1. 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

2. 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

3. 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

4. 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

5. 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

6. RADAR Members 25 core investigators –Internal Medicine (geriatrics, cardiology, infectious disease, neurology, dermatology, hematology, oncology) –Pharmacology –Epidemiology –Statistics –Pharmacy

7. 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

8. RADAR Dissemination Medical journals Revised package insert “Dear Doctor” letters National medical conferences Meetings with the FDA Meetings with Pharmaceutical company representatives

9. ADR Investigation Flow

10. 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

11. RADAR Case Reports DrugADRSource of 1 st Case # Cases Source of Cases FDA/CDCPub.RADARAttorneyPatientQueryCT AmiodaroneOptic neuritisClinical 26221448-- EpoetinPRCAClinical 191180-- 11 ThalidomideDVT/PEClinical 19010131-- 49 GemcitabinePneumonitisPublished report 1758931-- 55 TiclopidineTTPRADAR 101844-- 13-- GemtuzumabSOSClinical 937914-- ClopidogrelTTPRADAR 39262-- 29 NevirapineHepatic failureRADAR 22144-- 4 FlutamidePneumonitisPublished report 16151-- CYPHERHypersensitivityRADAR 13814-- rHu-MGDFThrombocytopeniaAttorney 13-- 1 12 BicalutamidePneumonitisPublished report 12111-- ZolendronateOsteonecrosisRADAR 7-- 7 EnoxaparinHemorrhageRADAR 5-- 5 rHu-MGDFLymphoproliferati ve disorders Attorney 3-- 21 TAXUSHypersensitivityRADAR 32--1

12. RADAR Findings cont. DrugClinical Setting- 1 st Occurrence Findings to Clarify Path Peak at risk per year # pts/ deathsRate% in FDA data rHu-MGDFVolunteersNeutralizing antibodies --13/01 in 330% rHu-MGDFVolunteers-- 3/0--0% EnoxaparinCardiac catheterization Known toxicity--5/01 in 200% NevirapinePost HIV exposure prophylaxis Biopsy results--30/01 in 520% ClopidogrelCardiac stentAntibodies5 million37/51 in 20,000*35% TiclopidineAtrial fibrillationAntibodies1 million60/201 in 6,20060% ZolendronateCancer--50,0002/01 in 1000% CYPHERCADAutopsy finding1 million12/2--43% TAXUSCADAutopsy finding1 million3/1--67% AmiodaroneArrythmia--50,000214/0--95% EpoetinAnemiaNeutralizing antibodies --208/01 in 9,000*100% GemtuzumabAcute MMBiopsy findings50,00093/671 in 3-7100% ThalidomideRenal cellLaboratory studies 17,00096/121 in 3-571% BicalutamideMonotherapy PCa--90,00012/31 in 10,000*91% FlutamideCAB for PCa--40,50016/71 in 2,500*94% GemcitabineHodgkin’s-- 150/521 in 11100%

13. Timing Info on ADRs Dissemination DrugFDA Approval RADAR Index Case Package InsertDear Doctor letter BBWPrecautionAE Clopidogrel19971998--2000-- 2000 Ticlopidine1989 1998-- 1998 Procrit/Epogen19882002--2002-- Darbepoetin20012002--2001-- CYPHER2003 -- 2003 TAXUS2004 -- Flutamide19891999-- Nilutamide199419991994-- 1994 Bicalutamide19951999-- 2001-- Zolendronate20012003-- 2004--2005 Gemcitabine19961998-- 2000-- Enoxaparin19932002-- Nevirapine19962000-- 2001 Thalidomide19982001--2003-- Gemtuzumab200020032001-- 2001 Amiodarone19852002-- 2004 rHu-MGDF (thrombo) None1998-- rHu-MGDF (lymphoma) None2003--

14. 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

15. 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”

16. 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

17. 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

18. 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.