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Overview Outline

Development and Approval of Drugs and Devices EPI260 Lecture 6: Late Phase Clinical Trials May 5, 2010 Richard Chin, M.D. Overview Outline. GXP Protocol design and writing Case report forms Investigators brochure Operations Budget; staff training Safety reporting

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Overview Outline

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  1. Development and Approval ofDrugs and DevicesEPI260 Lecture 6: Late Phase Clinical TrialsMay 5, 2010Richard Chin, M.D.

  2. Overview Outline • GXP • Protocol design and writing • Case report forms • Investigators brochure • Operations • Budget; staff training • Safety reporting • Site initiation, monitoring and closeout • Data management and data analysis • Report writing • Regulatory requirements for approval; NDA/BLA and pre-NDA meeting

  3. GXP • Good clinical practice • Good manufacturing process • Good laboratory process

  4. GCP • Goal: to protect • Patient safety • Patient rights • Data integrity • What is it? • Instructions on how to responsibly conduct a study • Process, not outcome • SOPs on all aspects of study conduct • Must exercise control over study • Must document • Must take corrective action as needed

  5. GMP • Similar but more strict than GCP • Criminal liabilities for failure • Even for intentional failures • Guilty until proven innocent • Focus on how a drug is manufactured • Lots of documentation

  6. Protocol design • Best to have CRF before protocol • Keep it short • Keep it simple • Minimize number of procedures • Minimize data collection (unless you are an academician) • Keep instructions clear • Don’t ask for more precision than you need • Work with a statistician

  7. Key Drivers of Study Design • Patient population • Dose • Endpoint

  8. Key documents • Investigators Brochure • Must list all adverse events • Protocol • CRF • ICF

  9. Operations • Project management • Multinational studies • Key personnel • Medical director • Clinical operations • Statistician • Data manager • Programmer • Project leader • Project manager • Regulatory • Safety • CMC • Pharmacology • Pharmacoeconomics • Quality • Compliance • Contracts • Finance

  10. Operations • Budget • $10,000 - $200,000 per patient • Per patient costs increase with smaller study size, longer duration, more procedures, certain specialties, number of sites, number of countries • Timeline • 12 months or more for Phase 1 • 18 months or more for Phase 2 or 3 • Key drivers for timeline: drug labeling, IRB approval, regulatory approval, contracts, enrollment, follow-up

  11. Safety Reporting • Adverse event reporting • Adverse event monitoring • Pharmacovigilance systems • Reconciling with clinical database • Breaking the blind

  12. Site Monitoring • Feasibility study • Site identification • Site qualification • Site initiation • Investigators meeting • Monitoring visits • Drug storage • ICF • Adverse events • Audits • Site closeout visits • Drug accountability

  13. Data Management and Analysis • Case report form • Statistical Analysis Plan • Data Quality Plan • % target query resolution • Maintaining the blind • DSMB • Adaptive design • Administrative looks • Safety unblinding • Electronic Data Capture • Double data entry • Query generation and resolution

  14. Data Management • Validation • IT system and CFR Part 11 • Program installation • Data listings and tables • Double programming • Dummy data • Sensitivity analysis • Imputations for missing data • Data management costs are about 25% of trial costs

  15. Report Writing • Clinical Study Reports • Integrated summary of efficacy and safety • Tables, Listing, Graphs • Trial Conduct Report

  16. Regulatory Requirements for Approval • Requirements • Risk/Benefit • Accelerated approval • Pre-NDA/BLA meeting • MAA

  17. Regulatory Requirements for Approval • Common Technical Document Format • Administrative and prescribing information • Overview and summary of modules 3 to 5 • Quality (pharmaceutical documentation) • Safety (toxicology studies) • Efficacy (clinical studies) • REMS • Filing • Rolling submission • Acceptance of filing

  18. Regulatory Requirements for Approval • PDUFA requirements • Major amendment • Advisory Committee Meeting • Approval vs. Complete Response

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