Randomised controlled trials (RCTs) are the gold standard to address clinical questions on the efficacy and safety of therapies, using strict criteria and specific methods. This stringency means that RCTs may not fully reflect treatment outcomes in routine clinical practice.1,2 Real-world data (RWD) are generated from studies that more closely represent routine clinical practice, and can include longer-term safety, effectiveness and patient-reported outcome measures. When these data are collected and analysed appropriately, the resulting real-world evidence (RWE) complements information from RCTs, providing additional information to support informed clinical decisions and enhance patient care.1-3
In the context of neovascular age-related macular degeneration (nAMD), the approval and widespread application of intravitreal anti-vascular endothelial growth factor (VEGF) agents has offered the potential to improve and stabilise patients’ visual acuity. Clinical experience from routine practice has contributed to an increased understanding of the impact of these agents on patients and their disease, and is reflected in an increasing body of RWE from a number of RWD sources.2,4 These real-world studies have provided valuable insight into long-term outcomes and utilisation of anti-VEGF agents in nAMD, but have also revealed differences in outcomes achieved with anti-VEGF agents in clinical practice, compared with RCTs.5 Identification of these disparities has allowed for variations in treatment practices to be highlighted, resulting in the opportunity to improve services, understand the need for proactive treatment and establish new treatment regimens, such as treat-and-extend.5
As with all forms of data generation, there are inherent limitations to the study designs associated with RWD collection. It is therefore important that the quality of each piece of RWE is carefully assessed, to ensure reliable conclusions can be drawn that are applicable to clinical practice.1,4,6,7
Specific biases that can influence RWE quality reflect the generation of data from patients outside the stringently controlled environment of an RCT and are summarised in Figure 1. Appropriate statistical analyses are necessary to control for the presence of biases and confounding factors, to allow robust, clinically relevant conclusions to be made.
Figure 1. Types of bias that can impact the quality of RWD
A non-interventional study is one in which the treatment is prescribed in the usual manner, according to usual day-to-day clinical practice patterns, rather than the assignment of a patient to a treatment being decided in advance by a trial protocol. The prescription of a treatment is therefore clearly separated from the decision to include the patient in the study. These studies can be prospective or retrospective and can follow a range of different designs. Some of the most commonly used non-interventional study designs are described below.
Case studies/series typically report on one or a series of patients with the condition of interest;5 for example, case series from Japan have provided data on the effectiveness of intravitreal aflibercept monotherapy in polypoidal choroidal vasculopathy, a subtype of nAMD.3 They can focus on interesting or key elements of disease history and treatment, such as adverse events, or assess treatments and practices not yet studied in RCTs. However, since patient numbers are often low, there is a risk of selection bias that can lead to overestimation or misinterpretation of outcomes.5
Data from patient registries are typically prospectively collected to evaluate specified outcomes for a predefined population. Patients are included in registries via an exposure (drug/medical device/environmental exposure) or via having a certain pre-specified disease. These registries serve predetermined scientific, clinical or policy purposes and can be used to collect post-marketing safety data, understand the natural history of a condition, or assess various qualities of care experienced by patients.7 The Fight Retinal Blindness! (FRB!) project is a registry that tracks RWD on nAMD, choroidal neovascularisation, diabetic macular oedema and retinal vein occlusion from public and private health settings in Australia, New Zealand, Singapore and European countries, including Switzerland, the Netherlands, the UK, Spain, France and Austria. The database is unique in holding 10 years of international data on treatment outcomes for nAMD.5,15,16
Electronic health records can provide a comprehensive record of an individual’s health and clinical history, including demographic data, medical history, diagnostic and laboratory test results, treatments and procedures. Medisoft Ophthalmology and mediSIGHT are UK electronic health record systems17 that hold information on clinical visits, assessments, ophthalmic procedures and clinical outcomes, and aim to make electronic health record data available for quality control/research purposes. Electronic health records can be used relatively simply to retrospectively compare outcomes between patients treated using different approaches (e.g. different anti-VEGF agents or dosing regimens), but are dependent on the completeness of record-keeping to provide complete datasets.5
Reimbursement claims databases provide data on the types and frequency of diagnostic procedures and medications routinely used in clinical practice. Databases comprising data from both public and private systems exist worldwide, such as the US Medicare database18 and the UK Clinical Practice Research Datalink.19 Claims data are a valuable source of large, diverse patient populations that lack selection bias, and longitudinal follow-up data are often available – because of their large size, insights into rare events can be gained from these databases.3 However, there are inherent limitations of claims data, including incomplete, inaccurate, or missing data, the inability to evaluate the appropriateness of care,20 and their primary purpose not being to collect safety and/or effectiveness data.
Patient surveys can be conducted in person or remotely (electronically or by phone) and can be used to collect patient-relevant data on aspects such as adherence, preferences, functional status and quality of care. For example, the VISION 2020 UK Eye Survey aims to find out about the eye health of 250,000 people living in the UK.21 While patient surveys and questionnaires are able to collect information on outcomes rarely reported in other studies, limitations include introduction of subjectivity on outcome reporting, the potential for survey wording to influence answers, and recall bias.5
The increasing importance of RWE in clinical decision-making means that it is important for practising ophthalmologists to be able to easily evaluate the quality of published RWE and the applicability of findings to clinical practice. In order to do this, simple tools are required to facilitate critical evaluation of published RWE, considering important factors including the data source, study design and analyses in relation to the research question.5
Some resources are available to aid practising ophthalmologists in their evaluation of the quality of RWE. For example, the International Consortium for Health Outcomes Measurement (ICHOM) has defined a minimum set of standardised and patient-oriented outcome measures that should be collected and reported as RWD on macular degeneration. These include patient baseline status, clinical outcomes, patient treatment and management, patient safety, quality of life, and healthcare economics.22 The Good Research for Comparative Effectiveness (GRACE) principles can also be used to support clinicians, researchers, and decision-makers in evaluating the quality of observational comparative effectiveness studies (Figure 2).23 However, availability of a framework to facilitate the systematic assessment of quality and relevance of RWE concerning intravitreal anti-VEGF therapy, specifically, would be valuable. Inclusion of retinal disease-specific considerations, such as method of administration and injection clinic set-up, would help ophthalmologists to more easily and accurately assess the quality of the RWE relating to the use of anti-VEGFs.
Figure 2: GRACE checklist to support ophthalmologists in the evaluation of RWE
RWE can provide insights into key outcomes in retinal disease as experienced in every-day practice, including long- and short-term effects on vision, as well as patient-reported outcomes. In this way, findings from RWE can positively influence the treatment of retinal disease in clinical practice, for example by providing insights into optimising treatment adherence and injection frequency, to improve and preserve visual acuity.5 Critical evaluation of the method of RWD collection, the subsequent analysis and reporting, and the conclusions drawn are important to permit effective assessment of the quality of published RWE. This enables judgement of the relevance and applicability of RWE to clinical practice and supports confidence in translation of the findings from RWE into clinical practice, to optimise care for patients with nAMD.