment was to compare the clinical effectiveness and safety of brolucizumab in the treatment of nAMD with relevant comparators. The EUnetHTA PICO survey identified aflibercept, ranibizumab and bevacizumab as relevant comparators. Ranibizumab and aflibercept are licensed drugs for the treatment of nAMD and for which the patents are ceasing in the USA in 2020 and in Europe in 2022 (ranibizumab) and in 2025 (aflibercept) (67). Bevacizumab does not have an approved indication for nAMD. However, bevacizumab has shown similar efficacy and safety compared to ranibizumab in clinical trials (20, 68, 69) and its use as a treatment for nAMD is widespread in Europe1.

6.1 Direct comparisons

The efficacy and safety of brolucizumab have been directly compared only with aflibercept in two phase III RCTs. The studies demonstrated noninferiority of brolucizumab in comparison to aflibercept for the primary efficacy endpoint, mean change in BCVA.

Study level risk of bias was assessed to be low in both HAWK and HARRIER studies. On outcome level, the risk of bias was low for most of the outcomes and unclear for some of the outcomes such as visual function related QoL (measured by NEI VFQ-25) and part of the safety outcomes.

In comparison to aflibercept, the incidence of intraocular inflammation and retinal artery occlusive events was higher for brolucizumab. These safety concerns were also raised in the European public assessment report and a close monitoring is requested in post-marketing setting to further investigate these events (27). The clinical trial data presented for brolucizumab did not raise previously undetected safety concerns for anti-VEGF treatments, at least up to 2 years of use. There are no safety data for brolucizumab beyond 2 years of treatment or in bilateral use.

Moreover, in real life most patients need treatment for longer than 2 years and some patients will need to be treated simultaneously for both eyes, so the safety of long-term use and systemic exposure needs to be monitored. Moreover, in real life patients might be previously treated with other anti-VEGF treatments and efficacy and safety of treatment in these patients is unclear. However, after the launch of brolucizumab in USA, safety signals of retinal vasculitis events has raised concerns and updated information on use and safety of brolucizumab (70).

Brolucizumab has not been directly compared to ranibizumab or bevacizumab in an RCT setting.

6.1.1 Key notes on the outcomes assessed

In all trials (HAWK, HARRIER, OSPREY) the ETDRS chart was used to measure VA. ETDRS charts can reliably identify changes in VA of two lines (10 letters) or more, but not changes of one line (5 letters) or less (71). A loss or gain of three lines (15 letters) is considered a moderate degree of change and is commonly used as an outcome in clinical trials (72). From this perspective, the rationale for choosing a noninferiority margin of four letters (in HAWK and HARRIER) or five letters (in OSPREY) seems justified. In addition, noninferiority compared to aflibercept in terms of the mean change in BCVA can be fairly reliably concluded from the clinical perspective.

However, it should be noted that VA is only one component contributing to overall visual function and the ability to perform everyday visual tasks (e.g., reading, recognising faces, driving and using the telephone). Overall visual function also depends on variables such as contrast sensitivity, near vision, colour vision and sensitivity to glare. The use of distance acuity to measure the effectiveness of drug treatments in AMD is established practice but is not optimal. Difficulty in reading is a common complaint among persons with nAMD and distance VA is usually two ETDRS lines better than reading vision (72). Contrast sensitivity is an important contributor to reading performance (72).

1 At the time of publication of the Joint Assessment (March 2020), bevacizumab did not have an EU marketing authorisation for

the indication under assessment. Bevacizumab is included as a comparator because of its importance identified in the EUnetHTA

PICO survey; however its inclusion in the Joint Assessment should not be understood or quoted as a recommendation for its

unlicensed use.

https://redfoxsanakirja.fi/sanakirja/-/s/eng/fin/established%20practice



In the HAWK and HARRIER trials, optical coherence tomography was used to measure retinal thickness. The change in retinal thickness is an intermediate outcome measure that is modestly correlated with changes in vision and cannot be interpreted separately from VA change or used as a substitute for VA or other patient-reported outcomes (73). The correlation between change in retinal thickness and VA is one-way: a gain in VA is related to a decrease in retinal thickness, but a reduction in retinal thickness is not always related to a gain in VA, especially in late stages of nAMD. In the HAWK and HARRIER studies, statistically significant difference in the change in CSFTtot was observed between brolucizumab and aflibercept. CSFTtot is an intermediate outcome and therefore the clinical relevance of this difference cannot and should not be evaluated separately from changes in VA. The clinical relevance of possible differences observed for other anatomic outcomes such as IRF, SRF, sub-RPE fluid and CNV cannot be evaluated either.

Vision-related QoL was measured using the NEI VFQ-25 instrument, which includes 25 items relevant to 11 vision-related constructs, in addition to a single-item general health component. Determination of a clinically meaningful change in NEI VFQ-25 appears to be linked to its correlation with VA. A three-line (15 letters) change in VA has been used as the outcome of interest in clinical trials, and corresponding changes in NEI VFQ-25 are suggested as clinically meaningful endpoints (73). For patients with nAMD and specifically for the study eye, which is typically the worse-seeing eye, a 15-letter change in VA corresponds to a 4-point change in overall NEI VFQ-25 score. For the better-seeing eye, the clinically relevant difference for NEI VFQ-25, based on a three-line change in VA, is 7–8 points in the overall score (74, 75). For the worse-seeing eye in patients with AMD, the NEI VFQ-25 instrument showed weaker correlation or was not responsive to changes in VA (76). This may have implications when evaluating patients with unilateral disease. In the HAWK and HARRIER studies there were no data on whether the treated eye was the first (worse seeing) or second (better seeing) affected eye. In addition, the analysis of visual function–related QoL (NEI VFQ-25) was not performed separately for the first and second affected eye, although the assessment team asked the MAH to provide this information. The mean changes in NEI VFQ-25 scores from baseline to week 96 (3.8 for brolucizumab 6 mg vs. 2.8 for aflibercept 2 mg in HAWK and 3.8 vs. 2.6, respectively, in HARRIER) suggest that the change in vision-related QoL is not clinically meaningful.

6.1.2 Brolucizumab 3 mg

The marketing authorisation is for brolucizumab 6 mg in nAMD. It should be emphasised that the benefit–risk balance is also positive for brolucizumab 3 mg. The European public assessment report states that no strong evidence was provided by the MAH to clearly support the choice of 6 mg instead of 3 mg. However, the 6 mg dose could be accepted on the basis of limited numerical differences in efficacy and the similarity of the safety profile in unilateral administration between the two doses.(27)

6.1.3 Regarding the direct evidence, the following key limitations were identified during the assessment:

In both the HAWK and HARRIER trials, the study eye in each patient had to be treatment-naïve for any anti-VEGF agents. The efficacy and safety of brolucizumab have not been studied as a second- or third-line treatment. However, the therapeutic indication for brolucizumab does not include any limitations in terms of prior anti-VEGF treatments;

The first three loading doses of brolucizumab are given Q4W. In maintenance treatment the dosing interval is based on disease activity and injections are given Q12W or Q8W. At treatment initiation, it is not possible to know which patients will be able to remain on Q12W dosing. It would be beneficial for both patients and hospitals if brolucizumab treatment could be targeted to patients who are able to remain on Q12W dosing;

In the HAWK and HARRIER trials the treatment duration and follow-up time were only up to 96 weeks. Therefore, the long-term efficacy and safety of brolucizumab are not known. In clinical practice the treatment duration is often longer than 2 years;

Brolucizumab has only been compared to aflibercept 2 mg with fixed Q8W dosing and not to other dosing schemes commonly used in clinical practice (e.g., PRN or TREX). Because dosing schemes differed for brolucizumab and aflibercept in the HAWK and HARRIER trials, the trial design does not allow any conclusions to be drawn regarding treatment burden (injection frequency) between these two regimens. Further investigations involving comparable treatment regimens would be needed;



Data on general HRQoL (e.g., EQ-5D) are not available. However, vision-related QoL (measured using NEI VFQ-25) was included.

6.2 Indirect comparisons

Direct comparisons to ranibizumab and bevacizumab were not performed. The MAH provided an NMA of RCTs in which the main focus was comparison of brolucizumab 6 mg and different dosing schemes for aflibercept 2 mg and ranibizumab 0.5 mg. No differences were observed for the main outcome (mean change in BCVA) or for most of the other outcomes.

The quality of the NMA provided by the MAH was evaluated by the assessment team using the tool developed by Ortega et al. Quality assessment of the individual trials was perfomed by the MAH. The main limitation of the NMA is related to the external validity and applicability of the results and conclusions obtained, because one of the relevant comparators from the European perspective has not been considered.

Overall, the credibility and validity of the NMA rely on a few key assumptions (homogeneity, transitivity and consistency assumptions) and have well-known limitations that should be taken into account in drawing conclusions from these results. In this NMA, some simplifying assumptions were made for practical reasons. These include assuming equivalence between the dosing regimens at year one and year two for the treatments in VIEW 1&2 studies. The other key assumptions were: (1) CRT, CFT, CSFT and CMT were considered as the same measure; and (2) equivalence was assumed for assessment times between 48 and 52 weeks for 12-month outcomes, and between 96 and 104 weeks for 24-month outcomes. Furthermore, the NMA results are reported as mean differences only and not as absolute values or absolute changes. Therefore, it is difficult to evaluate the clinical relevance of the NMA results. However, despite the above limitations the methodological approach and conduct of the NMA can be considered adequate.

6.3 Literature review of bevacizumab

Two systematic reviews (29, 30) that included bevacizumab as a comparator in the treatment of nAMD were identified in the literature search. According to the AMSTAR-2 tool, the SR by Solomon et al. is a low quality review and the SR by Pham et al a critically low quality review. However, the main limitations of the SRs are related to the level of details included in the methodology description of the SRs, and the authors of this REA consider that the results are robust enough to derive some conclusions on the effectiveness of bevacizumab in this setting.

On the basis of two SRs, bevacizumab and ranibizumab were similar in terms of vision-related outcomes and numbers of AEs among participants followed for at least 1 year (29, 30). Similarly, the SR by Pham et al. (29) found no difference in vision-related outcomes between ranibizumab and aflibercept. The authors estimated that the mean difference between bevacizumab and aflibercept in terms of the change in BCVA suggests no difference between these regimens, but the planned NMA performed by the same authors has not been published.

Differences between brolucizumab and bevacizumab remain unknown since direct comparisons are not available and indirect comparison between these two treatments was not formally conducted.

6.4 Patient perspective

The key message from the EUnetHTA patient survey is that patients with AMD often lose their autonomy and mobility and experience many difficulties in daily life. With current anti-VEGF treatments, regular hospital visits are a significant burden in terms of time, travel arrangements, financial issues, fear of injections and injection-related AEs. Patients expect new treatments to have long-lasting efficacy and less frequent injections. Unfortunately, the HAWK and HARRIER trial designs do not allow any conclusions regarding injection frequency between brolucizumab and aflibercept. The same limitation applies to other treatment options included in the NMA: the different dosing schemes cannot be compared with each other in terms of injection frequency.



7 CONCLUSIONS

Two pivotal phase III RCTs showed the noninferiority of brolucizumab in comparison to aflibercept in terms of visual function measured as BCVA in the treatment of patients with nAMD. Brolucizumab 6 mg Q8W or Q12W has only been compared to aflibercept 2 mg dosed at fixed intervals of Q8W and not to other dosing schemes commonly used in clinical practice. Because the dosing schemes were different for brolucizumab and aflibercept in the HAWK and HARRIER trials, the trial design does not allow any conclusions to be drawn about treatment burden (injection frequency) between these two drugs. Consequently, it is unknown how brolucizumab compares with existing flexible dose regimens, so no advantages related to treatment burden can be anticipated with available data. Further investigations involving comparable treatment regimens would be needed.

In comparison to aflibercept, the incidence of intraocular inflammation and retinal artery occlusive events were higher for brolucizumab. These safety concerns were raised also in European public assessment report and a close monitoring is requested in post-marketing setting to further investigate these events (27). The clinical trial data presented for brolucizumab did not raise previously undetected safety concerns for anti-VEGF treatments, at least up to 2 years of use. There are no safety data for brolucizumab beyond 2 years of treatment or in bilateral use.

Evidence of the efficacy and safety of brolucizumab is based only on data for anti-VEGF treatment– naïve patients. There is no evidence regarding the efficacy and safety of brolucizumab in patients with nAMD previously treated with an anti-VEGF agent.

Direct comparisons to ranibizumab and bevacizumab are not available. Indirect comparisons based on NMA between brolucizumab and ranibizumab showed no differences in the main outcome (mean change in BCVA) or most of the other outcomes. Differences between brolucizumab and bevacizumab remain unknown since direct comparisons are not available and indirect comparisons between these two treatments were not formally conducted.



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https://www.eunethta.eu/wp-content/uploads/2018/01/Applicability.pdf

https://www.eunethta.eu/wp-content/uploads/2018/01/Applicability.pdf

https://eunethta.eu/wp-content/uploads/2018/01/eunethta_position_paper_on_research_recommendations_0-1.pdf

https://eunethta.eu/wp-content/uploads/2018/01/eunethta_position_paper_on_research_recommendations_0-1.pdf

https://www.novartis.com/news/novartis-provides-update-use-and-safety-beovu-patients-wet-amd

https://www.novartis.com/news/novartis-provides-update-use-and-safety-beovu-patients-wet-amd

http://www.madrid.org/cs/Satellite?blobcol=urldata&blobheader=application%2Fpdf&blobheadername1=Content-Disposition&blobheadervalue1=filename%3DCriterios_DMAE.pdf&blobkey=id&blobtable=MungoBlobs&blobwhere=1352885261145&ssbinary=true






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101. Schmucker C, Ehlken C, Hansen LL, Antes G, Agostini HT, Lelgemann M. Intravitreal bevacizumab (Avastin) vs. ranibizumab (Lucentis) for the treatment of age-related macular degeneration: a systematic review. Curr Opin Ophthalmol. 2010;21(3):218-26.



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111. Costagliola C, Romano MR, Rinaldi M, dell'Omo R, Chiosi F, Menzione M, et al. Low fluence rate photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration. Br J Ophthalmol. 2010;94(2):180-4.

112. Kaiser PK, Boyer DS, Cruess AF, Slakter JS, Pilz S, Weisberger A, et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study. Ophthalmology. 2012;119(5):1001-10.

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APPENDIX 1: GUIDELINES FOR MANAGEMENT OF AMD

Table A1. Overview of guidelines used for this assessment

Name of society/organisation issuing guidance

Date of issue Country/ies to which applicable

Summary of recommendation

Agencia de Evaluación de Tecnologías Sanitarias de Andalucía (50)

2011 Spain Efficacy: bevacizumab and ranibizumab provide similar gains in visual acuity and in reduction of visual acuity loss at 1 year follow-up.

Safety: systemic adverse effects are rare for both bevacizumab and ranibizumab.

(No level of evidence/strength of recommendation provided)

American Academy of Ophthalmology (51)

2020 United States of America With the introduction of the VEGF inhibitors pegaptanib sodium, off-label bevacizumab, ranibizumab, and aflibercept, more effective treatments for neovascular AMD exist. The VEGF inhibitors have demonstrated improved visual and anatomic outcomes compared with other therapies. Anti-VEGF therapies have become first-line therapy for treating and stabilizing most cases of nAMD and a Cochrane systematic review demonstrates the effectiveness of these agents to maintain visual acuity.

(I+, Good quality, Strong recommendation)

Presently, there does not appear to be a significant difference in efficacy between ranibizumab and bevacizumab. SRs and NMAs have concluded that bevacizumab and ranibizumab have equivalent efficacy for BCVA, whereas ranibizumab has greater reduction in central macular thickness. Aflibercept and ranibizumab have comparable efficacy for BCVA and central macular thickness. If a difference in safety between these anti-VEGF drugs exists, it is minimal.

(I+, Good quality, Strong recommendation)

Belgian Retina Society (9) 2019 Belgium Three different intravitreal anti-VEGF agents (bevacizumab, ranibizumab, and aflibercept) are currently available for treating nAMD. Until now, no clinically significant differences in the efficacy and safety between the different anti-VEGF drugs have been shown in the treatment of nAMD during the first few years of follow-up. In case of recent cardiovascular event (within 3 months), anti-VEGF treatment can be considered after careful evaluation of the possible treatment related benefits and adverse effects.


Consejería de Sanidad, Servicio Madrileño de Salud (77)

2012 Spain Taking into account the efficacy and safety evidence on the use ranibizumab and bevacizumab, and the wide accumulated experience of use, it is considered that both drugs have a similar benefit/risk profile for the treatment of patients with nAMD.







European Society of Retina Specialists (EURETINA) (2)

2014 Europe Ranibizumab continuously for 2 years on a PRN regimen with strict monthly monitoring and retreatment, whenever any evidence of fluid is noted by retinal imaging has been found to be the regimen that secures the optimum results in vision outcome. The recommendations are based on the ANCHOR, MARINA, PIER, EXCITE, HARBOR and CATT study data (evidence level I) and as well as the SECURE and HORIZON study data (evidence level II).

The CATT and IVAN studies results indicate that ranibizumab and bevacizumab both confer solid visual function benefits. Non-inferiority was proven with monhtly use of both drugs, and among as-needed treatments. Bevacizumab used in a PRN regimen failed to demonstrate non-inferiority to monthly ranibizumab. Therefore, the choice of fixed month regimen is relevant when off-label bevacizumab is used. How much reduction in ocular efficacy one would be willing to sacrifice for reducing the number of injections and/or costs might depend on individual circumstances. No major safety issues have emerged, but conclusive data are lacking, and none of the trials were powered for safety. Nevertheless, bevacizumab’s impact on plasma concentrations of VEGF and its prolonged half-life in the circulation are proven. Therefore, the individual physical condition of each patient should be considered in the choice of therapy. Informed consent after discussing the optimal benefit, comfort and risks and the off-label status of the drug is mandatory. (Evidence level I).

The EU label for Eylea (aflibercept) recommends three initial injections at monthly intervals, followed by eight weekly injections without any subsequent monitoring. However, based on VIEW 1 study data, monthly aflibercept provided statistically superior visual gains compared with aflibercept dosed every 8 weeks. Many interventional studies suggest a superior anatomic efficacy of aflibercept compared with ranibizumab and bevacizumab. The bimonthly fluctuations in BCVA and CRT values are small when averaged but are more impressive individually. This suggests patients with more intensive disease activity who can benefit from a monthly regimen should be identified. Beyond the first year, increased dosing with continued monthly/bimonthly injections may be needed in eyes with morphologic signals which are likely associated with aggressive progression of CNV disease. (Evidence level I)

Finnish Ophthalmological Society (11)

2017 Finland Bevacizumab and ranibizumab seem to have the same efficacy in maintaining visual acuity in the treatment of nAMD during 1-2 years of follow-up. (Evidence level B).

Monthly or less frequent intravitreal injections of aflibercept seem to be as effective as monthly injected ranibizumab in maintaining visual acuity. (Evidence level B).

There seem to be no clinically significant short-term safety differences between ranibizumab and bevacizumab in the treatment of nAMD. (Evidence level B).

Monthly or less frequent intravitreal injections of aflibercept may be as safe as monthly injected ranibizumab in the treatment of nAMD. (Evidence level C).






Fondazione G.B. Bietti per lo Studio e la Ricerca in Oftalmologia (12)

2008 Italy Taking into account only clinical evidence, anti-VEGF drugs administered at a high frequency (pegaptanib every 6 weeks or ranibizumab every 4 weeks) should be given to patients with nAMD. (Strong recommendation of pegaptanib and ranibizumab; high quality of evidence for ranibizumab; moderate quality evidence for pegaptanib).

Anti-VEGF therapy must consist of a loading phase of three doses, followed by individualized regimens. (Strong recommendation based on very low quality evidence for pegaptanib and low quality evidence for ranibizumab).

Haute Autorité de Santé (13) 2017 France Be aware that no clinically significant differences in effectiveness and safety between the different anti-VEGF treatments have been seen in the trials considered by the guideline committee.

Given the guideline committee’s view that there is equivalent clinical effectiveness and safety of different anti-VEGF agents (aflibercept, bevacizumab, and ranibizumab), comparable regimens will be more cost effective if the agent has lower net acquisition, administration and monitoring costs. (No level of evidence/strength of recommendation provided).

Sociedad Española de Retina y Vítreo (15)

2014 Spain Based on CATT and IVAN study data, bevacizumab and ranibizumab have equivalent effects on BCVA when administered in equivalent regimens, while anatomical outcomes favour ranibizumab. No significant differences in safety have been identified after 2 years of treatment. Monthly treatment regimens have better visual outcomes than PRN regimens, although the difference is not clinically relevant. The risk of geographic atrophy is higher with monthly regimens (Evidence level I, strength of recommendation A)

Aflibercept every eight weeks has demonstrated equivalent efficacy and safety to monthly ranibizumab (Evidence level I, strength of recommendation A)

Abbreviations: AMD=age-related macular degeneration; BCVA=best corrected visual acuity; CNV=choroidal neovascularisation; CRT=central retinal thickness; nAMD=neovascular age-related

macular degeneration; PRN=pro re nata, VEGF=vascular endothelial growth factor.



APPENDIX 2: SEARCHES STRATEGIES FOR BEVACIZUMAB LITERATURE

REVIEW

Strategies to select NMAs and SRs

Database: Ovid MEDLINE to October 24, 2019

1 exp Macular degeneration/

2 exp retinal degeneration/

3 exp retinal neovascularization/

4 exp choroidal neovascularization/

5 exp macula lutea/

6 maculopath$.tw.

7 ((macul$ or retina$ or choroid$) adj3 degener$).tw.

8 ((macul$ or retina$ or choroid$) adj3 neovasc$).tw.

9 (macula$ adj2 lutea).tw.

10 (AMD or ARMD or CNV).tw.

11 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10

12 angiogenesis inhibitors/

13 angiogenesis inducing agents/

14 endothelial growth factors/

15 vascular endothelial growth factors/

16 (anti adj2 VEGF$).tw.

17 (endothelial adj2 growth adj2 factor$).tw.

18 (anti adj1 angiogen$).tw.

19 *Antibodies, Monoclonal/ad, tu [Administration & Dosage, Therapeutic Use]

20 (bevacizumab or avastin or R435 or RG435 or rhuMAbVEGF).ti,ab.

21 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20

22 11 and 21

23 (letter or "case report*" or "historical article*" or (commentor editorial or in vitro or news)).pt.

24 22 not 23

25 animals/ not (animals/ and humans/)

26 24 not 25

27 limit 26 to "reviews (maximizes specificity)"


26 24 not 25

27 limit 26 to "reviews (maximizes specificity)"

Database: Embase to October 24, 2019

#1 'macular degeneration'/exp

#2 'retina degeneration'/exp

#3 'retina neovascularization'/exp

#4 'subretinal neovascularization'/exp

#5 'retina macula lutea'/exp

#6 maculopath$:ti,ab

#7 ((macul* OR retina* OR choroid$) NEAR/3 degener*):ti,ab

#8 ((macul* OR retina* OR choroid*) NEAR/3 neovasc*):ti,ab

#9 (macula* NEAR/2 lutea):ti,ab

#10 amd:ti,ab OR armd:ti,ab OR cnv:ti,ab



#11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10

#12 'angiogenesis inhibitor'/exp

#13 'angiogenic factor'/exp

#14 'endothelial cell growth factor'/exp

#15 'vasculotropin'/exp

#16 (anti NEAR/2 vegf*):ti,ab

#17 (endothelial NEAR/2 growth NEAR/2 factor*):ti,ab

#18 (anti NEAR/1 angiogen*):ti,ab

#19 'monoclonal antibody'/mj

#20 #19 AND ('drug administration'/lnk OR 'drug dose'/lnk OR 'drug therapy'/lnk)

#21 bevacizumab:ti,ab OR avastin:ti,ab OR r435:ti,ab OR rg435:ti,ab OR rhumabvegf:ti,ab

#22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #20 OR #21

#23 #11 AND #22

#24 'conference abstract'/it OR 'conference paper'/it OR 'note'/it OR 'short survey'/it OR 'abstract report'/exp OR 'abstract report' OR 'letter'/exp OR 'letter'

#25 #23 NOT #24

#26 #25 AND [embase]/lim NOT ([embase]/lim AND [medline]/lim) AND [systematic review]/lim AND ([systematic review]/lim OR [meta analysis]/lim)

Database: CRD to October 24, 2019

1 (MeSH DESCRIPTOR Macular Degeneration EXPLODE ALL TREES)

2 (MeSH DESCRIPTOR retinal degeneration EXPLODE ALL TREES)

3 (MeSH DESCRIPTOR retinal neovascularization EXPLODE ALL TREES)

4 (MeSH DESCRIPTOR choroidal neovascularization EXPLODE ALL TREES)

5 MeSH DESCRIPTOR macula lutea EXPLODE ALL TREES

6 (maculopath*)

7 (((macul* or retina* or choroid*) NEAR3 degener*))

8 ((macula* NEAR2 lutea))

9 ((AMD or ARMD or CNV))

10 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9

11 MeSH DESCRIPTOR angiogenesis inhibitors EXPLODE ALL TREES

12 MeSH DESCRIPTOR angiogenesis inducing agents EXPLODE ALL TREES

13 MeSH DESCRIPTOR endothelial growth factors EXPLODE ALL TREES

14 MeSH DESCRIPTOR Vascular Endothelial Growth Factors EXPLODE ALL TREES

15 ((anti NEAR2 VEGF*))

16 ((endothelial NEAR2 growth NEAR2 factor*))

17 ((anti NEAR1 angiogen*))

18 MeSH DESCRIPTOR Antibodies, Monoclonal WITH QUALIFIERS AD, TU

19 ((bevacizumab or avastin or R435 or RG435 or rhuMAbVEGF))

20 #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19

21 #10 AND #20

Database: Cochrane to October 24, 2019

#1 [mh "Macular Degeneration"]

#2 [mh "retinal degeneration"]

#3 [mh "retinal neovascularization"]

#4 [mh "choroidal neovascularization"]

#5 [mh "macula lutea"]



#6 maculopath*:ti,ab

#7 ((macul* or retina$ or choroid*) NEAR/3 degener*):ti,ab

#8 ((macul* or retina* or choroid*) NEAR/3 neovasc*):ti,ab


#10 (AMD or ARMD or CNV):ti,ab

#11 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10

#12 [mh "angiogenesis inhibitors"]

#13 [mh "angiogenesis inducing agents"]

#14 [mh "endothelial growth factors"]

#15 [mh "vascular endothelial growth factors"]

#16 (anti NEAR/2 VEGF*):ti,ab



#19 [mh ^"Antibodies, Monoclonal"/AD,TU]

#20 (bevacizumab or avastin or R435 or RG435 or rhuMAbVEGF):ti,ab


#22 #11 AND #21 in Cochrane Reviews

Strategies to update the included NMAs and SRs

Database: Ovid MEDLINE January 1, 2018 to November 19, 2019

1 exp Macular degeneration/

2 exp retinal degeneration/

3 exp retinal neovascularization/

4 exp choroidal neovascularization/

5 exp macula lutea/

6 maculopath$.tw.

7 ((macul$ or retina$ or choroid$) adj3 degener$).tw.

8 ((macul$ or retina$ or choroid$) adj3 neovasc$).tw.

9 (macula$ adj2 lutea).tw.

10 (AMD or ARMD or CNV).tw.

11 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10

12 angiogenesis inhibitors/

13 angiogenesis inducing agents/

14 endothelial growth factors/

15 vascular endothelial growth factors/

16 (anti adj2 VEGF$).tw.

17 (endothelial adj2 growth adj2 factor$).tw.

18 (anti adj1 angiogen$).tw.

19 *Antibodies, Monoclonal/ad, tu [Administration & Dosage, Therapeutic Use]

20 (bevacizumab or avastin or R435 or RG435 or rhuMAbVEGF).ti,ab.

21 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20

22 11 and 21

23 (letter or "case report*" or "historical article*" or (commentor editorial or in vitro or news)).pt.

24 22 not 23


26 24 not 25

27 limit 26 to randomized controlled trial

28 limit 27 to yr="2018 -Current"



Database: Embase January 1, 2018 to November 19, 2019

#1 'macular degeneration'/exp

#2 'retina degeneration'/exp

#3 'retina neovascularization'/exp

#4 'subretinal neovascularization'/exp

#5 'retina macula lutea'/exp

#6 maculopath$:ti,ab

#7 ((macul* OR retina* OR choroid$) NEAR/3 degener*):ti,ab

#8 ((macul* OR retina* OR choroid*) NEAR/3 neovasc*):ti,ab


#10 amd:ti,ab OR armd:ti,ab OR cnv:ti,ab

#11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10

#12 'angiogenesis inhibitor'/exp

#13 'angiogenic factor'/exp

#14 'endothelial cell growth factor'/exp

#15 'vasculotropin'/exp

#16 (anti NEAR/2 vegf*):ti,ab



#19 'monoclonal antibody'/mj

#20 #19 AND ('drug administration'/lnk OR 'drug dose'/lnk OR 'drug therapy'/lnk)

#21 bevacizumab:ti,ab OR avastin:ti,ab OR r435:ti,ab OR rg435:ti,ab OR rhumabvegf:ti,ab OR lucentis*:ti,ab OR rhufab*:ti,ab OR '347396 82 1':ti,ab


#23 #11 AND #22

#24 'conference abstract'/it OR 'conference paper'/it OR 'note'/it OR 'short survey'/it OR 'abstract report'/exp OR 'abstract report' OR 'letter'/exp OR 'letter'

#25 #23 NOT #24

#26 #25 AND [embase]/lim NOT ([embase]/lim AND [medline]/lim) AND [2018-2019]/py AND [randomized controlled trial]/lim



APPENDIX 3: SEARCHES PERFORMED BY THE INFORMATION SPECIALIST

TO THE COMPLETENESS OF THE STUDY POOL

Search 1: Search in study registries for Brolucizumab

1. ClinicalTrials.gov

Provider: U.S. National Institutes of Health

URL: http://www.clinicaltrials.gov

Input interface: Advanced Search

Search strategy

Condition of disease Age Related Macular Degeneration

Other terms brolucizumab OR esba1008 OR esba 2008 OR dlx1008 OR dlx 1008 OR rth258 OR rth 258

2. EU Clinical Trials Register

Provider: European Medicines Agency

URL: https://www.clinicaltrialsregister.eu/ctr-search/search

Input interface: Basic Search

Search strategy

age related macular degeneration AND (brolucizumab OR esba1008 OR esba 2008 OR dlx1008 OR dlx 1008 OR rth258 OR rth 258)

3. International Clinical Trials Registry Platform Search Portal

Provider: World Health Organization

URL:http://apps.who.int/trialsearch/

Input interface: Standard Search

Search strategy

age related macular degeneration AND brolucizumab OR esba1008 OR esba 2008 OR dlx1008 OR dlx 1008 OR rth258 OR rth 258

http://www.clinicaltrials.gov/

https://www.clinicaltrialsregister.eu/

http://apps.who.int/trialsearch/



Search 2: Search in study registries for ranibizumab, bevacizumab and aflibercept

1. ClinicalTrials.gov

Provider: U.S. National Institutes of Health

URL: http://www.clinicaltrials.gov

Input Interface: Advance Search

Search strategy

(ranibizumab OR lucentis OR rg3645 OR rhuFab) OR (aflibercept OR eylea OR AVE 0005 OR AVE0005 OR AVE005 OR AVE 005 OR Zaltrap OR VEGF trap) OR (bevacizumab OR avastin OR rhumbab-vegf OR R435 or RG435) | Age Related Macular Degeneration

2. EU Clinical Trials Register

Provider: European Medicines Agency

URL: https://www.clinicaltrialsregister.eu/ctr-search/search

Input interface: Basic Search

Search strategy

age related macular degeneration AND ((ranibizumab OR lucentis OR rg3645 OR rhuFab) OR (aflibercept OR eylea OR AVE 0005 OR AVE0005 OR AVE005 OR AVE 005 OR Zaltrap OR VEGF trap) OR (bevacizumab OR avastin OR rhumbab-vegf OR R435 or RG435) )

3. International Clinical Trials Registry Platform Search Portal

Provider: World Health Organization

URL:http://apps.who.int/trialsearch/

Input interface: Standard Search

Search strategy

age related macular degeneration AND ranibizumab OR lucentis OR rg3645 OR rhuFab OR aflibercept OR eylea OR AVE 0005 OR AVE0005 OR AVE005 OR AVE 005 OR Zaltrap OR VEGF trap OR bevacizumab OR avastin OR rhumbab-vegf OR R435 or RG435

http://www.clinicaltrials.gov/

https://www.clinicaltrialsregister.eu/ctr-search/search

http://apps.who.int/trialsearch/



Search 3: Search focused in Pubmed

Provider: National Library of Medicine

Search Query Items found

#1 Search neovascular age related macular degeneration 4747

#2 Search BROLUCIZUMAB 21

#3 Search (neovascular age related macular degeneration) AND BROLUCIZUMAB

9

#4 Search 30986442[uid] 1

#5 Similar articles for PubMed (Select 30986442) 111

#6 Select 20 document(s) 20

#7 Search 28551167[uid] 1

#8 Similar articles for PubMed (Select 28551167) 315

#9 Select 20 document(s) 20

#10 #3 OR #6 OR #9 40



APPENDIX 4: RESULTS FROM THE SCREENING OF THE SEARCHES OF

BEVACIZUMAB

Table A2. Information about the screening of the records from the searches of bevacizumab to include SRs and NMAs.

MEDLINE Embase CRD Cochrane TOTAL

Total number of records retrieved 212 22 125 12 371

Duplicated records 5 9 45 12 71

Excluded based on title or abstract 167 10 67 - 244

Different population 90 5 31 - 126

Different interventions 37 4 17 - 58

Different comparators (combination therapy)

3 - - - 3

Different outcomes 4 - 12 - 16

Different objectives 32 - 5 - 37

Different designs 1 1 2 - 4

Number of records to be reviewed by full text

40 3 13 - 56

Full text not available, excluded based on abstract

2 - 5 - 7

Excluded based on full text 9 1 4 - 14

Included in the assessment report 29 2 4 - 35

Table A3. Information about the screening of the records from the searches to update included SRs and NMAs.

MEDLINE Embase TOTAL

Number records retrieved from databases 87 23 110

Duplicated 2 - 2

Excluded based on title or abstract 85 23 108

Different population 60 14 74

Different interventions 13 6 19

Different comparators (combination therapy) 1 - 1

Different outcomes - - -

Different objectives 11 3 14

Excluded based on full text 0 0 0

Included 0 0 0



APPENDIX 5: STUDIES (SR OR NMA) THAT MET THE ELIGIBILITY CRITERIA FOR THE BEVACIZUMAB LITERATURE

REVIEW

Table A4. Studies (SR or NMA) that met the eligibility criteria for the bevacizumab literature review

Author and publication year

Eligibility criteria Date of search strategies and searched databases

Studies included in the SR and/or NMA *

Solomon SD. 2019 (30)

Inclusion criteria: - Population: patients with nAMD; - Interventions and comparators: anti-VEGF treatment versus another treatment, sham treatment, or no treatment; - Primary outcome: BCVA at one-year follow-up; - Study design: Only RCTs; - Follow up time of the included studies: at least one year and outcomes at two-year follow-up, when these data were available. Exclusion criteria: Interventions: - No control or comparator group; - Comparison of different doses of one anti-VEGF treatment against another; - Anti-VEGF agents in combination with other treatments; - Studies of aflibercept (not considered because other Cochrane reviews have evaluated it); - Comparison of different treatment schedules (e.g. monthly vs. as needed dosing) (not considered because other Cochrane reviews have evaluated those interventions).

Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register; MEDLINE Ovid; Embase Ovid; the Latin American and Caribbean Health Sciences Literature Database (LILACS); the International Standard Randomized Controlled Trials Number (ISRCTN) Registry; ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The search included no language or publication year restrictions. The date of the most recent search was January 31, 2018.

The review included a total of 6347 participants from 16 RCTs: ABC 2010 ANCHOR 2006 BISWAS 2011 BRAMD 2016 CATT 2011 GEFAL 2013 IVAN 2013 LUCAS 2015 MANTA 2013 MARINA 2006 PIER 2008 SACU 2009 SAVE-AMD 2017 SCHOLLER 2014 SUBRAMANIAN 2010 VISION 2004






Pham B. 2019 (29)

Inclusion criteria: - Population: patients ≥ 18 years of age and with retinal conditions including wet AMD, diabetic macular edema, macular edema due to retinal vein occlusion and myopic choroidal neovascularisation. - Interventions: anti-VEGF drugs in use in Canada, namely ranibizumab, intravitreal bevacizumab and aflibercept. - Comparators: placebo, ranibizumab, intravitreal bevacizumab or aflibercept. - Outcomes: 14 outcomes (including five efficacy and nine safety outcomes) were selected a priori at the protocol stage according to feedback from the research team, clinical experts, patient advocacy groups, industry stakeholders and CADTH. - Study design: parallel- and cluster-RCTs. - Follow-up: all reports pertaining to an RCT were located to obtain data at the longest follow-up duration. Exclusion criteria: - Population: RCTs reporting only results for paediatric patients - Interventions: studies evaluating the anti-VEGF drug pegaptanib, or studies that compared an anti-VEGF drug with other comparators (such as photodynamic therapy, intravitreal corticosteroids, grid laser photocoagulation or cataract removal surgery).

MEDLINE, Embase and Cochrane Central Register of Controlled Trials were searched from inception to 17 August 2017

Twelve RCTs were included for patients with nAMD: BRAMD 2016 LUCAS 2015 Scholler 2014 IVAN 2013 GEFAL 2013 MANTA 2013 VIEW1 2012 VIEW2 2012 Biswas 2011 a y b CATT 2011 Subramanian 2010

Low A. 2019 (78)

- Population: adults with nAMD, diabetic macular edema, or branch or central retinal vein occlusion; - Intervention: aflibercept, bevacizumab or ranibizumab; -Comparators: One anti-VEGF intervention versus another anti-VEGF intervention (head-to-head). - Outcomes of interest: Short- and long-term outcomes; Visual acuity, functional status, quality of life, systemic adverse events, ocular harms or cost-effectiveness; - Study design: controlled clinical trials (randomized or non-randomized); and cohort and modelling studies that reported cost outcomes in the USA; - Follow-up: There was no minimum length of follow-up specified.

Ovid MEDLINE, PubMed, Elsevier EMBASE, Ovid EMB Reviews, trial registries and regulatory agency websites were searched from database inception to 6 February 2017

Eleven studies in nAMD: Biswas 2011 BRAMD (Schauwvlieghe 2016) CATT (Martin 2012) GEFAL (Kodjikian 2013) IVAN (Chakravarthy 20139 LUCAS (Berg 2015) MANTA (Krebs 2013) Scholler 2014 Subramanian 2010 VIEW 1; Heier 2012 VIEW 2; Heier 2012






Nguyen CL. 2018 (79)

Inclusion criteria: - Population: nAMD; - Interventions and comparators: anti-VEGF treatment (pegaptanib, ranibizumab, bevacizumab, aflibercept or conbercept) compared to another treatment or each other. -Outcomes: Efficacy: mean change in BCVA and in central macular thickness; Safety: death, arteriothrombotic and venous thrombotic events, and serious systemic adverse events. - Study design: RCTs; - Follow up: at least one year, and outcomes at two-year follow-up, when these data were available. Exclusion criteria: Interventions: - No control or comparator group; - Anti-VEGF agents used in combination with other treatments; - Studies in which different doses of one anti-VEGF agent were compared with each other.

CENTRAL, Ovid MEDLINE, EMBASE, the metaRegister of Controlled Trials (mRCT) ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). The final search was performed on June 2016.

VISION 2004 ANCHOR 2006 MARINA 2006 PIER 2008 ABC 2010 SACU 2009 CATT 2011 IVAN 2013 GEFAL 2013 MANTA 2013 Subramanian Biswas 2011 LUCAS 2015 BRAMD 2016 VIEW 1 VIEW 2

Thulliez M. 2018 (80)

- Population: AMD, diabetic macular edema, or retinal vein occlusion diseases; - Interventions: all anti-VEGF available treatments were considered (pegaptanib, bevacizumab, ranibizumab, and aflibercept); - Comparators: All comparators were considered (treatments with comparison anti-VEGF medication, sham procedures, absence of anti-VEGF treatments, and absence of treatments of any kind); - Outcomes: focused only on safety: serious adverse events; - Study design: meta-analyses or systematic reviews of clinical trials or observational studies; - Follow-up: There was no minimum length of follow-up specified.

PubMed and the Cochrane Central Register of Controlled Trials databases Systematic reviews published between January 1, 2011, and June 30, 2016 were included.

The article is an overview of Systematic Reviews and Meta-analyses. The individual trials in each of the ten SRs that were included related to patient with AMD were not reported in the overview of SRs.

Wang X. 2018 (81)

To be considered eligible for inclusion in the meta-analysis, the studies had to meet the following criteria: - Population: previously untreated nAMD; - Intervention: bevacizumab versus ranibizumab; - Primary outcome: BCVA; - Study design: non-inferiority RCT; - Follow-up: one year.

PubMed, Embase, the Cochrane Library, and clinicaltrials.gov from inception of the study until August 2017.

5 RCTs CATT 2011; LUCAS 2015; IVAN 2012; GEFAL 2013, and BRAMD 2016.






Arnold JJ. 2016 (82)

- Population: exudative AMD; - Interventions: bevacizumab, ranibizumab and aflibercept. - Outcomes: Visual acuity; quality of life; adverse effects (thrombotic events [myocardial infarction, stroke], infection, bleeding), and death; - Study design: systematic reviews and RCTs at least single blinded, and containing 20 or more patients (10 in each arm), of whom more than 80% were followed up; - Follow-up: Authors indicated that there was no minimum length of follow-up to include studies.

Medline, Embase, and the Cochrane Database of Systematic Reviews up to January 2014.

Two SRs (Mitchell 2011 and Schmucker 2012), 10 RCTs [MARINA (Rosenfeld 2006 and Chang 2007), PIER, CATT, MANTA, GEFAL, HARBOR Study, EXCITE Study, IVAN, View 1 and View 2] and four further reports (Subgroups analysis from MARINA and ANCHOR) were included.


- Population: patients with nAMD; - Interventions and comparators: direct comparisons among intravitreal injections of bevacizumab and ranibizumab, in comparable dosages and regimens; - Outcomes: The primary outcome was 1-year gain in best-corrected visual acuity (BCVA) of 15 or more logMAR letters; - Study design: RCTs; - Follow-up: Trials in which participants were followed for at least one year. When data were available, two years of follow up. Exclusion criteria: Interventions and comparators: Trials of aflibercept and trials that used bevacizumab or ranibizumab in combination with other treatments.

CENTRAL (Cochrane Eyes and Vision Group Trials Register), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, EMBASE and LILACS. The metaRegister of Controlled Trials, clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). Databases were searched last on 27 March 2014.

Six RCTs: Biswas 2011; CATT 2011; GEFAL 2013; IVAN 2013; MANTA 2013; Subramanian 2010.

Chen G. 2015 (84)

- Population: patients with nAMD with minimum age of 50 years; - Intervention: bevacizumab versus ranibizumab; - Outcomes: mean change in BCVA from baseline, mean change in central macular thickness from baseline, and safety (death, arteriothrombotic events, venous thrombotic events, and serious systemic adverse event); - Study design: RCTs; - Follow-up: There was no minimum length of follow-up specified.

PubMed, EMBASE, and the Cochrane Library. The final search was performed on December 2013.

A total of six studies were included in the meta-analysis: CATT, IVAN, MANTA, GEFAL Biswas, 2011 and Subramanian 2010.






Schmid MK. 2015 (85)

- Population: AMD; - Interventions and comparators: aflibercept, bevacizumab or ranibizumab against placebo or in a head-to-head fashion; - Outcomes: visual acuity and serious side effects; - Study design: RCTs; - Follow-up: Studies had to include 1-year follow-up data.

Medline, Premedline, EMBASE, SCOPUS and the Cochrane Library The search was last updated in June 2013.

Eleven trials assessing five active treatments (ranibizumab 0.3mg, ranibizumab 0.5mg, bevacizumab 1.25mg, aflibercept 0.5mg and aflibercept 2mg): ANCHOR 2006; CATT 2011; IVAN 2013; MARINA 2006; VIEW1, VIEWS2; SAILOR 2009; FOCUS 2006; EXCITE 2011; MONT BLANC 2012 and DENALI 2012.

Barbosa BRD. 2014 (86)

Although in the abstract it is stated that the record is a systematic review, in the full text, the methodology is not detailed. The inclusion and exclusion criteria are not described. The study aimed at reviewing the literature related to the off-label indication and the risks associated with the use of multi-dose vials in AMD treatment.

The databases for the literature search are not specified. A systematic survey of scientific works and of electronic database relevant information up to November 2012 was carried out.

CATT; IVAN; Marina and ANCHOR (Brown et al., 2006; Rosenfeld et al., 2006).

Jiang S. 2014 (87)

- Population: AMD; - Interventions and comparators: ranibizumab or bevacizumab, treatment regimen clearly stated as monthly or as-needed/ quarterly; - Outcomes: efficacy: visual acuity outcomes (letters gained or number of patients ≥15 visual acuity letters); - Study design: Randomized- controlled clinical phase III or IV trials; - Follow-up: at least one-year follow-up.

A systematic literature search was conducted using PubMed, Web of Science and Google Scholar from Jan 2004 to March 2013.

Eight studies met the inclusion criteria: ANCHOR 2006; MARINA 2006; FOCUS 2007; PIER 2010; CATT 2011; Subramanian 2010, SAILOR 2009 and EXCITE 2011.

Kodjikian L. 2014 (88)

- Population: only patients with AMD; - Interventions and comparators: ranibizumab or bevacizumab; - Outcomes: efficacy (Functional and anatomical endpoints) and/or safety: adverse events; - Study design: RCTs; - Follow-up: at least one-year follow-up (whatever the injection regimen).

Medline, Embase, and the Cochrane Library and Trial registers up to October 2013. Trial registers were also checked for unpublished studies.

Five studies were included: Subramanian et al.; the CATT study; the IVAN study; MANTA; and GEFAL.






Moja L. 2014 (20)

- Population: nAMD; - Interventions and comparators: bevacizumab and ranibizumab irrespective of the dosage, whether treatment is continuous or discontinuous; - Outcomes: Primary outcomes: death and all serious systemic adverse events. Secondary outcomes: specific serious systemic adverse events such as fatal and non-fatal myocardial infarctions, strokes, arteriothrombotic events, serious infections; - Study design: Head-to-head RCTs; - Follow-up: Trials were included irrespective of the duration of follow-up.

CENTRAL, MEDLINE, EMBASE and other online databases were searched up to 27 March 2014.

Nine RCTs met eligibility criteria. Of these, six RCTs were completed and published (Biswas 2011; CATT; GEFAL; IVAN; MANTA; Subramanian 2010),. Three RCTs were unpublished: two were completed (BRAMD; LUCAS), and one was still ongoing (VIBERA) at the time of the report.


- Population: Participants had nAMD as defined by study investigators; - Interventions and comparators: anti-VEGF treatment (pegaptanib, ranibizumab, or bevacizumab) versus each other or a control treatment (e.g., sham treatment or photodynamic therapy) or no treatment; - Outcomes: Primary outcomes: BCVA at one year of follow up; - Study design: RCTs only - Follow-up: Trials in which participants were followed for at least one year. When data were available, two years of follow up. Exclusion criteria: Interventions: - Different doses of one anti-VEGF treatment compared with each other, - No control or comparator group. - Aflibercept - Anti-VEGF agents in combination with other treatments.

CENTRAL (Cochrane Eyes and Vision Group Trials Register), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, EMBASE and LILACS. The metaRegister of Controlled Trials, clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). Databases were searched last on 27 March 2014.

ANCHOR 2006; VISION 2004; CATT 2011; MARINA 2006; PIER 2008; Subramanian 2010; MANTA 2013; Sacu 2009; ABC 2010; IVAN 2013; GEFAL 2013 and Biswas 2011.

Thulliez M. 2014 (90)

- Population: patients with wet AMD, diabetic macular edema, or retinal vein occlusion. - Interventions and comparators: intravitreal ranibizumab or bevacizumab with no treatment (sham) or a non-antiangiogenic treatment. Trials that compared different treatment regimens were also included for a dose-response analysis; - Outcomes: Clinically relevant cardiovascular outcomes as well as mortality; - Study design: parallel RCTs; – Follow-up: studies with a minimum 3-month follow-up period.

MEDLINE and Cochrane Central Register of Controlled Trials databases from inception until June 30, 2013.

21 studies were included in quantitative synthesis. 12 in patients with AMD: MARINA, ANCHOR, FOCUS, PIER, SAILOR, EXTEND-I, EXCITE, ABC, Subramanian, CATT, IVAN, MANTA.






Wang W. 2014 (91)

- Population: patients with wet AMD; - Interventions: intravitreal bevacizumab and intravitreal ranibizumab, which were directly compared in head-to-head design; - Outcomes: incidence of systemic adverse events; - Study design: RCTs with at least ten patients in each arm; - Follow-up: at least one year. Exclusion criteria: Population: patients with other indications than wet AMD, patients previously treated with VEGF inhibitors, or patients receiving systemic anti-VEGF therapy.

Pubmed, Embase, the Chinese Biomedicine Database, and the Cochrane library from inception up to December 2013.

CATT, IVAN, GEFAL, and MANTA.

Wu B. 2014 (92)

- Population: patients with ophthalmic diseases related to neovascularization; - Interventions and comparators: ranibizumab and bevacizumab. - Outcomes: BCVA as primary outcome. Secondary outcomes: any ocular/systemic adverse events (death from any cause, arteriothrombotic event, or serious ocular event). - Study design: comparative RCTs and head-to-head comparison -Follow- up: at least six months. Exclusion criteria: - Population: patients previously treated with VEGF inhibitors or patients receiving systemic anti-VEGF therapy; - Study design: non-RCT and studies without data from a comparison group; RCTs that enrolled less than 20 patients.

Four electronic databases, including PubMed and EMBASE until August 2013.

Nine articles were incorporated in the meta-analysis. Five of those included patients with AMD: GEFAL; CATT; IVAN; MANTA 2013, and Subramanian 2010.

Zhang XY. 2014 (93)

- Population: patients with AMD; - Interventions and comparators: bevacizumab and ranibizumab; - Outcomes: at least one of the primary outcomes (BCVA, foveal thickness, retina thickness and central macular thickness) or secondary outcomes (serious adverse effects, such as ocular inflammation, deaths and thromboembolic events); - Study design: RCTs, non-RCTs, case control and cohort studies that enrolled a minimum of 10 eyes. - Follow-up: There was no minimum length of follow-up specified.

PubMed (1966-October 2012) and the Cochrane Library (1988-October 2012).

Four RCTs (IVAN, CATT, Biswas and Subramanian). In addition of the RCTs, ten retrospective chart series met the inclusion criteria.

Anothaisintawee T. 2012 (94)

- Population: at least one participant with AMD, diabetic macular edema, or retinal vein occlusion; - Interventions and comparators: any pairs of the following interventions – bevacizumab, ranibizumab, photocoagulation, and sham; - Outcomes: visual acuity or central macular thickness; - Study design: RCTs with sufficient data for pooling treatment-effect sizes. - Follow-up: There was no minimum length of follow-up specified.

Medline and Scopus were searched until December 2011.

Six studies eligible for review for AMD: Sacu 2009; Martin 2011 (CATT); Biswas 2011; Subramanian 2010; Bashshur 2007 and Lazic&Gabric 2007.






Pitlick JM. 2012 (95)

There is no methods section. The inclusion and exclusion criteria are not clearly stated. Interventions and comparators are not detailed. It is only indicated that search terms included bevacizumab, Avastin, neovascular macular degeneration, age-related macular degeneration, VEGF, intravitreal, and safety; and that only RCTs were described in detail in the article while safety data from observational trials were summarized.

Literature was searched using MEDLINE and EMBASE until September 2011.

It is not clear which RCTs were included (nor the number of trials, neither which trials). The authors remarked upon ABC study, CATT and Subramanian. On the other hand, Biswas and MANTA studies appear among the references.

Schmucker C. 2012 (96)

- Population: nAMD; - Interventions and comparators: bevacizumab or ranibizumab in direct comparisons (head-to-head studies) or against any other control group (for potential indirect comparison). RCTs which compared different treatment regimens of ranibizumab or bevacizumab were also included; - Outcomes: long-term harm, such as myocardial infarction or stroke; - Study design: randomised phase III/IV trials; - Follow-up: one year follow-up data had to be available. Exclusion criteria: - Population: patients previously treated with VEGF inhibitors or patients receiving systemic anti-VEGF therapy; - Study design: RCTs that enrolled less than 20 patients.

Medline, Premedline, Embase and the Cochrane library from inception until May 2011.

The inclusion criteria were met by 11 RCTs: CATT, ANCHOR, MARINA, PIER, SAILOR, EXCITE, SACU, ABC, Biswas, Subramanian, and Costagliola 2010.

Wild C. 2012 (97)

Not found. The full text is in German. Not found. The full text is in German. There is no English language summary available.

The rapid assessment report includes CATT, IVAN and MANTA trials (those RCTs were completed at the time of the assessment). It also includes 4 more RCTs which were ongoing at the time of the assessment (VIBERA, LUCAS, GEFAL and SAFETY). Observational studies were included to report safety outcomes.

Mitchell P. 2011 (98)

- Population: wet AMD; - Interventions and comparators: ranibizumab and bevacizumab; - Outcomes: ocular and systemic safety and efficacy (BCVA; central macular thickness; central retina thickness; central foveal thickness);

PubMed.gov in June 2010. MARINA, ANCHOR, FOCUS, PIER, Rosenfeld et al., SAILOR, EXTEND-I, ABC, Bashur et al. 2007, Lazic et al. 2007, Potter et al. (VIA); and Sacu et al. 2009.






- Study design: Clinical studies that met Level I or Level II criteria (as assessed by the author) Level I criteria indicates strong evidence (e.g., well-designed, randomized, controlled clinical trials that address the issue in question); Level II criteria indicates substantial evidence that lacks some qualities (e.g., derived from randomized trials but with flaws, such as a lack of clearly defined primary outcomes, inclusion and exclusion criteria, or sufficiently long follow-up); - Follow-up: There was no minimum length of follow-up specified.


- Population: nAMD. - Interventions and comparators: intravitreal bevacizumab or ranibizumab as monotherapy compared with any other treatment; - Outcomes: focused only on safety: adverse effects and the reporting of harm - Study design: RCTs and non-RCTs. Case series were included if they enrolled a minimum of 10 patients and met predefined quality standards (the publication had to provide adequate information regarding patient selection criteria or the selection of patients had to be consecutive). - Follow-up: There was no minimum length of follow-up specified. Exclusion criteria: - Population: patients previously treated with VEGF inhibitors or patients receiving systemic anti-VEGF therapy.

Medline (Ovid), Embase and the Cochrane Library from inception until March 2008. An update search focusing on RCTs was carried out in August 2009.

Four RCTs (ANCHOR, MARINA, PIER and Heier; 11 publications) evaluating ranibizumab vs. PDT, sham or usual care; and four RCTs (SACU, Bashshur, Lazic&Gabric, and Hahn; five publications) evaluating bevacizumab vs. PDT with or without triamcinolone. In addition, 17 case series examining bevacizumab (11 prospective and 6 retrospective series).

Jyothi S. 2010 (100)

- Population: detailed as terms or combinations used in the search strategy: CNV; choroidal neovascularisation;; age-related macular degeneration; age-related maculopathy. - Interventions and comparators: detailed as terms or combinations used in the search strategy: anti-VEGF; bevacizumab; avastin; pegaptanib; macugen; ranibizumab; lucentis - Outcomes: mean change in visual acuity and central retinal thickness. - Study design and follow-up: RCTs and observational case series with at least 3-month follow-up, both prospective and retrospective, which met the STROBE criteria.

MEDLINE (2005 to January 2009) and the National Institutes of Health clinical trial databases (up to January 2009).

55 reports met the inclusion criteria. These included 5 RCTs that compared bevacizumab to other treatment options (Bashshur 2007, Hahn 2007,Lazic 2007, Sacu 2009 and Wiegert 2008) and 50 STROBE-qualified studies, of which 12 studies evaluated the combination of bevacizumab with another treatment modality.


- Population: exudative AMD; - Interventions and comparators: intravitreal bevacizumab or ranibizumab as monotherapy against any other treatment; - Outcomes: efficacy and safety (not detailed in eligibility criteria) - Study design: RCTs and case series which were included if they enrolled a minimum of 10 patients and met predefined quality standards (the publication had to provide adequate information regarding patient selection criteria or the selection of patients had to be consecutive).

Medline (Ovid), Embase and the Cochrane Library without date limit [main search for randomized clinical trials (RCTs): August 09].

The RCTs included in this paper are the same ones as the RCTs included in the previous article (same final date of search). However, the number of case series included differed between both records.






- Follow-up: There was no minimum length of follow-up specified. Exclusion criteria: - Population: patients previously treated with VEGF inhibitors or patients receiving systemic anti-VEGF therapy.

Andriolo RB. 2009 (102)

- Population: diagnosis of ocular diseases with the same underlying pathophysiological mechanism of increased local levels of VEGF, according to the criteria established by the authors of the primary studies, such as age-related macular disease, corneal neovascularization, retinal angiomatous proliferation or angiogenic retinal diseases, among others; - Interventions and comparators: bevacizumab alone or in association with other strategies available; - Outcomes: primary outcome of interest was visual acuity. Adverse events, e.g. ocular or systematic hypertension, ocular toxicity, local inflammation, retinal detachment, vitreous hemorrhage, corneal abrasions, lens injury and thromboembolic events; - Study design: Only randomized or quasi-randomized clinical trials; - Follow-up: There was no minimum length of follow-up specified. Exclusion criteria: - Studies in which the analysis unit was based on the eyes were not included, since there is evidence demonstrating an adverse event (vitritis) associated with bevacizumab in the contralateral eye. - Outcomes: Surrogate outcomes, such as central foveal thickness, and fluorescein angiography.

Medline, Controlled Trials Register of the Cochrane Collaboration (2008, issue 2) and Lilacs to June 2008.

Nine studies satisfied the pre-established inclusion criteria. Of those, three studies included patients diagnosed with AMD and one study tested bevacizumab on patients with subfoveal choroidal neovascularization associated with AMD (Bashshur 2007, Hahn 2007, Lazic 2007 and Wiegert 2008)

Schouten JS. 2009 (103)

- Population: exudative AMD; - Interventions and comparators: Bevacizumab systemic or intravitreal therapy; - Outcomes: visual acuity, central retinal thickness and adverse events; - Study design: RCTs, nonrandomized controlled studies, or before-and-after studies in more than one patient; - Follow-up: There was no minimum length of follow-up specified. Exclusion criteria: Studies that did not have visual acuity as the primary outcome or that had as the primary objective to study differences between subgroups.

MEDLINE, EMBASE, and the Cochrane database. All years were included up to March 2008.

26 studies with different design met the criteria. Three randomised controlled trials (Bashshur 2007, Hahn 2007 and Lazic 2007) were identified. The authors combined the data of the patients of these 3 RCTs who had received only intravitreal bevacizumab, and the data of patients of 23 before-and-after studies (prospective and retrospective studies).






Ziemssen F. 2009 (104)

- Population: subfoveal CNV secondary to neovascular AMD; - Intervention: bevacizumab monotherapy; - Comparator: PDT with verteporfin for the subgroup of patients with a confirmed diagnosis of classic with no occult subfoveal wet AMD; - Outcomes: BCVA as primary outcome measure; - Study design: not specified; - Follow-up: There was no minimum length of follow-up specified.

MEDLINE between June 1, 2005 and July 31, 2008.

Thirty-three studies and case series were found to meet the inclusion and exclusion criteria; of these, 13 studies declared a prospective study design. The highest grade studies were one non-randomized controlled trial and three RCTs (Lazic 2007, Bashshur 2007 and Wiegert 2008). CATT, VIBERA, IVAN and MANTA studies are mentioned as ongoing trials.

Brown A. 2008 (105)

- Population: adults 40 years of age or more with nAMD. - Interventions and comparators: comparison of V-PDT with pegaptanib, bevacizumab, ranibizumab, anecortave acetate, placebo, or clinically relevant combinations (intravitreal triamcinolone in combination with one or more of the others was acceptable.). - Outcomes: Primary outcome: a measure of visual acuity convertible to utility values. Secondary outcomes: quality of life indicators, size of the lesion before/after (measured by fluorescein angiography or ocular coherence topography); as well as adverse events and other harm information. - Study design: RCTs (though later non-RCTs were included to search for information on combination therapies). - Follow-up: There was no minimum length of follow-up specified.

MEDLINE, EMBASE, BIOSIS Previews, CINAHL, PubMed, and The Cochrane Library. All relevant articles were searched until November 2, 2007.

Twelve reports of RCTs and 6 of non-RCTS (one controlled trial, and five case series) were identified. The RCTs compared V-PDT vs placebo; anecortave acetate vs V-PDT; different regimens of V-PDT; ranibizumab + vs V-PDT; ranibizumab + V-PDT vs verteporfin; bevacizumab vs V-PDT; and bevacizumab + V-PDT vs V-PDT.

Ip MS. 2008 (106)

- Population: nAMD; - Interventions and comparators: anti-VEGF pharmacotherapies (bevacizumab, ranibizumab and pegaptanib); - Outcomes: efficacy and safety; - Study design: not specified; - Follow-up: There was no minimum length of follow-up specified.

PubMed and Cochrane Central Register of Controlled Trials The literature search was conducted on January 25, 2007. An update search was conducted on October 11, 2007.

The RCTs included were ANCHOR, MARINA, PIER and VISION.

Escassi C. 2007 (107)

- Population: adults 45 years of age or more diagnosed with nAMD with any type of choroideal neovascular lesions; - Intervention: pegaptanib, ranibizumab or bevacizumab; - Comparison: the before mentioned treatments compared with each other, with placebo or with other treatments, such as: photodynamic therapy with verteporfin;

MEDLINE, Embase, Cochrane Library and other Internet resources (INAHTA, ECRI and Centre for

26 articles (out of 25 studies) were selected. Four were RCTs (5 articles) MARINA (Rosenfeld 2006), ANCHOR (Brown 2006), Gragoudas (2004), Mills (2006).






- Outcomes: efficacy and/or safety; - Study design: phase II and III RCTs, observational studies with or without control group (case series with at least two patients). - Follow-up: There was no minimum length of follow-up specified. Exclusion criteria: - Population: patients previously treated.

Reviews and Dissemination of University of York). The search strategy covered until May 2007. Full text in Spanish.

The trials were ranibizumab vs placebo, ranibizumab vs verteporfin, pegaptanib vs placebo and pegaptanib continued treatment vs pegaptanib with treatment discontinuation. The remaining 21 articles were 2 trials in phase I / II trial and one case series of ranibizumab; 5 case series of pegaptanib; and 13 case series of bevacizumab.

Iu LP 2007 (108)

There is no methodology section with the inclusion and exclusion criteria. Key words/terms ‘treatment’ and ‘age-related macular degeneration were used to retrieve relevant original papers and review articles. This information only appears in the abstract.

Medline till March 2007. This information only appears in the abstract.

The phase III clinical trials MARINA and ANCHOR are briefly described in ranibizumab section, and the study of Bashshur 2007 is succinctly described in bevacizumab section.

Wild C. 2007 (109)

- Population: AMD; - Intervention: bevacizumab intravenous /systemic and intraocular; - Outcomes: safety risks; - Study design: prospective and retrospective clinical trials with more than 5 patients; - Follow-up: There was no minimum length of follow-up specified.

This report is based on a simple literature review, using Medline and Embase Dates of search strategies not found. Full is in text in German, it has English abstract and appendices.

21 published prospective and retrospective clinical trials on safety and side effects of bevacizumab and 56 partially unpublished references concerning the topic were evaluated. The follow-up of the 10 prospective trials on the safety of intravitreal bevacizumab therapy was between 4 weeks and 26 weeks. The follow-up of the 11 retrospective trials was between 4 weeks and 4.5 months. IVAN was included as an ongoing trial at the time of the assessment.

* All the RCTs highlighted in bold are included in the SR by Solomon SD. 2019(30).



The RCTs that are not highlighted in bold in the last column of Table A4 were not included in the most up-to-date systematic review (Solomon 2019) mainly due to one of the following reasons: follow-up less than one year; administration of combination therapy; or different drug doses or regimens compared with each other within a trial.

These criteria (combination therapy; or comparison of different doses of the same drug in a trial) are also considered for exclusion in the JA report. Therefore, from the 35 previous included articles, 33 are not further described in detail in this systematic review of the relative efficacy and safety of bevacizumab in patients with nAMD as the RCTs considered in those reviews are included in the most up-to-date and complete systematic review by Solomon 2019.

Table A5. RCTs not included in the SR by Solomon 2019 which are considered in the other references and reasons for exclusion in Solomon SR.

Bashshur 2007 (110) RCT with a follow-up less than 1 year.

Costagliola 2010 (111) This RCT assessed combination therapy: intravitreal bevacizumab alone vs intravitreal bevacizumab plus low-fluence PDT

DENALI 2012 (112) Compared ranibizumab vs. combination therapy (ranibizumab+PDT)

EXCITE (113) Different regimens of ranibizumab were assessed (monthly versus quarterly ranibizumab treatment)

EXTEND-I 2008 (114) Dosing study. Different doses/regimens of ranibizumab were compared.

FOCUS 2006 (115) The study compared intravitreal ranibizumab alone vs. combination therapy with intravitreal ranibizumab plus verteporfin PDT.

Hahn 2007 (116) RCT with a follow-up less than 1 year.

HARBOR (117) Comparison of 2 doses of ranibizumab administered monthly or on a PRN basis after 3 monthly loading doses.

Heier 2006 (118) RCT with a follow-up less than 1 year.

Lazic&Gabric 2007 (119)

RCT with a follow-up less than 1 year

MONT BLANC 2012 (120)

Compared ranibizumab vs. combination therapy (ranibizumab+PDT)

Potter et al (VIA) (121) Combination therapy

Rosenfeld 2006 (54) Dosing study. Different doses/regimens of ranibizumab were compared.

SAILOR 2009 (122) Tolerability and efficacy of multiple escalating doses of ranibizumab were compared.

VIEW 1; Heier 2012 (53)

RCTs that evaluated aflibercept, drug not considered in Solomon.

VIEW 2; Heier 2012 (53)

RCTs that evaluated aflibercept, drug not considered in Solomon

Weigert 2008 (123) RCT with a follow-up less than 1 year.



APPENDIX 6: EXCLUDED ARTICLES FROM BEVACIZUMAB LITERATURE REVIEW

Table A6. Excluded articles, based on the full text, from the literature search regarding the relative efficacy and safety of bevacizumab for nAMD.

Study reference Reason for non-consideration of the study

Li J, Xu J, Chen Y, Zhang J, Cao Y, Lu P. Efficacy Comparison of Intravitreal Anti-VEGF Therapy for Three Subtypes of Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis. J Ophthalmol. 2018;2018:1425707.(124)

The report was excluded because of its objective. The study aimed to compare the efficacy among different subtypes of neovascular AMD. A systematic review and meta-analysis were carried out in order to determine the relationship between treatment efficacy and lesion subtype.

Zhang Y, Chioreso C, Schweizer ML, Abràmoff MD. Effects of Aflibercept for Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis of Observational Comparative Studies. Invest Ophthalmol Vis Sci. 2017;58(13):5616-5627.(125).

The report was excluded because of its design. RCTs were not included. The review and meta-analysis were based on evidence from observational studies. Available studies from January 2011 through July 2017 were examined. Articles were considered only if they compared the functional or anatomic outcomes between aflibercept monotherapy and other anti- VEGF agents (ranibizumab or/and bevacizumab) among nAMD patients with no previous therapy. All included studies were retrospective observational cohort studies.

Hussain RM, Hariprasad SM, Ciulla TA. Treatment Burden in Neovascular AMD: Visual Acuity Outcomes are Associated With Anti-VEGF Injection Frequency. Ophthalmic Surg Lasers Imaging Retina. 2017;48(10):780-784(126).

No abstract, it is a five-page article. The report was excluded because of its objective. The meta-analysis reviewed RCTs employing the treat and extend regimen for nAMD through a PubMed search (in January 2016) of “bevacizumab treat and extend” and “ranibizumab treat and extend.”

Gemenetzi M, Patel PJ. A Systematic Review of the Treat and Extend Treatment Regimen with Anti-VEGF Agents for Neovascular Age-Related Macular Degeneration. Ophthalmol Ther. 2017;6(1):79–92(127).

The report was excluded because of its objective. Clinical trials, prospective and retrospective studies, systematic reviews and meta-analyses to February 2017 linked to the treat and extend treatment regimen with anti-VEGF agents in neovascular AMD were considered. The article includes six prospective studies (RCTs and non-controlled non-randomised studies) and eleven real-world studies (one prospective and 10 retrospective studies).

Gerding H. Long-term Results of Intravitreal Anti-VEGF Injections in Wet AMD: A Meta-Analysis. Langzeitergebnisse der intravitrealen anti-VEGF-Injektionstherapie bei feuchter altersabhangiger Makuladegeneration Eine Meta-Analyse. 2016;233(4):471–4(128).

The report was excluded because of its design. The study does not include RCTs. The selection of the studies was performed by analysis of available abstracts in order to identify those publications reporting original data of long-term case series. 13 publications, including 14 case series, remained for definite analysis. 9 of 13 studies (69%) represent retrospective single centre case series, the remaining (n = 4, 31%) either extension- or follow-up studies of previously randomized controlled or prospective multicentre studies, prospective single centre evaluations (n = 1, or retrospective multicentre analysis n = 1).




Mikacic I, Bosnar D. Intravitreal Bevacizumab and Cardiovascular Risk in Patients with Age-Related Macular Degeneration: Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Studies. Drug Saf. 2016;39(6):517–41(129).

The report was excluded because of its design. The article includes studies pertained to intravitreal administration of bevacizumab in humans with AMD. RCTs, case–control studies, stratified cohort studies, or clinical non-randomized controlled or uncontrolled studies (prospective or retrospective) were eligible. A total of 15 studies (ten RCTs in 12 publications; one non-randomized controlled clinical study; two population-based stratified cohort studies, and two uncontrolled clinical cohorts) met the inclusion criteria. Meta-analysis of randomized controlled trials of more versus less frequent bevacizumab dosing in patients with age-related macular degeneration in respect to cardio-/cerebrovascular adverse events were reported.

Ba J, Peng R-S, Xu D, Li Y-H, Shi H, Wang Q, et al. Intravitreal anti-VEGF injections for treating wet age-related macular degeneration: a systematic review and meta-analysis. Drug Des Devel Ther. 2015;9:5397–405(19).

The report was excluded because it considered combination therapy as comparator. RCTs that compared ranibizumab vs. bevacizumab; ranibizumab vs. aflibercept; and ranibizumab monotherapy to the combination of ranibizumab with PDT in patients undergoing intravitreal anti-VEGF injection for wet AMD PubMed, Embase, the Cochrane Library, and CNKI from inception until May 2014 were searched Twelve RCTs were eligible based on the inclusion criteria and were selected for the meta-analysis. Five of those 12 studies compared ranibizumab monotherapy vs ranibizumab plus PDT.

New Zealand National Health Committee (NHC). Age-related macular degeneration. Wellington: New Zealand National Health Committee (NHC). 2015(130).

The report was excluded because of its objective. Its purpose was to explore the model of care for patients with AMD and identify interventions where the New Zealand Health Committee could conduct further assessment in order to improve health outcomes and efficiency.

CADTH. Long-term use of bevacizumab for the treatment of age-related macular degeneration: safety. Ottawa: Canadian Agency for Drugs and Technologies in Health (CADTH). Rapid Response. 2014(131).

The report is a summary of findings which was prepared from the abstracts of the relevant information. The aim of this rapid response report was to assess the clinical evidence regarding the long-term safety (at least 2 years) of bevacizumab for the treatment of AMD. One systematic review and two randomized controlled trials (IVAN and CATT) were identified.

Thomas M, Mousa SS, Mousa SA. Comparative effectiveness of aflibercept for the treatment of patients with neovascular age-related macular degeneration. Clin Ophthalmol. 2013;7:495-501(132).

In the full text, it is indicated that “Using databases such as PubMed, Medline, and ClinicalTrials.gov, data were collected to compare the efficacy of aflibercept versus other therapies in the treatment of wet AMD”. However, in the methodology section, the authors did not state the "other therapies" that had been considered nor the date of the search strategies. No RCTs related to the use of bevacizumab were included in the results section.

Fadda V, Maratea D, Trippoli S, Messori A. Treatments for macular degeneration: summarising evidence using network meta-analysis. Br J Ophthalmol. 2011;95(10):1476-7(133).

No abstract, it is a two-page article. Publication date 2011. A simplified NMA was conducted to examine all controlled trials evaluating treatments for AMD. A PubMed search (on 20 April 2011) identified five controlled studies (ANCHOR, FOCUS, MARINA, VISION, ABC). The preliminary results of the CATT trial were also available at the time of the search.

van der Reis MI, La Heij EC, De Jong-Hesse Y, Ringens PJ, Hendrikse F, Schouten JSAG. A systematic review of the adverse events of intravitreal anti-vascular endothelial growth factor injections. Retina. 2011;31(8):1449–69(134).

The report was excluded because its design. The article is focus on safety. It included randomized trials, and observational studies including more than 5 patients and case reports describing adverse events after anti-VEGF injections. Based on the mentioned inclusion and exclusion criteria, 278 articles were included and these were published from 2002 to 2009.




Micieli JA, Micieli A, Smith AF. Identifying systemic safety signals following intravitreal bevacizumab: systematic review of the literature and the Canadian Adverse Drug Reaction Database. Can J Ophthalmol. 2010;45(3):231-8(135).

Studies that evaluated systemic adverse events following intravitreal injection of bevacizumab alone or in combination for any ocular condition (age-related macular degeneration, diabetic retinopathy, retinal vascular occlusion, central retinal vascular occlusion, and diabetic macular oedema) were eligible for inclusion.

Kymes S, Vollman D, Spry C. Supplement to “The Role of Pharmacologic Management in Neovascular Age-Related Macular Degeneration: Clinical and Cost-Effectiveness”. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009(136).

The report was excluded because its objective. It is a supplement to “The Role of Pharmacologic Management in Neovascular Age-Related Macular Degeneration: Clinical and Cost-Effectiveness” from Brown et al. The publication is only focused on cost-effectiveness. The research questions were about the impact on the incremental cost-effectiveness ratio (ICER) of the economic evaluation taking into account different scenarios.

Table A7. Articles excluded, by title and abstract (full text not available), from the literature search regarding the relative efficacy and safety of bevacizumab for nAMD.


Mengarelli C, Augustovski, Pichon-Riviere A, García Martí S, Alcaraz A, Bardach A, Ciapponi A, López A, Rey-Ares L. Ranibizumab, bevacizumab ya para degeneración macular asociada a la edad. [Ranibizumab, bevacizumab y aflibercept for age-related macular degeneration] Buenos Aires: Institute for Clinical Effectiveness and Health Policy (IECS). Informe de Respuesta Rápida No. 398. 2015(137).

This record is a brief technical report in Spanish. Full text is not available and was not requested to IECS. This record was excluded because due to its publication date, 2015, there are more up-to-date SRs.

Ma N, He X-G. [Efficacy and safety in treatment of ocular neovascularization by Bevacizumab versus Ranibizumab: a meta-analysis]. Chinese Journal of Ophthalmology. 2010;46(3):263–7(138).

Date of search strategy unknown as the full text article in Chinese was not requested. This record was excluded because due to its publication date, 2010, there are more up-to-date SRs. The article considers clinical controlled trials comparing bevacizumab and ranibizumab in treatment of ocular neovascularization. Medline, EMbase, the Cochrane Library and CBM were searched. Only 7 literatures came into meta-analysis (1620 eyes).

Bevacizumab (Avastin) for age-related macular degeneration. Lansdale: HAYES, Inc.. Directory Publication. 2008.

Full text is not available and was not purchased from Hayes due to its publication date as the report is now outdated.

Augustovski F, Colantonio L, Pichon Riviere A. Vascular endothelial growth factor inhibitors (pegaptanib, ranibizumab and bevacizumab) in age-related macular degeneration treatment. Buenos Aires: Institute for Clinical Effectiveness and Health Policy (IECS). Informe Técnico Breve No.33. 2007.

This record is a brief technical report in Spanish. The objective of the report was to assess the usefulness of VEGF inhibitors in the treatment of AMD. Full text is not available and was not requested to IECS. Nevertheless, this record was excluded because due to the publication date, 2007, there are more up-to-date SRs.

Bock F, Konig Y, Dietrich T, Zimmermann P, Baier M, Cursiefen C. [Inhibition of angiogenesis in the anterior chamber of the eye]. Antiangiogene Ther am Vor Augenabschnitt. 2007;104(4):336–44.

The authors only searched in one database, Pubmed. Date of search strategy unknown as the full text article in German was not requested. This record was excluded because due to its publication date, 2007, there are more up-to-date.




Pichon-Riviere A, Augustovski F, Colantonio L. Vascular endothelial growth factor inhibitors (pegaptanib, ranibizumab and bevacizumab) in age-related macular degeneration treatment. Buenos Aires: Institute for Clinical Effectiveness and Health Policy (IECS). Informe Técnico Breve No.33. 2007.

This record is a brief technical report in Spanish. Full text is not available and was not requested to IECS. Nevertheless, this record was excluded because due to the publication date, 2007, as there are more recent SRs.

BlueCross BlueShield Association. Special report: current and evolving strategies in the treatment of age-related macular degeneration. Chicago: BlueCross BlueShield Association (BCBS). TEC Assessment 20(11). 2005.

This report aims to provide an understanding of emerging therapies in the context of the treatment options available around 2005 and the underpinnings on which age-related macular degeneration treatments are based. Full text is not available and was not requested to BSBS. The BlueCross BlueShield Association Technology Evaluation Center website includes the most recent 3 years of TEC Assessments. Older reports have to be requested. Nevertheless, this record was excluded because due to the publication date not all the interventions which we want to compare in this assessment report were available to be used in clinical practice.



APPENDIX 7: BASELINE CHARACTERISTICS OF HAWK AND HARRIER STUDY

POPULATIONS

Table A8. Baseline characteristics of the study populations (FAS, excluding brolucizumab 3 mg group in HAWK study)

Characteristics HAWK study (NCT02307682) HARRIER study (NCT02434328)

Brolucizumab 6 mg

(N=360)

Aflibercept 2 mg

(N=360)

Brolucizumab 6 mg

(N=370)

Aflibercept 2 mg

(N=369)

Age (years)

Mean (SD) 76.7 (8.95) 76.2 (8.80) 74.8 (8.58) 75.5 (7.87)

Median (range) 78.0 (51–97) 77.0 (51–96) 75.0 (50–94) 76.0 (52–95)

Age category (years) – n (%)

<50 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

50-64 35 (9.7) 37 (10.3) 44 (11.9) 28 (7.6)

65-74 103 (28.6) 112 (31.1) 124 (33.5) 126 (34.1)

75-84 155 (43.1) 148 (41.1) 150 (40.5) 167 (45.3)

≥85 67 (18.6) 63 (17.5) 52 (14.1) 48 (13.0)

Sex – n (%)

Male 155 (43.1) 166 (46.1) 160 (43.2) 157 (42.5)

Female 205 (56.9) 194 (53.9) 210 (56.8) 212 (57.5)

Race – n (%)

White 285 (79.2) 287 (79.7) 340 (91.9) 341 (92.4)

Asian 61 (16.9) 53 (14.7) 22 (5.9) 23 (6.2)

Other 9 (2.5) 17 (4.7) 5 (1.4) 4 (1.1)

Multiple 3 (0.8) 1 (0.3) 2 (0.5) 1 (0.3)

Black or African American 1 (0.3) 1 (0.3) 1 (0.3) 0 (0.0)

American Indian or Alaska Native

1 (0.3) 1 (0.3) 0 (0.0) 0 (0.0)

Native Hawaiian or other Pacific Islander

0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Ethnicity – n (%)

Not Hispanic or Latino 329 (91.4) 319 (88.6) 321 (86.8) 322 (87.3)

Hispanic/Latino 29 (8.1) 40 (11.1) 23 (6.2) 25 (6.8)

Unknown 1 (0.3) 1 (0.3) 18 (4.9) 17 (4.6)

Not reported 1 (0.3) 0 (0.0) 8 (2.2) 5 (1.4)

Japanese ancestry – n (%)

Japanese 60 (16.7) 53 (14.7) NR NR

Non-Japanese 300 (83.3) 307 (85.3) NR NR

Time since diagnosis of nAMD (months) – n (%)

<1 159 (44.2) 154 (42.8) 136 (36.9) 139 (37.7)

1–3 184 (51.1) 190 (52.8) 191 (51.8) 197 (53.4)

>3 17 (4.7) 16 (4.4) 42 (11.4) 33 (8.9)

Unilateral versus bilateral nAMD – n (%)

Unilateral 271 (75.3) 268 (74.4) 268 (72.4) 255 (69.1)

Bilateral 89 (24.7) 92 (25.6) 102 (27.6) 114 (30.9)

BCVA (letters read)

Mean (SD) 60.8 (13.66) 60.0 (13.92) 61.5 (12.59) 60.8 (12.93)

Median (range) 64.0 (23–85) 63.0 (16–83) 64.0 (22–78) 64.0 (23–79)



Characteristics HAWK study (NCT02307682) HARRIER study (NCT02434328)

Brolucizumab 6 mg

(N=360)

Aflibercept 2 mg

(N=360)

Brolucizumab 6 mg

(N=370)

Aflibercept 2 mg

(N=369)

BCVA (letters read) – n (%)

≤55 101 (28.1) 116 (32.2) 102 (27.6) 107 (29.0)

56-70 157 (43.6) 153 (42.5) 171 (46.2) 170 (46.1)

≥71 102 (28.3) 91 (25.3) 97 (26.2) 92 (24.9)

CSFT total (μm)

Mean (SD) 463.1 (166.62) 457.9 (146.37) 473.6 (171.39) 465.3 (151.21)

Median (range) 417 (217–1204) 425 (215–1082)

434 (200–1192) 442 (206–1319)

CSFT total (μm) – n (%)

˂400 157 (43.6) 146 (40.6) 148 (40.0) 130 (35.2)

≥400 203 (56.4) 214 (59.4) 222 (60.0) 239 (64.8)

Type of CNV – n (%)

Predominantly classic 113 (31.4) 116 (32.3) 154 (41.6) 144 (39.5)

Minimally classic 39 (10.8) 34 (9.5) 33 (8.9) 34 (9.3)

Occult 208 (57.8) 209 (58.2) 183 (49.5) 187 (51.2)

Area of lesion associated with CNV (mm2)

Mean (SD) 4.6 (4.1) 4.4 (3.7) 2.6 (2.8) 2.9 (4.0)

Median (range) 3.4 (0–20) 3.7 (0–19) 1.5 (0–14) 1.6 (0–34)

Presence of fluid – n (%)

SRF 250 (69.4) 245 (68.1) 251 (67.8) 268 (72.6)

IRF/cyst 194 (53.9) 194 (53.9) 149 (40.3) 139 (37.7)

SRF and/or IRF 334 (92.8) 336 (93.3) 330 (89.2) 332 (90.0)

Sub-RPE fluid 168 (46.7) 158 (43.9) 125 (33.8) 127 (34.4)

PCV (Japanese patients only)

39 (66.1) 30 (56.6) NR NR

Source: Submission dossier, European Medicines Agency public assessment report. Abbreviations: FAS=full analysis set; nAMD=Neovascular (Wet) Age-Related Macular Degeneration; BCVA=best-corrected

visual acuity; CSFT=central subfield thickness; CNV=choroidal neovascularisation; IRF=intraretinal fluid; PCV=polypoidal choroidal vasculopathy; RPE=retinal pigment epithelium; SD=standard deviation; SRF=subretinal fluid.



APPENDIX 8: POOLED RESULTS OF HAWK AND HARRIER STUDIES

As part of the network meta-analysis, MAH presented direct comparison results of HAWK and HARRIER studies. Results of the key outcomes are presented here. More detailed analysis, including also safety results, are available in the submission dossier.

Table A9. Summary of direct comparison results (pooled results) for HAWK and HARRIER studies

Outcome and comparison

Trials

Mean Difference [95% CI] I-square p-value of the Cochran test Fixed-effects

model Random-effects

model

Mean change in BCVA from baseline to one year

Afli 2 mg vs Bro 6 mg

HARRIER HAWK

0.43 [-0.85; 1.71]

0.43 [-0.85; 1.71]

0.00% 0.763

Mean change in BCVA from baseline to two years

Bro 6 mg vs Afli 2 mg

HARRIER HAWK

0.01 [-1.46;1.49]

0.01 [-1.46;1.49]

0.00% 0.467

Odds of losing at least 15 letters from baseline to one year


HARRIER HAWK

0.97 [0.61; 1.55]

0.97 [0.61; 1.55]

0.0% 0.390

Odds of losing at least 15 letters from baseline to two years


HARRIER HAWK

1.00 [0.68; 1.47]

1.00 [0.68; 1.47]

0.0% 0.686

Odds of gaining at least 15 letters from baseline to one year


HARRIER HAWK

1.19 [0.95; 1.49]

1.19 [0.79; 1.80]

69.7% 0.069

Odds of gaining at least 15 letters from baseline to two years


HARRIER HAWK

1.11 [0.89; 1.39]

1.12 [0.73; 1.71]

72.4% 0.057

Mean change in central retinal thickness from baseline to one year

Afli 2 mg vs Bro 6 mg

HARRIER HAWK

39.28 [26.02; 52.55]

39.41 [19.03; 59.79]

57.6% 0.125

Mean change in central retinal thickness from baseline to two years


HARRIER HAWK

-34.69 [-48.64; -20.74]

-34.60 [-50.77; -18.44]

25.4% 0.247

Source: modified from Submission dossier.

Abbreviations: Afli=aflibercept; BCVA=best corrected visual acuity; Bro=brolucizumab; CI=confidence interval.



APPENDIX 9: CHECKLIST FOR CRITICAL APPRAISAL OF INDIRECT

COMPARISONS – EVALUATION OF THE NMA PROVIDED BY MAH

Table A10. Evaluation of the NMA provided by MAH

(A) Are indirect comparison results valid?

1. Is it justified to conduct an indirect comparison (IC)?

Some criteria must be fulfilled to conduct an IC:

Are the objective(s), inclusion criteria, methods (assumptions included) and results clear?

Are the studies clinically comparable? (patients, general conditions, co-interventions, drug dosing, treatment duration, variables, etc, that act as effect modifiers?

Are outcomes comparable in definition and presentation?

Are outcomes clinically relevant?

Yes.

There are no direct comparisons between brolucizumab and ranibizumab which is one of the drug considered in the NMA, in addition to aflibercept which is the control drug in the pivotal trials.

2. Is the IC methodology appropriate? Yes.

NMA has been used for the IC.

In addition, several sensitivity analyses were conducted to assess the robustness of the base case results.

3. Was the search strategy for study selection adequate?

Was the search question correctly established?

Are all relevant studies included?

Is the comparator relevant?

Yes

After answering the previous questions, do you consider that you should continue analysing the study/paper?

Yes

(B) Detailed questions: checklist for an indirect comparison evaluation

1. Common comparator

Are comparator and studies represented graphically?

How many intermediate comparators are there between the two alternatives (A and B) we are most interested in comparing?

Yes, thus reliability high

2. Search strategy

Are systematic methods used to find all relevant studies? Were the different databases as well as the search strategy included? Were references checked? Were strict limits used? Was publication bias evaluated?

Multiple databases were searched for. Strategy was reported. References were not checked and publication bias was not evaluated. Thus. reliability is low

3. Criteria for selection of studies

Are they stated? Are they reasonable? Are they systematically applied?

Reliability acceptable

A flowchart was presented and the reasons to exclude studies were stated. However, the rationale for the selection criteria does not match the European PICO and a relevant comparator has not been considered.

4. Common outcome measure

Do studies share the same outcome measure (defined in the same manner, including same time horizon and reported in the same way)?


5. Outcome relevance

Is outcome measure clinically relevant? Is the main outcome included in the studies?


6. Clinical similarity, patient similarity

Are inclusion/exclusion criteria similiar between studies? Were randomised patients within each study similar?




7. Common comparator

Is the common comparator or control drug used at the same dose and for the same duration?

And are the same concomitant treatments that can act as effect modifiers permitted?

Regarding the duration of the treatment, the MAH stated as a limitation of the NMA that time equivalence was assumed for one-year and two-year outcomes. In order to include all available evidence for treatments of interest, equivalence was assumed between 48 and 52 weeks for one-year outcomes and between 96 and 104 weeks for two-year outcomes. No publication was found to validate this hypothesis, but the results for HAWK and HARRIER at Week 52 were similar to those at Week 48. In addition, the results from sensitivity analyses that extrapolated endpoints that were published at 48 weeks and 104 weeks were similar to the base case. This demonstrated that there was no impact on the results with the equivalence assumption used.

Uncertain. Combination intravitreal therapy was not allowed in the trials.

8. Outcome result in the control group (or common compartor group)

Is this similar in the studies being compared?


9. Study quality

What is the quality of the studies being combined?

Are results within each study reported?

Reliability high

The MAH has assessed the RoB of the RCTs included in the NMA. They stated that overall evidence was of moderate to high quality. The greatest risk of bias was due to insufficient information identified in the publication during the quality assessment. The majority of studies did not have unexpected imbalances in drop-outs between groups. The RoB of each trial, as reported by the MAH, is shown in Figure 4.19.

10. Missing patient/data

In studies being combined: are missing patient/data similar? Were they handled in the same way? Is data analysis similar (pP, ITT)?

Reliability low.

This information was not avaible in the NMA from the MAH

11. Reliability of studies data

Are data obtained from the studies? Or was there a previous extrapolation or any manipulation of data?

Reliability high

12. Adjusting by control group

Was an adjusted IC (Bucher method, NMA, etc) conducted?

Are reltive effects to common comparator group of each study compared?


13. Data/statistical analysis conducted in the IC or NMA

Is it adequate? Are assumptions acceptable? When a sensitivity analysis is necessary, was it done correctly?


14. Study similarity

Is there anything more that makes studies not comparable?

No, thus reliability high

15. Answer this question only if there is a published direct comparison of the treatments being compared:

Is there inconsistency?

Are results from direct and indirect comparisons different?

Not applicable

16. External validity and applicability No

The main limitation of the NMA is regarding the external validity and applicability of the



Were conclusions obtained from the results? Can the results be extrapolated to our patients? Has the relevant alternative for our practice been analysed?

results and conclusions obtained because one of the relevant comparators form the European perspective has not been considered.

17. Conflict of interest

Is there any conflict stated? Is the study independent?

NMA performed by the MAH

Abbreviations: MAH=marketing authorisation holder; NMA=network meta-analyis; RoB=risk of bias.



APPENDIX 10: CRITICAL APPRAISAL FOR THE SYSTEMATIC REVIEWS

SELECTED FROM THE SLR OF BEVACIZUMAB

Table A11. Critical appraisal for the SRs selected from the SLR of bevacizumab

AMSTAR-2 items Solomon et al Pham et al

1. Did the research questions and inclusion criteria for the review include the components of PICO?

For Yes: Population Intervention Comparator group Outcome

Optional (recommended): Timeframe for follow-up

Yes Yes

2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?

For Partial Yes: The authors state that they had a written protocol or guide that included ALL the following: - review question(s) - a search strategy - inclusion/exclusion criteria - a risk of bias assessment

For Yes: As for partial yes, plus the protocol should be registered and should also have specified: - a meta-analysis/synthesis plan, if appropriate, and - a plan for investigating causes of heterogeneity - justification for any deviations from the protocol

Yes In the Cochrane website, the protocol with all the detailed information required is available. In addition, the differences between the protocol and the review have been indicated.

No In the appendix of the SR, the authors referred to the published protocol, which answered to 5 out of the 7 requested items by AMSTAR-2. The search strategies were not provided in the published protocol. There is no information in the SR about existence or not of deviations.

3. Did the review authors explain their selection of the study designs for inclusion in the review?

For Yes, the review should satisfy ONE of the following: - Explanation for including only RCTs - OR Explanation for including only NRSI - OR Explanation for including both RCTs and NRSI

No The study design considered was stated. However, there is no explanation regarding the inclusion of only RCTs

No The authors specified the study design (parallel- and cluster-RCTs) However, they did not explain the reasons for including only RCTs

4. Did the review authors use a comprehensive literature search strategy? For Partial Yes (all the following): - searched at least 2 databases (relevant to research question) - provided key word and/or search strategy - justified publication restrictions (e.g. language) For Yes, should also have (all the following): - searched the reference lists / bibliographies of included studies - searched trial/study registries - included/consulted content experts in the field - where relevant, searched for grey literature - conducted search within 24 months of completion of the review

Yes Yes

5. Did the review authors perform study selection in duplicate? For Yes, either ONE of the following: - at least two reviewers independently agreed on selection of eligible studies and achieved consensus on which studies to include

Yes Two review authors independently evaluated the titles and abstracts obtained through electronic searches. A

Yes All titles/abstracts and potentially relevant full-text articles were screened by two reviewers, independently.



- OR two reviewers selected a sample of eligible studies and achieved good agreement (at least 80 percent), with the remainder selected by one reviewer.

third review author resolved discrepancies

Discrepancies were discussed and if necessary, resolved with input from a third reviewer.

6. Did the review authors perform data extraction in duplicate? For Yes, either ONE of the following: - at least two reviewers achieved consensus on which data to extract from included studies - OR two reviewers extracted data from a sample of eligible studies and achieved good agreement (at least 80 percent), with the remainder extracted by one reviewer.

Yes Two review authors independently extracted study characteristics. One review author entered data into Review Manager and a second review author verified the data entered

Yes Data extraction was conducted by two reviewers, independently. Discrepancies were discussed and if necessary, resolved with input from a third reviewer

7. Did the review authors provide a list of excluded studies and justify the exclusions? For Partial Yes: - provided a list of all potentially relevant studies that were read in full-text form but excluded from the review For Yes, must also have: - Justified the exclusion from the review of each potentially relevant study

Yes

Partial yes

8. Did the review authors describe the included studies in adequate detail?

For Partial Yes (ALL the following): - described populations - described interventions - described comparators - described outcomes - described research designs

For Yes, should also have ALL the following: - described population in detail - described intervention in detail (including doses where relevant) - described comparator in detail (including doses where relevant) - described study’s setting - timeframe for follow-up

Yes Partial yes Detailed information is provided in the supplementary online content. However, the timeframe for follow-up for each study was not detailed.

9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? For Partial Yes, must have assessed RoB from unconcealed allocation, and lack of blinding of patients and assessors when assessing outcomes (unnecessary for objective outcomes such as all-cause mortality) For Yes, must also have assessed RoB from: allocation sequence that was not truly random, and selection of the reported result from among multiple measurements or analyses of a specified outcome

Yes Two review authors assessed potential sources of bias in trials according to methods set out in the Cochrane Handbook for Systematic Reviews of Interventions

Yes Quality assessment was done by two reviewers, independently, using the Cochrane risk of bias tool for RCTs

10. Did the review authors report on the sources of funding for the studies included in the review? Must have reported on the sources of funding for individual studies included in the review. Note: Reporting that the reviewers looked for this information but it was not reported by study authors also qualifies.

Yes Funding sources and Declarations of interest are reported for each RCT included in the SR.

Yes The authors reported that 2 of the 19 RCTs (10.5%) were industry funded.

11. If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results?

No The weighted technique used is not detailed to judge its appropriateness

No. Authors performed a meta-analysis, although the justification for



RCTs For Yes: The authors justified combining the data in a meta-analysis AND they used an appropriate weighted technique to combine study results and adjusted for heterogeneity if present AND investigated the causes of any heterogeneity.

combining the data and the weighted technique to combine study results was not described. Causes of heterogeneity were investigated. A publication of the NMA is pending.

12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? For Yes: included only low risk of bias RCTs OR, if the pooled estimate was based on RCTs and/or NRSI at variable RoB, the authors performed analyses to investigate possible impact of RoB on summary estimates of effect.

Yes Authors indicated that they planned to conduct sensitivity analyses to assess the impact of studies graded as having high risk of bias on any parameter, unpublished data only, or industry funding. After assessing the studies included and the data collected, authors of the SR determined that these analyses were not needed because studies within each meta-analysis did not differ on the basis of these factors.

Yes The authors performed a sensitivity analysis by restricting results to trials determined to be at low risk of selection bias.

13. Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review? For Yes: - included only low risk of bias RCTs - OR, if RCTs with moderate or high RoB, or NRSI were included the review provided a discussion of the likely impact of RoB on the results

Yes The authors provided in the discussion section the impact of RoB of the selected RCTs.

No RoB methodology was described in methods, but how this assessment impacted the results is not included in the discussion

14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? For Yes: There was no significant heterogeneity in the results OR if heterogeneity was present the authors performed an investigation of sources of any heterogeneity in the results and discussed the impact of this on the results of the review

Yes When heterogeneity was present Solomon et al commented on the impact of it on the SR.

No Assessment of heterogeneity is described in methods, but the impact on results is not detailed in the discussion

15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? For Yes: performed graphical or statistical tests for publication bias and discussed the likelihood and magnitude of impact of publication bias

No The authors stated that in future updates of the SR, when outcome data from 10 or more studies are included in a meta-analysis, they will use a funnel plot to judge potential publication bias.

No

16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? For Yes: The authors reported no competing interests OR The authors described their funding sources and how they managed potential conflicts of interest

Yes The authors stated the internal and external sources of support received. The authors of the SR declared that there were no interests known.

Yes The authors stated the funding and declared no conflicts of interest.

Abbreviations: RCT=randomised clinical trial; RoB=risk of bias SR=systematic review.



APPENDIX 11: PROTOCOL DEVIATIONS IN HAWK AND HARRIER STUDIES

Table A12. Protocol deviations by deviation category (RAN) in HAWK study - week 48 analysis

Brolucizumab 6 mg

(N = 361) n (%)

Aflibercept 2 mg

(N = 361) n (%)

Overall (N = 1082)

n (%)

Number of subjects with at least 1 protocol deviation

46 (12.7)) 52 (14.4) 156 (14.4

Inclusion / exclusion criteria not met

12 (3.3) 13 (3.6) 41 (3.8)

Withdrawal criteria met but subject not withdrawn

0 (0.0) 0 (0.0) 0 (0.0)

Deviation related to active treatment*

26 (7.2) 30 (8.3) 92 (8.5)

Prohibited concomitant medication administered

7 (1.9) 4 (1.1) 17 (1.6)

Other 4 (1.1) 7 (1.9) 17 (1.6)

Source: HAWK CSR. A subject with multiple occurrences of a protocol deviation category is counted only once in the protocol deviation category. A subject may have protocol deviations in more than one protocol deviation category. Percentages (%) are calculated based on N.

*Deviations related to active treatment include subjects who were randomized but not treated, received wrong treatment, missed active treatment due to reason other than lack of efficacy or any safety event, received active treatment when schedule was for sham or were reassigned to q8w regimen although no disease activity was identified by the Investigator.

Table A13. Protocol deviations by deviation category (RAN) in HARRIER study - week 48 analysis

Brolucizumab 6 mg (N = 372)

n (%)

Aflibercept 2 mg (N = 371)

n (%)

Overall (N = 743)

n (%)

Number of subjects with at least 1 protocol deviation

43 (11.6) 43 (11.6) 86 (11.6)

Inclusion / exclusion criteria not met

22 (5.9) 24 (6.5) 46 (6.2)

Withdrawal criteria met but subject not withdrawn

0 (0.0) 0 (0.0) 0 (0.0)

Deviation related to active treatment*

17 (4.6) 13 (3.5) 30 (4.0)

Prohibited concomitant medication administered

3 (0.8) 2 (0.5) 5 (0.7)

Other 6 (1.6) 7 (1.9) 13 (1.7)

Source: HARRIER CSR. A subject with multiple occurrences of a protocol deviation category is counted only once in the protocol deviation category.

A subject may have protocol deviations in more than 1 protocol deviation category. Percentages (%) are calculated based on N. *Deviations related to active treatment include subjects who were randomized but not treated, received wrong treatment,

missed active treatment due to reason other than lack of efficacy or any safety event, received active treatment when schedule was for sham or were reassigned to q8w regimen although no disease activity was identified by the Investigator.

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