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?
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Federal Regulations
In the beginning, there was chaos…
Then someone created the regulations…
And made things worse!
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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
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Current Pharmaceutical Development Process
Phase 1
12-18 months
Poor
understanding of
disease and lack
of predictive
capabilities
Phase 2a
Phase 2b
15 months
18 months
Decision points often rate limiting
Ethical concerns regarding placebo
controlled trials
Phase 3
35 months
High late stage
attrition
Commercial
Efficacy
Patient ‘wastage’ in dose ranging trials
High attrition –
large number of
NME’s needed
Safety ensures it is not a “rat poison”
Minimal Safety
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“Reasonable”
Safety
established in
majority of
population
Registration
12-18 months
Patients exposed
to non-efficacous
drugs (> 50%)
Side effects and
drug interactions
emerge postlaunch
FDA Motto
“In God we trust,
all others need to bring data”
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GxP
GLP
GMP GCP
IND
Drug
Discovery
Preclinical
Research
Preclinical
Development
ADME, Tox
TRD
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NDA Approval
Clinical Development
Ph 0 Ph I Ph II Ph III
Ph IV
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
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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)
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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
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Data Entry and Retrieval
Systems Documentation
Systems Controls
Change Control
Training of Personnel
Validation Process
Application
Validation
Governing SOPs and
Policies
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Layered Software
Operational
Qualification
Hardware/OS
Installation
Qualification
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
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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.
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Systems Development Lifecycle
Archiving
Mandate
Risk
Assessment
User
Requirements
Systems
Decommission
Change
Management
Systems
Release
Documentation
Training
Buy - Build
Technical
Specifications
Validation
Plan (Protocol)
Validation
Report
IQ, OQ, PQ
Programming
PQ
Scripts
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Traceability
Matrix
Systems
Test
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
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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
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Pharmacovigilance
Adverse Events from all Sources
Adverse Event Assessment & Data Entry
Expedited
Safety
Reports
Risk Management
Planning
Safety
Database
Benefit-Risk
Balance
Assessment
Signal Detection/
Query Handling
Reports
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Expert
Review
PSURs
Signal
Evaluation
Actions
Epidemiological Studies Clinical Development
The three I’s of Safety
Intake
Investigation
QC of Intake
Coding, Assessment
Narrative
Active Query Generation
Integrity
QC of Investigation
Company Assessment
Causality
Query Approval
Intake
Metrics and Case Management
Complete data Entry
Auto-coding, Auto-Narrative
Attach Source
QC
Investigation
QC
Integrity
QC
Reporting
File
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Revisions
Safety System Costs - Implementation
Config & Validation
20%
Vendor Audit
2%
Project Mgmt
17%
SOP
6%
HW
15%
Installation
12%
SW
28%
Implementation: $ 0.5 -1.5 Mio
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Safety System Costs - Operations
MedDRA Upgrade
13%
OS and DB Upgrade
41%
WHODrug Upgrade
3%
Software
Maintenance
15%
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
• Safety issue and
signal identification
• Safety / risk
management /
monitoring plans
Case Mgmt &
Operations
• Case processing
and submission
for Adverse Event
reports
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Systems
• Maintenance of
safety database
and supporting
applications
• Signal detection
support
• Query support
Support
•
•
•
•
Training
QA
Compliance
Process Mgmt and
Control
• Standards
• Project Mgmt
• Affiliate Control
Medical Surveill
& Epi
•
•
•
•
Aggregate Reports
Safety Summaries
Queries
Epidemiological
Analyses
• Medical Review of
cases
• Signal Identification
and Analysis
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
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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
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The new Safety Data Collection
Patients
Collect Demographics and
Basic Data
Drug correctly administered
and well tolerated
Collect additionally Patient History and
Health Records
Known Problem
Known Cause
Additionally request (and pay for) Lab
Tests, Collect DNA (if consent)
Unknown
Serious
Additionally enroll Patient in Follow-up
Monitoring Program.
Change Treatment
Related
Collect everything possible, especially Autopsy
Reports, Issue Warnings
Death
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What now?
“You cannot tailor-make the situations in life,
but you can tailor-make the attitudes to fit
those situations”
Zig Ziglar
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[email protected]
Tobacco Merchants Association, Williamsburg, VA