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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
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)

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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 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)
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

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
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Tobacco Merchants Association, Williamsburg, VA
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
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
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
Tobacco Merchants Association, Williamsburg, VA
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
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 Investigation
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QC of Intake
Coding, Assessment
Narrative
Active Query Generation
 Integrity

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
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
Tobacco Merchants Association, Williamsburg, VA
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
Tobacco Merchants Association, Williamsburg, VA
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
Tobacco Merchants Association, Williamsburg, VA
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
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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
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
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
utrinks@foresight-grp.com
Tobacco Merchants Association, Williamsburg, VA