# Presentation: 745684

**The Need for Postmarketing Drug Surveillance**
- Ralph Lillie, RPh, MPH
- Director, Office of Information Technology
- December 8, 1999

## A Medicated Population

-   Four (4) Billion Prescriptions
-   9,000 Different Medications
-   10 Billion Doses

## Historical Perspectives

- 1973:  28% of Hospitalized Patients Have Adverse Drug Reactions (AM J Hosp Pharm 1973;30:584)
- 1979:  Adverse Drug-attributed Events in 17% of Hospitalized Children (Am J Epid 1979;110:196)
- 1991:  Iatrogenic Injury:  180,000 Deaths Annually with 69% Preventable (NEJM 1991;324:370)
- 1995:  Drug-related Morbidity/Mortality Estimated at $77 Billion (Arch Int Med 1995;155:1949)

## Newer Information

- 1998:  Estimate 106,000 Deaths Annually Due to Adverse Drug Reactions (JAMA 1998;279:1200-1205)
- 1999:  Estimate 98,000 Deaths Annually Due to Medical Mistakes (Washington Post - Institute of Medicine, December 1999)

## Postmarketing Surveillance  Challenges

- What Problem Are We Trying to Solve?
- All Medical Products are Associated with Inherent Risks
- Risk Management is Complex - Many Partners in Process

## Why Postmarketing Surveillance?

- Limitations of Phase 3 Trials
- Too small, too short, too healthy
- Population of Users Expands After Drug Approval
- Age (Children/Elderly), Sex, Race/Ethnicity, Use in pregnancy
- Rare Events
- _Window_ to Actual Impact of Drug

**Notes:**
Phase  3 trials are generally too small enrolliing hundreds and rarely thousausands of people.
Generally too short not allowing for the assessment of latent or long term health outcomes.
Generally too healthy, the population is carefully selected with study inclusion and exclusion criteria to select only the healthiest acandidates for the study.
Population using the drug expands after drug approval: Population would expand to various age (Pediatric population and the elderly population-Concomitant Illnesses and Medication), gender and race groups.
Example: 	Off-Label use of Cisapride in Pediatrics for GERD
	Viagra used in patients with advanced cardiovascular 		disease
Rare events: would not be seen frequently during Clinical trials incidence of Torsades de Pointe, Aplastic anemia, Liver Failure.

## Types of ADRS

- Product Quality Problems
- Medication Errors
- Known Problems
- Avoidable and Unavoidable
- Remaining Uncertainty
- ADRs, Rare, Unexpected, Serious
- ADRS, Usage Uncertainty
- New Populations
- Pts with Underlying Illnesses
- Off-Label Use, Overdoses

##       Sources of Risk From Medical Products

- Known Side Effects
- Unavoidable     Avoidable

- Medication and Device Error

- Product
-     Defects

- Preventable
- Adverse
- Events

- Injury or
- Death

**Remaining**
**Uncertainties:**
- - Unexpected
-      side effects
- - Unstudied uses
- - Unstudied
-      populations

## How Are Drug Safety Risks Managed?

- For Approved Drugs and Known Risks -- Prescriber
- Delivery Systems - Formularies, Restricted Access
- Professional Societies - FDA Attempts to Influence
- For Unexpected Risks, FDA and Manufacturer
- Voluntary Reporting
- Other Approaches

## Slide 10

## Traditional Interventions

- Labeling changes
- Warnings, Contraindications, Boxes
- Education
- Dear Health Practitioner Letters
- Restricted Distribution
- Withdrawal

## Potential Interventions

- Third Class of Drug
- Modify Standards of Approval
- New Label Model(s)
- Patient Inserts/MedGuides
- Special Advertising
- Formal Risk Management Plan
- Informed Consent, Restrictions
- Mandatory Monitoring - Registries

## Draft Report to the FDA Commissioner byHHS Office of Inspector General

- “...need to identify additional resources for [postmarketing] initiatives.”
*by re-allocating funds within FDA’s existing budget parameters*
*by increasing FDA’s annual budget appropriations*
*by expanding pre-market user fees to provide post-market coverage*
*institute post-market user fee*

## Report to the FDA Commissioner by Task Force on Risk Management

- Recommendations included:
*“...**provide cross-agency access to *_*external health care databases*_*...”*
*“**Increase resources to *_*conduct focused epidemiological studies*_* when support of these studies by manufacturers is not feasible.”*
*“...**establishing and supporting institutions to serve as *_*sentinel sites*_* for adverse event reporting...”*

## Components of a Comprehensive Postmarketing Program

- Passive and Active Surveillance
- Appropriate Drug Company Reporting
- Interactions with New Drugs Reviews
- Medication Error Program
- Communications
- International Videoconferences/Systems
- Information Output - Medwatch

## Surveillance Components of a Comprehensive Postmarketing Program 

- Drug Utilization data:
- * Outpatient
** Inpatient*

- External Health                care databases:  **General popn*
**Special popn’s*

-    Passive surveillance

*Repository of background incidence rates*

-      *Active*
*Surveillance*

## Relies Upon Voluntary Reporting of Cases of Suspected Drug-Induced Disease
Adverse Event Reporting System (AERS)
Designed to detect serious, rare, unlabeled reactions

- Adverse Event Reporting System (AERS)
- Designed to detect serious, rare, unlabeled reactions

*    *

- Passive Surveillance

## Passive Reporting - Voluntary Reporting

- In Place in Some Form Since 1969
- Medwatch - Early 90’s
- Excellent for Designed Purposes

## Count of All Domestic + Foreign Cases By Type of Report By Year - 1985 to Present

## AERS

- Production System December, 1999

## Electronic Submission Pilot Program Participants

- Glaxo-Wellcome Inc.
- Zeneca Pharmaceuticals
- Schering-Plough Research Institute
- Sanofi Pharmaceuticals Inc.
- Merck Research Laboratories
- Bristol-Myers Squibb Pharmaceutical Research Institute

- Pharmacia and Upjohn
- Roche Pharmaceuticals
- DuPont Pharmaceuticals
- TAP Holdings Inc.
- Wyeth-Ayerst Research
- Parke-Davis Pharmaceutical Research
- Pfizer Inc.

## New Methods - Data-Mining

- Potential Use as Screening Tool for the Spontaneous Reports Database
- Bayesian Based Collaborative Effort
- OWH and W. DuMouchel, AT&T Labs
- Aggregate Assessment
- Drug-Adverse Event Signals
- Visualization Tools

## IMS Health databases - Outpatient Data
National Estimates of Exposures to Rx drugs
Trends in Prescribing Practices/Off-label use
Drug Shortage Issues, Rx/OTC switches
Inpatient Data
Utilization of Drugs In-hospital, Including Intravenous Drugs (alatrafloxacin)
Provide Procedure-specific Information On Products Such as Contrast Agents, Anesthetics

- National Estimates of Exposures to Rx drugs
- Trends in Prescribing Practices/Off-label use
- Drug Shortage Issues, Rx/OTC switches
- Inpatient Data
- Utilization of Drugs In-hospital, Including Intravenous Drugs (alatrafloxacin)
- Provide Procedure-specific Information On Products Such as Contrast Agents, Anesthetics

- Drug Utilization data:
-          *** Outpatient**
-          * Inpatient

## Potential Utility:
Exposure/Outcome studies
Tramadol & Risk of seizures
Longitudinal Drug Utilization
Chronically used drugs - pemoline, troglitazone, trovafloxacin, bromfenac
Examine Impact of Regulatory Decisions
Troglitazone & liver function monitoring
Cisapride labeling on concomitant drugs

- Exposure/Outcome studies
- Tramadol & Risk of seizures
- Longitudinal Drug Utilization
- Chronically used drugs - pemoline, troglitazone, trovafloxacin, bromfenac
- Examine Impact of Regulatory Decisions
- Troglitazone & liver function monitoring
- Cisapride labeling on concomitant drugs

- External Health                Care Databases:  ********General popn***
****Special popn’s***

## Current resources
Published medical literature
Ad hoc questions to National Center for Health Statistics
National Center for Health Statistics survey data (NCHS)  
Health care utilization data:  hospital, MD office, nursing home, clinic, ER 
Contain data from patient Interview/Exam

- Published medical literature
- Ad hoc questions to National Center for Health Statistics
- National Center for Health Statistics survey data (NCHS)
- Health care utilization data:  hospital, MD office, nursing home, clinic, ER
- Contain data from patient Interview/Exam

***Repository of background incidence rates***

## Active Surveillance -- Periodic Solicitation of Case Reports
Acute Severe Hepatotoxicity Surveillance program
National Electronic Adverse Event Surveillance System
Active Postmarketing Surveillance in Hospitals
Death Certificate Surveillance Project

- Acute Severe Hepatotoxicity Surveillance program
- National Electronic Adverse Event Surveillance System
- Active Postmarketing Surveillance in Hospitals
- Death Certificate Surveillance Project

- Active Surveillance

## Medication Errors -- Postmarketing Evaluation 

- Monitoring All Medication Error Reports Through AERS
- Evaluate Causality of Reports, Perform Trend Analysis
- Provide Safety Evaluations  & Recommendations
- Measure Outcomes

## Medication Errors -- Premarketing Evaluation Proposal 

-  Trade-Name Analysis
- Focus Groups, Verbal Analysis, Handwritten Analysis
- IT Tools -- Repository, Phonic Tools
- Packaging Analysis & Labeling

## Relevant Websites

- http://www.fda.gov    (FDA)
- http://www.fda.gov/cder    (CDER)
- http://www.fda.gov/cder/aers/regs.htm
- Reporting Regs, Guidances and Updates
- http://www.fda.gov/medwatch/report/mfg.htm
- Reporting Regs, Guidances and Updates
- http://www.fda.gov/opacom/hpwhats.html
- http://www.fda.gov/oc/tfrm/1999report.html

## MedWatch Listserv

- To receive immediate e-mail notification whenever new safety information is posted on internet
- Send message to medwatch@oc.fda.gov asking to be added to the MedWatch listserv

## MedWatch Homepage(www.fda.gov/medwatch)

- What’s new the past two weeks
- What is MedWatch?
- How to report
- Safety information
- Dear Dr letters & other safety notifications
- Safety-related labeling changes
- CE articles & other publications

## Slide 32