Strategies for eliciting and synthesizing evidence for guidelines in rare diseases

BACKGROUND: Rare diseases are a global public health priority. Though each disease is rare, when taken together the thousands of known rare diseases cause significant morbidity and mortality, impact quality of life, and confer a social and economic burden on families and communities. These conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment. Clinical practice guidelines are necessary to support clinical and policy decisions. However, creating guidelines for rare diseases presents specific challenges, including a paucity of high certainty evidence to inform panel recommendations. METHODS: This paper draws from the authors’ experience in the development of clinical practice guidelines for three rare diseases: hemophilia, sickle cell disease, and catastrophic antiphospholipid syndrome. RESULTS: We have summarized a number of strategies for eliciting and synthesizing evidence that are compatible with the rigorous, internationally accepted standards for guideline development set out by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. These strategies include: use of pre-existing and ad hoc qualitative research, use of systematic observation forms, use of registry data, and thoughtful use of indirect evidence. Their use in three real guideline development efforts, as well as their theoretical underpinnings, are discussed. Avenues for future research to improve clinical practice guideline creation for rare diseases – and any disease affected by a relative lack of evidence - are also identified. CONCLUSIONS: Rigorous clinical practice guidelines are needed to improve the care of the millions of people worldwide who suffer from rare diseases. Innovative evidence elicitation and synthesis methods will benefit not only the rare disease community, but also individuals with common diseases who have rare presentations, suffer rare complications, or require nascent therapies. Further refinement and improved uptake of these innovative methods should lead to higher quality clinical practice guidelines in rare diseases.