Pharmacovigilance in the Post-Marketing Setting: Results from the RADAR Project

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Pharmacovigilance in the Post-Marketing
SettingResults from the RADAR Project

• Charles L. Bennett MD PhD MPP

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Barriers to Identifying Adverse Events

• Limited size of clinical trials
• Undetected toxicities at time of FDA approval
• Many AEs identified after several years on the
  market

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Presentation Overview

• Comparison of post-marketing pharmacovigilance
  activities by
• Academic organizations
• The Food and Drug Administration (FDA)
• Pharmaceutical manufacturers

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Objectives

• Describe 3 types of pharmacovigilance methods
• Illustrate strengths/weaknesses of each approach
• Suggest novel collaborations and possibility for
  new public-private partnerships

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Pharmacovigilance Organizations
Academic Organizations FDA Pharmaceutical Manufacturers
Data Case assessments Prospective data MedWatch Proprietary databases
Science Pathology histology None None
Timeliness 1-2 years post approval 3 years or more 7-12 years
Dissemination Manuscripts presentations Package inserts Dear Doctor letters
Network Broad international Mostly internal Mostly internal
Funding R01-based CERTs Internal Not known
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Lessons Learned The RADAR method

• Detect ADR signals
• Investigate possible ADR occurrence
• Analyze data
• Disseminate results

Bennett CL, Nebeker JR, Lyons EA, et al. The
Research on Adverse Drug Events and Reports
(RADAR) Project. JAMA 2005, 29317, 2131-40.
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Timing and Dissemination
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Report Completeness RADAR vs. FDA
History/Physical examination () History/Physical examination () Laboratory/ Radiology () Laboratory/ Radiology () Basic science correlative () Basic science correlative ()
RADAR FDA RADAR FDA RADAR FDA
Overall mean completeness 92 45 54 46 34 4
P lt .005 for completeness of RADAR vs. FDA

• Includes data from 1998- 2006.
• Includes the drugs gemtuzumab, clopidogrel,
  ticlopidine, gemcitabine, sildenafil, tadalafil,
  amiodarone, paclitaxel or sirolimus coated
  cardiacstents, epoetin alfa, nevirapine,
• thalidomide, lenalidomide, MGDF, enoxaparin, and
  bisphosphonates.

Bennett CL, Nebeker JR, Yarnold PR, et al.
Evaluation of Serious Adverse Drug Reactions A
proactive pharmacovigilance program (RADAR) vs.
safety activities conducted by the Food and Drug
Administration and pharmaceutical manufacturers.
Arch Int Med. 2007 167 1041-49.
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Report Completeness RADAR vs. Supplier
Incidence Rate Incidence Rate Outcome Outcome Treatment/ prophylaxis Treatment/ prophylaxis References included in report References included in report
RADAR Supplier RADAR Supplier RADAR Supplier RADAR Supplier
Number of reports that contain information 14/15 6/15 15/15 1/15 14/15 3/15 12/15 1/15

• Includes data from 1998- 2006.
• Includes the drugs gemtuzumab, clopidogrel,
  ticlopidine, gemcitabine, sildenafil, tadalafil,
  amiodarone, paclitaxel or sirolimus coated
  cardiacstents, epoetin alfa, nevirapine,
• thalidomide, lenalidomide, MGDF, enoxaparin, and
  bisphosphonates.

Bennett CL, Nebeker JR, Yarnold PR, et al.
Evaluation of Serious Adverse Drug Reactions A
proactive pharmacovigilance program (RADAR) vs.
safety activities conducted by the Food and Drug
Administration and pharmaceutical manufacturers.
Arch Int Med. 2007 167 1041-49.
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Major RADAR Publications
Drug ADR N Publication
Sirolimus/paclitaxel coated cardiac stents Thrombotic events 139 JAMA 2007
G-CSF/ GM-CSF Acute myeloid leukemia and myelodisplastic syndrome 16 J Natl Cancer Inst 2007
Epoetin/ darbepoetin Venous thromboembolism Meta-analysis J Natl Cancer Inst 2006
Sirolimus/paclitaxel coated cardiac stents Hypersensitivity reactions 6 J Am Coll Cardiol 2006
Thalidomide/ lenalidomide Venous thromboembolism Meta-analysis JAMA 2006
Epoetin Pure Red-Cell Aplasia 9 N Engl J Med 2004
Clopidogrel Thrombotic thrombocytopenic purpura 13 N Engl J Med 2000
Ticlopidine Thrombotic thrombocytopenic purpura 21 Lancet 1998
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Postmarket Pharmacovigilance
Hampton, T. Postmarket Pharmacovigilance
Program on Alert for Adverse Events from Drugs.
JAMA, August 22/29 2007, 298 (8) 851-2.
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Example 1 Epoetin and Pure Red-Cell Aplasia
Bennett CL, Luminari S, Nissenson AR, et al. Pure
red-cell aplasia and epoetin therapy. N Engl J
Med 2004 3511403-8.
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Epoetin and Pure Red-Cell Aplasia
Bennett CL, Luminari S, Nissenson AR, et al. Pure
red-cell aplasia and epoetin therapy. N Engl J
Med 2004 3511403-8.
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Pharmacovigilance Chart Epoetin and PRCA
Academic Organizations FDA Pharmaceutical Manufacturers
Data 191 cases 81 cases Johnson Johnson- 170 cases
Science Antibodies None Each company had its own test
Timeliness First case- 1998 Publications- 2002 and 2004 Warning- 2000 Letter- 2000
Dissemination N Engl J Med Letter to N Engl J of Med Package insert Dear Doctor letter
Network France, Canada, Italy, U.S. Internal advisory groups Advisory groups of European MDs
Funding R01 Internal Internal
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Summary Epoetin and PRCA

• Safety of epoetin improved to normal sales
  maintained
• Data exchange between different entities was
  important
• Fear of appearing self-serving limited companies
  ability to monitor epoetin safety

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Example 2Clopidogrel/Ticlopidine and TTP
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Clopidogrel/Ticlopidine and TTP
Ticlopidine

Clopidogrel
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Thienopyridine-Associated TTP Onset
Thienopyridine-Associated TTP Onset ADAMTS13
Deficient versus near normal levels of ADAMTS13
activity (pgt0.05).
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Thienopyridine-Associated TTP Onset
Thienopyridine-Associated TTP Onset Ticlopidine
versus Clopidogrel (p0.0016).
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Clopidogrel/Ticlopidine and TTP

• Two suspected pathogenic mechanisms
• 1. In TTP patients with near normal ADAMTS13
  levels, the pathopyshiology resembles that of
  clopidogrel-associated TTP.
• 2. In TTP patients with deficient ADAMTS13
  levels, the pathophysiology resembles that of
  ticlopidine-associated TTP.

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Comparison of findings for ticlopidine- versus
clopidogrel-associated TTP
Category Ticlopidine-associated TTP Clopidogrel-associated TTP
Basic Science Probable underlying pathophysiology Antibody mediated toxicity and microvascular endothelial cell damage Microvascular endothelial cell damage
Basic Science High molecular weight vWF identified during the acute TTP phase Yes Yes
Basic Science ADAMTS13-deficiency during the acute TTP phase Yes No
Basic Science Functional IgG inhibitors to ADAMTS13 identified during acute phase Yes No
Ticlopidine received its original FDA approval
in 1991 current sales are 100,000.
Clopidogrel received its original FDA approval
in 1998 current sales are 5.6 billion.
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Comparison of findings for ticlopidine- versus
clopidogrel-associated TTP
Category Ticlopidine-associated TTP Clopidogrel-associated TTP
Clinical Usual time-period for onset Two to 12 weeks after drug initiation Within two weeks of drug initiation
Clinical Renal insufficiency Mild to none Severe
Clinical Thrombocytopenia Severe Mild
Clinical Survival following plasma exchange gt 90, usually within days of initiation of plasma exchange 70, often takes several weeks of plasma exchange
Clinical Survival without plasma exchange 30 70
Clinical Spontaneous relapse Occasional Infrequent
Clinical Likelihood of relapse occurring with exposure to the other thienopyridine High Low
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Comparison of findings for ticlopidine- versus
clopidogrel-associated TTP
Category Ticlopidine-associated TTP Clopidogrel-associated TTP
Epidemiologic Epidemiologic studies identifying an association of thienopyridine administration with TTP Surveys Case-control studies
Epidemiologic Estimated incidence (as listed in the package insert) 0.01 - 0.02 0.0001
Epidemiologic Case-control studies Not done Two studies- neither identified a significantly increased risk of TTP with clopidogrel
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Comparison of findings for ticlopidine- versus
clopidogrel-associated TTP
Category Ticlopidine-associated TTP Clopidogrel-associated TTP
Pharmacovigilance Number of cases in the first case reports 4 (year 1991) 2 (year 1999)
Pharmacovigilance Number of cases included in the largest reported case series 98 patients (1998) 50 patients (year2004)
Pharmacovigilance Cases identified by surveying interventional cardiology laboratory directors/ directors of plasma exchange centers/case-control epidemiology studies 24 patients/13 patients/2 patients 2 patients/13 patients/6 patients
Pharmacovigilance Time from FDA approval to identification of first cases 0 years (4 cases) 1 year (2 cases)
Pharmacovigilance Time from FDA approval to reporting of first case series 7 years (60 cases) 1 year (11 cases)
Pharmacovigilance Rank in FDA MedWatch database in association with drug-associated TTP reports (1998- 2006) First Second
Pharmacovigilance Advisories from the FDA Package insert (1995) Black Box (1998) Package insert warning (2000)
Pharmacovigilance Dear Doctor warnings frompharmaceutical supplier 1998 2000
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Pharmacovigilance Chart Clopidogrel/Ticlopidine
and TTP
Academic Organizations FDA Pharmaceutical Manufacturers
Data Prospective cases MedWatch Retrospective case-control study
Science Antibody test Plasma test None Not known
Timeliness 1 year Used academic data Used academic data
Dissemination N Engl J Med 2000 JACC (in press) Package insert Dear Doctor letter
Network International Internal Internal
Funding R01 Internal Internal
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Summary Clopidogrel/Ticlopidine and TTP

• Prospective data collection and basic science
  support were important
• Mechanism characterized
• Reporting was timely (1 year post approval)

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Example 3 Erythropoietin/darbepoetin in cancer

• Since 2003, Market-expanding indications
  explored
• Anemia of cancer
• Anemia caused by radiotherapy
• Prevention of anemia prior to chemotherapy
  initiation
• Raising hemoglobin levels beyond the correction
  of anemia

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Effect of ESA on survival studies before 2003
vs. after 2003
Number of Patients (Pre-2003) Number of Patients (Post-2003)
PFS, DFS, RFS as 1 or 2 endpoint 0/3217 2025/7517
Overall Survival as 1 or 2 endpoint 375/2885 3556/7517
HR gt1 1069/2754 5583/7327
HR lt1 1685/2754 1744/7327
Target hb gt12.5 1924/2523 5854/7370
Target hb 12.5 599/2523 1516/7370
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Effect of ESA on survival studies before 2003
vs. after 2003
Number of Pati ents (Pre-2003) Number of Patients (Post-2003)
Solid Cancer 3124/4902 5619/6516
Mixed Cancer 695/4902 508/6516
Hematologic Cancer 1083/4902 389/6516
Low dose 40000U/wk 2046/2885 6021/7172
High dose gt 4000U/wk 839/2885 1151/7172
Treatment without Chemotherapy 0/3217 2649/7010
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Effect of ESA on survival studies with and
without survival endpoint
 Category Number of patients (non-survival) Number of patients (survival)
PFS, DFS, RFS as 1 or 2 endpoint 0/7212 2835/4080
Overall Survival as 1 or 2 endpoint 0/7212 3857/4080
Solid Cancer 3097/6113 3961/4006
Hematologic Cancer 1427/6113 45/4006
Mixed Cancer 1589/6113 0/4006
Low Dose 40000U/wk 4981/5645 2680/4006
High Dose gt 4000U/wk 664/5645 1326/4006
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Effect of ESA on survival studies with and
without survival endpoint
 Category Number of patients (non-survival) Number of patients (survival)
HR gt1 4175/7011 2739/4080
HR lt1 2836/7011 1341/4080
Studies before 2003 2842/7212 375/4080
Studies post 2003 4370/7212 3705/4080
Target hb? 12.5 1900/5934 215/3631
Target hb? gt 12.5 4034/5934 3416/3631
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Pharmacovigilance Chart Erythropoietin/darbepoeti
n in cancer
Academic Organizations FDA Pharmaceutical Manufacturers
Data Published and unpublished studies FDA advisory mtg. Primarily on-label data advisory committee meeting Primarily on-label studies
Science EPO receptor EPO receptor EPO receptor
Timeliness 16 years post approval 16 years 16 years
Dissemination ASCO abstract 2007 JAMA (under review) Issued warnings Dear Doctor letter
Network Germany U.S. Mostly internal International registry
Funding R01 Internal Internal
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Summary Epoetin/darbepoetin in cancer

• Both on- and off-label data was important
• Took 16 years to notice safety concern
• Basic science research on-going

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Example 4Erythropoietin in chronic kidney
disease

• Project
• Evaluate meta-analyses, randomized controlled
  clinical trials, and observational trials
  regarding the safety of erythropoietin in
  dialysis patients
• Purpose
• Determine if safety signals have been
  under-reported or muted due to heterogeneity of
  trials and meta-analyses, specifically when major
  adverse events were not included as a primary or
  secondary outcome

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Risk of all-cause mortality in the higher
hemoglobin target group compared with the lower
hemoglobin target group
Mortality and target haemoglobin concentrations
in anaemic patients with chronic kidney disease
treated with erythropoietin a meta-analysis.
Lancet 2007 369381-88.
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Risk of mortality as an efficacy endpoint versus
a safety endpoint
Safety 0.67(0.37, 1.19)
Efficacy 1.27(1.08, 1.49)
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In Summary

• Per the Lancet meta-analysis
• risk of all-cause mortality in higher versus
  lower Hb target group RR (95CI) 1.17(1.01,
  1.35)
• Our meta-analysis
• risk of all-cause mortality as an efficacy
  endpoint versus a safety endpoint in higher
  versus lower Hb target group RR (95CI)
  1.27(1.08, 1.49)

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Unadjusted 1-year mortality rates by hematocrit
group according to epoetin dose quartile
Zhang Y, Thamer M, et al. Epoetin requirements
predict mortality in hemodialysis patients. Am J
Kidney Dis, 2004 Nov44(5)866-76
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Pharmacovigilance Chart Erythropoietin in
chronic kidney disease
Academic Organizations FDA Pharmaceutical Manufacturers
Data Observational trials RCTs meta-analyses To be determined Sept. 11 To be determined Sept. 11
Science None To be determined To be determined
Timeliness 18 years post approval 17 years 17 years
Dissemination ASH Abstract (to be submitted) Issued warnings Dear Doctor letter sales reps met with MDs
Network Tokyo, Germany, Sweden, Canada, US, UK US based Worldwide experience
Funding Cochrane Rand group NHMRC Center for Clinical Research NIH CMS Internal Internal
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New Paradigm for Pharmacovigilance
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Future Pharmacovigilance Efforts
R-01 Funded
Hematology and Oncology RADAR
SERF-TTP Chicago
Acute Liver Failure Texas UT Southwestern Dallas
FDA Funded (20)
Pediatric University of North Carolina CERT
FDA
U-01 Funded
CERT Data Coordinating Center
Cardiovascular Duke CERT
Ocular Toxicities Oregon Health and Sciences
No Funding
Physicians
CERT Communication Center
Nurses
Pharmacists
Q-T Cardiac Arrhythmia Arizona CERT
GI Vanderbilt CERT
CERT Funded
Cleveland Clinic Cleveland
Cardiology/GI/Peds/ID University of
Pennsylvania Philadelphia
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Conclusions

• Current pharmacovigilance methods have
  limitations
• Quality vs. Quantity
• Timing and dissemination
• Novel public-private collaborations are needed to
  improve ADR detection/reporting and improve
  patient safety