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Label Enabling Clinical Trials: What Could Be Simpler ?!

Label Enabling Clinical Trials: What Could Be Simpler ?!. William E. Smoyer, M.D. C. Robert Kidder Chair, Vice President and Director, Center for Clinical and Translational Research The Research Institute at Nationwide Children’s Hospital Professor of Pediatrics, The Ohio State University

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Label Enabling Clinical Trials: What Could Be Simpler ?!

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  1. Label Enabling Clinical Trials: What Could Be Simpler ?! William E. Smoyer, M.D. C. Robert Kidder Chair, Vice President and Director, Center for Clinical and Translational Research The Research Institute at Nationwide Children’s Hospital Professor of Pediatrics, The Ohio State University FDA Pediatric Clinical Investigator Training Workshop Silver Spring, MD February 28, 2019

  2. Overview • Early Research Career (Basic) • Translation of Basic Science Findings • Research Compounds / FDA-Approved Drugs • Early Efforts to Develop a Clinical Trial • Design • Investigator-Initiated vs. Industry-Sponsored • Investigational New Drug (IND) Application • Conversion to FDA Label-Enabling Trial • Lessons Learned… :-o

  3. Early Research Career (Basic)

  4. Early to Mid Career • B.S. in Engineering (Univ. of FL) • M.D. at Univ. of FL • Pediatric Residency at UTMB (Galveston) • Nephrology Fellowships • CHOP • Boston Children’s • Assistant Professor (Univ. of MI) • Podocyte biology • Molecular mechanisms of podocyte injury during NS • Associate Professor / Professor (Univ. of MI) • Fellowship Director / Division Director

  5. Translation ofBasic Science Findings

  6. Translation of Basic Science Findings • Nephrotic Syndrome • Among most common kidney diseases in children • Clinical: • Massive proteinuria / Hypoalbuminemia / Edema • Molecular: • ? Circulating factors  Podocyte injury • Treatment: • Glucocorticoids • Podocyte biology  Molecular mechanisms of glucocorticoid action in podocytes during NS

  7. Translation of Basic Science Findings • Developed interest in drugs already approved by FDA for other uses that might potentially also be effective in NS • Drug “repurposing” … • 1) Glucocorticoids • Approved by FDA in 1950s (prior to expectation for efficacy) • 2) Pioglitazone • PPARg agonist (TZD) • Originally developed to treat diabetes (insulin sensitizer) • 3) Rituximab • Anti-CD20 mAb directed at B cells • Originally developed for cancer (B cell NHL) • Subsequently found to induce remission in NS

  8. Canonical and Alternate Modesof Action of PPARg Agonists (Greenbaum, Benndorf, Smoyer, Nat Rev Nephrol, 2012 )

  9. Pioglitazone Protects Podocytes from Injury Similar to Steroids (Agrawal, Smoyer, et al., Molec Pharm, 2011)

  10. Pioglitazone Reduces PAN-Induced Proteinuria (Agrawal, Smoyer, et al., Scientific Reports, 2016 )

  11. Pioglitazone Effectively Reduces Proteinuria in a Child with SRNS

  12. Early Efforts toDevelop a Clinical Trial

  13. Early Efforts to Develop a Trial • Rituximab recently found to dramatically prolong remissions vs. control infusions in Japan * • Led to Japanese FDA approval for NS • Developed plans for a randomized controlled trial • Planned to compare Rituximab to currently used alternative NS treatment (MMF) • NOT “does it work” but “is it better than current care”... • Created Randomized Controlled Trial (RCT) design • Direct comparison of IV Rituximab vs. oral MMF (RAMP Study) • IND application filed and approved by FDA • Submitted trial as an NIDDK U34 application… twice… :-o • Scored twice… but not funded ! • (* Iijima K et al., Lancet, 2014 )

  14. Early Efforts to Develop a Trial • Expected outcome: Trial not able to be performed… • Instead… We approached manufacturer (GNE) again… • Would you again agree to pay for drug? • Would you also agree to fund entire trial?!!! • Would you still agree for trial to be Investigator-Initiated (IIT) ? • GNE agreed on basis of unmet need in Peds. Nephrology • Numerous conference calls  multiple protocols (~8) • GNE input • Academic Key Opinion Leaders (KOLs) in NS • Outstanding scientific collaboration (GNE – Academics) • Very difficult contract negotiations (GNE – Contracting) • Aggressive legal / financial positions…no interest in compromise..

  15. Conversion toFDA Label-Enabling Trial

  16. Conversion to FDALabel-Enabling Clinical Trial • Email from FDA 9 months later • Asked to submit request for Type B meeting (90 min) • FDA interested in converting trial to label-enabling study ! • Discussions with GNE • Supportive of change (but VERY surprised!) • Agreed to provide >10 years of safety data • Agreed to attend FDA meeting (NOT as sponsor…) • Extensive preparation for FDA meeting • Outstanding mentorship by GNE scientists/regulators !

  17. Conversion to FDALabel-Enabling Clinical Trial • FDA Type B meeting went well ! • FDA recommendations led to numerous trial design changes • Overall notably improved trial design …  • Extensive process to alter RAMP Study (9 month delay!) • Gain nephrologists’ support for changes • Amend IRBs / Informed consents (x10) • Amend contracts (more rigorous data/sample collection) • GNE refused additional funds for FDA-suggested changes • Trial halted after first 3 patients enrolled ! • GNE closed funding program due to end of commercial lifespan • PI (Sponsor) left with ~$57,000 in unreimbursed expenses !

  18. Lessons Learned…

  19. Lessons Learned… • Challenging to design high-quality pediatric clinical trial • Scientifically innovative with potential to improve care • Close enough to standard of care to attract site PIs / Parents • Obtain site PI/RN feedback early to achieve best design • Scientific (feasibility, etc.) / Operational (budget, sample handling, etc.) • Effective but realistic inclusion / exclusion criteria • Achieve scientific goals / Adequate eligible patients available • Academic–Industry partnerships have enormous potential • More resources, but also more complicated … • Contracting with Industry Partner requires expertise ! • Clinical Research / Contracting / Legal / Tech Commercialization • Data ownership vs. Data usage / Intellectual Property / Publication • NEED to include up-front funding for planning and start-up !!! • DO NOT accept only per-patient funding !!!

  20. Lessons Learned… • Contracting with Sites critical ! • Sufficient funds to perform ALL required activities • Strong and clear performance and payment expectations… • Aim for the greatest impact for your clinical trials !!! • Publication of clinical trial results important… But NOT sufficient ! • Obtaining IND approval also very valuable ! • Adding information to (or creating) an FDA a label can greatly enhance impact of your clinical trial on child health • FDA approval certifies drug is both safe and effective ! • FDA approval ensures insurance coverage for treatment... • Ideal Goal: Strive to perform FDA label–enabling studies !

  21. Nationwide Children’s Hospital

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