Collaborative Networks as Tools for Improving Clinical Care Pat Furlong Keynote Speaker November 14, 2015

Why are we here? A drug development ecosystem is a community of stakeholders (universities, companies, patient organizations, patients, government organizations) in conjunction with the nonliving components of their environment (things like regulations, economic factors, reimbursement potential), interacting as a system. These components are regarded as linked together through clinical research cycles and funding flows Universities Companies Patient Organizations Government Patients Reimbursement Economy Regulations An ecosystem is a community of living organisms (plants, animals and microbes) in conjunction with the nonliving components of their environment (things like air, water and mineral soil), interacting as a system. These components are regarded as linked together through nutrient cycles and energy flows

About Duchenne muscular dystrophy X-linked, pediatric neuromuscular disease, with onset in early childhood Incidence rate: 1:4600 boys (30% spontaneous) Diagnosis: 3-5 years of age Predictable course Progressive loss of function 100% lethal

CURRENT DUCHENNE CLINICAL TRIALS

ADDITIONAL DUCHENNE TRIALS AND TRIALS QUEUED UP FOR 2015 DRUG TARGET GOAL COMPANY/INVESTIGATOR TIME LINE NBD PEPTIDE Blocks Iĸĸb in the NF-kB pathway Reduce inflammation, boost muscle growth Dennis Guttridge at Nationwide Childrens and TheraLogics Need to complete IND-enabling toxicology; Seeking partner for trial GALGT2 GENE TRANSFER Muscle membrane-extracellular matrix interface Decrease muscle injury Paul Martin and Kevin Flanigan, Nationwide Children’s Need to complete GMP manufacturing run; Phase I in 2015 MINI-DYSTROPHIN GENE TRANSFER Muscle membrane-extracellular matrix Jerry Mendell, Nationwide Children’s 2015 BIGLYCAN Justin Fallon, Tivorsan Phase I in 2015 VBP-15 NF-kB pathway Blocks inflammation and stabilizes membrane Reveragen Phase I started in 2015; Phase 2 in late 2015 CAT-1004 Blocks inflammation Catabasis Phase I/II in 2015 (+)-EPICATECHIN Mitochondria Improve energettics Cardero Phase 1/II in 2015 TAMOXIFEN (ORAL SERM) Estrogen Receptor Not Known Lee Sweeney Phase I/II 2015; need a clinical collaborator FOR DMD TRIAL Ant-Inflammatory Finding optimal steroid regimen NIH/ R.Griggs Phase IIII DEFLAZACORT Anti-Inflammatory Extended Access Program for approval in US Marathon EAP in 2015 SRP-4045 Exon 45 Skip Restores dystrophin Sarepta Phase I/II 2015 BMS-986089 myostatin Increases muscle mass Bristol Myers Squibb Phase I/II 2015

An (Evolving) Example of Stakeholder Influence Parent Project Muscular Dystrophy Began following the Food and Drug Administration Safety and Innovation Act (FDASIA) and Prescription Drug User Fee Act (PDUFA V)- 2012 Committed FDA to Patient-Focused Drug Development Program Aims to inform FDA’s benefit/risk assessments and systematically obtain patient perspective on disease impact and treatment benefits Anticipating that Duchenne/Becker would not be chosen… (http://www.fda.gov/forindustry/userfees/prescriptiondruguserfee/ucm326192.htm) © 2015 DIA, Inc. All rights reserved.

PPMD Realized the Importance of Measuring Preferences The FDA: Wants to improve their benefit-risk framework Is mandated to better understand the patient experience and preferences Is interested in testimony but… deals in data

Beyond Testimony: PPMD Models Advocacy-Led Stated Preference Research © 2015 DIA, Inc. All rights reserved.

Beyond Testimony: PPMD’s “Share Your Story” “I understand the need for caution and care, but I also know that our children are dying. Parents should be able to decide the risk/benefit of a drug that has gone through and passed preliminary testing. I would rather my son die trying and fighting than waiting and wondering and wishing….I am one parent willing to take an educated risk!” 11/10/2018

PPMD Policy Forum Dec, 2013

FDA Draft Guidance 11/10/2018

Current PPMD Stated Preference Projects Study supported by Santhera Pharmaceuticals To what extent do parents and patients assess the pulmonary outcomes associated with the clinical trial as meaningful benefits? What are the maximal acceptable risks, harms, and/or burden that patients and parents will be willing to accept? Is there significant heterogeneity in the estimates of meaningful benefit or maximal acceptable risk among parents and patients? © 2015 DIA, Inc. All rights reserved.

Current PPMD Stated Preference Projects Phase II of PPMD’s benefit/risk research Exploring meaningful benefit Understanding risk tolerance © 2015 DIA, Inc. All rights reserved.

Demands and Benefits to a Disorder Community Highly collaborative process Resource and time intensive Outcomes inform advocacy You may not get the results you “want” A large number of people can participate, even those who cannot/do not want to testify Requires larger sample sizes; more generalizable than testimony

The Vital Role of Patient/Advocacy Organizations Collaborating with experts in stated preference research to: Set the research agenda Develop a meaningful study Weigh in on interpreting the results Disseminate to sponsors and regulators (and your community)

Robust Clinical Pipeline Assessing Barriers Robust Clinical Pipeline Increasing numbers of trials Increasing need for patient participants Major sites reaching saturation/capacity Underutilized minor sites Site selections is important Many sites, More room for error

Clinical Trials Network APPROVED THERAPIES Halofuginone NBD Peptide CAT-1000 Clinical Trials Network Central IRB Certified Centers We need to Standardize Care and improve capacity for Clinical Trials

Phase I: Improving and Standardizing Care Phase II PPMD’s Approach Phase I: Improving and Standardizing Care Certified Duchenne Care Center Program Phase II Improving and Standardizing Clinical Trials

Improving and Standardizing Care

Why is Certification Important? Certification based on same criteria Standards for Certification Care Considerations Optimize and standardize care Improve patient access to comprehensive care Reduce variations in patient care across clinical trial sites, which will help to reduce variation in clinical trial outcomes

Certified Duchenne Care Center Program Creates a network that will: Provide standardized care in alignment with the Standards of the Certified Duchenne Care Center Program which are in agreement with the CDC Care Considerations

Required Clinical and Subspecialty Services Available at each visit Available if needed Center director Clinic coordination Neuromuscular provider Cardiology provider Pulmonary provider Genetic counselor Physical therapist Social work Gastroenterology/urology Orthopedics Endocrinology Palliative care Surgery Durable medical equipment Nutrition Orthotics Occupational therapy Psychology/neuropsychology/counseling/developmental peds/neurodevelopmental disabilities Speech therapy Wheelchair specialist

Comprehensive Approach to Comprehensive Care Application, site visit, chart reviews, decision of CDCCP Certification Committee Results reported Back to the center Certification for 5 years Parent /patient report: DuchenneConnect And Clinical Experiences Survey Annual Center Metrics, follow up on committee suggestions Results publically available on PPMD website

Improving and Standardizing Clinical Trials

Certified Duchenne Clinical Trials Network Summer meeting of CDCC Directors Assess the program at one year Development of “Hub and Spoke” model Assess feasibility of building a Clinical Trials Network Common Contract Central IRB

Certified Duchenne Clinical Trials Network Criteria for certification as a Certified Duchenne Clinical Trial site PPMD’s Drug Development Roundtable 70 global thought leaders in therapy development Development of working group Assess existing models of clinical trial site certification Make recommendations of standards that can be applied across Duchenne clinical trial sites

Questions?

Thank you.