Transcript DSG - TMA
Dealing with the FDA – The Pharma Experience
Uwe P. Trinks, Ph.D
TMA Annual Meeting, Williamsburg, VA
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?
Tobacco Merchants Association, Williamsburg, VA
Federal Regulations
In the beginning, there was chaos… Then someone created the regulations… And made things worse!
Tobacco Merchants Association, Williamsburg, VA
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 Tobacco Merchants Association, Williamsburg, VA
Current Pharmaceutical Development Process
Phase 1 Phase 2a Phase 2b Phase 3 Registration 12-18 months Poor understanding of disease and lack of predictive capabilities High attrition – large number of NME’s needed Minimal Safety 15 months 18 months 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” 35 months High late stage attrition Commercial Efficacy “Reasonable” Safety established in majority of population 12-18 months Patients exposed to non-efficacous drugs (> 50%) Side effects and drug interactions emerge post launch
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FDA Motto
“ In God we trust, all others need to bring data” Tobacco Merchants Association, Williamsburg, VA
GxP
GLP GMP GCP
IND NDA Approval
Drug Discovery Preclinical Research Preclinical Development ADME, Tox TRD Clinical Development Ph 0 Ph I Ph II Ph III Ph IV Tobacco Merchants Association, Williamsburg, VA
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 Tobacco Merchants Association, Williamsburg, VA
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 21 st 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) Tobacco Merchants Association, Williamsburg, VA
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 Tobacco Merchants Association, Williamsburg, VA
Validation Process
Governing SOPs and Policies Application Validation Layered Software Operational Qualification Hardware/OS Installation Qualification Tobacco Merchants Association, Williamsburg, VA
Why Validate ?
It ’ s good business practice FDA ’ s reaction to non-compliance
Form 483
FDA form, used to report inspectoral Usually combined with timelines to fix the problems Addressed to Top-Management Usually results in another inspection observations
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 Tobacco Merchants Association, Williamsburg, VA
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.
Tobacco Merchants Association, Williamsburg, VA
Systems Development Lifecycle
Mandate Risk Assessment User Requirements
Buy - Build
Technical Specifications Validation Plan (Protocol) Programming PQ Scripts Archiving Systems Decommission Change Management Systems Release Documentation Training Validation Report IQ, OQ, PQ Traceability Matrix Systems Test Tobacco Merchants Association, Williamsburg, VA
Risk Management
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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 Tobacco Merchants Association, Williamsburg, VA
FDAAA 2007
Title I – Title II – Title III – Prescription Drug User Fee Amendments Medical Device User Fee Amendments Pediatric Medical Device Safety and Improvement Act Title IV – Title V – Pediatric Research Equity Act 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 – Title XI – Food Safety Other Provisions Tobacco Merchants Association, Williamsburg, VA
Pharmacovigilance
Adverse Events from all Sources Risk Management Planning Benefit-Risk Balance Assessment Adverse Event Assessment & Data Entry Expedited Safety Reports Expert Review Safety Database PSURs Signal Detection/ Query Handling Signal Evaluation Actions Reports Epidemiological Studies Clinical Development Tobacco Merchants Association, Williamsburg, VA
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 Tobacco Merchants Association, Williamsburg, VA
Intake QC Investigation QC Integrity QC Reporting File Revisions
Safety System Costs - Implementation
Config & Validation 20% SOP 6% Vendor Audit 2% Project Mgmt 17% HW 15% Installation 12% SW 28%
Implementation: $ 0.5 -1.5 Mio
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Safety System Costs - Operations
MedDRA Upgrade 13% WHODrug Upgrade 3% Software Maintenance 15% OS and DB Upgrade 41% Operations and Support 28%
Annual Operation: $ 0.4 - 1.2 Mio
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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
• 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
Support Medical Surveill & Epi
• 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 Tobacco Merchants Association, Williamsburg, VA
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 Tobacco Merchants Association, Williamsburg, VA
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 single incident Tobacco Merchants Association, Williamsburg, VA
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
Drug correctly administered and well tolerated Known Problem Known Cause Unknown Serious Tobacco Merchants Association, Williamsburg, VA
What now?
“You cannot tailor-make the situations in life, but you can tailor-make the attitudes to fit those situations” Zig Ziglar
Tobacco Merchants Association, Williamsburg, VA
Tobacco Merchants Association, Williamsburg, VA