The Canadian Agency for Drugs and Technologies in Health ("CADTH"), in collaboration with Health Canada and the Institut national d'excellence en santé et en services sociaux ("INESSS"), has published guidance on reporting real-world evidence ("RWE"). The guidance defines RWE as evidence surrounding the use, safety, efficacy, and cost of a health product, derived from analysis of real-world data ("RWD") (RWD may be derived from a variety of sources, including medical records, clinical and disease registries, administrative databases, and pragmatic and hybrid clinical trials). According to CADTH, the guidance harmonizes principles for the use of RWE in regulatory approval and health technology assessments in Canada by CADTH, Health Canada, and INESSS and prioritizes transparent reporting while maintaining alignment with international standards.
Although prospectively planned, randomized controlled trials ("RCTs") will continue to be the most robust means of generating evidence of drug safety and efficacy, the guidance states that RWE can supplement and complement RCT data in certain circumstances. Notably, RWE can be used to fill gaps in RCT data, such as evidence from patient populations that are underrepresented in RCTs (e.g., children, the elderly, pregnant women, underserved and understudied communities, or patients with a high burden of multimorbidity) or in circumstances where the generation of robust RCT data is not feasible (e.g., evaluation of drugs for rare diseases or leveraging larger sample sizes and longer follow-up periods than are typical in RCTs). RWE can thus be used to overcome some of the limitations on the generalizability of RCT data. RWE can also be used to gain insights into subjective metrics, such as individuals' perspectives on issues like accessibility and ease of use of health products. Importantly, the guidance also notes that RWE has inherent limitations including risks of bias and confounding.
CADTH's guidance provides detailed recommendations on the following topics as they relate to generating and reporting RWE:
- Research questions and study design;
- Setting and context;
- Data specifications, access, cleaning methods, and linkage;
- Data sources, data dictionary, and variables;
- Participants;
- Exposure definitions and comparators;
- Outcomes;
- Bias, confounding, and effect modifiers or subgroup effects;
- Statistical methods;
- Study findings;
- Interpretation and generalizability; and
- Limitations.
The guidance recognizes that operationalization of the recommendations may depend on the context, which will be informed by the diversity of sources of RWD, designs and uses of RWE, and the relevant therapeutic area. CADTH states that the recommendations may be applied flexibly and selectively so as to enable their use for RWE in a variety of contexts. For example, CADTH cites utilization or burden of disease studies, which may not require application of certain recommendations contained in the guidance, and rare diseases and medical devices, which may necessitate flexible application of the recommendations to accommodate for challenges in the generation of RWE in those contexts.
Following the publication of CADTH's guidance, Health Canada published an announcement outlining its position on the guidance. Health Canada invites regulatory submissions relying on high quality RWE in certain situations, including:
- Expanding evidence-based indications for populations often excluded from clinical trials (e.g., children, older adults and expectant mothers);
- Addressing diseases where clinical trials are not feasible (e.g., rare diseases); or
- Responding to emergencies where clinical trials are unethical.
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