drug safety and risk management advisory committee may 18-19, 2005 1 overview of drug safety...

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

6

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

7

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

8

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

9

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

11

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

15

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

16

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

19

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

20

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

21

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

22

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

23

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

24

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

28

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