drug safety and risk management advisory committee may 18-19, 2005 1 overview of drug safety...
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Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
1
Overview of Drug Safety Challenges
Gerald J. Dal Pan, MD, MHS
Director
Division of Surveillance, Research & Communication Support
Office of Drug Safety
FDA
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
2
Post-marketing Drug Safety Risk Assessment:Multifaceted Challenges
• Identification of new adverse events
• Investigation of risk
• Characterization of context
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
3
Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
• A fundamental goal of post-marketing drug safety programs
• Must account for many different types of risk
• Must account for many potentially confounding factors
• Must account for time course of events
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
4
Post-marketing Drug Safety Risk Assessment:What Pre-marketing Safety Data Tell Us
Pre-clinicalPharmacology
And Toxicology
ClinicalPharmacology
Clinical Safety DataOpen-label Studies
Clinical Safety DataControlled Studies
Pre-MarketingSafety Data
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
5
Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
? ? ?
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Rare but serious adverse event
•Aplastic anemia
•Drug-induced liver injury
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Also common in the population
•Myocardial infarction
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Also a manifestation of the underlying disease
•Myocardial infarction
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
10
Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
How do we separate a potential signal from the background?
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Long latency between drug exposure and event
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
12
Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Multiple Effect Modifiers
Drug-drug, drug-disease, drug-herbal, drug-food interactions
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
13
Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Proper Identification of Medication Errors
Medication Errors
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
14
Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Rare but serious adverse event
Intensive case evaluation
Look back at pre-marketing safety database
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Common in the population OR
Manifestation of the underlying disease
Intensive case
evaluation
Look back at pre-marketing
safety databaseStill hard to establish
and quantify risk
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskClinical Trial
Random Allocation
Treatment of Interest
Control Treatment
Follow-up Period
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
17
Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskClinical Trial
Random Allocation
Treatment of Interest
Control Treatment
Follow-up Period
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
18
Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskClinical Trial
Random Allocation
Treatment of Interest
Control Treatment
Follow-up Period
Excess Risk
Risk Ratio
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskEpidemiological Study - Case-Control
Case Ascertainment
Control Ascertainment
Exposure
Ascertainment
Treatment No Treatment
Case
Control
Odds Ratio
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskEpidemiological Study - Cohort Study
Start observation Time
Relative risk or hazard ratio
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskRegistry
Case-control studies
Estimate magnitude of problem
Study natural history or survival
Persons with disease of interest
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskRegistry
Risk factors for exposure
Estimate magnitude of exposure
Outcome of exposure
Persons with exposure of interest
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Understanding Context - Duration of Exposure
Duration of Exposure
Ris
k
Initial Exposure
Critical period to study
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Understanding Context - Population Exposure
Duration of Exposure
Num
ber
of P
erso
ns E
xpos
ed
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
25
Post-marketing Drug Safety Risk Assessment:Understanding Context - Population Exposure
Duration of Exposure
Num
ber
of P
erso
ns E
xpos
ed
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
26
Post-marketing Drug Safety Risk Assessment:Understanding Context - Population Exposure
Duration of Exposure
Num
ber
of P
erso
ns E
xpos
ed
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
27
Post-marketing Drug Safety Risk Assessment:Understanding Context
Duration of Exposure
Num
ber
of P
erso
ns
Exp
osed
Duration of Exposure
Ris
k
Potential for many adverse events
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
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Post-marketing Drug Safety Risk Assessment:Understanding Context: Concomitant Use
No concomitant
use
A B
Population database studies can help us
understand where risk exists in the population
Prevalence of Concomitant Use
Pre
vale
nce
of
Adv
erse
Eve
nts
High level concomitant
use
A B
Low level concomitant
use
A B
Drug Safety and Risk Management Advisory CommitteeMay 18-19, 2005
29
Post-marketing Drug Safety Risk Assessment:Summary
• Multifaceted challenges
• Many ways to explore risk
• Context can be important