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HCC-MUSC Phase I Program Development

HCC-MUSC Phase I Program Development. Melanie B. Thomas, M.D. Associate Director of Clinical Investigations Hollings Cancer Center Associate Professor of Medicine Division of Hematology-Oncology. Clinicians Perspective: Why do we need BIOMARKERS in Clinical Trials?.

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HCC-MUSC Phase I Program Development

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  1. HCC-MUSCPhase I Program Development Melanie B. Thomas, M.D. Associate Director of Clinical Investigations Hollings Cancer Center Associate Professor of Medicine Division of Hematology-Oncology

  2. Clinicians Perspective:Why do we need BIOMARKERS in Clinical Trials? • 90% of drugs that enter Phase II clinical trials will fail. • 21% of all drugs that enter Phase I testing ever reach the market. • 2-4% of newly-diagnosed adult cancer patients enroll in clinical trials. • Of over 700,000 physicians in the US, only 4% of them have participated in clinical trials since 1988. • Tumor shrinkage (RR), the primary endpoint of most Phase II trials, is a poor biologic signal • The likelihood of new anti-cancer agent that enter Phase 1 trials reaching the commercial market? • 1993 - 14% • 2008 - 8% • The failure rate of Phase III cancer trials: • 1998 - 20% 2008 - 50%

  3. Decreased tumor vascularity, increased necrosis after 8, 16 weeks treatment with targeted agents bevacizumab and erlotinib. CT abdomen, 63 year old woman with hypervascular hepatocellular carcinoma, right lobe. Example of anti-tumor activity, but not “response” by RECIST Criteria 3

  4. Linking Targeted Agents to Molecular Targets:What is the Evidence:

  5. Drug Clinical Development - Overview BLA/NDA/MA IND Drug Discovery Phase 1 Phase 2 Phase 3 Development Preclinical GLP GMP

  6. Phase Purpose Subjects Size Length (per phase) I Safety, tolerabiltity, bioactivity, drug-drug interaction Healthy volunteers or subj. w/ indications 20-80 6-12 mos II Short-term side effects & efficacy Subjects with indications Several hundred 1-2 yrs III Safety & efficacy Basis for labeling, new formulations Subjects with indications Hundreds-thousands 2-3 yrs IV New indications, QoL, surveillance Subjects with indications Hundreds-thousands 1-5 yrs Clinical Trials - Phases

  7. Phase I • First time in human subjects • Small number of healthy volunteers or advanced disease patients who have no other options. • Establish safety profile and dosage range • Single and multi-dose studies • Pharmacokinetics / pharmacodynamics • Open label, often single center • Commonly performed ex-U.S.

  8. Phase II • Safety, side effects • Efficacy • Tumor shrinkage (RR), • Progression-free survical, overall survival • Symptom palliation, QOL • Single arm with historical controls • Randomized PII • Phase IIa – proof of concept, pilot, feasibility, usually healthy volunteers • Phase IIb – well-controlled in target population • Seek to identify a “signal” of benefit to pave the way for “pivotal trials”

  9. Phase III • 2 or 3 studies are pivotal (critical) studies • To prove safety and efficacy of primary endpoints • Double-blind, positive or placebo control, multi-center • Study population resembles the intended population • Support package labeling • New Drug Application (NDA) • Special population, concomitant medications, multiple illnesses, etc. • IIIb studies – post NDA-submission trial looking at additional indications • Pre-NDA meeting with the FDA near conclusion of Phase III • Phase III trials can change standard of care without formal FDA approval

  10. Phase IV • Post-licensure studies to confirm the safety in large population (after NDA is filed) • Phase IV commitments • Possible types of studies • Compared versus competition • Post-marketing surveillance • Special population • Rare event incidences • Additional long-term usage safety data • Pharmacoecomonic and Quality of Life (QoL) 21 CFR 312.85

  11. There Are Many Types of Phase I Trials

  12. Current Phase I Trials

  13. Upcoming Phase I Trials

  14. Investigator Initiated Trials

  15. Investigator Initiated Trials

  16. HCC-MUSC Phase I Clinical Research Support Services • HCC Phase I portfolio: • 2007 7 - trials • 2011 – 13 trials • HCC Clinical Trials Office • Review and process Confidentiality Agreements • Assist investigators with reviewing industry trials • Coordinate all Regulatory submissions • PRC, IRB, INDs, ongoing Compliance monitoring • Negotiate, resolve COI issues • Coordinate study-specific training, forms, data management • Management multi-site studies • Seasoned staff to screen, evaluate, enroll patients

  17. HCC-MUSC Phase I Clinical Research Support Services • Clinical & Translational Research Center • Outpatient unit for early-phase trials (exam, treatment rooms, lab draws, ECG etc). • Priority inpatient bed assignment, dedicated unit • Nursing support services on study-specific basis. • Specialized services • Sample procurement, processing, banking, shipping (PK, PD, biomarkers) for in-house or external analysis • Clean Room Facility: human cell isolation, processing, vaccine development. • Developing Phase I “capacity” within HCC Infusion Center • Regular weekly Phase I meeting

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