The third international meeting on genetic disorders in the RAS/MAPK pathway: towards a therapeutic approach.

"The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach" was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion.

A Mixed-Method Study Exploring Patient-Experienced and Caregiver-Reported Benefits and Side Effects of Corticosteroid Use in Duchenne Muscular Dystrophy.

BACKGROUND: Corticosteroids are recommended to all people with Duchenne as standard of care; patient experience data is important to guide corticosteroid decision making and as a comparator for new treatment options. OBJECTIVE: This study assesses patient and caregiver-reported benefits and side effects from corticosteroids to treat Duchenne muscular dystrophy, their importance, and satisfaction. METHODS: Using one-on-one interviews (n = 28) and an online survey (n = 236), parents and adults with Duchenne reported corticosteroid benefits and side effects rated as both experienced and important. RESULTS: Benefits to breathing, heart function, arm strength, slowing progression of weakness, and getting around were rated as particularly important, regardless of ambulatory status. Important side effects included increased fracture risk, unwanted weight gain, and diabetes/prediabetes. Parents rated behavior issues and adults rated delayed puberty as having high importance. Being ambulatory was independently associated with reporting more net benefit (p = 0.02). For side effects, parent scores were significantly higher than adult score (p = 0.02). Corticosteroid type was not significant. Participants were, overall, satisfied with corticosteroids (means ranging from 6.2 to 7.7 on a scale of 0-10), with no significant differences based on corticosteroid type. CONCLUSIONS: Overall, most participants were satisfied with the use of corticosteroids. While a range of side effects were rated as important and relatively common, individuals using corticosteroids and their caregivers indicate that benefits outweigh the side effects. Qualitative data indicate that high acceptability is influenced by lack of treatment alternatives. Patient experience data on use of corticosteroids in Duchenne may be relevant to drug development, regulatory assessment of new treatments, and to families making decisions about corticosteroid use.

Practical Considerations in Using Online Modified-Delphi Approaches to Engage Patients and Other Stakeholders in Clinical Practice Guideline Development.

Patients and caregivers are increasingly recognized as key stakeholders in developing clinical practice guidelines (CPGs). Online engagement approaches offer the promise of a rigorous, scalable, and convenient engagement method. This paper illustrates how an online modified-Delphi approach could be used to engage patients, caregivers, and other stakeholder in CPG development. It provides practical guidance for conducting online modified-Delphi panels that covers (1) joint development of the engagement approach with relevant stakeholders, (2) adaptation of methods used by experts in guideline development, (3) pilot testing, (4) participant recruitment, (5) determining panel size and composition, (6) building participant capacity, (7) facilitation of two-way interaction, (8) continuous engagement and retention of participants, (9) rigorous data analysis, (10) evaluation of engagement activities, and (11) result dissemination. The paper is based on a recently completed study about engaging individuals with Duchenne muscular dystrophy (DMD) and their caregivers in determining the patient-centeredness of DMD care guidelines.

Patient and caregiver perspectives on guideline adherence: the case of endocrine and bone health recommendations for Duchenne muscular dystrophy.

BACKGROUND: Clinical care guidelines are typically developed by clinicians and researchers. Including patient and caregiver voices in guideline development may help create guidelines that are more useful for patients and consequently improve their guideline adherence. Although there is substantial research on the factors the affect providers' adherence to guidelines, there is less research on the factors that affect patients' compliance with guideline recommendations, especially among those with rare disorders. The purpose of this study is to explore factors that are likely to affect patient/caregiver adherence to endocrine and bone health recommendations for Duchenne Muscular Dystrophy (DMD). To do so, we used qualitative data collected as part of the study designed to develop, implement, and evaluate a new online, modified-Delphi approach to engaging patients with rare diseases and their caregivers in guideline development, using care guidelines for DMD as a case study. METHODS: We thematically analyzed qualitative data collected from 95 adults with DMD and their caregivers who participated in at least one round of our online Modified-Delphi panel process. Participants rated and commented on the patient-centeredness of 19 recommendations about vertical growth, weight management, bone health, and delayed puberty included in the 2018 DMD care considerations. Patient-centeredness was operationalized as the importance and acceptability of care recommendations. RESULTS: Thematic analyses revealed six factors that affect guideline adherence from the patient/caregiver perspective: content and format of recommendations, patient and provider characteristics, and social and financial factors. CONCLUSIONS: This study used a novel approach to exploring patient and caregiver perspectives on factors that may affect guideline adherence. The six factors identified by DMD patients and caregivers are similar to the factors affecting provider adherence and are not limited to DMD. Understanding consistency between provider- and patient/caregiver-identified barriers to following guideline recommendations can lead to developing more successful interventions for increasing guideline adherence.

The RAND/PPMD Patient-Centeredness Method: a novel online approach to engaging patients and their representatives in guideline development.

Although clinical practice guidelines (CPGs) provide recommendations for how best to treat a typical patient with a given condition, patients and their representatives are not always engaged in CPG development. Despite the agreement that patient participation may improve the quality and utility of CPGs, there is no systematic, scalable method for engaging patients and their representatives, as well as no consensus on what exactly patients and their representatives should be asked to do during CPG development. To address these gaps, an interdisciplinary team of researchers, patient representatives, and clinicians developed the RAND/PPMD Patient-Centeredness Method (RPM) - a novel online approach to engaging patients and their representatives in CPG development. The RPM is an iterative approach that allows patients and their representatives to provide input by (1) generating ideas; (2) rating draft recommendations on two criteria (importance and acceptability); (3) explaining and discussing their ratings with other participants using online, asynchronous, anonymous, moderated discussion boards, and (4) revising their responses if needed. The RPM was designed to be consistent with the RAND/UCLA Appropriateness Method used by clinicians and researchers to develop CPG, while helping patients and their representative rate outcome importance and recommendation acceptability - two key components of the GRADE Evidence to Decision (EtD) framework. With slight modifications, the RPM has the potential to explore consensus among key stakeholders on other dimensions of the EtD, including feasibility, equity, and resource use.

Participant experiences with a new online modified-Delphi approach for engaging patients and caregivers in developing clinical guidelines.

BACKGROUND: Patient engagement in clinical practice guideline (CPG) development has increased significantly in recent years. However, only a few patients and caregivers join CPG development groups. OBJECTIVE: To describe participant experiences with a novel online, scalable approach for patient and caregiver engagement in CPG development. DESIGN: We developed and tested the RAND/PPMD Patient-Centeredness Method (RPM), a novel online modified-Delphi approach to patient engagement in CPG development that consists of an optional idea generation round and two rating rounds interspersed with an online discussion round. SETTING AND PARTICIPANTS: Using the online ExpertLens™ system, we ran 2 concurrent panels of patients and caregivers of individuals with Duchenne Muscular Dystrophy (DMD). MAIN OUTCOME MEASURES: We surveyed all 95 panel participants about their participation and satisfaction with the process. We also conducted telephone interviews with 25 participants. RESULTS: Participants expressed satisfaction with various ExpertLens™ features, noting that the system fostered lively interaction among them. Panelists also appreciated participating in an educational, interactive and convenient discussion forum that allowed them to share their opinions on the importance and acceptability of different recommendations. The RPM was viewed as empowering by patients and their caregivers who felt it would be useful for CPG developers. DISCUSSION AND CONCLUSION: The results of our study show the overall participant satisfaction with a novel, scalable, online approach to engaging patients and caregivers in CPG development, which allows them to share their perspectives and lived experiences using a rigorous, systematic and iterative way that is similar to how clinicians provide their input.

Using an Online, Modified Delphi Approach to Engage Patients and Caregivers in Determining the Patient-Centeredness of Duchenne Muscular Dystrophy Care Considerations.

Purpose. To determine the patient-centeredness of endocrine and bone health Duchenne muscular dystrophy (DMD) care considerations using the RAND/PPMD Patient-Centeredness Method (RPM), which is a novel, online, modified-Delphi approach to engaging patients and caregivers in clinical guideline development. Methods. We solicited input on the patient-centeredness of care considerations from 28 individuals with DMD and 94 caregivers, randomly assigned to 1 of 2 mixed panels. During a 3-round online modified-Delphi process, participants rated the importance and acceptability of 19 DMD care considerations (round 1), reviewed and discussed the initial results (round 2), and revised their original ratings (round 3). Patient-centeredness was operationalized as importance and acceptability of recommendations. We considered a care consideration to be patient-centered if both panels deemed it important and acceptable. Results. Ninety-five panelists (78%) participated in this study. Of these, 88 (93%) participated in round 1, 74 (78%) in round 2, and 56 (59%) in round 3. Panelists deemed 12 care considerations to be patient-centered: 3 weight management, 3 bone health, 4 vertical growth, and 2 puberty recommendations. Seven care considerations did not meet patient-centeredness criteria. Common reasons were lack of evidence specific to DMD and concerns about insurance coverage, access to treatment, and patient safety. Conclusions. Using the RPM, Duchenne families considered most care considerations to be patient-centered. Besides being clinically appropriate, these considerations are likely to be consistent with the preferences, needs, and values of Duchenne families. While all relevant care considerations should be discussed during patient-provider encounters, those that did not meet patient-centeredness criteria in particular should be carefully considered as part of joint decision making between Duchenne families and their providers. Study Registration: HSRProj 20163126.

Engaging Patients and Caregivers Managing Rare Diseases to Improve the Methods of Clinical Guideline Development: A Research Protocol.

BACKGROUND: Clinical guidelines provide systematically developed recommendations for deciding on appropriate health care options for specific conditions and clinical circumstances. Up until recently, patients and caregivers have rarely been included in the process of developing care guidelines. OBJECTIVE: This project will develop and test a new online method for including patients and their caregivers in this process using Duchenne muscular dystrophy (DMD) care guidelines as an example. The new method will mirror and complement the RAND/UCLA Appropriateness Method (RAM)-the gold standard approach for conducting clinical expert panels that uses a modified Delphi format. RAM is often used in clinical guideline development to determine care appropriateness and necessity in situations where existing clinical evidence is uncertain, weak, or unavailable. METHODS: To develop the new method for engaging patients and their caregivers in guideline development, we will first conduct interviews with experts on RAM, guideline development, patient engagement, and patient-centeredness and engage with Duchenne patients and caregivers to identify how RAM should be modified for the purposes of patient engagement and what rating criteria should patients and caregivers use to provide their input during the process of guideline development. Once the new method is piloted, we will test it by conducting two concurrently run patient/caregiver panels that will rate patient-centeredness of a subset of DMD care management recommendations already deemed clinically appropriate and necessary. The ExpertLens™ system-a previously evaluated online modified Delphi system that combines two rounds of rating with a round of feedback and moderated online discussions-will be used to conduct these panels. In addition to developing and testing the new engagement method, we will work with the members of our project's Advisory Board to generate a list of best practices for enhancing the level of patient and caregiver involvement in the guideline development process. We will solicit input on these best practice from Duchenne patients, caregivers, and clinicians by conducting a series of round-table discussions and making a presentation at an annual conference on Duchenne. RESULTS: The study protocol was reviewed by RAND's Human Subjects Protection Committee, which determined it to be exempt from review. Interviews with RAM experts have been completed. The projected study completion date is May 2020. CONCLUSIONS: We expect that the new method will make it easier to engage large numbers of patients and caregivers in the process of guideline development in a rigorous and culturally appropriate manner that is consistent with the way clinicians participate in guideline development. Moreover, this project will develop best practices that could help involve patients and caregivers in the clinical guideline development process in other clinical areas, thereby facilitating the work of guideline developers.