NATIONAL INSTITUTES OF HEALTH Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome December 9–10, 2014 DRAFT EXECUTIVE SUMMARY Carmen R. Green, M.D.; Penny Cowan; Ronit Elk, Ph.D.; Kathleen M. O’Neil, M.D.; Angela L. Rasmussen, Ph.D. 1 Introduction 2 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, complex, multi- 3 faceted condition characterized by extreme fatigue and other symptoms that are not improved by 4 rest. The etiology and pathogenesis remain unknown; there are no laboratory diagnostic tests; 5 and there are no known cures. An estimated one million people, mostly women, are affected. 6 ME/CFS is an unmet public health need with an economic burden estimated to be greater than $1 billion. 7 ME/CFS results in major disability for a large proportion of the people affected. Limited 8 knowledge and research funding creates an additional burden for patients and health care 9 providers. 10 Unfortunately, ME/CFS is an area where the research and medical community has frustrated its 11 constituents, by failing to assess and treat the disease and by allowing patients to be stigmatized. 12 On December 9‒10, 2014, the National Institutes of Health (NIH) convened a Pathways to 13 Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue 14 Syndrome. Specifically, the workshop sought to clarify the following key issues: 15 • How the research on ME/CFS, using multiple case definitions, has contributed to the 16 state of the current scientific literature on diagnosis, pathophysiology, treatment, cure, 17 and prevention of ME/CFS 18 • How the measurement outcomes (tools and measures) currently used by ME/CFS 19 researchers are able to distinguish among those patients diagnosed with ME/CFS, 20 including the sensitivity of tools and measures to identify subsets of patients according to 21 the duration, severity, nature, onset characteristics, and other categorizations of the illness 22 • How the research on treatments or therapies shown to be effective in addressing 23 symptoms of ME/CFS will lead to an understanding of the underlying pathology 24 • How innovative research approaches have provided an understanding of the 25 pathophysiology of ME/CFS, and how this knowledge can be applied to the development 26 of effective and safe treatments. 27 We critically reviewed the scientific literature and opinions presented by a group of experts and 28 the ME/CFS community during the public meeting, weighed the evidence, and developed a set of 29 conclusions. This report presents our findings and recommendations. 30 What is the incidence and prevalence of myalgic encephalomyelitis/chronic fatigue 31 syndrome (ME/CFS) and whom does it affect? 32 ME/CFS exists. Despite the absence of a clear definition, an estimated million people have 33 ME/CFS, and it overlaps with many other diseases (e.g., fibromyalgia, major depressive 34 disorder, chronic pain). There is no agreement from the research community on what needs to be 35 studied, no U.S. Food and Drug Administration (FDA)-approved drug treatments, and there are 36 no primary prevention strategies. The lack of a universally accepted case definition for ME/CFS 37 has led to difficulty in determining its prevalence and incidence, and has contributed to 38 variability in the estimates reported. The Oxford criteria (published in the Journal of the Royal 39 Society of Medicine in February 1991) are flawed and include people with other conditions, 40 confounding the ability to interpret the science. The lack of a consistent, specific, sensitive 41 diagnostic test and set of criteria has hampered all downstream research on pathogenesis and 42 treatment, causing harm and preventing ME/CFS from being considered as a distinct pathologic 43 entity. 44 ME/CFS has a physical, psychological, social, and economic impact at the individual, family, 45 and societal level. Patients are typically underserved, and clinicians have a poor understanding of 46 ME/CFS. We heard throughout the workshop that ME/CFS can affect anyone. Education, 47 financial security, and social standing will not prevent the disease. 48 Studies of ME/CFS are fraught with methodological problems, preventing a clear understanding 49 of who is affected by ME/CFS: there are no agreed-upon parameters for defining ME/CFS, no 50 accurate ways of identifying and diagnosing ME/CFS, and 163 symptoms have been associated 51 with ME/CFS. Small sample sizes, the inclusion of participants with differing symptoms across 52 studies, and the lack of inclusion of the homebound, rural residents, and a research focus on men 53 limits the applicability of current studies. Minorities also are rarely represented in studies, so 54 there are no data to confirm whether minorities have a higher or lower risk. Many instruments 55 used to evaluate ME/CFS are not validated, are inappropriate, and may be misleading. All this 56 leads to inconclusive results and a lack of knowledge of ME/CFS prevalence (i.e., how many 57 people have ME/CFS), incidence (new cases per year), and potential causes and treatments. 58 Fatigue has been the defining focus of recent research, but many other symptoms need to be 59 explored, primarily neurocognitive deficit (“brain fog”), post-exertion malaise, and pain. Most 60 ME/CFS studies focus on adults, excluding children with similar symptoms. We noted few 61 disease-specific clinical trials; a disconnect on ways in which patients, clinicians, and researchers 62 define meaningful outcomes; the lack of well-controlled, multifaceted studies using large, 63 diverse samples; and the limited research dollars directed at ME/CFS from both the public and 64 private sectors. 65 Often, patients with ME/CFS are labeled as lazy, deconditioned, and disability-seeking; this 66 hampers scientific progress. Both society and the medical profession often treat patients with 67 ME/CFS with disdain, suspicion, and disrespect. Patients are frequently treated with psychiatric 68 and other inappropriate drugs that may cause harm. Patients usually have to make extraordinary 69 efforts, at extreme personal costs, to find a physician who will correctly diagnose and treat 70 ME/CFS symptoms. In addition to high medication costs, the debilitating effects of ME/CFS can 71 result in financial instability due to the physical consequences of the illness (e.g., the loss of 72 employment, home, and other basic necessities). All of these factors contribute to the poor 73 quality of epidemiologic studies. 74 Given the unique challenges to ME/CFS, how can we foster innovative research to enhance 75 the development of treatments for patients? 76 Over the last 20 years, minimal progress has been made to improve the state of the science for 77 patients with ME/CFS, and the public and provider community is frustrated. Patients want their 78 concerns to be heard, a meaningful recovery (not just incremental improvement), and a cure. 79 Educational efforts are needed to help patients and their health care providers better understand 80 this disease and scientific processes. The scientific community also has a responsibility to 81 address issues that are meaningful to patients. 82 There is reproducible evidence of neurocognitive dysfunction with abnormalities in functional 83 magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies. Strong 84 evidence indicates immunologic and inflammatory pathologies, neurotransmitter signaling 85 disruption, microbiome perturbation, and metabolic or mitochondrial abnormalities in ME/CFS, 86 potentially important for defining and treating ME/CFS. 87 Overall, limited patient and professional education has impaired progress in managing ME/CFS. 88 Furthermore, treatments remain unproven. Clinical studies have focused on predominantly 89 Caucasian, middle-aged women. Representative, ethnically diverse samples across the lifespan 90 are lacking. Investigations of natural history and familial linkages may identify genetic 91 predispositions and lead to early identification and primary prevention. 92 Although psychological repercussions (e.g., depression) often follow ME/CFS, this is not a 93 psychological disease in etiology. A multitude of symptoms are associated with ME/CFS, with 94 substantial overlap with other pathologic diseases (e.g., fibromyalgia, major depressive disorder, 95 and a variety of chronic pain or inflammatory conditions). Focusing on fatigue alone may 96 identify many ME/CFS cases. However, this symptom taken in isolation fails to capture the 97 essence of this complex condition. Prior studies may have inadequately excluded individuals 98 with the distinct diseases listed above, leading to delayed diagnosis, conflicting diagnoses, 99 contradictory treatments, suboptimal care, and inappropriate health care utilization. Future 100 studies should distinguish between ME/CFS alone, ME/CFS with comorbidities, and other 101 diseases to better define cellular and molecular mechanisms for targeted treatments. 102 Carefully designed and adequately powered studies defining the spectrum of ME/CFS in urban 103 and rural communities are lacking, limiting their applicability to an increasingly diverse society. 104 Specifically, it is critical to include patients with limited access to clinical services (e.g., non- 105 ambulatory patients). A clear case definition with validated diagnostic tools is required before 106 studies can be conducted. We noted a consistent constellation of symptoms: fatigue, post- 107 exertional malaise, neurocognitive deficit, and pain. 108 Patients with ME/CFS are hopeful that research will lead to a cure. However, the few cross- 109 sectional studies with limited applicability have provided few insights to the disease or its 110 treatment. Clinical trials require large investments of time and energy, and may be associated 111 with other harms (e.g., increased symptoms, medication toxicity). Future studies must be 112 collaborative, multicenter efforts and must include large, diverse samples across the lifespan. 113 Existing treatment studies (cognitive behavioral therapy [CBT] and graded exercise therapy 114 [GET]) demonstrate measurable improvement, but this has not translated to improvements in 115 quality of life (QOL). Thus, they are not a primary treatment strategy and should be used as a 116 component of multimodal therapy. Overall, agreeing on a case definition and clarifying 117 comorbidities could launch bench-to-bedside science. 118 What does research on ME/CFS tell us about the presentation and diagnosis of ME/CFS in 119 the clinic? 120 Limited time during the clinical encounter has impaired patient/clinician communication and 121 quality of care for patients with ME/CFS. Patients experience stigma from the diagnosis of 122 ME/CFS, including social isolation and judgment. They often experience financial instability due 123 to the physical consequences of the illness and the inability to continue employment. Negative 124 interactions with the health care system are frequent, and the emotional burden is heavy. 125 Small, poor-quality studies and a lack of a gold standard for diagnosis and treatment of ME/CFS 126 has led to confusion. Most studies lack specificity and sensitivity, while primarily using specialty 127 clinics and homogeneous populations. Furthermore, they are observational in nature, with 128 unclear and poorly defined endpoints (which may not be meaningful to patients) and do not 129 provide information on why there were high dropout rates. 130 In general, little attention was given to how self-management may empower and improve health 131 and QOL for patients with ME/CFS. Physicians are inadequately trained to instruct patients in 132 self-management skills (e.g., pacing, realistic goals, physical self-awareness, basic rights, 133 understanding emotions, exercise, relaxation), and there is a lack of data demonstrating the 134 efficacy of self-management on health outcomes. The focus on exercise programs has further 135 stigmatized and discouraged research participation. In many cases, lack of instructions or 136 guidance for including graded exercise therapy often causes additional suffering, creating fear of 137 harm from a comprehensive self-management program that may include some physical activity 138 (e.g., mild stretching). 139 What tools, measures, and approaches help define individuals with ME/CFS? 140 and 141 How are tools and measures used to distinguish subsets of patients with ME/CFS? 142 Many patients with ME/CFS are misdiagnosed and treated erroneously with potentially toxic 143 therapies that may cause harm and diminish hope. There is little understanding of the inciting 144 event or the cellular and molecular mechanisms that underlie ME/CFS, preventing quantitative 145 assessments of disease severity or prognosis. There is a failure to give adequate attention to the 146 severity of the physical, social, and emotional implications of ME/CFS. Furthermore, a variety of 147 symptoms are often “lumped” into ME/CFS. Carefully defining comorbid conditions is 148 necessary to define ME/CFS subgroups and to move the field forward. There is also a lack of 149 interdisciplinary collaboration to develop tools or disease measures that encompass the full 150 spectrum of possible ME/CFS signs and symptoms. 151 Defining ME/CFS requires standard, validated tools and measures. Individual ME/CFS studies 152 are too small to have power for subgroup analyses; rarely meet the criteria for good quality 153 evidence; frequently do not address early disease or ME/CFS in children; fail to adequately 154 address harms or who dropped out and why; and include only a short follow-up. In addition, 155 participant variability at different study centers may, in part, be responsible for conflicting 156 results. 157 Endpoints need to be clarified: what is statistically significant, what is clinically significant, and 158 what is significant to the patient. To move the research forward, there is an urgent need to get all 159 of the information possible from the control population, responders, and non-responders. Patient- 160 centered tools that use simple statements need to be developed to ensure that the patients 161 understand the questions. Overall, there is a need to simplify measures while prioritizing face-to- 162 face interactions. 163 To advance the field, retrospective, prospective, and longitudinal studies that are practical and 164 reproducible are needed. Longer follow-up and a lifespan perspective are needed to understand 165 ME/CFS effects on the whole individual (e.g., patient decision-making, patient expectations, 166 sexual health and childbearing). The symptoms patients consider clinically meaningful are not in 167 the scientific literature; this discordance must be rectified. 168 Current research has neglected many of the biological factors underlying ME/CFS onset and 169 progression. Research priorities should be shifted to include basic science and mechanistic work 170 that will contribute to the development of tools and measures such as biomarker or therapeutics 171 discovery. The following questions need to be answered: 172 • What is the pathogenesis of ME/CFS? What is the role of virologic mechanisms, 173 especially herpes viruses? Does mononucleosis lead to ME/CFS in adolescents? 174 • What is the role of other pathogenic agents? 175 • Is this a genetic disease? Is there a gene-environment interaction? 176 • Is ME/CFS a spectrum disease? 177 • Are different pathways responsible for different symptoms? 178 Future Directions and Recommendations 179 ME/CFS is a chronic, complex condition of unknown cause and with no cure. We have learned 180 some about the mechanisms of the disease, but nothing has improved the lives of the patients. 181 Overall, there has been a failure to implement what we already know for patients with ME/CFS 182 while it steals their health and well-being. However, scientifically rigorous research is needed. 183 The subjective nature of ME/CFS, associated stigma, and the lack of a standard case definition 184 has stifled progress. Patients must be at the center of the research efforts, and their engagement is 185 critical, as is outreach to underserved and vulnerable populations. 186 Innovative biomedical research is urgently needed to identify risk and therapeutic targets, and for 187 translation efforts. The scientific community is responsible for conducting trials in a way that is 188 meaningful and ethical for patients. The influence of health literacy and cognitive impairment on 189 informed consent must be considered. Investigators have a responsibility to hear the patient’s 190 perspective, engage the community, and be accountable for translating and reporting research 191 results to the ME/CFS community while responding to their feedback. The dissemination of 192 diagnostic and therapeutic recommendations should focus on primary care providers. Potential 193 conflicts of interest among investigators need to be properly vetted, discussed, and addressed by 194 all stakeholders. 195 The panel was charged with: (1) identifying research gaps, (2) determining methodological 196 limitations, and (3) providing future research recommendations. During the workshop, we 197 learned that the potential cause of ME/CFS and possible treatments are poorly understood, and 198 that there are many unresolved issues, including overlapping comorbid conditions. Findings in 199 the literature are inconsistent, and there are many gaps (e.g., Is ME/CFS one disease?). 200 To accelerate the progress of ME/CFS treatment, we recommend the following overarching 201 research strategies: 202 1. Define disease parameters. Assemble a team of stakeholders (e.g., patients, 203 clinicians, researchers, federal agencies) to reach consensus on the definition and 204 parameters of ME/CFS. A national and international research network should be 205 developed to clarify the case definition and to advance the field. There are 206 tremendous opportunities on which we have not yet capitalized to learn across 207 disciplines and from other diseases such as Gulf War Syndrome, Lyme disease, 208 fibromyalgia, multiple sclerosis, and Parkinson’s disease, to determine commonalities 209 and differences. Additional NIH Institutes and Centers not presently represented in 210 the Trans-NIH ME/CFS Working Group should be included in the effort. Thus, we 211 encourage the convening of a conference of scientific leaders that is open, inclusive, 212 and transparent. 213 2. Create new knowledge. Investing in bench-to-bedside to policy research for ME/CFS 214 is recommended and will create opportunities for junior and new investigators in the 215 field, thereby energizing and diversifying the field. The NIH Institutes and Centers 216 (e.g., the National Center for Advancing Translational Sciences [NCATS], the 217 National Center for Complementary and Alternative Medicine [NCCAM]) and other 218 U.S. Department of Health and Human Services (HHS) agencies should coordinate 219 research efforts to promote efficiency and effectiveness, while also using 220 public/private partnerships to leverage and catalyze the use of existing NIH 221 infrastructure and dollars. Specific activities should focus on: 222 • Developing valid prognostic tests that can guide treatment strategies using 223 genomic, epigenomic, proteomic, and metabolomic strategies to identify 224 critical biomarkers that will be clinically applicable. Gene expression, protein, 225 or metabolite signatures that can correctly diagnose patients with ME/CFS and 226 distinguish them from patients with other chronic conditions, while predicting 227 disease severity and clinical outcomes, are needed. Determining the most 228 important physiologic measures and pathophysiology, as well as genome-wide 229 association studies (GWAS) and phenotyping, is essential for stratifying 230 patients. fMRI and imaging technologies should be further studied as 231 diagnostic tools and as methods to better understand the neurologic 232 dysfunction of ME/CFS. 233 • Biologic samples—which may include serum and saliva, RNA, DNA, whole 234 blood or peripheral blood mononuclear cell, and tissues—as well as de- 235 identified survey data—should be linked in a registry/repository for studies of 236 pathogenesis, prognosis, and biomarker discovery. Research is needed 237 investigating the effect of the intestinal microbiome on ME/CFS using 238 cutting-edge technologies such as high-throughput sequencing. In addition, 239 further exploration of the effect, if any, of the environment and microbiome 240 on ME/CFS development using neurocognitive tests and neuroimaging should 241 be conducted. 242 • Epidemiological studies of ME/CFS, including incidence and prevalence, who 243 is at high risk, risk factors, geographical distribution, and the identification of 244 potential health care disparities are critical. Researchers should be encouraged 245 to develop a repository for qualitative and quantitative work. Similar to cancer 246 registries, there is much to learn by developing a registry/repository of all 247 patients with ME/CFS. 248 • While there is a clear need for more trials, previously collected research data 249 should be analyzed to advance knowledge and inform clinical trial 250 development and design. For instance, drugs therapies used for fibromyalgia 251 or other pain-related syndromes and disorders should be examined for their 252 effectiveness in those with ME/CFS, and existing registries should be 253 leveraged. 254 • Studies that stratify by clinical characteristics should be used to develop 255 diagnostic and prognostic algorithms to identify those patients who will 256 develop ME/CFS following infection or other triggers. 257 There is a need for “omics”-based drug repurposing and neurobiology studies. 258 Using bioinformatics techniques, large datasets such as those generated by 259 “omics” methods should be developed and stored in a central, publicly 260 accessible database for future investigations as new knowledge is developed. 261 This new knowledge might include a new understanding of molecular 262 mechanisms underlying ME/CFS, new ways to perform pathway analyses, 263 and/or new pharmacogenomic drug discovery or repurposing. 264 • An integrated, systems-level approach should be followed to understand how 265 immunologic, neurologic, and metagenomic factors may contribute to 266 ME/CFS. Immunologic mechanisms of ME/CFS and pathways associated 267 with disease progression must be defined and characterized (e.g., defining 268 cytokine profiles involved in pathogenesis; studying inflammation; and 269 comprehending the basis for natural killer cell dysfunction observed in many 270 patients with ME/CFS). These also should be longitudinal studies to explore 271 the possibility of a progressive immune exhaustion or dysfunction in 272 ME/CFS. 273 • We need studies of gene expression among identical twins to identify gene 274 expression biomarkers. Any animal model used should include males and 275 females to explore the role of gender, X-chromosome genes, and hormones in 276 the development of ME/CFS. 277 • How patients’ background medications (including psychiatric drugs) affect 278 function and outcome should be explored. Patients often choose clinical trials 279 or complementary and alternative medicine because effective treatment is not 280 available and because traditional health care is not meeting their needs. 281 Studies investigating homeopathy, non-pharmacologic, complementary, and 282 alternative medicine treatments are needed. Studies addressing 283 biopsychosocial parameters (including the mind-body connection), function, 284 and QOL should be encouraged. 285 3. Improve methods and measures. There is a critical need for improved measures to 286 identify ME/CFS while including the patient’s voice through patient-reported 287 outcomes. Without a diagnostic test, stratification must occur to reduce and 288 comprehend variability (e.g., onset, time course, comorbid conditions), and to identify 289 clearly defined endpoints for treatment trials and interventions. The NIH 290 should develop an ME/CFS methodological workgroup. 291 • A community-based participatory research approach is needed to increase 291 patient involvement in determining priorities for research and care. 293 Use of already well-validated measures developed by the NIH such as the 294 Patient-Reported Outcomes Measurement Information System (PROMIS) and 295 the Center for Epidemiological Studies Depression scale (CESD) should be 296 encouraged. Although ME/CFS is not a psychiatric disease, exploring 297 psychiatric comorbidities such as depression, anxiety, and fear is critical to 298 improve quality of life. Response burden must be considered; a battery of 299 simplified measures is strongly encouraged, as well as the triangulation of 300 qualitative and quantitative data. The NIH should leverage the power of other 301 longitudinal studies (e.g., the Health and Retirement Study, the Nurses’ Health 302 Study) to better understand ME/CFS. 303 • Telemedicine or home visits for those unable to participate in clinical 304 trials/treatment in person and outreach to underserved communities are 305 needed. New technologies to address underserved populations and unmet 306 needs (e.g., mobile technology, online tracking tools) should be employed. 307 Mobile monitoring instruments should be developed to measure progress and 308 to enable communication. Research methodology should include strategies for 309 reaching patients who are not served in the clinic setting to ensure that their 310 voice is heard. 311 4. Provide training and education. Although many health care providers do not fully 312 understand ME/CFS, primary care clinicians will be instrumental in ensuring that 313 patients are treated or referred to appropriate specialists. We believe ME/CFS is a 314 distinct disease that requires a multidisciplinary care team (e.g., physicians, nurses, 315 case managers, social workers, psychologists) to optimize care. Thus, properly 316 training that workforce is critical, and we strongly encourage engaging with: 317 • Health professional licensing and accreditation agencies to ensure a 318 curriculum that facilitates ME/CFS knowledge acquisition 319 • Health Resources and Services Administration (HRSA) to facilitate training 320 • Professional societies (e.g., International Association for the Study of Pain) 321 and patient organizations (e.g., International Alliance of Patients’ 322 Organizations) to facilitate a public-private partnership, as well as training and 323 funding of health care professionals 324 • Clinicians and researchers, who have a responsibility to encourage and track 325 progress 326 • Patients—in addition to the medical therapies they are receiving, patients must 327 become active participants in their overall treatment. 328 5. Finding new funding resources. With a relatively small number of researchers in the 329 field and finite resources, there is a need for partnerships across institutions to 330 advance the research and develop new scientists. New collaborative models, 331 investigator-initiated studies, career development, and small grant mechanisms with 332 specific attention to developing a cadre of junior investigators, including women and 333 minorities who may offer innovative new approaches, are needed. Opportunities exist 334 within HHS to engage new ME/CFS working group members, to create efficiency, 335 and to co-fund research that will promote diversity in the pipeline, eliminate 336 disparities, and enhance the quality of the science (e.g., the National Institute on 337 Minority Health and Health Disparities [NIMHD], the National Cancer Institute 338 [NCI], the Department of Education’s National Center for Medical Rehabilitation 339 Research, [NCMRR], the Department of Defense [DoD]). 340 • Create a network of collaborative centers working across institutions and 341 disciplines, including clinical, biological, and social sciences. These centers 342 will be charged with determining the biomarkers associated with diagnosis 343 and prognosis, epidemiology (e.g., health care utilization), functional status 344 and disability, patient-centered QOL outcomes, cost-effectiveness of 345 treatment studies, and the role of comorbidities in clinical and real-life 346 settings. The centers should provide a complete characterization of control 347 populations, as well as those who recover from ME/CFS. Ideally, these 348 collaborative studies will recruit from the broad spectrum of Americans and 349 will use measures that are reproducible. 350 • Establish a central archive of de-identified data and tissue samples from prior 351 and ongoing studies to enable data and sample sharing. 352 6. Conduct clinical trials. An ongoing need for participants in clinical trials was noted. 353 The NIH should work with ME/CFS partners and stakeholders to create a website for 3554 patient and clinician educational materials as well as information regarding clinical 355 trials. Opportunities to utilize the NIH Clinical Center for clinical trials and to fast- 356 track new therapies should also be explored. 357 7. Improve treatment. Patients should be active participants in care and decision- 358 making. Lessons can be learned from palliative care, such as compassion, 359 communication, and symptom management to improve the quality of care. Studies 360 examining the role of self-management techniques as part of a comprehensive 361 treatment plan for patients with ME/CFS during and after clinical interventions 362 should be explored. The modest benefit from CBT should be studied as adjunct to 363 other modalities of treatment such as self-management. Future treatment studies 364 should evaluate multimodal therapies. Comparative effectiveness research is also 365 needed. We recommend that the NIH and the FDA convene a meeting on the state of 366 ME/CFS treatment. 367 Conclusions 368 Quality care begins with assessment and depends upon optimizing patient and clinician decision- 369 making. Unfortunately, patient- and clinician-related barriers were identified (e.g., attitudes, 370 perceptions, knowledge, communication styles, time constraints, stigma) that inhibit quality care. 371 For example, patients do not want to be labeled as complainers and want their stories to be heard. 372 Interpersonal factors (e.g., age, race, ethnicity, gender, class, personality) influence 373 communication. Patients and their advocates may benefit from education on how to effectively 374 communicate their symptoms and concerns to clinicians, while health care providers could 375 benefit from enhanced active listening skills and increased education. We note that education 376 alone cannot fix this problem, but will facilitate a partnership in medical decision-making, 377 thereby optimizing care. Furthermore, the multiple case definitions for ME/CFS have hindered 378 progress. Specifically, continuing to use the Oxford definition may impair progress and cause 379 harm. Thus, for needed progress to occur we recommend (1) that the Oxford definition be 380 retired, (2) that the ME/CFS community agree on a single case definition (even if it is not 381 perfect), and (3) that patients, clinicians, and researchers agree on a definition for meaningful 382 recovery. 383 Attention should be focused on providing access to high-quality, multidisciplinary care; refining 384 assessment; and clarifying endpoints that suggest improvement and quality care. We believe 385 there is a specific role for multimodal therapy. Although no data on primary prevention were 386 presented, this does not prohibit secondary and tertiary prevention efforts. Once a cause is 387 determined, primary prevention efforts should begin. The NIH should incorporate concepts from 388 public health prevention and HHS efforts to decrease disability and promote health and well- 389 being for the ME/CFS population. 390 There is a role for new and ongoing policies to spark innovation and fund new research. For 391 instance, new avenues are needed to fund research, such as the Prescription Drug User Fee Act. 392 The NIH should work with the Centers for Medicare & Medicaid Services (CMS) and the 393 Patient-Centered Outcomes Research Institute (PCORI) to develop demonstration projects of 394 patient-centered medical homes for people with ME/CFS. This should be done using a 395 comparative effectiveness research framework with clear endpoints and continuous evaluations 396 to improve health care and to determine best practices that are evidence-based. Best practices 397 should then be translated to primary care clinicians. Federal agencies (e.g., AHRQ, the U.S. 398 Department of Veterans Affairs [VA]) and professional societies should work together to create 399 quality metrics and a standard of care. We also recommend that federal departments, advocacy 400 groups, and industry work together in public-private partnerships to help advance research for 401 ME/CFS. Lastly, we recommend that the ODP convene another ME/CFS Expert Panel in the 402 future to monitor progress. We hope our work has dignified ME/CFS and those affected, while 403 providing expert guidance to the NIH and the broader research community.