Accelerating Cures: Addressing Unmet Patient Need Or Putting Patients At Risk? Speaker

Transcription

1 Speaker Patricia Furlong Parent Project Muscular Dystrophy (PPMD) Middletown, OH, USA Accelerating Cures: Addressing Unmet Patient Need Or Putting Patients At Risk? 1

2 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 -mean age of death 28 What does Dystrophin Do? 2

3 Duchenne is not just a muscle disease Lungs Bone Muscles Brain Heart Stomach Why are we here? A drug development ecosystem is a community of stakeholders (universities, companies, patient organizations, patients, government organizations) living in conjunction with the nonliving components of their environment (regulations, economic factors, reimbursement potential), interacting as a system. These components are linked together through clinical research cycles and funding flows. Companies Economy Regulations Government Patients Reimbursement Patient organizations Universities 3

4 Stop-codon Readthrough Exon-Skipping Gene Therapy Functional replacement with other proteins Anti-fibrotics Inflammation & Fibrosis Dystrophin Restoration/ Replacement Poloxymer Steroid Replacements Treating Duchenne Cardiac Serca 2A Ryanodine Receptor Calcium Regulators Muscle Mass Blood Flow Traditional cardiac drugs GsMTx4 Muscle growth pathways Stem Cells PDE5 4

5 FDA Safety and Innovation Act (FDAISIA) Opportunities (FDA) PDUFA (FDAISIA) Food and Drug Administration Safety and Innovation Act d Rare Disease Comunity collaborated to ensure strongest language included in final law Results Accelerated Approval provision Breakthrough Therapy provision Patient-Focused Drug Development initiative/benefit Risk FDASIA - Creating New Tools Under Patient Focused Drug Development (PFDD) Benefit-Risk/Patient Preference studies BR pilot study BR Santhera study Patient Report Outcomes Expanding Registry data (PCORnet) Patients Are Waiting whitepaper Guidance for Industry S Patient Focused Impact Assessment 5

6 White paper To fully realize the potential to speed responsible access to new therapies for Duchenne, the FDA should: Expand the use of accelerated approval for therapies intended to treat rare diseases, including Duchenne muscular dystrophy. Issue clear guidance outlining the level of evidence required for the use of surrogate endpoints in order to expand the scope of acceptable endpoints, including novel surrogate and intermediate clinical endpoints, used to approve drugs for serious or life-threatening diseases with unmet medical need. Pilot the use of adaptive approval for serious and lifethreatening disorders with significant unmet medical need, using existing authority under current law. Give greater weight to the demonstrated benefit/risk preferences of patients, as well as caregivers in the case of pediatric illness, when making risk benefit determinations. Subpart D considerations must be evaluated here, yet benefit/risk should also be addressed within the context of patients living with Duchenne. Making sense of DATA collecting, combining, and analyzing real world evidence 6

7 13 DuchenneConnect Patient Registry Over 3000 patients registered Data Collected Patient demographics Diagnosis Ambulation and assistive devices Family history Genetic test report Cardiac data (MRI & echo) Pulmonary data (spirometry) Corticosteroids and other medication use Learning and behaviour diagnoses Insurance information Clinical trial participation 7

8 Partners Cincinnati Children Leiden UMC Pfizer PTC Therapeutics Santhera Sarepta University of Michigan Purpose (D-RSC) Aimed at developing tools to make Duchenne trials more efficient, and to inform the regulators about how the disease progresses in patients. Gather existing data from the community Develop CDISC standards Use database to develop disease progression model Get regulatory endorsement. Make available to the community The Reality of Rare Disease Limited number of available patients Heterogenity of patient population Duchenne + chronic steroids (variable age, dose and regimen *20 years for clinicians to adopt/patients saw a difference within 6 mo) Imperfect (or nonexistent) natural history comparator Lack of sensitive outcome measures Expectations vs realty of a 48 week study? 8

9 Duchenne as an example Inclusion criteria ambulatory between 7 and 10 years Ambulatory- 6mwt between m 4 stair climb <8 seconds Rise from the floor 10 seconds 6 months steady state steroids 9

10 Benefit Risk - Uncertainty Doing nothing = doing harm Limited available patients Often subsets (mutation specific) further limiting available patients FDA s role is to protect public safety learning as we fly the plane PPMD initiated Benefit Risk Studies Advancing the Science of Patient Input Pilot study on caregiver preference (completed) Santhera study on pulmonary outcomes (completed) Tell your story survey and white paper (completed) Expansion of pilot (initiated) BIO/PPMD case study white paper (initiated) 10

11 Case Study: Parent Project Muscular Dystrophy Anticipated FDA legislation introducing Patient-Focused Drug Development Needed to inform the FDA about our community preferences and priorities for therapeutic dev t Developed pilot research study on benefit/risk as part of a comprehensive engagement effort with the FDA Study data jump-started FDA engagement Comprehensive effort led to community-engaged development of draft guidance for DMD Subsequent therapeutic-specific study Subsequent preference study focused on meaningful benefit and uncertainty 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 11

12 Relative Best-Worst Score Does This Approach Replace Testimony? 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! [PPMD Share Your Story] StoSloNo 5 2 No 2 1 No NoMilMo NoMil ps ws ne yr yr ne yr yr ne ne d d ne d Sev NoMil ne d Sev Levels CASE STUDY: THERAPEUTIC PRIORITIES AND PREFERENCES This study conducted by PPMD in collaboration with Johns Hopkins and sponsored by Santhera Pharmaceuticals. 12

13 Goals 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? Preliminary: Priority Order for Non- Skeletal Muscle Treatment Targets 1. Weaker heart pumping 2. Lung infections 3. Weaker ability to cough 4. Bone factures 5. Non-healthy weight 6. Depression 7. Headaches 8. Constipation 9. Feeling tired 10. Frequent waking at night 11. Poor attention span 13

14 Example Survey Item Preliminary findings: Treatment Preferences Treatment Preferences Cough weakening Lung infections Diarrhea Blood draws 14

15 MUST Consider Alternative Concepts in Rare Disease Regulatory Decision Making Or is the message to patient with Rare Diseases not for you, but for the next generation? Alternative Concepts in Rare Diseases The Imperative Unmet needs- patients with progressive, debilitating, life-threatening complications for which no currently approved treatments are available (all stakeholders MUST have sense of urgency & flexibility); acceptability of any incremental benefits when balanced with risks Timothy R. Franson, M.D. Chief Medical Officer - YourEncore 15

16 Alternative Concepts in Rare Diseases The Imperative- Unmet Need The Dilemma FDA s mandate to protect public safety, as well as facilitate development of new treatments, within well defined laws and regulations governing such processes (standards); the challenge (opportunity) is to develop approaches which are creative and within the regulatory boundaries/standards (OR, to change guidances in collaboration with FDA. OR, to change legislation/regulations by administrative procedures) Possible solutions - Definition of ICE - Background, precedents and ancillary considerations Proposed ways forward Alternative Concepts in Rare Diseases Possible solutions or approaches: ICE-breakers *ICE= intermediate clinical endpoints* - Definition of ICE - Background, precedents and ancillary considerations Conditional approval.. 16

17 ICE (Intermediate Clinical Endpoints) Definition: -Intermediate= not final/definitive (final/immutable outcomesdeath, permanent disability, irreversible morbidity) -Clinical= not lab markers -Endpoints= measurable factors on causal pathway of disease Frame of reference - Surrogate markers: biomarkers (lab), ICE (clinical). Alternative measures reasonably likely to predict clinical benefit (or risk) - Clinically meaningful outcomes not lab measures (key features are feel, function and survive ); could be intermediate or final - Clinically meaningful benefits (oncology)- live longer (survival) or live better(implies + benefit/risk or time to progression/relapse) ICE background, precedents and ancillary concerns Background: accepted standard of 2 adequate, well controlled studies to provide substantial evidence of effect PDUFA-2/FDAMA: created Subpart H/accelerated approval (approvals based on features other than survival or traditional definitive outcomes, such as surrogate endpoints/biomarkers with post-approval requirements) and provided more interpretive latitude in number & nature of studies required for approvals in general PDUFA-5/FDASIA: Sect.901 amended FD&C Act to allow accelerated approvals for drugs addressing unmet needs for serious conditions based on surrogate or ICE. -FDA s definition of ICE: a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug (such as effect on irreversible morbidity and mortality) - FDA use of ICE for approvals: oncology, hepatitis B, other (*not all divisions are alike) 17

18 2-D-ICE: Duchenne Development Intermediate Clinical Endpoints Quantify clinically meaningful benefits (PROs & similar tools) - validation process (?) Integration of ICE into benefit-risk calculus - tradeoff assessments (disease control vs. toxicity)- at what timepoints? - utilization of ICE measures would be enhanced by refinement of approval processes to approve more faster using ICE- coupled with faster withdrawal of those accelerated approvals which do not prove out on post-marketing efficacy studies (may or may not require legislative changes) and likely not viewed as lowering standards Alternative Concepts in Rare Diseases - Develop ICE measures and test acceptability by regulators (without prolonged validation process) - Explore possible impact of more natural history studies to identify subset features/predictors of disease course - Consider other approaches- statistical modeling of disease progression, post-hoc analyses for AA approvals - Pursue additional interactions with regulators to advance these concepts (ICE and accelerated approvalwithdrawal) - Expand data-sharing across all stakeholders to move more rapidly 18

19 BUT in the meantime, If this was someone you loved? Prognosis well known Unmet Need ZERO options FDA mandated to listen/include the Patient/Caregiver voice Safety established Failed primary Outcome measure Post-hoc analysis? Benefit/Risk data available Patient Reported Outcomes available Is the P-value the only way About me and my family Married to a Physician Children: Jenny, Michelle, Chris, Patrick 1984 Duchenne enters their lives no family history Diagnosis: no hope, no help go home and love them WE MUST DO BETTER. 19