Dealing with the FDA – The Pharma Experience Uwe P. Trinks, Ph.D TMA Annual Meeting, Williamsburg, VA

1. Dealing with the FDA –The Pharma ExperienceUwe P. Trinks, Ph.DTMA Annual Meeting, Williamsburg, VA

2. Agenda • The World of FDA • Code of Federal Regulations • Drug Development and Approval • GLP, GCP, GMP • Computerized Systems Validation • 21 CFR Part 11 • Systems Development Life Cycle Management • Change Control • Risk Management • Pre- and Post-marketing Safety • FDAAA • REMS and RiskMAP • What now?

3. Federal Regulations In the beginning, there was chaos… Then someone created the regulations… And made things worse!

4. US Code of Federal Regulations • 50 Titles (Books) • Title 21: Food and Drugs • Clinical Trials: Part 50, GLP: Part 58 • GMP: Part 210 et al. • Drug Safety: 21 CFR Parts 310, 312, 314, 320, 600, 601, and 606 • Devices: 21 CFR Part 803 • Quality: 21 CFR Part 820 • Electronic Signatures: 21 CFR Part 11 • HIPAA: 45 CFR Part 160 - 164

5. Poor understanding of disease and lack of predictive capabilities High attrition – large number of NME’s needed Minimal Safety Decision points often rate limiting Ethical concerns regarding placebo controlled trials Patient ‘wastage’ in dose ranging trials Safety ensures it is not a “rat poison” High late stage attrition Commercial Efficacy “Reasonable” Safety established in majority of population Patients exposed to non-efficacous drugs (> 50%) Side effects and drug interactions emerge post-launch Current Pharmaceutical Development Process Phase 1 Phase 2a Phase 2b Phase 3 Registration 12-18 months 15 months 18 months 35 months 12-18 months

6. FDA Motto “In God we trust, all others need to bring data”

7. GLP GMP GCP GxP IND NDA Approval Drug Discovery Preclinical Research Preclinical Development ADME, Tox TRD Clinical Development Ph 0 Ph I Ph II Ph III Ph IV

8. GxP • Good Laboratory Practices (Part 58) • Animal Handling, Lab Test, Laboratory Notebooks, SOPs etc. • Good Manufacturing Practices (Part 210, 211) • Process, Shop Floor Control, Manufacturing, QC, QA, Handling and Shipping, SOPs etc. • Quality Mgmt System (Part 820) • Good Clinical Practices (Part 310, 312, 314) • Protocols, Trial Design, Trial Site Monitoring, Statistics, QC, QA, Clinical data Management, SOPs etc. • Computerized Systems Validation (Part 11) • Predicate Rules: GCP/GLP/GMP (GxP) • FDA Guidances • Industry Guidance G@MP

9. Computerized Systems Validation • Definition • Establishing documented evidence which provides a high degree of assurance that a computerized system will consistently perform according to predetermined specifications and quality attributes • FDA’s cGMP for the 21st Century • Risk based approach to CSV • Tailored Validation Approach • 21 CFR Part 11 • Electronic signatures • “Mother of all laws” for CSV • 45 CFR Part 160-164 (HIPAA) • Privacy Rule 160 • Security Rule 162 –164 • IT best practices document • FDA Guidance Documents • Electronic Signatures (2003) • Computerized Systems in Clinical Trials (1999) • General Principles of Software Validation (2002)

10. 21 CFR Part 11 Guidance • Supersedes all old Guidance Documents • Contains detailed Recommendations on • Study Protocol • SOPs • Source Documents and Retention • Internal and External Security Safeguards • System Features such as • Data Entry and Retrieval • Systems Documentation • Systems Controls • Change Control • Training of Personnel

11. Validation Process

12. Why Validate ? • It’s good business practice • FDA’s reaction to non-compliance • Form 483 • FDA form, used to report inspectoral observations • Usually combined with timelines to fix the problems • Addressed to Top-Management • Usually results in another inspection • Warning Letter • Published letter by the FDA • Reports that a company has not satisfactory corrected problems previously cited in a 483 • Usually combined with a threat of action • Extremely damaging to a company’s reputation

13. Systems Development Lifecycle An approach to computer system development that begins with identification of the user's requirements; continues through design, integration, qualification, validation, control, and maintenance; and ends only when commercial use of the system is discontinued.

14. Change Management Systems Development Lifecycle Archiving Mandate Systems Decommission Risk Assessment User Requirements Systems Release Buy - Build Documentation Training Technical Specifications Validation Report Validation Plan (Protocol) IQ, OQ, PQ Programming Systems Test PQ Scripts Traceability Matrix

15. Risk Management

16. Risk - Benefit • Benefit poorly understood • Efficacy ≠ Benefit • Risk hard to quantify • Even harder to disproof • Risk Benefit Management is the constant measure, assessment, mitigation and communication of risk against demonstrable benefit • Based on a solid, scientifically sound platform for data collection and processing

17. FDAAA 2007 • Title I – Prescription Drug User Fee Amendments • Title II – Medical Device User Fee Amendments • Title III – Pediatric Medical Device Safety and Improvement Act • Title IV – Pediatric Research Equity Act • Title V – Best Pharmaceuticals for Children Act • Title VI – Reagan-Udall Foundation • Title VII – Conflicts of Interest • Title VIII – Clinical Trial Database • Title IX – Enhanced Authorities Regarding Post-market Safety of Drugs • Title X – Food Safety • Title XI – Other Provisions

18. Adverse Events from all Sources Expedited Safety Reports PSURs Pharmacovigilance Adverse Event Assessment & Data Entry Expert Review Safety Database Risk Management Planning Signal Detection/ Query Handling Signal Evaluation Actions Benefit-Risk Balance Assessment Reports Epidemiological Studies Clinical Development

19. The three I’s of Safety • Intake • Complete data Entry • Auto-coding, Auto-Narrative • Attach Source • Investigation • QC of Intake • Coding, Assessment • Narrative • Active Query Generation • Integrity • QC of Investigation • Company Assessment • Causality • Query Approval Intake Metrics and Case Management QC Investigation QC Integrity Revisions QC Reporting File

20. Safety System Costs- Implementation Implementation: $ 0.5 -1.5 Mio

21. Safety System Costs - Operations Annual Operation: $ 0.4 - 1.2 Mio

22. Pharmaceutical Safety Department • Expedited Safety Reports (7 day, 15 day) • Periodic Reports (Quarterly – Annually) • Risk Evaluation and Mitigation Systems Head of Safety Clinical Safety Case Mgmt & Operations Systems Support Medical Surveill & Epi • Safety issue and signal identification • Safety / risk management / monitoring plans • Case processing and submission for Adverse Event reports • Maintenance of safety database and supporting applications • Signal detection support • Query support • Training • QA • Compliance • Process Mgmt and Control • Standards • Project Mgmt • Affiliate Control • Aggregate Reports • Safety Summaries • Queries • Epidemiological Analyses • Medical Review of cases • Signal Identification and Analysis

23. Components of Risk Management Plans Safety Specifications Summary of important identified risks, important potential risks and missing Information (ICH E2E) Pharmacovigilance Plan Based on Safety Specifications: Routine PV practices and Action plan to investigate specific safety concerns (ICH E2E) Risk Minimization REMS Activities to be taken to minimize the impact of specific safety concerns on the Benefit-Risk balance

24. Risk Evaluation and Minimization (REMS) • Communication plan to Health Care Professionals • Medication guide or patient package insert • Patient registries • HCP education/certification • Restricted distribution programs • Limitations on HCP who may administer the drug • Patient certification • Limitations on the patients who may use the drug • Linked prescribing/dispensing to lab tests • Regular measurements of effectiveness (1.5, 3, 7 years) • Failure to comply • Penalties from $ 250,000 to $ 1,000,000 per incident • After warning $ 250,000 per 30 days, doubling every 30 days up to $ 10,000,000 per singleincident

25. Drug correctly administered and well tolerated Known Problem Known Cause Unknown Serious Related Death The new Safety Data Collection Patients Collect Demographics and Basic Data Collect additionally Patient History and Health Records Additionally request (and pay for) Lab Tests, Collect DNA (if consent) Additionally enroll Patient in Follow-up Monitoring Program. Change Treatment Collect everything possible, especially Autopsy Reports, Issue Warnings

26. What now? “You cannot tailor-make the situations in life, but you can tailor-make the attitudes to fit those situations” Zig Ziglar

27. Thank you! utrinks@foresight-grp.com