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Clinical Trials: Challenges and Opportunities

Clinical Trials: Challenges and Opportunities. Erika Augustine ,MD University of Rochester Medical Center October 31, 2012. Current state of treatment in NCLs. No FDA approved disease-modifying therapy for any NCL Symptomatic treatments At least 5 recent or ongoing clinical trials

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Clinical Trials: Challenges and Opportunities

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  1. Clinical Trials: Challenges and Opportunities Erika Augustine ,MD University of Rochester Medical Center October 31, 2012

  2. Current state of treatment in NCLs • No FDA approved disease-modifying therapy for any NCL • Symptomatic treatments • At least 5 recent or ongoing clinical trials • Goals: stabilization, improvement, or reversal of symptoms

  3. Clinical trials in rare diseases • <200,000 persons in US • >8,000 rare diseases affecting 6-10% of US population RC Griggs, et al. Molec Genet Metab 2009; 96: 20-26.

  4. Drug Development Timeline H Liu and M Schmid. J Comm Biotech 2009; 15: 199–214.

  5. Challenges to Therapeutic Development in Rare Diseases Proof-Of-Concept Trial Execution

  6. Proof-Of-Concept: Opportunities Therapeutics for Rare and Neglected Diseases (TRND program)

  7. Gold Standard – blinded RCT • Gold standard for establishing cause and effect • Random allocation of subjects- minimizes bias (selection bias)- balances known and unknown confounders- facilitates blinding • Large samples, long follow-up, high cost Schulz, et al. Lancet 2002; 359: 696–700

  8. Trial Execution: Study Design CHALLENGES Purpose Selection of subjects Selection of controls, placebo Measures to minimize bias- randomization Statistical analysis- Sample size = Power- Individual Variability Dickson, et al. Mol Genet Metab. 2011 March ; 102(3): 326–338

  9. Trial Execution: Study Design CHALLENGES OPPORTUNITIES Purpose Selection of subjects Selection of controls, placebo Measures to minimize bias- randomization Statistical analysis- Sample size = Power- Individual Variability Historical controls Self controls Alternative trial design Science of Small Clinical Trials

  10. Opportunity: Alternative designs • Parallel group • Cross-over • Factorial • Three-stage • Historical controls • Randomized withdrawal • n-of-1 • Group sequential • Selection studies • Dose-response • Adaptive

  11. Trial Execution: Outcomes CHALLENGES Well-defined, reliable outcome measures and endpoints Clinical Measures Biomarkers Patient-Centered Outcomes Natural History

  12. Trial Execution: Outcomes CHALLENGES OPPORTUNITIES Well-defined, reliable outcome measures and endpoints Clinical Measures Biomarkers Patient-Centered Outcomes Natural History Rating Scale refinement Patient-engagement Biomarker development Consensus – preclinical and clinical outcomes Outcomes conference

  13. Trial Execution: Recruitment, Ethics CHALLENGES Participant Accrual in a timely manner Early, Accurate Diagnosis Geography Controls, Placebo Therapeutic Misconception Consent Risk/benefit

  14. Trial Execution: Recruitment, Ethics CHALLENGES OPPORTUNITIES Participant Accrual in a timely manner Early, Accurate Diagnosis Geography Controls, Placebo Therapeutic Misconception Consent Risk/benefit Patient Organization Registry development Education - NDC Symposium Telemedicine Networks – NORD, LDN, RDCRN, Centers of Excellence Education

  15. Trial Execution: Funding, Resource Allocation • Small populations = small $ = small interest • Orphan Drug Act 1983 • Orphan Product Grant Program • Academic-Industry Partnership • Funding mandates for rare disease • Consensus

  16. Melnikova, et al. Nature Reviews Drug Discovery 11, 267-268 (April 2012)

  17. Trial Execution: Clinical Trialists CHALLENGES Dwindling number of clinician scientists Statland, et al. Neurology 2012; 79: e106-108

  18. Trial Execution: Clinical Trialists CHALLENGES OPPORTUNITIES Dwindling number of clinician scientists Experimental Therapeutics Fellowships NINDS Clinical Trial Methods Course ASENT Training for Neurotherapeutics Discovery NeuroNEXT Statland, et al. Neurology 2012; 79: e106-108

  19. INCL – HuCNS-SC • Design: open-label, single group • Sample size = 3 • Recruitment: siblings with INCL • Outcomes: developmental assessment, EEG, ERG, VEPs, Tc-HMPAO SPECT, MRI, PPT1 enzyme activity Lonnqvist, et al. Hematopoietic stem cell transplantation in infantile neuronal ceroid lipofuscinosis. Neurology 2001;57:1411–1416

  20. INCL - Cystagon • Design: open-label, single group • Sample size = 10 • Inclusion restriction: patients with specific PPT1 mutations; restricted age range • Centrally conducted – NIH • Outcomes: MRI, EEG, ERG, VEP, skin biopsy http://clinicaltrials.gov/ct2/show/NCT00028262?term=cystagon&rank=6

  21. LINCL – AAV2CUhCLN2 • Design: open-label case series, sequential • Sample size = 11- Group A severe (5), Group B moderate (6) • Outcomes: safety and efficacy- LINCL clinical rating scale, MRI/MRS http://clinicaltrials.gov/ct2/show/NCT00151216?term=LINCL&rank=1

  22. INCL/LINCL – HuCNS-SC

  23. JNCL - Mycophenolate • Design: Phase II crossover study • Sample size = 30 • Recruitment: BDSRA, contact registry • Measures: UBDRS • 1o outcome: tolerability • 2o outcomes: safety, preliminary efficacy http://clinicaltrials.gov/ct2/show/NCT01399047?term=mycophenolate+jncl&rank=1

  24. Jonathan Mink, MD, PhD • Frederick Marshall, MD • Heather Adams, PhD • Amy Vierhile, NP • Elisabeth de Blieck, MPA • Jennifer Kwon, MD, MPH • Paul Rothberg, PhD • Alyssa Thatcher • Sara Defendorf • Chris Beck, PhD • Laurie Seltzer, MD • Jennifer Cialone, MD

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