Drug Development for CFS and ME: Public Workshop

Drug Development for CFS and ME: Public Workshop April 26, 2013 Bethesda Marriott 5151 Pooks Hill Road, Bethesda, MD 20814 1 Welcome RADM Sandra Kweder, MD Deputy Director, Office of New Drugs Center for Drug Evaluation and Research U.S. Food and Drug Administration 2 FDA Workshop: Drug Development for Chronic Fatigue Syndrome and Myalgic Encephalomyelitis Drug Development Scientific Workshop April 26, 2013 RADM Sandra Kweder, MD Deputy Director, Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration 3 Objectives Listen and learn Day 1 · To engage patients and patient representatives · Most significant symptoms and negative impacts of disease · Range of therapies Day 2 · Examine common issues in drug development · Consider tools scientific and regulatory Move forward! 4 Chronic Fatigue Syndrome · Serious, complex, and debilitating disease · Unknown etiology · Characterized by profound fatigue >6 months duration; worsened by physical or mental activity · Multiple body systems affected · No diagnostic tests · No approved therapies · Lack of consensus on nomenclature and disease definition 5 Nomenclature · Chronic Fatigue Syndrome and Myalgic Encephalomyelitis (CFS and ME) Disease definition · Drug development 6 CDER's Mission ....promote and protect the public health by assuring that safe and effective drugs are available to Americans ...Careful judgment applied to scientific assessment of risk and benefit balance. 7 Marketed drugs: Balance of Safe & Effective · Safe Risks are managed Quality is assured Advertising is appropriate Information is available · Effective Studied with proper endpoints & standards Drugs of today not a century ago Quality is maintained Code of Federal Regulations Safe and effective for their Intended use in the intended population 8 Who does the work and who makes the decisions? · FDA regulations began as interstate commerce Companies who intend to market drugs usually fund their development Engage academic and community researchers to conduct the studies · FDA oversees drug development Assures safety and that appropriate regulations are being followed to protect patients Work with "sponsors" · Review their strategies, protocols for study, etc. · Review all findings when submitted to FDA for review NDA (New Drug Application) or BLA (Biologic License Application) 9 Review work incorporates FDA regulations, science and judgment Chemistry Animal toxicology Statisticians Physicians Clinical Pharmacology Plant inspectors Public Advisory Committees that include patient perspective 10 Between IND & NDA: What are we looking at? · Chemical composition · Animal studies first Is it safe to give to humans? · How will you assure their safety? What is the range of possible doses? What are you trying to show? · What are your plans for clinical trials? How do you know you have the optimal dose? How large should the clinical trials be? What will you compare the drug to and what study endpoints? · Multiple points of interface between FDA and industry sponsor Every clinical trial is addressed in detail Seek careful, well designed development program 11 The gold standard: Substantial Evidence of Effectiveness Adequate and well-controlled study: Study has been designed well enough so as to be able "to distinguish the effect of a drug from other influences, such as spontaneous change..., placebo effect, or biased observation" (§314.126) 12 Adequate and Well-Controlled Study Design · Permits a valid comparison with a control Concurrent: placebo, notreatment, active, dosecomparison Historical · Well defined patient population · Adequate measures to minimize bias · Methods of assessment of response are well- defined and reliable · Analysis of the results is adequate to assess the effects of the drug itself · This is straightforward when disease is well defined and has objective, established measures 13 Clinical trials matter a lot · Essential to assess the effect and safety of a drug · Measures matter Objective, easy to quantify, "signs" · Blood pressure; kidney function; viral counts in blood; MI; death · Available for most well understood diseases Subjective, "symptoms" · Pain; fatigue; weakness; headache; depression · All involve how the patient feels or functions · Complex to measure and quantify 14 What also matters is the patient · The disease frames scientific and regulatory considerations Greater need calls for greater attention to detail · Seriousness of disease shifts risk tolerance Creative use of regulatory tools It may call for utilization of novel endpoints in clinical trials they still need to be rigorous and validated · Regardless of disease, the standard of evidence is the same Adequate and well controlled trials establish safety and efficacy 15 Agenda · Panel 1--Drug Development: Innovation, Expedited Pathways, Regulatory Considerations · Panel 2--Symptoms and Treatments: A View from Patients and Clinicians · Panel 3--Clinical Trial Endpoints and Design · Panel 4--Summary and Path Forward · Closing Remarks 16 g{tÇ~ lÉâ4 17 Panel 1: Drug Development: Innovation, Expedited Pathways, Regulatory Considerations Moderator: RADM Sandra Kweder, MD Deputy Director, Office of New Drugs Center for Drug Evaluation and Research U.S. Food and Drug Administration 18 Background and Meeting Goals Sandra Kweder, MD 19 Drug Innovation and Derisking Drug Discovery Bernard Munos, MS, MBA Founder InnoThink Center for Research in Biomedical Innovation 20 How to energize innovation and de-risk drug R&D for CFS? InnoThink Bernard Munos Founder InnoThink Center For Research in Biomedical Innovation Washington, DC, April 26, 2013 21 The challenge How to develop treatments for a disease that is complex, poorly understood, and with multiple etiologies? 22 InnoThink Traditional drug R&D has not risen to the challenge · Dearth of translatable research · Lack of research infrastructure · "Fuzzy" disease routinely misdiagnosed · Treatments address symptoms · Ill-equipped regulators 23 InnoThink CFS needs an innovation supply chain Goal: make it easier, cheaper, and faster to work on CFS · Need data · Need tools · Need partners · Need money · Need leadership and passion 24 InnoThink Need data There can't be any science without data "If you think about the scientific revolutions in history, they've been driven by one thing -- the availability of data. From Copernicus to quantum mechanics, it's data that drives innovation." 25 InnoThink Need data · CFS is a complex disease. Disease heterogeneity magnifies data requirements · Need lots of data Patient registry (better international) Natural history data to understand disease progression and identify midpoints and endpoints that can be used in future clinical trials Genomic data · Such data collection is unlikely to be funded by industry · Technology makes it possible to collect high-quality data cheaply TLS' patient monitoring Patient-Like-Me Biosensors to track effort/mobility Phone/computer apps · Data must be available in free open-access to scientists 26 InnoThink If you build it, they will come · Example: Multiple Myeloma Research Foundation · Founded 1998 · Heterogeneous disease with many subtypes · Has raised $225m, sequenced the myeloma genome, opened 45 trials of 23 drugs--6 of which have approved by the FDA-- which have doubled the life span of multiple myeloma patients · Incidence: 4 per 100,000 (vs. 7 to 3,000 for CFS) 27 InnoThink Need tools There can't be much research without tools Tools leverage the value of data 28 InnoThink Need tools · Tools + data make up the basic research infrastructure · Need the tools of drug discovery, e.g., Tissue bank, animal models, biomarkers, assays Networking tools · Tool development is unlikely to be funded by industry · Technology makes it possible, even for small disease foundations, to fund such effort Chordoma Foundation · Tools must be available in free open-access to scientists 29 InnoThink If you build it, they will come · Example: Open-Source Drug Discovery Project · Launched 2008 · Over 6,000 scientists collaborating to develop new treatments for tuberculosis · Generate 65% of the published papers on TB · Runs on <$2m budget per year 30 InnoThink Need partners · Scientists Established scientific leaders Young investigators Physicians who treat patients · Companies Need to see IP and the outline of a drug · Regulators Need patients to help them understand the disease, assess risks and trade-offs, and improve the design of clinical trials 31 InnoThink If you ask them, they will respond · 80% of the time and cost of research projects is generating high-quality data The availability of such data is a major factor in de-risking R&D · Passion shortens timelines, lower costs, and raises the probability of success · It's more exciting to work with passionate people for whom failure is not an option 32 InnoThink Need money · Good news: it is getting cheaper! New research models make it possible (indeed advisable) to run ambitious research programs on a shoestring e.g., open-source, crowdsource, virtual pharma, public-private partnerships, prizes, drug repurposing, etc. · CFS community is larger than many rare disease communities with successful drug development programs 33 InnoThink Need leadership and passion · It's already there! · CFIDS created 1987 · Raised over $30m · Has already created the networks and some of the infrastructure required 34 InnoThink Thank you! Questions? (b hm unos@stanfordal um ni. org) 35 Knowledge and Intuition to Reposition Drugs for CFS Suzanne Vernon, PhD Scientific Director The CFIDS Association of America 36 Knowledge and Intuition to Reposition Drugs for CFS Suzanne D. Vernon, Ph.D. Scientific Director Development of Safe and Effective Drug Therapies for Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME) April 25-26, 2013 37 The CFIDS Association of America Leader in ME/CFS Translational Research Strategic shift in 2008 to bridge the "Valley of Death" Patient-centered research to de-risk and foster CFS drug R&D Our Innovation Pathway Build an infrastructure that makes it faster, easier and cheaper · SolveCFS BioBank 800 ME/CFS and healthy controls; partnered with pharma and 8 academic investigators since 2010 · Built a knowledgebase and data analysis/sharing platform · Our unique and extensive library, publications and knowledgebase New research avenues drug repurposing 38 Chronic Fatigue Syndrome (CFS) What's in a name? CFS, ME, ME/CFS, CFS/ME, CFIDS 6,000 publications in PubMed describing all aspects of CFS 1 million people in US, 17 million worldwide Risk factors, pathophysiology described $51 billion annual direct and indirect costs FDA considers CFS a "serious condition" Over the past 25 years, >$150 million spent Cause(s) have been elusive Lack validated biomarkers for diagnosis and treatment No regulatory framework for CFS No FDA-approved treatment No standardized, widely accepted clinical guidelines, symptom-based treatment 39 Drug Repurposing for CFS Immune Dysfunction HPA Dysfunction Energy Deficits Genomics Drug Candidates Postexertion Exhaustion Cognitive Impairments Sleep Fatigue Pain · Well suited to multifactorial diseases · Ideal for unmet medical need diseases where effective treatments are lacking and research spending is inadequate · Drug safety is known, this accelerates development and reduces costs 40 Clinical Outcomes Search Space (COSSTM) 29,000 clinical outcomes 25,000 human targets 90,000 compounds Extraction Engine RNA polymerase II CTD phosphorylation in some context A Unique Profile 41 COSSTM for Repositioning for CFS Identify novel drug candidates for the treatment of CFS Bibliographic knowledge on CFS pathophysiology and symptoms Identify biomarkers that may be used to monitor the response to treatment Relevant to CFS pathophysiology and drug mechanism of action (MoA) Use existing data including the SolveCFS BioBank to evaluate/validate 42 Correlation of Drugs with Symptoms · The drugs that correlated with CFS symptoms and pathophysiological mechanisms that are related to the regulation of neurotransmitters (mostly monoamines) · In order of decreasing bibliographical association: Serotonin > Dopamine > Acetylcholine > Histamine >= Epinephrine. 43 eHealthMe Adverse Events and Chronic Fatigue · Serotoninergic & noradrenergic drugs associated with exhaustion · frequency of exhaustion co-reported with the drugs shown on the horizontal axis is represented by the orange graph (right vertical axis). · frequency of chronic fatigue that is co-reported with each drug is represented by the blue graph (left vertical axis) 44 Adverse Events and Chronic Fatigue · Frequency of fatigue reports from eHealthMe and AERS for selected drugs · Red indicates drugs that are used by CFS patients as reported in the SolveCFS BioBank 45 Summary of Results using COSSTM · CFS symptoms and pathophysiology correlate with the known mechanisms neurotransmitters as described in the biomedical literature · Counterintuitive observation: Serotoninergic and noradrenergic drugs cause fatigue more frequently than neuroleptics. Fits with "Central Fatigue Hypothesis" · Drug repurposing using the COSSTM platform has identified a two drugs that target at least 2 CFS symptoms · The knowledge-based identification of these drugs was validated by patient-reported data from the SolveCFS Biobank data and clinical intuition data (shown next) · Currently designing a proof-of-concept clinical trial to test these drugs as a combination therapy 46 Capturing Clinical Intuition "...But the key is that a lot of the research in this to date have been out there on their own. They're clinicians who are following a series of patients for decades. And no one's been able to tap into the kind of information that they have ..." Dr. Kweder, 9/13/2012 Stakeholder Teleconference · The CFIDS Association and Biovista created a web-based tool to investigate three main areas: Efficacy of drugs currently used in the treatment of CFS symptoms Alternative treatment options (nutritional supplements, fluids, pacings, etc.) Treatment strategies: How are symptoms interrelated? Which symptoms are more important to treat first? Depression/Anxiety Muscle Aches Arthralgia Sleep Problems Pelvic Pain Bladder Pain Light/Sound Sensitivity Orthostatic Hypotension POTS Bowel Difficulties Headache Nausea/Vertigo Fatigue (Post Exertional Malaise) Brain Fog Sore Throat Dyspnea Fever/Chills Lymph Node Enlargement Urinary Frequency 47 Very Effective Moderately Effective Somewhat Effective Minimally Effective Not Effective Clinical Intuition Results Depression/Anxiety Muscle Aches Arthralgia Sleep Pelvic pain Bladder pain Light/Sound Orthostatic hypotension POTS Bowel difficulties Headache Nausea/Vertigo Fatigue/PEM Brain fog Sore throat Dyspnea Fever/chills LN enlargement Urinary frequency 48 Clinical Intuition Validates Published Knowledge · Drugs identified as moderate to very effective for treating specific symptoms (sleep, pain, fatigue) were those identified using the Biovista COSSTM platform based on correlations of symptoms and drug MoA. · Vitamin B12 injections were reported as moderate to very effective for treating brain fog, although effect is transient · Gut microbiome differences between CFS and matched controls. · Biovista COSS platform and clinicians identify 2 predominant CFS phenotypes: Immune - sore throat, lymph node enlargement, fever and chills Autonomic - fatigue, post-exertional malaise, non-restorative sleep, pain, headache, cognitive problems, and orthostatic intolerance are thought to be inter-related symptoms Clinicians identified young versus older CFS patients clear subtype 49 Drug Development Survey Survey the patient community to gather responses to questions posed by the 20 questions posed by the FDA · open-ended text responses Questions were related to disease impact, symptoms and treatment Analyzed using Part-of-Speech parsing, word-sense disambiguation by matching UMLS concept IDs followed by PCA and bi-clustering. 50 Drug Development Survey 51 Pain Muscle, lumbar, abdominal, facial, back eye, neck, chest, general body pain, joint, stomach exhaustion arthralgia malaise weakness, spasms, food sensitivities sore throat Patient Survey Results muscle pain exhaustion, sickness, headache joint pain, post-exertion malaise, fatigue, sore throat, brain fog Non-drug therapies Nutritional therapies Diet modification Anti- inflammatory drugs Pain Prednisone Migraines Activity modification 52 Next Steps Drug repurposing · Document preparation to request a pre-IND meeting for proof-of-concept (PoC) clinical trial for a combination therapy for ME/CFS · Use SolveCFS BioBank participants for PoC trial Optimize clinical intuition platform and expand use · Attempt to understand patient phenotype and co- morbid conditions Operationalize patient-centered passive and active data collection 53 The Physicians and Providers ME/CFS Patients, Family and Friends Thank you! 54 Drug Development and Review: FDA's Expedited Programs for Serious Conditions Melissa Robb Associate Director for Regulatory Affairs Office of Medical Policy Initiatives Office of Medical Policy Center for Drug Evaluation and Research U.S. Food and Drug Administration 55 Drug Development and Review: FDA's Expedited Programs for Serious Conditions Melissa Robb Associate Director for Regulatory Affairs Office of Medical Policy Initiatives, CDER, FDA CFS and ME Workshop April 26, 2013 56 Disclosure · I have no relevant financial relationships to disclose. 57 Background Longstanding FDA goal to facilitate and expedite development and review of new drugs to address unmet medical need for serious conditions · Existing Programs Subpart E regulations (1988) - speeding the availability of new therapies for serious conditions with unmet medical need, while maintaining safety and efficacy standards Accelerated Approval Regulations (1992) Fast Track (1997) Priority Review (1992) 58 FDASIA (2012) Title IX · Reinforces FDA commitment to expedited development · Clarifies Accelerated Approval requirements · Creates Breakthrough Therapy provision · Requires FDA to issue draft guidance On accelerated approval by July 2013 On breakthrough therapy designation by January 2014 59 How FDA Expedites Drug Development and Review · Four expedited programs Fast track designation Breakthrough therapy designation Accelerated approval Priority Review 60 Common Terms · Serious conditions - associated with morbidity that has substantial impact on day-to-day functioning. Includes life- threatening conditions. · Seek to satisfy an unmet medical need by showing an advantage over available therapy (existing therapy, alternative treatment), if one exists. 61 Fast Track Designation · Criteria Serious condition Nonclinical or clinical data demonstrate the potential to address unmet medical need · Features Actions to expedite development and review · Meetings with FDA to discuss study design and requirements for marketing approval Rolling review allows for earlier submission and initiation of review 62 Breakthrough Therapy Designation · Criteria Serious Condition Preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development · Features Intensive guidance on efficient drug development Organizational commitment · Involving senior managers and experienced review staff · Assigning a cross-disciplinary project lead to facilitate efficient review 63 Accelerated Approval · Existing regulations- 21 CFR part 314, subpart H, and part 601, subpart E · FDASIA provides additional flexibility and clarity to the accelerated approval pathway Flexibility: Approval takes into account the availability or lack of alternative treatments Clarity: Approval can be based on aclinical endpoint (intermediate clinical endpoint) that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit. 64 Accelerated Approval · Criteria Serious condition Meaningful therapeutic benefit over available therapies Demonstrates an effect that is reasonably likely to predict clinical benefit or an effect on an endpoint that can be measured earlier that is reasonably like to predict an effect · Features Shortens time to approval 65 Accelerated Approval · Uses Long disease course and extended period of time to measure clinical benefit of drug Effect on surrogate or intermediate clinical endpoint occurs rapidly · Examples Cancers HIV · Requirements Promotional materials Postmarketing confirmatory trials 66 Priority Review Designation · CDER Criteria Demonstrates potential to be a significant improvement in safety or effectiveness · Features Marketing application reviewed in 6 months (compared to 10 months for priority review) 67 Tools and Approaches for Expedited Development · Early communication between sponsor and FDA · Flexible drug development programs that enable shorter, smaller, or fewer studies · Emphasis on regulatory science 68 Looking Forward · Anticipate draft guidance will publish July 2013 · Comment period · Develop final guidance (FDASIA goal dates) 69 Resources · Fast Track, Accelerated Approval and Priority Review http://www.fda.gov/ForConsumers/ByAudience/ForPatientA dvocates/SpeedingAccesstoImportantNewTherapies/ucm128 291.htm · Fact Sheet: Breakthrough Therapies http://www.fda.gov/RegulatoryInformation/Legislation/Fede ralFoodDrugandCosmeticActFDCAct/SignificantAmendmentst otheFDCAct/FDASIA/ucm329491.htm · FY 2012 Innovative Drug Approvals http://www.fda.gov/downloads/AboutFDA/ReportsManualsF orms/Reports/UCM330859.pdf 70 Panel 1: Audience Question and Answer Period All Panelists 71 Break 10 Minutes CHERRY BLOSSOMS ON THE TIDAL BASIN 72 Panel 2: Symptoms and Treatments: A View from Clinicians and Patients Moderators: Nancy Klimas, MD, FACP, FIDSA Chair, Department of Clinical Immunology Director, Institute of Neuro-Immune Medicine Nova Southeastern University Theresa Michele, MD Clinical Team Leader Division of Pulmonary, Allergy, and Rheumatology Products Office of Drug Evaluation II, Office of New Drugs Center for Drug Evaluation and Research U.S. Food and Drug Administration 73 Panel 2: Symptoms and Treatments: A View from Clinicians and Patients · Lucinda Bateman, MD Fatigue Consultation Clinic, Salt Lake City, Utah · Lisa Corbin, MD, FACP Associate Professor, Division of General Internal Medicine, University of Colorado Denver School of Medicine · Lily Chu, MD, MSPH International Association for CFS/ME, Patient · Jose Montoya, MD, FACP, FIDSA Professor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine · Jennifer Spotila, JD Patient · Christine Williams, MEd Patient 74 Panel 2: Question 1 · What were your key takeaway messages from the discussion yesterday on the most significant symptoms experienced by patients with CFS and ME? Please describe any significant differences in your experiences as clinicians and patients compared to yesterday's discussion. 75 Panel 2: Question 2 · Based on your expertise as clinicians and experience as patients, which symptoms of CFS and ME could be identified as valid, quantifiable and reliable outcome measures or endpoints in clinical trials to evaluate potential drugs to treat CFS and ME? 76 Panel 2: Question 3 · What are the key factors you take into account when making decisions to prescribe (as clinicians) or use (as patients) therapies to treat symptoms associated with CFS and ME? 77 Panel 2: Question 4 · Are there candidate agents that you think particularly warrant exploration in clinical trials? If so, what endpoints do you think would be most valuable to study in association with the product(s)? 78 Panel 2: Audience Question and Answer Period All Panelists 79 Lunch 1 Hour CHERRY BLOSSOMS ON THE TIDAL BASIN 80 Panel 3: CFS and ME Clinical Trial Endpoints and Design Moderators: Jordan Dimitrakoff, MD, PhD Assistant Professor Tufts University Boston, MA Edward Cox, MD, MPH Director Office of Antimicrobial Products Office of New Drugs Center for Drug Evaluation and Research U.S. Food and Drug Administration 81 Clinical Trial Designs in CFS Peter Rowe, MD Professor of Pediatrics Johns Hopkins University School of Medicine Director Chronic Fatigue Clinic Johns Hopkins Children's Center 82 Clinical Trial Design in CFS Peter C. Rowe, MD Professor of Pediatrics Sunshine Natural Wellbeing Foundation Professor of Chronic Fatigue and Related Disorders Director, Pediatric CFS Clinic Johns Hopkins University School of Medicine, Baltimore, MD 83 · Clinical trials in CFS from 1988-2013: What has and hasn't worked? Lessons from specific trials · What is the ideal patient population? Lessons from other illnesses Lessons from CFS and FM studies · What is the ideal endpoint? · Potential designs to decrease heterogeneity 84 · Randomized crossover study of 27 with CFS (8M/19F) · Mean duration of CFS 6.8 years · All underwent clinical evaluation at NIH · Subjects had to meet 1988 CDC criteria for CFS · To select a group with an improved likelihood of treatment response, eligible subjects had to have titers > 1:40 of antibodies to EBV EA. 85 INTERVENTION · Each received IV acyclovir q8h for 7 days (500 mg/M2) or placebo, then 30 days of outpatient therapy with 800 mg q8h or placebo. · Outcomes: daily energy level, wellness score (0-100), temp; weekly POMS for fatigue, vigor, anger, depression, anxiety 86 RESULTS · 3/27 developed renal failure with IV acyclovir and were withdrawn · 21/24 who completed the study rated themselves as improved during one stage of the study or the other · 11 felt better during acyclovir phase, 10 during placebo · Anxiety, depression significantly worse during acyclovir treatment phase · Wellness score worse during acyclovir phase (mean difference of -1.08 ± 3.01; P > .5) 87 SYSTEMATIC REVIEWS OF TREATMENT Whiting P, et al. JAMA 2001;286:1360-8 Chambers D, et al. J Royal Soc Med 2006;99:506-20. · By 2006, 56 randomized and 14 non-randomized controlled clinical trials were included in review Category Examples Behavioral CBT, GET, Rehab Immunological Acyclovir, IVIG, Staph toxoid, Inosine pranobex, Terfenadine Corticosteroids Hydrocortisone, fludrocortisone Other pharmacologic Fluoxetine, galantamine, NADH, GH, Dextroamphetamine Complementary Massage, EFA, carnitine, liver extract 88 SYSTEMATIC REVIEWS OF TREATMENT: MAIN FINDINGS Chambers D, et al. J Royal Soc Med 2006;99:506-20. · A number of RCTs suggest that CBT, GET, and rehab may reduce symptoms and improve physical function · Immunologic and anti-viral treatments may have beneficial effects but also can be associated with harmful side effects · Most pharmacological treatments have not shown beneficial effects 89 CFS TRIALS: THE CHALLENGE OF HETEROGENEITY Onset Abrupt/infectious Gradual Co-morbidities Pain/FM Migraine, IBS, TMD, dysmenorrhea Allergies Orthostatic intolerance Joint hypermobility Anxiety/depression 90 CFS TRIALS: THE CHALLENGE OF HETEROGENEITY · Heterogeneity can be reduced by careful subject selection, clear case definition and eligibility criteria (especially for subsets) · Flares in co-morbid illnesses can occur in RCTs and have the potential to obscure treatment effects · Given the heterogeneity of CFS and OI, studies of single agents will need large sample sizes 91 SF-36 Physical Function Score in CFS Patients with and without milk sensitivity 55 Non-Milk Sensitive 50 Milk Sensitive SF-36 Physical Fx Score 45 40 35 30 initial 12 months Johns Hopkins Pediatric CFS Cohort Study Study Visits 92 SAMPLE SIZES IN EARLY NEGATIVE TRIALS · Acyclovir · IVIG · IVIG · Terfenadine · HC · HC · Phenelzine · Fludrocort Crossover RCT RCT RCT RCT Crossover RCT Crossover N=27 (24) per group N=15 per group N= 23 IVIG, 26 placebo N=15 per group N=35 per group N=32 per group N=12 per group N=25 per group 93 SAMPLE SIZE IN POSITIVE TRIALS Pregabalin in FM N=529 131 placebo 132 pregabalin 150 mg daily 134 pregabalin 300 mg daily 132 pregabalin 450 mg daily 1o outcomes: Daily pain scale (0-10) 21.4% had > 30% improvement (P < .003) 94 Pregabalin for the treatment of fibromyalgia syndrome: Results of a randomized, double-blind, placebo-controlled trial Arthritis & Rheumatism Volume 52, Issue 4, pages 1264-1273, 7 APR 2005 DOI: 10.1002/art.20983 http://onlinelibrary.wiley.com/doi/10.1002/art.20983/full#fig2 95 SAMPLE SIZE IN SUCCESSFUL TRIALS PACE study N=641, ~ 160 per group 1o outcomes: SF-36 physical function (0-100) Chalder fatigue scale (0-33) 2o outcomes: Clinical Global Impression Scale Work and Social Adjustment 6 minute walk Sleep, HADS, CFS symptoms, PEM 96 PACE TRIAL RESULTS Specialist Medical Care (SMC) vs. SMC + CBT SMC FATIGUE Baseline 28.3 52 weeks 23.8 Mean Difference % improved by 2 points 65% SF-36 PHYSICAL FUNCTION Baseline 39.2 52 weeks 50.8 Mean Difference % improved by 8 points 58% SMC + CBT P 27.7 20.3 - 3.4 < .001 76% 39.0 58.2 + 7.1 .001 71% 97 12 wks 24 wks 52 wks White PD et al. PACE trial. Lancet 2011 98 JHU: PC Rowe, K DeBusk, H Calkins, S Snader NIH: R McKenzie, G Sharma, N Soto, P Hohman, B Cuccherini, S Straus Supported by grant AI 39500 (Dr. Rowe), GCRC RR00052, and the CFIDS Assoc. of America to the JHU investigators 99 16 year old with fatigue Healthy and active until 9 mo. before visit Insidious onset of fatigue Sleeps 12 hrs per night, awakens unrefreshed Has to lie down after showering Has to lie down the day after an active day Difficulty concentrating, muscles sore, HA, LH Unable to attend school 100 16 year old with fatigue · On exam: · Standing test: · Tilt test: · Diagnosis: · Treatment: Acrocyanosis HR 80 121 in 10 min Symptoms: fatigue, warmth, LH, nausea, diaphoresis Presyncope at 17 minutes BP 117/81 78/48 (HR 70) CFS, POTS, NMH Increased salt and fluid intake Fludrocortisone, potassium 101 16 year old with CFS: Early Follow-up · Improvement in all symptoms within 2 wks · Began working 2 jobs, feeding livestock at family farm, able to spend time with friends · Full school attendance · Fatigue only after 45 minutes of swimming · Standing test on Florinef: HR 76 to 86 after 10 min 102 STUDY QUESTION Will individuals with CFS and NMH have a greater improvement in (1) self-reported well being (2) objective orthostatic tolerance 9 weeks after starting treatment with fludrocortisone than they will after starting placebo? 103 INCLUSION CRITERIA · Age 18-50 yrs · Satisfy 1994 Fukuda criteria for CFS · Have undergone an evaluation to exclude other causes of chronic fatigue · Hypotension during stage 1 or 2 of HUT · At least moderate severity of symptoms at baseline · Able to walk without assistance 104 STUDY DESIGN · Randomized, placebo-controlled, double-blinded · Stratified by center and by disease duration (< 3 yrs vs > 3 yrs) · Fludrocortisone 0.025 mg/d for week 1, then 0.05 mg for week 2, then 0.1 mg/d X 7 weeks. · Fluid intake 2 L/d · All patients received potassium chloride 10 mEq/d, and were asked to remain on usual sodium intake 105 STUDY DESIGN Fludro Tilt 1 R Tilt 2 Week Assessments Placebo Off meds 1 2 3 4 5 6 7 8 9 10 11 X X X 106 OUTCOME MEASURES: PRIMARY · % with a clinically important 15 point improvement in well being, as measured by the global Wellness Score: "How have you felt over the past 24 hours?" "For the wellness score, record a number between 0 and 100 (0=dying, 100=the best you can imagine a person to feel)." · Recorded daily throughout the study 107 OUTCOME MEASURES: SECONDARY · Changes in symptom scores Profile of Mood States Wood Mental Fatigue Inventory Duke Activity Status Index Beck Depression Inventory SF-36 · % tolerating one further stage of tilt · Adverse effects 108 SAMPLE SIZE ASSUMPTIONS · 15-point change in global Wellness score is clinically meaningful · 35% with 15-point improvement in treatment group · 10% with 15-point improvement in control group · alpha 0.05, Beta 0.20 · Sample size: N=100; 50 per group 109 CLINICAL FEATURES AT ENTRY Characteristic Age Female (%) Working (%) Duration of CFS CFS > 3 yr (%) Placebo N=50 37.3 (9.3) 66 53 6.0 (4.9) 72 Fludrocortisone P N=50 36.2 (7.4) .50 66 1.00 56 .84 6.9 (6.4) .40 70 .83 110 RESULTS: PRIMARY OUTCOMES Improvement Placebo Fludro P in Wellness 5-point 10-point 15-point 20-point Mean change 34% 28% .52 12% 18% .58 10% 14% .76 6% 10% .72 2.7 (10.0) 3.8 (11.5) .71 111 RESULTS: SECONDARY OUTCOMES No differences between groups in: WMFI, BDI, DASI POMS vigor or fatigue subscales SF-36 physical function or mental health Supine HR, SBP, DBP at 2nd tilt Normal tilt in week 9 (9/41 vs 4/33) Outcome by center Adverse events 112 CONCLUSION · Fludrocortisone is not efficacious when used alone for treating NMH in adults with CFS 113 The PI returns to the clinic . . . 114 16 yr old with CFS: 10 year Follow-up · After RCT, any attempt to wean Florinef was associated with the return of impressive fatigue, despite good level of exercise and physical conditioning · Off Florinef: wellness 50-70/100 On Florinef: wellness 85-90/100 115 How to reconcile the study results and the clinical observations? 116 CLINICAL FEATURES AT ENTRY Characteristic Age Female (%) Working (%) Duration of CFS CFS > 3 yr (%) Placebo Fludrocortisone P N=50 N=50 37.3 (9.3) 36.2 (7.4) .50 66 66 1.00 53 56 .84 6.0 (4.9) 6.9 (6.4) .40 72 70 .83 117 RESULTS: SUBGROUP ANALYSES (defined before unblinding) Feature CFS < 3 yrs Age < 30 yrs N with 15-point improvement Placebo Fludrocortisone 0/14 4/15 0/9 3/12 Patients with prolonged CFS may be more refractory to treatment; 71% had CFS > 3 years. 118 · Clinical trials in CFS from 1988-2013: What has and hasn't worked? Lessons from specific trials · What is the ideal patient population? Lessons from other illnesses Lessons from CFS and FM studies · What is the ideal endpoint? · Potential designs to decrease heterogeneity 119 Influence of Past Treatment Resistance on Future Treatment Response* Patients (% of total) Response 60 Remission 50 40 [ *10 weeks of open label VNS + pharmacotherapy ] 30 20 10 2-3 (n=21) 4-5 (n=17) 6-7 (n=8) >7 (n=13) Number of Failed ATHF - Qualified Trials (n) Sackeim, et al (2001) 120 Slide courtesy of MA Demitrack Acute Outcome Worsens with Increasing Number of Prior Treatment Failures No or Limited Prior Rx Three One Prior Two Prior Prior Failure Failures Failures % Remission Rate (HAMD 17) Sample Size (N): 2876 727 221 Trivedi et al. (Am J Psychiatry, 2006); Rush et al. (NEJM, 2006); Fava et al (Am J Psychiatry, 2006); McGrath et al (Am J Psychiatry, 2006) 58 Slide courtesy of MA Demitrack 121 CFS STUDY SUBJECTS "...because CFS by definition develops after a substantial period of time has elapsed, and as many treatment studies have obtained treatment samples based on self or clinician referral to tertiary care medical centers, the populations under study often represent patients who are among the more refractory to any further treatment intervention." Demitrack MA, Pharmacogenomics 2006;7 (3):521-8. 122 NEW ONSET CASES FOR CFS STUDIES? observations from studies with positive findings STUDY DURATION OF ILLNESS PACE trial (CFS) 2.7 yrs (1.3-5.7) Rituximab trial (CFS) 5.1 yrs Rituximab 8.1 yrs placebo (P=.09) Dextroamphetamine trial (CFS) 7.1 yrs Dexamphet 5.6 yrs placebo Pregabalin (FM) 8.5 yrs Milnacipran (FM) 4.1 yrs 123 · Clinical trials in CFS from 1988-2013: What has and hasn't worked? Lessons from specific trials · What is the ideal patient population? Lessons from other illnesses Lessons from CFS and FM studies · What is the ideal endpoint? · Potential designs to decrease heterogeneity 124 e OPEN ACCESS Freelyavailable onllne :~.· p1os one Benefit from B-Lymphocyte Depletion Using the Anti CD20 Antibody Rituximab i1n Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study 0ystein Fluge1*, Ove Bruland 1 ·2 , Kristin Risa1, Anette Storstein3, Einar K. Kristoffersen4 , Dipak Sapkota1 , Ha Ivor Ncess3 , Olav Dahl1 '5 , Harald Nyland3 , Olav Mella1 ' 5 1 Department of Oncology and Medical Physics, Haukeland Uni versity Hospital, Bergen, Norway, 2 Department of Medi cal Genetics and Molecular Medicine, Haukeland Univ ersity Hospital, Bergen, Norway, 3 Department of Neurology, Haukeland Univ ersity Hospital, Bergen, Norway, 4 Department of Immunology and Transfusion Medi cine, Haukeland Univ ersity Hospital, and The Gade Inst itute, Univ ersity of Bergen, Bergen, Norway, 5 Inst itute of Internal Medicine, Section of Oncology, Uni versity of Bergen, Bergen, Norway October 20 11 Vo lume 6 Issue 10 e26358 125 OUTCOME MEASURES: PRIMARY · Baseline VAS symptoms 1= no symptom, 10=very severe symptom · Follow-up VAS of change in last 2 weeks vs. baseline: 0 Major worsening 1 Moderate worsening 2 Slight worsening 3 No change 4 Slight improvement 5 Moderate improvement 6 Major improvement · Fatigue score calculated as mean VAS for Fatigue, Post-exertional exhaustion, need for rest, daily functioning 126 Clinical responses in the Rituximab and Placebo groups, and response durations for patients with significant responses, derived from self-reported fatigue scores during 12 month follow-up. Rituximab Placebo P N=15 N=15 Clinical Major responses 9 (60%) 1 (7%) .002 Moderate 1 (7%) 1 (7%) Overall (%); 10 (67%) 2 (13%) .003 95% CI (41-85%) (4-38%) Response duration in wks, mean (range) 25 (8 - > 44) 41 (34 - > 48) n=10 n=2 127 CFS STUDY ENDPOINTS · VAS scores of fatigue and specific CFS symptoms (including frequency and severity/impact) · Fatigue scale · Measures specific to outcome of interest · General QOL measure · Activity measure (questionnaire or mean # steps/day) · Functional measure (work/school attendance) · Global Clinical Measure of Change (patient) · Global Clinical Measure of Severity (clinician) 128 · Clinical trials in CFS from 1988-2013: What has and hasn't worked? Lessons from specific trials · What is the ideal patient population? Lessons from other illnesses Lessons from CFS and FM studies · What is the ideal endpoint? · Potential designs to decrease heterogeneity 129 DESIGNING CFS TRIALS TO ACCOUNT FOR PHENOTYPIC HETEROGENEITY Larger studies needed to detect signal from noise caused by co-morbid disorders Different trial strategies Stratification to address duration of illness, subsets Run-in periods for treating co-morbid disorders or identifying responders Randomized trials of withdrawing ostensibly effective therapies Crossover designs N-of-1 trials 130 Undifferentiated CFS/ME Current approach Randomization Intervention Placebo Outcomes 131 Undifferentiated CFS/ME Randomization Run-in treatment Run-in active treatment period General: CBT, graded exercise Specific: treat and stabilize co- morbid conditions (e.g, allergies, migraines) Intervention Placebo Outcomes 132 Undifferentiated CFS/ME Randomized withdrawal of meds Open treatment success with hypothesized effective medication Randomization Withdraw medication Continue medication Outcomes 133 Undifferentiated CFS/ME Randomization Intervention Placebo Crossover Period 1 Intervention Washout Placebo Period 2 134 Undifferentiated CFS/ME Enrichment approaches Select drug responders, placebo non- responders Identify sub-groups expected to respond (e.g, those with OI, infectious onset) Randomization Intervention Placebo Outcomes 135 SELECTED REFERENCES · Robert Temple. Enrichment strategies. FDA/DIA Statistics Forum. April 25, 2012. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov- afda-orgs/documents/document/ucm303485.pdf · Demitrack MA. Clinical methodology and its implications for the study of therapeutic interventions for chronic fatigue syndrome: a commentary. Pharmacogenomics 2006;7:521- 8 136 ACKNOWLEDGEMENTS · Grants from NIAID, DoD, CFIDS Association of America · Sunshine Natural Wellbeing Foundation (endowed Chair) · Volunteer RA Colleen Marden · Summer students (John Fan, Alli Johns, Marissa Flaherty, Jocelyn Ray, Samantha Jasion, Erica Cranston) · Many families and patients: Special thanks to the following: Boies, Cornell, Smith, Caldwell, Newbrand, Kelly, Kiely, McFerron Megan Lauver, Hannah Vogel 137 Repeated CPET Results as Clinical Endpoints for ME/CFS Research Christopher Snell, PhD Professor Health, Exercise and Sport Sciences University of the Pacific 138 Repeated CPET Results as Clinical Endpoints for ME/CFS Research Christopher Snell, PhD., Staci Stevens, MA., Mark VanNess, PhD. & Brian Moore, PhD. Workwell Foundation Clinical Services www.workwellfoundation.org 139 Assessing Function Vs 140 Asking the Right Questions Exercise testing is a noninvasive procedure that provides diagnostic and prognostic information and evaluates an individual's capacity for dynamic exercise. American Heart Association 141 Value of Exercise Testing Organs and organ systems have built-in reserve capacity Disease states reduce this capacity In the absence of stress, reduction in functional capacity isn't always seen Exercise is an effective way to induce stress 142 Stressing the System jogging 143 What is goal of exercise testing? Assess function of the cardio-respiratory system Determine functional capacity Focus on aerobic capacity 144 Energy Production Two Main Energy Liberation Systems: Aerobic Metabolism - oxygen dependent - very efficient - time intensive - predominates at lower workloads - CO2 is byproduct Anaerobic metabolism - No oxygen needed - Contributes more at higher workloads - 2 ATP per glucose vs. 30-36 - Lactic acid is byproduct Exercise Intensity 145 Why the fuss over Lactic Acid? H+ Lactic Acid Lactate Altered muscle and blood pH! · Pain · Reduced muscle function · Altered enzyme activity · Cessation or reduction in activity 146 Quantifying Aerobic Capacity VO2 MAX Anaerobic Threshold Maximum amount of oxygen system can deliver and combust (L/min). AKA maximal oxygen consumption. The level of exercise oxygen consumption above which aerobic energy production is supplemented by anaerobic mechanisms. Both VO2Max and Anaerobic Threshold (AT) can be determined: 1) Directly measured during a graded exercise test · Gas exchange techniques · Measurement of blood lactate levels 2) Indirectly estimated by recording HR response or onset of fatigue during a graded exercise test and apply regression equations developed from study populations 147 Modes of Testing Aerobic Capacity with a Graded Exercise Test Field tests Cooper 12-minute test Rockport One-Mile Fitness Walking Test 6 minute walk test Step tests Treadmill tests Cycle ergometer tests 148 Field Tests 149 Field Tests Advantages Easy to administer Ability to test many individuals at once Require minimal equipment Disadvantages Unmonitored BP and HR Aerobic capacity is estimated. May result in inadvertent max testing in some populations Motivation and pacing plays a big role in results 150 Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial* 6-min walking test n=110 (69%) Baseline distance 341 yards 52-week distance 414 yards 1.9-2.3 mph *White, et al. The Lancet, 377:9768, 823-836, March 2011 151 1.9 mph vs 2.3 mph 2 Mets = 7ml/min/kg O2 Weber/NYHA Severely Disabled 152 Treadmill Cycle Ergometer Step Test 153 Indirect Estimation of Aerobic Capacity Employ regression equations derived from experimental data to estimate Vo2max and anaerobic threshold from performance on field tests, step tests, treadmill or ergometer 154 Limitations of Indirect Assessment May not apply to special populations/disease states Biased by tested population Biologic variability of heart rate response to exercise Dangers of using regression models outside tested values Assumptions must be made Steady state of HR achieved during exercise Linear relationship between measured variable and VO2 Response for given age group is uniform Mechanical efficiency is same for every individual Individual is not on medications that affect measured variable 155 May not apply in Disease "Mild exercise led to rapid fatigue, with hyperventilation and disproportionate tachycardia." Cardiovascular and Metabolic Responses to Exercise in a Patient with McArdle's Syndrome, Daniel Porte, Jr., M.D., N Engl J Med 1966; 275:406412August 25, 1966 "In conclusion, the association of an abnormal stress response with nonmetabolic factors, including backscatter and blunted peak heart rate..." Usefulness of at rest and exercise hemodynamics to detect subclinical myocardial disease in type 2 diabetes mellitus. Jellis CL, Am J Cardiol. 2011 Feb 15;107(4):615-21. Epub 2010 Dec 31. 156 Biologic Variability of Heart Rate "SRBD is associated with reduced physical working capacity and a modified hemodynamic response to exercise." The heart rate response to exercise is blunted in patients with sleep-related breathing disorder. Grote L. Cardiology. 2004;102(2):93-9. Epub 2004 Apr 19 Variables affecting heart rate response Medications Ambient temperature Environmental noise Body temperature Elevation Time of day Illness 157 Biased by Tested Population "These findings demonstrate that a novel treadmill-based PRET can yield predictions of VO2max that are acceptably reliable and valid amongst young, healthy, and active adults." The validity and reliability of predicting maximal oxygen uptake from a treadmill-based sub-maximal perceptually regulated exercise test. Morris M, Eur J Appl Physiol. 2010 Jul;109(5):983-8 "These results indicate that a four minute aerobic dance test provides a valid and reliable sub-maximal protocol for estimating VO2max and providing an index of aerobic fitness in apparently healthy 18 to 40 yr old females." A test to estimate VO2max in females using aerobic dance, heart rate, BMI, and age.Olson MS, J Sports Med Phys Fitness. 1995 Sep;35(3):159-68. 158 Regression Modeling Limitations Linear relationship may break down outside of a specified range 159 Direct Assessment of Aerobic Capacity Maximum Oxygen Consumption (VO2max) Anaerobic Threshold (AT) 160 Principles of Gas Exchange Aerobic metabolism burns O2 and produces CO2 By measuring the difference between inspired and expired gases, it can be determined how much O2 is consumed and how much CO2 is produced 161 Maximal Oxygen Uptake VO2 max is strongly correlated with endurance performance capability Dependent on cardiovascular limitations; ability of heart, lungs, and circulatory system to deliver O2 to working muscle VO2Max 162 Anaerobic Threshold Exercise intensity above which aerobic metabolism is significantly supplemented by anaerobic energy production. Can be identified through measuring gas exchange Anaerobic Threshold Exercise Intensity 163 Measuring AT with Gas Exchange Respiratory Exchange Ratio RER (R) CO2 Produced O2 Consumed 164 Measuring AT with Gas Exchange AT 165 Accuracy of Direct vs Indirect Measurements of Aerobic Capacity Indirect estimates of VO2max can routinely vary by + 25% Ventilatory threshold is highly correlated to blood lactate threshold and aerobic performance. Measuring gas exchange allows you to accurately and reliably determine effort 166 Respiratory Exchange Ratio (VCO2:VO2) This physiological response to exercise is consistent in apparently healthy subjects and all patient populations, which makes peak RER the most accurate and reliable gauge of subject effort. A peak RER of 1.10 is generally considered an indication of excellent subject effort" Circulation. 2010;122:191-225. © 2010 American Heart Association, Inc. 167 Summary Determining aerobic capacity is crucial when assessing level of function. Oxygen uptake and anaerobic threshold are two parameters that are closely correlated to aerobic performance. Direct measurements of aerobic capacity are much more accurate, especially in special populations and disease states. 168 Moderate to Severe Impairment in CFS/ME Severity of Impairment Peak VO2 (ml/kg/min) # of patients Group VO2 Predicted VO2 (ml/kg/min) (ml/kg/min) None to Mild Mild to Mod Mod to Severe Severe >25 20-25 15-20 <15 33 29.5 ± 0.9 38.6 ± 1.2 72 22.1 ± 0.2 35.3 ± 0.8 77 17.2 ± 0.2 34.2 ± 0.6 21 12.1 ± 0.5 33.0 ± 0.6 169 Reduced Functional Capacity Riley et al., 1990 Demitrack et al., 1998 DeBecker et al., 2000 VanNess et al., 2003 Vermulen et al., 2010 Jones et al, 2011 *Difficult to separate "CFS effects" from detraining 170 Exercise Test-Retest Paradigm Waxing and waning of symptoms Fluctuations in fatigue levels *"Induced" Post-Exertional Effect Test 1 Test 2 171 Reduced Ability to Utilize Oxygen in the Post-Exertional State Peak VO2 (ml/kg/min) 35 Metabolic Dysfunction 30 CFS 25 Control 20 15 Test 1 Test 2 VanNess, J.M., C.R. Snell and S.R. Stevens. J of CFS, 14(2):77-86, 172 2007. Repeated Exercise Tests Demonstrates the effect of post- exertional malaise Quantifies the magnitude of the post- exertional effect (Fatigue Effect) Informs the mechanisms of the response Reproducibility? 173 The Abnormal Stress Test: Objective Evidence of PEM? Decline in VO2peak/AT/workload values: 1. Atypical recovery response Abnormal stress test Post-exertional malaise 2. Distinguishes CFS from other illnesses CFS 24.5% decrease. VanNess et al. 2007 Other illnesses 7.28% variability. Clinical Exercise Testing (Weisman & Zeballos), p.28 174 Test 1 Test 2 CFS Controls n=51 n=10 CFS Controls n=51 n=10 VO2 1 peak 21.51 25.04 20.44 23.96 VTO21 12.74 13.83 11.36 14.12 WL 2 peak 109.57 137.20 101.63 VTWL2 49.51 58.00 22.20 140.00 63.50 1 ml/kg/min; 2 watts. 175 ATVO2 (ml/kg/min); ATWL (Watts) TEST-RETEST 70 60 50 40 30 20 10 0 T1 T2 Test ME/CFS ATVO2 CONTROL ATVO2 ME/CFS ATWL CONTROL ATWL 176 Failure to Reproduce? Inflammatory cytokine elevation (Klimas et al., 2007) Neuroendocrine dysfunction Cardiovascular abnormalities Mytochondrial abnormalities (Whister et al., 2006, Wong et al.,1992) 177 Conclusions Cardiopulmonary exercise testing can provide objective measures of fatigue in CFS/ME (functional endpoint for clinical trials; disability assessment) As a quantifiable stressor, CPET has the capacity to reveal abnormalities across multiple systems Availability of the RER, a measure exclusive to analysis of expired gases, provides the most accurate and reliable gauge of subject effort A single exercise test may be insufficient to distinguish between CFS/ME and sedentary controls 178 CPET AROUND THE WORLD Clinicaltrials.gov 179 Measures of CFS in a Multi-site Clinical Study Elizabeth Unger, PhD, MD Chief Chronic Viral Diseases Branch Division of High-Consequence Pathogens and Pathology Centers for Disease Control and Prevention 180 Measures of CFS in a Multi-site Clinical Study Elizabeth R. Unger PhD, MD Chief, Chronic Viral Diseases Branch FDA Scientific Drug Development Workshop April 26, 2013 The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. National Center for Emerging and Zoonotic Infectious Diseases Division of High-Consequence Pathogens and Pathology 181 Background Physicians world-wide recognize CFS with similar features Different case definitions in use Heterogeneity of patients in clinical trials and research studies could confound results Duration of illness Severity of and types of symptoms Co-morbid conditions Medications Demographics (age, race, sex, BMI, socio-economic, etc.) 182 Study Objectives and Design Capitalize on clinical expertise of physicians experienced in care and treatment of CFS patients Collect standardized data on major illness domains of CFS from patients in these practices Describe heterogeneity of CFS patients between practices Evidence-based data to address case definition and CFS- subgroups Enrollment criteria: Any patient (18-70 years old) diagnosed with CFS in participating clinics Exclusions: HIV +, age at diagnosis older than 62 years 183 Participating Clinics Beth Israel Medical Center, New York City NY Benjamin Natelson, MD Center for Neuro-Immune Disorders, Miami FL Nancy Klimas, MD Open Medicine Institute Consortium Fatigue Consultation Clinic, Salt Lake City UT Lucinda Bateman, MD Hunter-Hopkins Center, Charlotte NC Charles Lapp, MD Open Medicine Clinic, Mountain View CA Andreas Kogelnik, MD Richard Podell Medical, Summit NJ Richard Podell, MD Sierra Internal Medicine, Incline Village NV Daniel Peterson, MD 184 Protocol Developed by participating clinics and CDC Fit into clinic routine as much as possible Minimize burden to patients IRB approved Phase 1 Cross-sectional data Physical examination at time of clinic visit (or within one year) Questionnaires for self-reported measures of illness · Patient completed Data abstraction of medical records by clinic personnel 185 Data Abstraction Forms Not Standardized Data Collected by Clinic Personnel New patient intake form (scanned) Basic demographics Detailed medical history History of present illness Current medication list Lab and other diagnostic tests Family history Infection/immunization history Physical Examination 186 Data Collection Instruments Patient Self-reported Patient Health Questionnaire Depression Scale (PHQ-8) Generalized Anxiety Disorder 7-item Scale (GAD-7) Self-Rating Depression Scale (SDS) CDC Symptom Inventory (CDC-SI) Medical Outcomes Study 36-Item Short-Form (MOS SF-36 v2) Multidimensional Fatigue Inventory-20 (MFI-20) Questions from DePaul symptom inventory (DSQ) PROMIS Forms Fatigue, Sleep (Disturbance and Impairment), Pain (Behavior and Interference) Sleep Questions Brief Pain Inventory (BPI) 187 Interim Data Analysis Data from 393 participants ready for analysis Final enrollment of 450 anticipated Distribution among the 7 participating clinics: 188 Overall Patient Demographics Mean age 48.6 yrs* 71.0% Female* 95.4% White* Mean BMI 27.2* 58.1% Married* 16.1% Previously married 25.7% Never married 78.3%College educ.* 97.8% Insured* 75.4% Not working 15.4% Unempl. Benef. 189 *Differs by clinic Illness Onset Mean age at diagnosis - 38.2 yrs (SEM 0.62) 66.7% Sudden onset (range by clinic 52.3-76.1%; p<0.1) Mean duration of illness (fatigue) 15.0 yrs (SEM 0.51) Fatigue Duration (years) by Clinic 190 Measures of Fatigue PROMIS Score = 68.3 ± (0.36) Scores by clinic similar MFI-RA differs by clinic Other MFI scores similar MFI-GF shows ceiling effect (37.5% at max) PROMIS Fatigue correlates well with 3 MFI subscales Correlation PROMIS and MFI MFI Subscales GF PF RA RM MF PROMIS Fatigue 0.63 0.61 0.6 0.31 0.45 GF-General Fatigue RM-Reduced Motivation PF-Physical FatigueMF-Mental Fatigue RA-Reduced Activity 191 Measures of Function SF-36 indicates relative preservation of Mental Health and Role Emotional Lowest scores on Vitality and Role Physical No significant variation by clinic Daily activity hours-vertical (mean±SEM) = 7.6±0.2 Daily activity hours-horizontal (mean±SEM) = 12.8±0.2 Differs by clinic Mild exercise times per week, overall (mean±SEM) = 3.4±0.21 Differs by clinic 192 Measures of Pain BPI Overall 80% had pain in last week %Taking pain medication differed by clinic Severity score differed by clinic 0.75 Correlation between PROMIS Interference and BPI Interference 193 Measures of Sleep Severe sleep impairment noted in PROMIS, Sleep questions and CDCSI Differences by clinic in PROMIS SleepRelated Impairment and "Times Awakening Not Rested" 194 Distribution of CDC SI- Scores by Clinic Unrefreshing Sleep Muscle Aches/Pains Joint Pain Fatigue After Exertion Concentration Problems Headaches Sleep Problems Memory Problems Tender Lymph Nodes 195 Distribution of CDC SI Scores by Clinic 196 Distribution of DSQ- Severity by Clinic 197 Mean PROMIS T-Scores (SD) Patient Sample CFS This Study 1Chronic Pelvic Pain 2Spinal cord injury 2Muscular Dystrophy 2Post-polio syndrome 2Multiple Sclerosis Fatigue Sleep Disturbance Sleep Related Impairment 68. 3 (7.2) 59.3 (8.2) 62.2 (8.1) 56.0 (8.0) 59.0 (10.0) 52.4 (7.7) 52.6 (9.7) 49.8 (9.7) 56.1 (8.2) 51.8 (9.1) 52.0 (9.6) 58.7 (7.2) 51.6 (9.1) 49.7 (8.7) 58.2 (8.4) 52.4 (10.1) 53.3 (9.5) Pain Interference 61.9 (9.9) 56.8 (8.3) 54.3 (8.8) 58.0 (7.9) 56.4 (8.4) 1J Minim Invasive Gynecol (2011) 18:189; 2Arch Phys Med Rehabil (2012) 93:1289 Pain Behavior 57.2 (7.6) 60.0 (6.0) 198 Conclusions and Future Work Interim analysis indicates heterogeneity of CFS population as a whole as well as between clinic However phenotypic measures appear limited in their ability to identify subgroups Limitation of MFI-GF scale identified for CFS patients in specialty clinics Final dataset will allow comparison of instruments measuring domains of CFS illness Follow-up important to correlate measures with course of illness Additional measures of cognition and exercise capacity are planned in a subset of this study population 199 Acknowledgements and Thanks CFS Patient Study Participants Beth Israel Medical Center Benjamin Natelson Diana Vu Center for Neuro-Immune Disorders Nancy Klimas Elizabeth Balbin Open Medicine Institute Consortium Fatigue Consultation Clinic Lucinda Bateman Ali Allen Hunter-Hopkins Center Charles Lapp Wendy Springs Open Medicine Clinic Andreas Koglenik Catt Phan Richard Podell Medical Richard Podell Trisha Fitzpatrick Sierra Internal Medicine Daniel Peterson Gunnar Gottschalk Centers for Disease Control and Prevention Chronic Viral Diseases Branch *Sally Lin Jaeyong Bae Roumiana Boneva Kathleen Bonner Charlotte Campbell Irina Dimulescu James Jones Josef Limor *Lisa Oakley *Meredith Philyaw Ashish Rai *Hao Tian *Analysis for this report Emory University (MPH Students) Felicia Blocker Judith Chuang Esther Piervil Alyx Groth Ashley Hagaman Alex Pao Lulu Tian 200 Clinical Outcome Assessments to Evaluate Treatment Benefit in Clinical Trials for CFS and ME Ashley Slagle, MS, PhD Oak Ridge Institute for Science and Education (ORISE) Fellow - Contractor Study Endpoints and Labeling Development Staff Office of New Drugs Center for Drug Evaluation and Research U.S. Food and Drug Administration 201 CLINICAL OUTCOME ASSESSMENTS TO EVALUATE TREATMENT BENEFIT IN CLINICAL TRIALS FOR CFS AND ME Ashley F. Slagle, MS, PhD Study Endpoints and Labeling Fellow OND/CDER/FDA 202 DISCLOSURES I have no conflicts to declare I am not speaking on behalf of the FDA The views expressed are my own based on my experience during my fellowship with the FDA This presentation was supported in part by an appointment to the Research Participation Program at CDER administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the US FDA 203 EVIDENTIARY STANDARDS TO DOCUMENT TREATMENT BENEFIT Documented by "Substantial evidence" (21 CFR 201.56(a)(3)) Evidence from "Adequate and well-controlled clinical trials" The methods of assessment are "well-defined and reliable" (21 CFR 314.126) 204 WELL-DEFINED AND RELIABLE METHODS OF ASSESSMENT Measures are well-defined and reliable when Empiric evidence demonstrates that the score quantifies the concept of interest in the targeted context of use 205 ASSESSING TREATMENT BENEFIT IN CFS AND ME The impact of a treatment on how patients feel, function, or survive Outcome assessment options to evaluate treatment benefit include: Measures of survival Biomarkers Clinical Outcome Assessments (COA) 206 ASSESSING TREATMENT BENEFIT USING BIOMARKERS Biomarker: an objective measure of biologic process, pathologic process, or biologic response to therapeutic intervention Examples: VO2 max/anaerobic threshold; immune function markers Biomarkers do not directly reflect how patients feel, function, or survive May serve as indirect assessment of benefit, by showing biologic response to treatment Association ("replacement value") between the indirect assessment and how patients feel or function in daily life will need to be understood For example what do circulating antibody levels tell us about how a patient feels or functions in daily life? 207 CLINICAL OUTCOME ASSESSMENTS (COA) Any assessment that may be influenced by human choices, judgment, or motivation Depends on the cooperation, implementation, interpretation, and reporting by one of the following: A patient (PRO) A clinician (ClinRO) An observer (ObsRO) Comprised of: A measure that produces a score Clearly defined methods and instructions for administering the clinical outcome assessment Clearly defined methods for assessing response A standard format for data collection Well-documented methods for scoring, analysis, and interpretation of results in the targeted patient population 208 CLINICAL OUTCOME ASSESSMENT CONSIDERATIONS Not all patient reported, clinical-reported, or observer-reported assessments are appropriate Clinical Outcome Assessments May be useful for other purposes: Diagnostic Prognostic Trial eligibility and trial enrichment Epidemiologic or population studies Measures used successfully for these other purposes will not necessarily be appropriate outcomes assessments (i.e., they may not be able to reliably detect treatment benefit in clinical trials) Clinical outcome assessments may be used independently in clinical trials While biomarkers and clinical outcome assessments may be used together to identify patients or assess treatment benefit in clinical trials, there is no requirement to identify and use a biomarker in parallel with a clinical outcome assessments Requirement is that assessment is well-defined and reliable 209 CONSIDERATIONS FOR SELECTING A CLINICAL OUTCOME ASSESSMENT Context of Use Concept of interest (the thing we want to measure) Conceptual Framework Other (e.g., recall period; length of questionnaire, measurement properties) 210 SELECTION OF A CLINICAL OUTCOME ASSESSMENT Depends on a particular Context of Use Disease definition (explicit and specific to the clinical trial population) Disease characteristics (e.g., severity, duration) Clinical characteristics (e.g., co-morbidities) Demographics (e.g., age group) Setting (i.e., inpatient or outpatient if applicable) General plan for study design (e.g., superiority or non-inferiority; randomized and blinded) Endpoint positioning (i.e., how does this assessment fit in with the other endpoints selected for the study?) Type of claim sought (e.g., symptomatic improvement vs. delay to onset of acute episode) 211 CONTEXT OF USE CHALLENGE IN CFS AND ME In CFS and ME, the disease definition is still unclear For clinical trials, that's OK investigators will need to identify a rational set of clinical trial entry criteria and select outcome measures appropriate to that specific subpopulation It will be important to exclude other diseases, recognizing that in clinical practice some conditions may coexist, but clinical trial population needs to be pure, and must develop/evaluate potential outcome measures using this pure population There are many subpopulations, for whom outcome measures might be different Acute onset and gradual onset Patients with orthostatic postural symptoms and those without Adults and children (and others who may not be able to report for themselves) Those with abnormal neurological findings and those without Recent onset and those with long-time suffering Severe forms and less severe forms Patients with varying symptom experiences (e.g., general all-day fatigue vs. post-exertion fatigue) Others? 212 SELECTION OF A CLINICAL OUTCOME ASSESSMENT Depends on what concepts are relevant and important to assess (i.e., the things we want to measure) in the particular context of use 213 CONCEPTS OF INTEREST (THE THINGS WE MAY WANT TO MEASURE) Fatigue (Multidimensional) May be general / unchanging over the course of the day or related to exertion: Physical tiredness Mental tiredness/'brain fog' Related to lack of sleep, sleepiness Post-exertional (wired fatigue, energy fatigue, flu-like fatigue1) Others ? Sleep problems Pain (body, joints, eye, chest, abdomen) Headache Muscle difficulties (twitching, weakness, stiffness, numbness Sensitivity to stimuli (lights, noises, smells) Cognitive difficulties (remembering, paying attention, finding words, focus, comprehension) Bladder of GI problems Feeling unsteady or dizzy Weight changes or appetite problems Sweating (hands; night sweats) Feeling hot or cold Cold or flu-like symptoms (sore throat, sore lymph nodes, fever, others?) Nausea/Vomiting Shortness of breath Irregular heartbeat Depth perception problems Alcohol intolerance Reduced Activity Assistance needed with activities Emotional concerns (nervousness, anxiety, depressed feelings) Visual problems Altered taste or smell Ringing in the ears Gait/walking problems 1 Jason et al., 2009. Examining Types of Fatigue Among Individuals with ME/CFS. Available online: 214 http://dsq-sds.org/article/view/938/1113 . Disabil Stud Q. 2009 29(3). Things Related to How Patients Feel or Function (Concepts) in CFS and ME Subpopulation of Patients with Severe Post-exertional Fatigue Things clinical trial patients with severe post-exertional fatigue feel or experience Things that All Patients with CFS and ME feel or experience Things that Drug Y Impacts (How Patients Feel or Function) Things to Measure to Conclude Effectiveness (Feels or Functions) Measure in the Clinical Trial Subpopulation 215 Things Related to How Patients Feel or Function (Concepts) in CFS and ME Subpopulation of Patients with Severe Post-exertional Fatigue Things clinical trial patients with severe post-exertional fatigue feel or experience Things that All Patients with CFS and ME feel or experience Things that Drug Y Impacts (How Patients Feel or Function) Things NOT to Measure to Conclude Effectiveness (Feels or Functions) in the Clinical Trial Subpopulation 216 FOR EXAMPLE, CONCERNS ABOUT CONTENT VALIDITY... Study population = primarily bed-ridden, minimal physical activity (e.g., walking to the bathroom) very difficult Concept of interest to evaluate treatment benefit = physical functioning Clinical Outcome Assessment = patient-reported questionnaire to assess physical functioning One question in the assessment = "Do you have trouble running to the bus?" 217 CONCEPTUAL FRAMEWORK OF A CLINICAL OUTCOME ASSESSMENT Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Score of Domain A Domain Concept A Score of Domain B Domain DCoomncaeinpt B Total Score Overall Concept 218 OTHER CONSIDERATIONS FOR SELECTING CLINICAL OUTCOME ASSESSMENTS FOR USE IN CLINICAL TRIALS Things to consider that impact content validity: Recall period Length (number of questions) Long enough to capture all needed information, but not too long to overburden patients Repeated administration: administered multiple times (e.g., daily) in clinical trials Mode of administration Electronic data capture helps limit missing data Other measurement properties 219 EXAMPLES OF PATIENT-REPORTED OUTCOMES USED IN CFS AND ME Measures of Multiple Concepts (Include Symptoms and Impacts) DePaul Symptom Questionnaire (DSQ) CDC Symptom Inventory Patient Health Questionnaire (PHQ) Functional Capacity Scale (FCS) Measures of `Fatigue' ME/CFS Fatigue Types Questionnaire (MFTQ) Multidimensional Fatigue Inventory (MFI) PROMIS Fatigue short form Brief Fatigue Inventory (BFI) Fatigue Severity Scale (FSS) Fatigue Impact Scale (FIS) (CIS-20) Fatigue Scale Physical Function / Abilities Activities of Daily Living (ADLs) Measures of Health Status (SF-36): Health Status Measures of Pain Brief Pain Inventory (BPI) Measures of Sleep Epworth Sleepiness Scale (ESS) 220 EXAMPLES OF CLINRO AND OBSRO MEASURES USED IN CFS AND ME Clinician-reported Assessment of Disability Karnofsky Performance Scale Clinician-reported Assessment of Exercise Capacity Exercise Treadmill Testing Observer-reported Outcome Assessments None identified 221 EXAMPLES OF CHALLENGES IDENTIFIED WITH AVAILABLE CLINICAL OUTCOME ASSESSMENTS FOR USE IN CLINICAL TRIALS Developed as diagnostic or classification tool, not sensitive to treatment effects Developed as an epidemiological assessment, very comprehensive Generic measures, developed for a broad population, not specific to CFS and ME context of use Conceptual framework concerns No conceptual framework and scoring algorithm available (e.g., checklists) Concerns with individual items Items too general to determine what is being assessed (e.g., `some signs or symptoms of disease ` are present) Items use terms that are not clear or relevant to CFS and ME patients (e.g., "I feel fit"; "I feel peppy") Items ask about `fatigue', without defining Item content is confusing (e.g., `double-barreled' items: "trouble falling asleep or sleeping too much") 222 CURRENTLY IDENTIFIED CLINICAL OUTCOME ASSESSMENTS None of the reviewed instruments to date appear sufficiently well-defined and reliable to assess treatment benefit in clinical drug trials among CFS and ME patients Of course, no one wants the perfect to be the enemy of the good 223 WHAT ARE OUR CLINICAL OUTCOME ASSESSMENT OPTIONS IN CFS AND ME? Find an existing measure that is appropriate for use in clinical trials for a defined population(s) of CFS and ME patients Modify an existing assessment for use in clinical trials for a defined population(s) of CFS and ME patients Develop a new symptom assessment for use in clinical trials for a defined population(s) of CFS and ME patients 224 PARTNERING WITH THE FDA THROUGH THE DDT QUALIFICATION PROGRAM A novel and voluntary submission process for drug development tools (DDTs), intended for potential use, over time, in multiple drug development programs Goal: Publicly available drug development tools (e.g., clinical outcome assessments) Publication in the Federal Register and FDA DDT website Builds on developing public-private partnerships between FDA and consortia representing medical product industry, instrument developers, NIH, academia, and patients DDT Qualification Draft Guidance available: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM230597.pdf PRO Guidance describes good principles for measure development: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformat ion/Guidances/UCM193282.pdf DDT clinical outcome assessments qualification Liaison can discuss this in more detail/answer questions: SEALD.ENDPOINTS@fda.hhs.gov 225 Panel 3: Audience Question and Answer Period All Panelists 226 Break 15 Minutes CHERRY BLOSSOMS ON THE TIDAL BASIN 227 Panel 4: Roundtable Discussion Summary and Path Forward Moderators: Dennis Mangan, PhD Badrul Chowdhury, MD Director Division of Pulmonary, Allergy, and Rheumatology Products Office of Drug Evaluation II, Office of New Drugs Center for Drug Evaluation and Research U.S. Food and Drug Administration 228 Panel 4: Roundtable Discussion - Summary and Path Forward · Lily Chu, MD, MSPH · Jordan Dimitrakoff, MD, PhD · Nancy Klimas, MD, FACP, FIDSA · Nancy Lee, MD Deputy Assistant Secretary for Health; Director, Office of Women's Health, Department of Health and Human Services · Susan Maier, PhD Deputy Director, Office of Research of Women's Health, National Institutes of Health · Theresa Michele, MD · Robert Miller Patient · Jody Roth, MS, RAC Director Regulatory Affairs, Biomedicines, Eli Lilly and Company 229 Panel 4: Question 1 · What were the key messages on drug development you heard at this meeting? 230 Panel 4: Question 2 · What do you think are the most important factors in facilitating drug development in CFS and ME? 231 Panel 4: Question 3 · Based on the discussion from Panel 3, what clinical trial design elements are most important to ensure success of drug development programs for CFS and ME? 232 Panel 4: Question 4 · What do you think are the most important barriers to conducting research for CFS and ME and what can be done to overcome them? 233 Panel 4: Question 5 · How can we best leverage your individual experiences in order to facilitate drug development in CFS and ME? Please respond for your own group as identified below: Other Health and Human Services (HHS) Agencies FDA Pharmaceutical and Biotech Companies Academia Patient/Advocacy community 234 Panel 4: Question 6 · What are possible next steps following this meeting? Please respond for your own group as identified below: Other Health and Human Services (HHS) Agencies FDA Pharmaceutical and Biotech Companies Academia Patient/Advocacy community 235 Panel 4: Audience Question and Answer Period All Panelists 236 Closing Remarks RADM Sandra Kweder, MD Deputy Director, Office of New Drugs Center for Drug Evaluation and Research U.S. Food and Drug Administration 237

Drug Development for CFS and ME: Public Workshop

Drug Development, CFS, ME, Public Workshop

FDA/CDER