Introducing RADAR: The Research on Adverse Drug

Events And Reports (RADAR) Project

Charles L. Bennett MD, PhD, MPP

Feinberg School of Medicine, Northwestern University

Midwest Center for Health Services and Policy Research

ADR Definition

• “Drug or device-associated ADR that results in death, severe organ failure, or precipitates major therapeutic interventions”– Ex. cardiopulmonary resuscitation, intubation

and mechanical ventilation, plasmapheresis, frequent transfusion of blood or blood products, or organ transplantation [32]

– Prolonged hospitalization not included

Reasons for RADAR

• ADRs account for 100,000 deaths annually

• > half 45 ADRs associated with BB identified >7 yrs following FDA approval

• Size of many licensing clinical trials is too small to identify rare but serious ADRs

• MedWatch many limitations

RADAR Purpose

• Evaluates initial reports of previously unrecognized but serious ADRs

• Identifies additional reports of each ADR• Develops hypotheses for mechanistic pathways• Evaluates related laboratory and pathologic

findings• Derives reporting and incidence rate estimates

RADAR Grant Support

• National Heart, Lung, and Blood Institute

• National Cancer Institute

• American Cancer Society

• Department of Veterans Affairs

• Pharmaceutical companies have not financed this project in any manner

RADAR Members

• 25 core investigators – Internal Medicine (geriatrics, cardiology,

infectious disease, neurology, dermatology, hematology, oncology)

– Pharmacology– Epidemiology– Statistics– Pharmacy

Investigator Contact

• Weekly conference calls that includes RADAR members located in the Chicago area and those around the globe

• Meeting minutes and agendas are circulated based on these calls

RADAR Dissemination

• Medical journals

• Revised package insert

• “Dear Doctor” letters

• National medical conferences

• Meetings with the FDA

• Meetings with Pharmaceutical company representatives

ADR Investigation Flow

Reporting Rates/Incidence Rates

• Reporting Rates– numbers of identified cases of the particular

event / total estimated numbers of users of the particular drug

• Incidence Rates– derived from prospective phase II and phase III

clinical trials or large single-center retrospective studies

RADAR Case ReportsDrug ADR Source of 1st

Case#

CasesSource of Cases

FDA/CDC Pub. RADAR Attorney Patient Query CT

Amiodarone Optic neuritis Clinical 262 214 48 -- -- -- -- --

Epoetin PRCA Clinical 191 180 -- -- -- -- -- 11

Thalidomide DVT/PE Clinical 190 10 131 -- -- -- -- 49

Gemcitabine Pneumonitis Published report 175 89 31 -- -- -- -- 55

Ticlopidine TTP RADAR 101 84 4 -- -- 13 -- --

Gemtuzumab SOS Clinical 93 79 14 -- -- -- -- --

Clopidogrel TTP RADAR 39 26 2 -- -- 2 9 --

Nevirapine Hepatic failure RADAR 22 14 4 -- -- -- 4 --

Flutamide Pneumonitis Published report 16 15 1 -- -- -- -- --

CYPHER Hypersensitivity RADAR 13 8 1 4 -- -- -- --

rHu-MGDF Thrombocytopenia Attorney 13 -- -- -- 1 -- -- 12

Bicalutamide Pneumonitis Published report 12 11 1 -- -- -- -- --

Zolendronate Osteonecrosis RADAR 7 -- -- 7 -- -- -- --

Enoxaparin Hemorrhage RADAR 5 -- -- -- -- -- 5 --

rHu-MGDF Lymphoproliferative disorders

Attorney 3 -- -- 2 1 -- -- --

TAXUS Hypersensitivity RADAR 3 2 -- 1 -- -- -- --

RADAR Findings cont.Drug Clinical Setting-

1st OccurrenceFindings to Clarify Path

Peak at risk per year

# pts/ deaths Rate % in FDA data

rHu-MGDF Volunteers Neutralizing antibodies

-- 13/0 1 in 33 0%

rHu-MGDF Volunteers -- -- 3/0 -- 0%

Enoxaparin Cardiac catheterization

Known toxicity -- 5/0 1 in 20 0%

Nevirapine Post HIV exposure prophylaxis

Biopsy results -- 30/0 1 in 5 20%

Clopidogrel Cardiac stent Antibodies 5 million 37/5 1 in 20,000* 35%

Ticlopidine Atrial fibrillation Antibodies 1 million 60/20 1 in 6,200 60%

Zolendronate Cancer -- 50,000 2/0 1 in 100 0%

CYPHER CAD Autopsy finding 1 million 12/2 -- 43%

TAXUS CAD Autopsy finding 1 million 3/1 -- 67%

Amiodarone Arrythmia -- 50,000 214/0 -- 95%

Epoetin Anemia Neutralizing antibodies

-- 208/0 1 in 9,000* 100%

Gemtuzumab Acute MM Biopsy findings 50,000 93/67 1 in 3-7 100%

Thalidomide Renal cell Laboratory studies

17,000 96/12 1 in 3-5 71%

Bicalutamide Monotherapy PCa -- 90,000 12/3 1 in 10,000* 91%

Flutamide CAB for PCa -- 40,500 16/7 1 in 2,500* 94%

Gemcitabine Hodgkin’s -- -- 150/52 1 in 11 100%

Timing Info on ADRs DisseminationDrug FDA

ApprovalRADAR

Index CasePackage Insert Dear Doctor

letterBB W Precaution AE

Clopidogrel 1997 1998 -- 2000 -- -- 2000

Ticlopidine 1989 1989 1998 -- -- -- 1998

Procrit/Epogen 1988 2002 -- 2002 -- -- --

Darbepoetin 2001 2002 -- 2001 -- -- --

CYPHER 2003 2003 -- -- -- -- 2003

TAXUS 2004 2004 -- -- -- -- --

Flutamide 1989 1999 -- -- -- -- --

Nilutamide 1994 1999 1994 -- -- -- 1994

Bicalutamide 1995 1999 -- -- -- 2001 --

Zolendronate 2001 2003 -- -- 2004 -- 2005

Gemcitabine 1996 1998 -- -- -- 2000 --

Enoxaparin 1993 2002 -- -- -- -- --

Nevirapine 1996 2000 -- -- -- -- 2001

Thalidomide 1998 2001 -- 2003 -- -- --

Gemtuzumab 2000 2003 2001 -- -- -- 2001

Amiodarone 1985 2002 -- -- -- -- 2004

rHu-MGDF

(thrombo)

None 1998 -- -- -- -- --

rHu-MGDF

(lymphoma)

None 2003 -- -- -- -- --

Strengths/ Weaknesses Data Sources

• Clinical Trial Reports– Comprehensive description individual cases– Few of these reports obtainable

• MedWatch/ MAUDE– Contains large number of reports– Underreporting, incompleteness

• Physician Queries– Complete– Time and Labor Intensive

• Info from Pharmaceutical Company– Difficult to obtain

Difficulties Reporting Rates/ Incidence Estimation

• Reporting rates: 1-10% of ADRs reported to MedWatch

• Incidence rates: use toxicity info from phase I, II and III trials where drug is used “off-label”

Importance Legal System

• Instigated 2 of our ADR investigations

• Source of safety information– Ex. Plantiff’s expert testimony on cervistatin-

associated rhabdomyolysis

• Important end-user of comprehensive safety data– State Attorney General’s Office

Refinements to Post-marketing Surveillance

• Make MedWatch accessible online• Systems to prospectively identify persons with

ADRs that represent drug toxicities – Ex. plasmapheresis centers (TTP cases), oral surgeons

(osteonecrosis) or hematologists (agranulocytosis)

• Updating programs currently in place• Collaboration NCI and FDA to synthesize

information collected at comprehensive cancer centers

Conclusion

• RADAR has exemplify the potential benefits of establishing clinically based, post-marketing surveillance collaboratives that focus on serious ADRs.

• Efforts of the RADAR project will ultimately improve safety through early detection and treatment of serious ADRs.