SYSTEMATIC LITERATURE REVIEWS IN RARE DISEASES: CONSIDERATIONS, ISSUES AND RECOMMENDATIONS WHEN FACED WITH AN IMPERFECT EVIDENCE BASE

OBJECTIVES: Systematic literature reviews (SLRs) of real world evidence (RWE) are often conducted to summarize evidence on treatment patterns, natural history, and the epidemiological, humanistic and economic burden of illness. When the disease of interest is rare, the evidence can be difficult to find, and conventional approaches to SLR conduct may need to be adapted. Our objectives were: 1) to highlight key differences in SLR conduct between those focusing on RWE in rare diseases versus common diseases; and 2) to present a conceptual framework outlining pertinent considerations and recommendations for researchers designing and carrying out SLRs of RWE in rare diseases. METHODS: We conducted a targeted review of SLRs in rare diseases that used RWE, as well as of methodological guidance on SLRs. We used this literature base to develop and synthesize key considerations and recommendations regarding the conduct of SLRs in rare diseases as it compares with SLRs conducted for more common diseases, focusing on RWE. RESULTS: Our framework highlights key considerations relating to: inclusion criteria, search strategies, data sources, data extraction, risk of bias assessment, and analysis. Compared with SLRs in more common diseases, rare disease SLRs tend to require a broader approach: due to limited data availability, search strategies are often kept broad at the beginning to increase sensitivity, and may be narrowed iteratively. Furthermore, rare diseases SLRs can capture evidence from non-traditional research designs and data sources (e.g. patient or caregiver blogs) as well as employ additional analytics and modeling in order to make the best use of imperfect evidence. CONCLUSIONS: Limited methodological guidance is available on designing and conducting SLRs of RWE in rare diseases where evidence is scarce. Our comprehensive conceptual framework can serve as a methodological reference for researchers conducting SLRs in a rare disease.