Externally-led Juvenile Idiopathic Arthritis Patient-Focused Drug Development Meeting Report V 1.3 10/7/191 Table of Contents The Arthritis Foundation and CARRA 3 Purpose of the PFDD Project 4 History of JIA Treatment and Current State of the Art 5 Overview/Introduction of the Meeting and Pre-Meeting Content 9 Topic I: JIA Symptoms and Daily Impacts That Matter Most to Patients 12 Topic 2: Patients’ Perspectives on Current Approaches to Treating JIA 18 Topic 3: Patients’ Perspectives on Clinical Trial Design 26 FDA Engagement . 32 Treatment Horizon: Challenges and Opportunities 33 Arthritis Foundation/CARRA Research and Patient Engagement Efforts 34 Appendices Appendix 1 Project Team Appendix 2 Pre-Meeting Survey Results Appendix 3 Focus Group Summary Appendix 5 In-Meeting Polling Question Appendix 4 Speaker and Panelist Biographies Appendix 6 Meeting Transcript 2 Externally-led Juvenile Idiopathic Arthritis Patient-Focused Drug Development Meeting Report The Food and Drug Administration (FDA) seeks to understand and reflect the perspectives of patients and caregivers in the drug development process Over the past six years, the FDA has conducted 25 internally- led patient-focused drug development (PFDD) meetings on various conditions to systematically gather critical input regarding the issues and challenges that affect patients’ treatment needs, choices, compliance and quality of life. Recognizing that a significant number of diseases still needed to be addressed, the FDA issued a call for partners to conduct externally-led PFDD meetings to collaborate on these critical information-gathering initiatives The Arthritis Foundation answered that call in March 2017 hosting an Osteoarthritis externally-led PFDD meeting Then again in August 2018, the Arthritis Foundation partnered with the Childhood Arthritis and Rheumatology Research Alliance (CARRA) to co-host the externally-led PFDD meeting about Juvenile Idiopathic Arthritis. The Arthritis Foundation and CARRA are proud to engage with the FDA in this initiative to provide patient input regarding juvenile idiopathic arthritis (JIA) The Arthritis Foundation and CARRA For more than 70 years, the Arthritis Foundation has been the leading patient advocacy group for adults and children living with arthritis, the nation’s leading cause of disability. A core tenet of the Foundation’s mission is accelerating groundbreaking research through financial support and strategic partnerships. This mission served as the catalyst for the Foundation’s collaboration with the Childhood Arthritis and Rheumatology Research Alliance (CARRA) “Participation in research is the path to a cure and the Arthritis Foundation is committed to bringing new opportunities for researchers, clinicians, patients and families to actively pursue better treatments with us.” – Ann Palmer, Arthritis Foundation Established in 2002, CARRA is a pediatric rheumatology research network whose mission is to conduct collaborative research to prevent, treat and cure pediatric rheumatic diseases. CARRA’s research network includes almost all the pediatric rheumatology centers across the U.S. and Canada. Members include clinicians, researchers and research coo rdinators The Arthritis Foundation has funded CARRA’s infrastructure and operations since its inception and the organizations have been collaborative partners for more than a decade. In 2015, the partnership evolved to a more strategic one that aligns scientific agendas; expands research about the impact, unmet needs and treatment of pediatric rheumatic diseases; and prioritizes patients’ and families’ participation in meaningful and high-quality clinical and translational research Among recent collaborations has been an effort with the FDA to advance understanding of patient perceptions around treatment, risk/benefit analysis, and clinical trial design. A manuscript entitled “Toward Improvement in the Timely Authorization and Availability of New Medicines for Juvenile Idiopathic Arthritis: Multi-Stakeholder Perspectives” has been submitted for publication summarizing an April 2018 CARRA- and AF-sponsored meeting of FDA, European Medicines Agency (EMA), major pharmaceutical companies, clinicians, researchers, patients and parents arthritis.org | carragroup.org 3 Purpose of the PFDD Project Through its Division of Pulmonary, Allergy and Rheumatology Products, the FDA oversees drug development for rheumatic diseases including juvenile idiopathic arthritis (JIA) With the enactment of the Prescription Drug User Fee Act (PDUFA) in 1992, Congress created a mechanism for the FDA to accelerate the review and approval of innovative medicines and products based on the best available science As part of this initiative, the FDA recognizes the need to broaden patient and caregiver input to identify the critical variables, endpoints and outcomes that more accurately represent the burden of disease and the impact of available treatments. To help meet these needs, the PFDD initiative was launched in 2012 The goals of the PFDD initiative are to •Develop treatments that meaningfully address the aspects of disease most important to patients • Tailor clinical trials to reflect patient’s perspective on the benefits and harms of treatment in drug evaluation • Ensure the information and data accurately represent self-reported benefits and harms and is directly relevant to patient’s treatment needs and decisions Nikolay Nikolov, MD, Associate Director for Rheumatology, FDA Division of Pulmonary, Allergy, and Rheumatology Products, summed up the importance of PFDD meetings during his introductory comments at the Externally-led JIA PFDD Meeting “The information will help to better inform the benefits-risk assessment of new therapies, identify areas of unmet need and help drug developers and regulatory authorities, such as the FDA, design programs that are more relevant to addressing how patients feel and function.” – Nikolay Nikolov, MD, Food and Drug Administration In December 2016, the 21st Century Cures Act was enacted to accelerate the translation of scientific discovery into FDA-approved treatments, foster interdisciplinary and cross-functional collaboration, and integrate patient insights into the regulatory review process. The law builds on efforts of the FDA to include patient perspectives into the drug and medical product development process Through their PFDD and 21st Century Cures Act efforts, one goal of the FDA is to bring safe and innovative therapies to arthritis patients faster This will help minimize •Joint damage, disability and other barriers to optimal health-related quality of life. •Disruptions to educational and career experiences and opportunities •The negative impact on social, psychosocial and family dynamics 4 History of JIA Treatment and Current State of the Art More than 100 years ago when rheumatic diseases were first diagnosed in children, significant joint pain, loss of function, and deformity were the norm Aspirin and glucocorticoids were the only drugs regularly used However, the side effects of extended steroid use included increased osteoporosis risk, abnormal skeletal growth, obesity and increased infection risk. By the1970s, nonsteroidal anti- inflammatories became available. Older treatments, such as gold and penicillamine, were sometimes used despite a high toxicity rates with little benefit. It wasn’t until the 1980s and the availability of the disease-modifying antirheumatic drug (DMARD) methotrexate that an era of disease suppression with significant improvements in outcomes commenced. This paved the way for more aggressive use of DMARDs in JIA Biologic response modifiers, or biologics, became available in the late 1990s. These powerful and game-changing therapies for inflammatory arthritis specifically target specific components of the immune system. With small-molecule targeted therapies now available in adults, the JIA community is awaiting the first small-molecule indications for children. Table 1. Biologics and Small-Molecule Targeted Therapies for Arthritis TNF Inhibitors IL-1 Inhibitors •Infliximab (Remicade) •Anakinra (Kineret)** •Etanercept (Enbrel)* •Canakinumab (Ilaris)* •Adalimumab (Humira)* •Rilonacept (Arcalyst) •Golimumab (Simponi)** IL-17 Inhibitors •Certolizumab (Cimzia)** •Secukinumab (Cosentyx)** Inhibitor of CD28-B7 •Ixekizumab (Taltz) (T cell co-stimulation signal) IL-12/23 Inhibitor •Abatacept (Orencia)* •Ustekinumab (Stelara) IL-6 Inhibitors JAK Inhibitors [Small Molecule] •Tocilizumab (Actemra)* •Tofacitinib (Xeljanz)** •Sarilumab (Kevzara)** •Baricitinib (Olumiant)** B cell Inhibitor Phosphodiesterase Inhibitor •Rituximab (Rituxan) [Small Molecule] •Apremilast (Otezla) *FDA Approved for JIA. **Currently in clinical trial for FDA approval in JIA. 5 Table 2. JIA Disease Subtypes JIA Subtype Characteristics Oligoarthritis-persistent • Fewer than five affected joints with no additional joint involvement after the first six months • Highest risk for uveitis that may progress to glaucoma, cataracts and possibly blindness • Usually affects young girls Oligoarthritis-extended • Initially involves fewer than five joints for the first six months and then disease progresses to additional joints •High risk for uveitis •Usually affects young girls Polyarthritis RF negative • Involves five or more joints (small and large) within the first six months •Symmetric joint involvement of many joints is common •Rheumatoid factor blood test is negative •Occurs early in childhood •More common in girls Polyarthritis RF positive • Involves five or more joints