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Drug Safety Challenges: Considerations for Sources of Data. Gerald J. Dal Pan, MD, MHS Director Office of Drug Safety Center for Drug Evaluation and Research FDA. Known Side Effects. Avoidable. Unavoidable. Preventable Adverse Events. Injury or Death.

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drug safety challenges considerations for sources of data

Drug Safety Challenges:Considerations for Sources of Data

Gerald J. Dal Pan, MD, MHS

Director

Office of Drug Safety

Center for Drug Evaluation and Research

FDA

sources of risk from medical products

Known Side Effects

Avoidable

Unavoidable

Preventable

Adverse Events

Injury or Death

Sources of Risk From Medical Products

Medication and

Device Errors

Product Defects

  • Remaining
  • Uncertainties:
  • Unexpected side effects
  • Unstudied uses
  • Unstudied populations
post marketing drug safety risk assessment identification of new adverse events
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
post marketing drug safety risk assessment what pre marketing safety data tell us

Product Label

Post-marketing Drug Safety Risk Assessment:What Pre-marketing Safety Data Tell Us

Pre-clinical

Pharmacology

And Toxicology

Clinical

Pharmacology

Pre-Marketing

Safety Data

Clinical Safety Data

Controlled Studies

Clinical Safety Data

Open-label Studies

post marketing drug safety risk assessment identification of new adverse events1

Market Introduction

Post-marketing Period

Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events

Pre-marketing

Safety Data

how post marketing adverse event reports get to fda

voluntary

voluntary

Manufacturer

FDA MedWatch

FDA

FDA’s Adverse Event Reporting System (AERS) database

How post-marketing adverse event reports get to FDA

Patients, consumer, and healthcare professionals

regulatory requirements

post marketing drug safety risk assessment identification of new adverse events2

Market Introduction

Pre-marketing

Safety Data

Post-marketing Period

Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events

?

?

?

post marketing drug safety risk assessment identification of new adverse events3

Market Introduction

Pre-marketing

Safety Data

Post-marketing Period

Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events

Rare but serious adverse event

  • Aplastic anemia
  • Drug-induced liver injury
post marketing drug safety risk assessment identification of new adverse events4

Market Introduction

Pre-marketing

Safety Data

Post-marketing Period

Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events

Also common in the population

  • Myocardial infarction
post marketing drug safety risk assessment identification of new adverse events5

Market Introduction

Pre-marketing

Safety Data

Post-marketing Period

Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events

Also a manifestation of the underlying disease

  • Myocardial infarction
post marketing drug safety risk assessment identification of new adverse events6

Market Introduction

Pre-marketing

Safety Data

Post-marketing Period

Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events

How do we separate a potential signal from the background?

post marketing drug safety risk assessment investigation of new adverse event risk

Rare but serious adverse event

Market Introduction

Intensive case evaluation

Pre-marketing

Safety Data

Post-marketing Period

Look back at pre-marketing safety database

Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk
post marketing drug safety risk assessment investigation of new adverse event risk1

Common in the population OR

Manifestation of the underlying disease

Market Introduction

Intensive case

evaluation

Pre-marketing

Safety Data

Post-marketing Period

Look back at pre-marketing

safety database

Still hard to establish

and quantify risk

Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk
post marketing drug safety risk assessment investigation of new adverse event risk2

Treatment of Interest

Random Allocation

Control Treatment

Follow-up Period

Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk

Clinical Trial

post marketing drug safety risk assessment investigation of new adverse event risk3

Treatment of Interest

Random Allocation

Control Treatment

Follow-up Period

Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk

Clinical Trial

post marketing drug safety risk assessment investigation of new adverse event risk4

Excess Risk

Treatment of Interest

Random Allocation

Risk Ratio

Control Treatment

Follow-up Period

Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk

Clinical Trial

alternative sources of information
Alternative Sources of Information
  • Large health care utilization databases
  • Electronic medical record systems
  • Registries
  • Can be used for active surveillance or to answer specific drug safety questions
heath care utilization databases
Heath Care Utilization Databases
  • Large, population-based, integrated pharmacy and medical claims databases
    • filled prescriptions
    • professional services
    • hospitalizations
  • Can capture real-world practice patterns, in the context of the system that gives rise to the data (in US, generally within a given health insurance plan or set of plans)
heath care utilization databases1
Heath Care Utilization Databases
  • Strengths
    • size
    • based on actual care
    • data already collected
  • Limitations
    • specific clinical data not present
    • lack of some important health-related information (eg, smoking status)
    • only captures what is billed for
    • frequent patient turnover as insurance changes
post marketing drug safety risk assessment investigation of new adverse event risk5

Relative risk or hazard ratio

Start observation

Time

Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk

Epidemiological Study - Cohort Study

example of a cohort study statins and hospitalized rhabdomyolysis
Example of a cohort study:Statins and hospitalized rhabdomyolysis

Cohort: Drug-specific inception cohorts of statin and fibrate users, based on data from 11 US health plans using automated claims covering prescription drugs, outpatient care, hospitalizations, and medical procedures

Exposure: Algorithm developed to calculate person-time on drug for each patient based on prescription claims. Separate classifications for monotherapy and statin-fibrate combination therapy

Outcome: Medical record review of all patients based on hospitalization claims with at least one ICD-9-CM code suggestive of severe muscle injury, followed by a blinded review to determine cases of rhabdomyolysis.

Source: Graham D et al. JAMA 2004;292:25885-2590

example of a cohort study statins and hospitalized rhabdomyolysis1
Example of a cohort study:Statins and hospitalized rhabdomyolysis

Analysis: Relative risk estimates of rhabdomyolysis, adjusted for age, sex, and diabetes mellitus were calculated using Poisson regression. Incidence rates per 10,000 person-years of treatment, with 95% CIs, were calculated.

Source: Graham D et al. JAMA 2004;292:25885-2590

electronic medical records
Electronic Medical Records
  • Contain more information than claims databases:
    • medications prescribed
    • detail clinical information (eg, symptoms and signs)
    • physical examination results
    • results of diagnostic tests
  • Example: General Practitioner Research Database (GPRD)
post marketing drug safety risk assessment investigation of new adverse event risk6

Persons with disease of interest

Case-control studies

Study natural history or survival

Estimate magnitude of problem

Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk

Registry

post marketing drug safety risk assessment investigation of new adverse event risk7

Persons with exposure of interest

Risk factors for exposure

Outcome of exposure

Estimate magnitude of exposure

Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk

Registry

use of a postmarketing registry antiepileptic drugs and teratogenicity

Enrollment

7 months

Postpartum

Birth

Outcome ascertainment

Use of a Postmarketing Registry:Antiepileptic Drugs and Teratogenicity

Pregnant women with epilepsy on valproic acid

149 VPA-exposed, 16 with major malformations (10.7%, 95% CI: 6.3-16.9)

Internal comparator rate: 2.9% (95% CI: 2.0-4.1)

External comparator rate: 1.62%

Source: Wyszynski DF et al. Neurology 2005;64:961-965

new database acquisitions
New Database Acquisitions
  • Four organizations with linked pharmacy-medical claims databases
  • Contracts signed September 2005
  • Allows for collaborations between FDA epidemiologists and experts at these organizations
  • Four organizations:
    • HMO Research Network/Harvard Pilgrim Health
    • Kaiser Family Foundation
    • Vanderbilt University
    • Ingenix (i3Drug Safety)
new database acquisitions1
New Database Acquisitions
  • Four organizations:
    • Harvard Pilgrim Health/HMO Research Network
      • Eight geographically diverse health plans with 3.2 million members
      • Electronic medical records available for 6 of 8 sites
    • Kaiser Family Foundation
      • 6.1 current members in northern and southern California
      • Fully integrated databases, linked to vital statistics and cancer registries
      • Unique formulary limited to selected drugs and indications
    • Vanderbilt University
      • Two state Medicaid populations (Tennessee and Washington)
      • 2.2 millions members, some at high medical risk (eg, the poor, nursing home residents)
    • Ingenix
      • Geographically diverse insured population of 12 million members
      • Some laboratory data also available
active surveillance
Active Surveillance
  • Request for Information issued April 2005
  • Responses received June 2005
  • Responses currently under review
  • Agency will decide on next steps
cms interactions
CMS Interactions
  • ODS epidemiogists are working with CMS and AHRQ staff to understand better the nature of CMS data
  • Current efforts focused on using Part B data for a pilot drug safety study
  • Still in learning/exploratory stages