While many clinical practice guidelines that use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach have ample published evidence to support their recommendations, certain situations (e.g. rare, rapidly emerging, or understudied diseases) may be limiting. As a result, it is common for guideline developers to seek out indirect evidence from other areas to fill in these evidence gaps. The GRADE evidence-to-decision (EtD) framework, which offers a structured and transparent development process for guidelines, includes additional research evidence domains (e.g. feasibility, acceptability, equity) for panels to consider in their decision-making process. This confluence of both considerations of indirect information and increasing literature domain sources to draw from when making decisions weighs on the simplicity of literature presentation. Herein, firstly, we described an example of specific decision-rules for including indirect evidence and the implications of the rules for presenting results to decision-makers. Secondly, we provided a comprehensive overview of how guideline developers currently report economic information across GRADE evidence-to-decision frameworks. Lastly, we ranked the most important study characteristics suggested in the literature by economists to consider as decision-rules when assessing indirectness (transferability) of economic evaluations chosen as research evidence in a GRADE guideline. We conclude that developers, with the help of their panels, should work to establish and report clear decision-rules and the rationale for indirect evidence that they select for their clinical practice guidelines. This has the potential to simplify the presentation of indirect evidence for panels and developers, as well as, to reduce decision-making confusion, time demands and guideline funder costs. / Thesis / Candidate in Philosophy / While many clinical practice guidelines have ample published evidence to support their recommendations, certain situations (e.g. rare, rapidly emerging, or understudied diseases) may be limiting the available literature. As a result, it is common for guideline developers to seek out indirect evidence from other, but related areas, to fill in these evidence gaps. Selection of available indirect evidence may be better than basing decisions on no evidence, in particular in situations of clinical equipoise. However, including all potentially relevant indirect evidence may represent an overuse of evidence. Indirect evidence refers to information sources with related populations, interventions, outcomes or comparisons, which could reasonably be extrapolated; but, are not entirely specific to the research topic at hand. This confluence of both indirect information considerations and desire by many for increasing literature sources to draw from weighs on the simplicity of an overall summary of literature presented during a guideline recommendation decision-making process. Herein, firstly, we described an example of explicit decision-rules for including indirect evidence that were specific and the implications of the rules for presenting results to decision-makers. Secondly, we provided a comprehensive overview of how guideline developers currently report economic information across guideline frameworks, in particular with respect to indirectness. Lastly, we described the most important study characteristics suggested by economists to consider as decision-rules when assessing economic evaluations for use as research evidence in a guideline. This work presents important concepts for guideline developers to consider when choosing indirect evidence sources in their clinical practice guidelines. Our findings have the potential to simplify the presentation of indirect evidence for guideline panels and developers, as well as, to reduce decision-making confusion, time demands and guideline funder costs.

The guideline development process can be challenging when diseases are rare. The development of the NHF-McMaster Guideline on Care Models for Hemophilia Management presented an opportunity to identify methodological challenges for guideline development in rare diseases. Several methodological challenges were identified in the evidence gathering and assessment stages. Eight challenges were presented in the development of a systematic review on care models for hemophilia management. The barriers to conducting the systematic review were mostly due to the paucity of high quality evidence in hemophilia care models. Due to the paucity of high-quality evidence typical of a rare condition such as hemophilia, indirect evidence from other chronic conditions were sought through an overview of reviews. Seven challenges were identified in the development of an overview on integrated multidisciplinary care for the management of chronic conditions in adults. The barriers were mainly due to unestablished methodology for conducting overviews, and the challenge of applying this evidence in the context of hemophilia for the guideline. To overcome the methodological challenges with evidence gathering and assessment for rare disease guideline development, the decision-making process to derive solutions were transparently presented. Overall, the methodological challenges as well as apparent facilitators from a rare disease setting are shown to be related to the barriers and facilitators at the research, clinical, and guideline development phase. As a result, using an example from hemophilia, this thesis has demonstrated that it is possible to develop high quality guidelines for rare diseases. / Thesis / Master of Science (MSc)