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Pharmacovigilance in the
Post-Marketing Setting:
Results from the RADAR Project
Charles L. Bennett MD PhD MPP
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
Presentation Overview

Comparison of post-marketing pharmacovigilance
activities by:
– Academic organizations
– The Food and Drug Administration (FDA)
– Pharmaceutical manufacturers
Objectives

Describe 3 types of pharmacovigilance methods

Illustrate strengths/weaknesses of each approach

Suggest novel collaborations and possibility for new
public-private partnerships
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
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, 293:17, 2131-40.
Timing and Dissemination
Drug
sADR
Presentations/
Abstracts
Publications
RADAR
Communication
with Company Company Alerts
Epoetin/
Darbepoetin
Venous
thromboembolism
ASCO Abstract
(2007)
J Natl Cancer
Inst (2006)
2007
Epoetin/
Darbepoetin
Death
ASCO Abstract
(2007)
N/A
2007
Scientific
Program in the
Developmental
Therapeutics –
Immunotherapy
Presentation
(2004)
Epoetin
Pure Red-Cell
Aplasia
Ticlopidine
Thrombotic
thrombocytopenic
purpura (TTP)
ASH Abstract
(2002)
Clopidogrel
Thrombotic
thrombocytopenic
purpura (TTP)
ASH Abstract
(2002)
N Engl J of Med
(2004); Blood
(2005); Best
Pract Res Clin
Haematol
(2005); Best
Pract Res Clin
Haematol
(2005)
Ann Intern Med
(1998); Lancet
(1998); Arch
Intern Med
(1999); JAMA
(1999)
N Engl J of Med
(2000);
Transplantation
(2002); Stroke
(2004)
DHP Letter
(2005); Boxed
Warning (2006);
DHP Letter (2007)
DHP Letter
(2005); Warning
(2005); Warning
(2007); DHP
Letter (2007)
FDA Alerts
Additional Outcomes by
Regulating Agencies and Others
FDA alert
(2006/7)
ODAC meeting (2007) on drug
misuse
FDA alert
(2006/7)
ODAC meeting (2007) on drug
misuse
N/A
Canadian, European, and Australian
health officials mandate Eprex
delivery intravenously; PRCA
website now maintained and
updated by sponsor; ODAC meeting
held in 2004 on use
2003
Boxed warning
(2002); DHP
Letter (2005)
1998
DHP Letter
(1998); Boxed
Warning (1999)
N/A
Clopidogrel adopted as standard
antiplatelet for patients with
cerebrovascular or cardiovascular
disease
1999
Warning (2000);
Warning (2006)
N/A
N/A
Report Completeness:
RADAR vs. FDA
History/Physical
examination (%)
Laboratory/
Radiology (%)
Basic science
correlative (%)
RADAR
FDA
RADAR
FDA
RADAR
FDA
92*
45
54
46
34
4
Overall mean completeness
*P < .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.
Report Completeness:
RADAR vs. Supplier
Incidence Rate
Number of
reports that
contain
information
Outcome
Treatment/
prophylaxis
References
included in
report
RADAR
Supplier
RADAR
Supplier
RADAR
Supplier
RADAR
Supplier
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.
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
Metaanalysis
J Natl Cancer Inst
2006
Sirolimus/paclitaxel
coated cardiac stents
Hypersensitivity reactions
6
J Am Coll Cardiol
2006
Thalidomide/
lenalidomide
Venous thromboembolism
Metaanalysis
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
Postmarket Pharmacovigilance
Hampton, T. Postmarket “Pharmacovigilance” Program on Alert for Adverse Events from Drugs. JAMA, August 22/29
2007, 298 (8): 851-2.
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; 351:1403-8.
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; 351:1403-8.
Pharmacovigilance Chart:
Epoetin and PRCA
Academic
Organizations
FDA
Pharmaceutical
Manufacturers
Data
191 cases
81 cases
Johnson & Johnson170 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 MD’s
Funding
R01
Internal
Internal
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
Example 2:
Clopidogrel/Ticlopidine and TTP
▲Figure 1. Drug-associated TTP cases reported to the FDA
(1992-2006)
Total TTP cases for top ten reported drugs
to the FDA's Medw atch Program
Ticlopidine
90
Clopidogrel
TTP cases reported
80
Cyclosporine
70
Tacrolimus
60
Gemcitibine
50
40
30
20
10
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Year
Clopidogrel/Ticlopidine and TTP
Ticlopidine
Clopidogrel
Thienopyridine-Associated TTP Onset
70
60
50
ADAMTS13 Non deficient n=13
30
40
ADAMTS13 deficient n=26
0
10
20
Percentage of patients with TTP
80
90
Time to Onset
0
5
10
15
20
25
30
35
40
45
50
days
Thienopyridine-Associated TTP Onset: ADAMTS13 Deficient versus near normal levels
of ADAMTS13 activity (p>0.05).
Thienopyridine-Associated TTP Onset
30
40
50
60
70
Clopidogrel n=35
20
Ticlopidine n=93
0
10
Percentage of patients with TTP
80
90
Time to Onset
0
5
10
15
20
25
30
35
40
45
50
days
Thienopyridine-Associated TTP Onset: Ticlopidine versus Clopidogrel (p=0.0016).
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.
Comparison of findings for ticlopidine- versus
clopidogrel-associated TTP
Category
Basic
Science
Ticlopidine*associated
TTP
Clopidogrel**associated
TTP
Probable underlying
pathophysiology
Antibody mediated Microvascular
toxicity and
endothelial cell
microvascular
damage
endothelial cell
damage
High molecular weight vWF
identified during the acute TTP
phase
Yes
Yes
ADAMTS13-deficiency during the
acute TTP phase
Yes
No
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.
Comparison of findings for ticlopidine- versus
clopidogrel-associated TTP
Category
TiclopidineClopidogrelassociated TTP
associated TTP
Usual time-period for onset
Two to 12 weeks
after drug
initiation
Within two weeks of
drug initiation
Renal insufficiency
Mild to none
Severe
Thrombocytopenia
Severe
Mild
Survival following plasma exchange
> 90%, usually
within days of
initiation of
plasma
exchange
70%, often takes
several weeks of
plasma
exchange
Survival without plasma exchange
30%
70%
Spontaneous relapse
Occasional
Infrequent
Likelihood of relapse occurring with
exposure to the other
thienopyridine
High
Low
Clinical
Comparison of findings for ticlopidine- versus
clopidogrel-associated TTP
Category
Epidemiologic
Ticlopidineassociated
TTP
Clopidogrelassociated TTP
Epidemiologic studies identifying
an association of
thienopyridine administration
with TTP
Surveys
Case-control studies
Estimated incidence (as listed in
the package insert)
0.01% - 0.02%
0.0001%
Case-control studies
Not done
Two studies- neither
identified a
significantly
increased risk of
TTP with
clopidogrel
Comparison of findings for ticlopidine- versus
clopidogrel-associated TTP
Category
Pharmacovigilance
Ticlopidineassociated TTP
Clopidogrel-associated
TTP
Number of cases in the first case
reports
4 (year= 1991)
2 (year =1999)
Number of cases included in the largest
reported case series
98 patients (1998)
50 patients (year2004)
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
Time from FDA approval to
identification of first cases
0 years (4 cases)
1 year (2 cases)
Time from FDA approval to reporting of
first case series
7 years (60 cases)
1 year (11 cases)
Rank in FDA MedWatch database in
association with drug-associated
TTP reports (1998- 2006)
First
Second
Advisories from the FDA
Package insert
(1995);
Black Box (1998)
Package insert warning
(2000)
“Dear Doctor” warnings
frompharmaceutical supplier
1998
2000
Pharmacovigilance Chart:
Clopidogrel/Ticlopidine and TTP
Academic
Organizations
FDA
Pharmaceutical
Manufacturers
Data
Prospective cases
MedWatch
Retrospective casecontrol 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
Summary:
Clopidogrel/Ticlopidine and TTP

Prospective data collection and basic science
support were important

Mechanism characterized

Reporting was timely (1 year post approval)
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
Effect of ESA on survival: studies before
2003 vs. after 2003
Comparing Studies Pre and Post 2003
Pre-2003 % studies
PFS, DFS, RFS as
1° or 2° endpoint
Overall Survival as
1° or 2° endpoint
0
47
4.5
PFS, DFS, RFS
as 1° or 2°
endpoint
0/3217
2025/7517
Overall Survival
as 1° or 2°
endpoint
375/2885
3556/7517
HR >1
1069/2754
5583/7327
HR <1
1685/2754
1744/7327
Target hb >12.5
1924/2523
5854/7370
Target hb ≤12.5
599/2523
1516/7370
67
42
33
HR <1
58
83
Target hb > 12.5
Solid Cancer
Number of
Patients
(Post-2003)
Post-2003 % studies
33
HR >1
Target hb ≤12.5
Number of
Patients
(Pre-2003)
78
17
22
78
50
67
HR >1
42
Effect of ESA on survival: studies before
2003 vs. after 2003
33
HR <1
Target hb > 12.5
58
Comparing Studies Pre and Post 200378
Pre-2003 % studies
5619/6516
Mixed Cancer
695/4902
508/6516
Hematologic
Cancer
1083/4902
389/6516
Low dose ≤
40000U/wk
2046/2885
6021/7172
High dose >
4000U/wk
839/2885
1151/7172
Treatment without
Chemotherapy
0/3217
2649/7010
78
50
47
4.5
15
18
67
42
7
32
33
HR <1
Low dose ≤
40000U/wk*
Solid Cancer
3124/4902
0
HR >1
Target hb ≤12.5
Treatment without
0
Chemotherapy
Solid Cancer
33
Overall Survival as
1° or 2° endpoint
Mixed Cancer
Target hb > 12.5
High dose >
4000U/wk
Number of
Patients
(Post2003)
22
Solid Cancer
Hematologic Cancer
Number of
Pati
ents
(Pre-2003)
Post-2003 % studies
17
Target hb ≤12.5
PFS, DFS, RFS as
1° or 2° endpoint
83
58
88
79
83
78
12
21
17
21
22
78
50
Effect of ESA on survival: studies with
and without survival endpoint
Number of
patients
(survival)
Category
Number of
patients
(nonsurvival)
PFS, DFS, RFS as
1° or 2°
endpoint
0/7212
2835/4080
Overall Survival as
1° or 2°
endpoint
0/7212
3857/4080
3097/6113
3961/4006
1427/6113
45/4006
1589/6113
0/4006
4981/5645
2680/4006
664/5645
1326/4006
Comparing Studies with and without Survival Endpoint
% Non-survival studies
PFS, DFS, RFS as
1° or 2° endpoint
0
Overall Survival as
1° or 2° endpoint
0
% of survival studies
63
94
52
Solid Cancer
93
Mixed Cancer
Hematologic
Cancer
24
Hematologic Cancer
7
Mixed Cancer
24
0
Low Dose ≤
40000U/wk*
High Dose >
4000U/wk*
86
80
Low Dose ≤
40000U/wk*
High Dose >
4000U/wk*
14
20
55
HR >1
HR <1
Solid Cancer
63
45
37
24
Hematologic Cancer
Mixed Cancer
7
24
0
Effect of ESA on survival: studies with
and without survival endpoint
Low Dose ≤
40000U/wk*
86
80
Category
Number of
patients (nonsurvival)
Number of
patients
(survival)
HR >1
4175/7011
2739/4080
2836/7011
1341/4080
2842/7212
375/4080
4370/7212
3705/4080
Target hb● ≤12.5
1900/5934
215/3631
Target hb● >
12.5
4034/5934
3416/3631
Comparing Studies with and without Survival Endpoint
14
High Dose >
4000U/wk*
% Non-survival
studies
20
PFS, DFS, RFS as
1° or 2°HR
endpoint
>1
0
Overall Survival as
1° or 2° endpoint
0
% of survival studies
5563
37
52
Solid Cancer
40000U/wk*
24
43
94
24
Studies post
2003
0
25
86
7
80
14
High Dose >
Target hb● 4000U/wk*
> 12.5
75
20
93
55
HR >1
63
45
HR <1
Studies before 2003
Studies before
2003
7
Studies post 2003
Dose ≤
Target hb●Low
≤12.5
93
57
6
Hematologic Cancer
Mixed Cancer
HR <1
94
45
HR <1
Studies before 2003
63
37
57
6
Pharmacovigilance Chart:
Erythropoietin/darbepoetin
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
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
Example 4:
Erythropoietin 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
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; 369:381-88.
Risk of mortality as an efficacy
endpoint versus a safety endpoint
Events,
Events,
%
RR (95% CI)
Exp
Control
Weight
Kuriyama S 1977
2.71 (0.26, 28.56)
2/31
1/42
1.00
Revicki 1995
3.14 (0.13, 75.02)
1/41
0/43
0.56
Subtotal (I-squared = 0.0%, p = 0.941)
2.86 (0.43, 18.93)
3/72
1/85
1.56
Foley RN 2000
1.33 (0.31, 5.75)
4/73
3/73
2.51
Furuland H 2003
0.99 (0.61, 1.62)
29/216
27/200
15.17
Levin A 2005
0.35 (0.04, 3.30)
1/74
3/78
1.10
Parfrey
0.45 (0.23, 0.92)
12/396
20/300
9.08
Rossert J 2006
0.17 (0.02, 1.37)
1/195
6/195
1.24
Roger SD 2004
. (., .)
0/75
0/79
0.00
Subtotal (I-squared = 35.9%, p = 0.182)
0.67 (0.37, 1.19)
47/1029
59/925
29.11
Bahalman J 1991
1.15 (0.17, 7.86)
2/46
2/53
1.49
Subtotal (I-squared = .%, p = .)
1.15 (0.17, 7.86)
2/46
2/53
1.49
Besarab 1998
1.21 (1.01, 1.46)
183/618
150/615
33.14
Gouva C 2004
1.40 (0.33, 5.87)
4/43
3/45
2.59
Drueke 2006
1.49 (0.87, 2.53)
31/300
21/302
13.60
Singh AK 2006
1.45 (0.96, 2.19)
52/715
36/717
18.52
Subtotal (I-squared = 0.0%, p = 0.808)
1.27 (1.08, 1.49)
270/1676
210/1679
67.84
1.12 (0.88, 1.42)
322/2823
272/2742
100.00
Study ID
no - Epo vs No
no - High vs Low Epo
Safety:
0.67(0.37, 1.19)
yes - Epo vs No
yes - High vs Low Epo
Heterogeneity between groups: p = 0.057
Overall (I-squared = 25.4%, p = 0.195)
NOTE: Weights are from random effects analysis
.0133
1
Experimental better
75
Standard better
Efficacy:
1.27(1.08, 1.49)
In Summary:

Per the Lancet meta-analysis:
risk of all-cause mortality in higher versus lower Hb target
group: RR (95%CI): 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
(95%CI): 1.27(1.08, 1.49)
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 Nov;44(5):866-76
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 MD’s
Network
Tokyo, Germany, Sweden,
Canada, US, UK
US based
Worldwide experience
Funding
Cochrane; Rand group;
NHMRC Center for
Clinical Research; NIH;
CMS
Internal
Internal
New Paradigm for Pharmacovigilance
Clinical Trials
Registries
Referral Centers
Databases
Case Reports
Independent
Pharmacovigilance Center
Information Synthesis; Epidemiology; Basic
Science; Immunology; Pathology
Dissemination
Academic
Presentations/Abstracts
at National
Medical Conferences
Publications in
Peer-Reviewed
Medical Journals
Cochrane Collaboration
FDA
MedWatch Reports
FDA Alerts
Company
Other
Company Alerts,
Including Dear
HCP Letters and
Package Insert Updates
Company
Communication
w/RADAR
Eisenberg CenterConsumer Union Reports
VA MedSafe
CERTs
DEcIDE Centers
Evidence-Based Practice
Center Reports
R-01 Funded
CERT Funded
No
Funding U-01 Funded
FDA Funded
(20%)
Hematology and Oncology
RADAR
SERF-TTP
Chicago
Future
Pharmacovigilance
Efforts
Acute Liver Failure
Texas: UT Southwestern
Dallas
Pediatric
University of North
Carolina CERT
Cardiovascular
Duke CERT
Ocular Toxicities
Oregon Health and
Sciences
Q-T Cardiac Arrhythmia
Arizona CERT
GI
Vanderbilt CERT
Cleveland Clinic
Cleveland
Cardiology/GI/Peds/ID
University of Pennsylvania
Philadelphia
CERT Data
Coordinating Center
FDA
Physicians
CERT Communication
Center
Nurses
Pharmacists
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