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

Dealing with the FDA –The Pharma Experience

Uwe P. Trinks, Ph.DTMA Annual Meeting, Williamsburg, VA

Tobacco Merchants Association, 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?


In the beginning, there was chaos…

Then someone created the regulations…

And made things worse!

Federal Regulations


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


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

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


FDA Motto

“In God we trust,

all others need to bring data”


GxP

Drug DiscoveryPreclinical Research

Preclinical DevelopmentADME, ToxTRD

Clinical Development

Ph 0 Ph I Ph II Ph III Ph IV

IND NDA Approval

GLP GMP GCP


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


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)


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


Validation Process

Governing SOPs and Policies

Hardware/OS Installation

Qualification

Layered Software Operational Qualification

Application Validation


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


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.


Systems Development Lifecycle

Mandate

User Requirements

Technical Specifications

ProgrammingSystems

Test

DocumentationTraining

SystemsRelease

SystemsDecommission

Archiving

RiskAssessment

ValidationPlan (Protocol)

PQScripts Traceability

Matrix

IQ, OQ, PQ

ValidationReport

ChangeManagement

Buy - Build


Risk Management


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


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


Pharmacovigilance

Adverse Events from all Sources

SafetyDatabase

Adverse Event Assessment & Data Entry

ActionsSignal

EvaluationSignal Detection/Query Handling

Risk ManagementPlanning

Benefit-RiskBalance

Assessment

PSURs

ExpeditedSafety Reports

Reports Epidemiological Studies Clinical Development

ExpertReview


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

Investigation

Integrity

Reporting

Revisions

File

Metrics an

d C

ase Man

agem

ent

QC

QC

QC


Safety System Costs - Implementation

Implementation: $ 0.5 -1.5 Mio


Safety System Costs - Operations

Annual Operation: $ 0.4 - 1.2 Mio


Pharmaceutical Safety Department

Head of Safety

Clinical SafetyCase Mgmt & Operations

Systems SupportMedical 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

• Expedited Safety Reports (7 day, 15 day)• Periodic Reports (Quarterly – Annually)• Risk Evaluation and Mitigation Systems


Components of Risk Management Plans

Safety SpecificationsSummary of important identified risks,important potential risks and missing

Information (ICH E2E)

Pharmacovigilance PlanBased on Safety Specifications: Routine PV practices and

Action plan to investigate specific safety concerns(ICH E2E)

Risk MinimizationREMS

Activities to be taken to minimize the impactof specific safety concerns on the

Benefit-Risk balance


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


The new Safety Data Collection

Collect Demographics andBasic Data

Collect additionally Patient History andHealth Records

Additionally request (and pay for) LabTests, Collect DNA (if consent)

Additionally enroll Patient in Follow-up Monitoring Program. Change Treatment

Collect everything possible, especially AutopsyReports, Issue Warnings

Drug correctly administered and well tolerated

Known ProblemKnown Cause

UnknownSerious

Related

Death

Patients


What now?

“You cannot tailor-make the situations in life, but you can tailor-make the attitudes to fit

those situations”

Zig Ziglar


[email protected]

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

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