Charles L. Bennett MD PhD MPP

Limited size of clinical trials

Undetected toxicities at
time of FDA approval

Many AEs identified after
several years on the market
Hampton, T. Postmarket “Pharmacovigilance” Program on Alert for Adverse Events from Drugs. JAMA, August 22/29
2007, 298 (8): 851-2.
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

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.
Drug
ADR
N
Publication
Bisphosphonates
Osteonecrosis of the Jaw
Review of
case series
Lancet Oncology 2008
Epoetin/ darbepoetin
VTE and Mortality
Metaanalysis
JAMA 2008
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
Mortality and Venous Thromboembolism
Associated with Erythropoiesis
Stimulating Agents (ESAs)
Bennett CL, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin
and darbepoetin administration for the treatment of cancer-associated anemia. J Amer Med, 2008;
299(8):914-924.
Mortality
Meta-analysis
Meta-analysis of mortality
rates for 51 phase III
oncology trials with 13,613
patients for ESAs versus
placebo or control
HR= 1.10 (1.01, 1.20)
Study ID
HR(mortality) (95% CI)
%
Weight
AOC
Ables_1993
Smith_2003
Charu_2004
Mystakidou_2005
Gordon_2006
Amgen 200010103_2007
Subtotal (I-squared = 0.0%, p = 0.536)
0.89 (0.41, 1.93)
3.96 (0.29, 54.12)
1.38 (0.44, 4.33)
0.50 (0.05, 4.99)
0.67 (0.23, 2.00)
1.43 (1.06, 1.92)
1.29 (1.00, 1.67)
1.13
0.11
0.54
0.14
0.60
5.19
7.72
TRA
Case_1993
Rose_1994
Cazzola_1995
Henry_1995
Osterborg_1996
Del Mastro_1997
Oberhoff_1998
Ten Bokkel_1998
Dunphy_1999
Thatcher a_1999
Thatcher b_1999
Throuvalas_2000
Coiffier_2001
Dammacco_2001
Littlewood_2001
Vansteenkiste_2002
Bamias_2003
Hedenus_2003
Henke_2003
Kotasek_2003
EPO-CAN-15_2004
EPO-GBR-7_2004
INT-1_2004
INT-3_2004
Machtay_2004 (RTOG99-03)
N93-004_2004 (Grote)
P-174-2004
Razzouk_2004
Savonije_2004
Vadhan-Raj_2004 (PR0003-006)
DA 232_2005 (Taylor)
Leyland-Jones_2005 (INT-76)
O'Shaughnessy_2005
Osterborg_2005
STRAUSS_2005
Witzig_2005
WILKINSON_2006
BLOHMER_2007 (AGO/NOGG)
Chang_2007 (EPO-CAN-17)
DA 145_2007
DAHANCA-10-2007
EPO-GER22-2007
GOG-191_2007
MOEBUS_2007
PREPARE-2007
Wright_2007 (EPO-CAN-20)
Subtotal (I-squared = 21.1%, p = 0.108)
1.08 (0.44, 2.66)
1.68 (0.66, 4.29)
0.37 (0.06, 2.27)
0.75 (0.28, 2.01)
1.02 (0.51, 2.04)
0.36 (0.05, 2.56)
0.61 (0.24, 1.55)
1.01 (0.19, 5.31)
0.14 (0.00, 6.88)
0.49 (0.03, 8.71)
1.26 (0.24, 6.60)
0.13 (0.00, 332.66)
1.02 (0.38, 2.73)
0.32 (0.11, 0.95)
0.81 (0.62, 1.06)
0.78 (0.60, 1.01)
1.80 (0.53, 6.12)
1.36 (0.98, 1.89)
1.39 (1.05, 1.84)
0.55 (0.11, 2.71)
2.70 (1.17, 6.23)
1.07 (0.73, 1.57)
1.58 (0.32, 7.82)
1.56 (0.42, 5.79)
1.41 (0.80, 2.49)
1.53 (0.65, 3.61)
0.41 (0.03, 5.76)
0.98 (0.14, 6.90)
0.98 (0.36, 2.67)
0.15 (0.00, 415.90)
0.85 (0.45, 1.60)
1.37 (1.07, 1.75)
7.39 (0.15, 366.10)
1.04 (0.80, 1.35)
1.16 (0.69, 1.95)
1.09 (0.83, 1.43)
4.54 (0.40, 51.20)
0.67 (0.34, 1.33)
0.88 (0.49, 1.59)
0.93 (0.82, 1.05)
1.28 (0.97, 1.69)
1.02 (0.60, 1.74)
1.25 (0.65, 2.41)
1.14 (0.77, 1.69)
1.50 (0.96, 2.34)
1.84 (1.01, 3.35)
1.09 (0.99, 1.19)
0.86
0.80
0.22
0.72
1.38
0.19
0.80
0.26
0.05
0.09
0.27
0.01
0.73
0.59
5.82
6.01
0.48
4.54
5.53
0.29
0.99
3.67
0.28
0.42
1.97
0.94
0.11
0.19
0.70
0.01
1.64
6.39
0.05
5.91
2.28
5.74
0.13
1.43
1.85
10.44
5.59
2.17
1.54
3.50
2.92
1.79
92.28
Heterogeneity between groups: p = 0.133
Overall (I-squared = 19.5%, p = 0.114)
1.10 (1.01, 1.20)
100.00
NOTE: Weights are from random effects analysis
5.1e-05
1
ESA better
19684
Control better
Updated Mortality
Meta-analysis
Meta-analysis of mortality rates
for 53 oncology trials with
14,164 patients for ESAs
versus placebo or control
(updated to include BRAVE
study)
HR= 1.09 (95% CI, 1.01-1.18)
Study ID
HR(mortality) (95% CI)
%
Weight
AOC
Mystakidou_2005
Gordon_2006
Ables_1993
Glaspy_2007 (Amgen 200010103)
Charu_2007
Smith_2003
Subtotal (I-squared = 0.0%, p = 0.686)
0.51 (0.05, 4.99)
0.67 (0.23, 2.00)
0.89 (0.41, 1.93)
1.22 (1.03, 1.45)
1.38 (0.44, 4.33)
3.96 (0.29, 54.12)
1.19 (1.01, 1.40)
0.11
0.46
0.88
8.23
0.42
0.08
10.18
TRA
Throuvalas_2000
Dunphy_1999
Vadhan-Raj_2004 (PR0003-006)
Dammacco_2001
Del Mastro_1997
Cazzola_1995
P-174_2004
Thatcher_1999a
Kotasek_2003
Oberhoff_1998
Blohmer_2007 (AGO/NOGG)
Henry_1995
Vansteenkiste_2002
Littlewood_2001
Rosen_2003(phase II RCT)
DA 232_2005 (Taylor)
Chang_2007 (EPO-CAN-17)
DA 145_2007
Razzouk_2004
EPO-GBR-7_2004
Osterborg_1996
Coiffier_2001
Debus_2007 (EPO-GER22)
Osterborg_2005
ten Bokkel Huinink_1998 (Reed_2005)
Aapro_2008 (BRAVE)
Case_1993
Witzig_2005
Moebus_2007
Savonije_2005
Strauss_2005
Thatcher_1999b
DAHANCA-10_2007
Hedenus_2003
Leyland-Jones_2005 (INT-76)
Henke_2003
Machtay_2004 (RTOG99-03)
PREPARE_2007
N93-004_2004 (Grote)
INT-3_2004
INT-1_2004
Rose_1994
Thomas(GOG-191_2007)
Bamias_2003
Wright_2007 (EPO-CAN-20)
EPO-CAN-15_2004
Wilkinson_2006
O'Shaughnessy_2005
Subtotal (I-squared = 20.4%, p = 0.111)
0.13 (0.00, 332.66)
0.14 (0.00, 6.88)
0.15 (0.00, 415.90)
0.32 (0.11, 0.95)
0.36 (0.05, 2.56)
0.37 (0.06, 2.27)
0.41 (0.03, 5.76)
0.49 (0.03, 8.71)
0.55 (0.11, 2.71)
0.61 (0.24, 1.55)
0.67 (0.34, 1.33)
0.75 (0.28, 2.01)
0.78 (0.60, 1.01)
0.81 (0.62, 1.06)
0.84 (0.45, 1.55)
0.85 (0.45, 1.60)
0.88 (0.49, 1.59)
0.93 (0.82, 1.05)
0.98 (0.14, 6.90)
0.98 (0.62, 1.56)
1.02 (0.51, 2.04)
1.02 (0.38, 2.73)
1.02 (0.60, 1.74)
1.04 (0.80, 1.35)
1.06 (0.20, 5.53)
1.07 (0.87, 1.32)
1.08 (0.44, 2.66)
1.09 (0.83, 1.43)
1.14 (0.77, 1.69)
1.15 (0.87, 1.53)
1.16 (0.69, 1.95)
1.26 (0.24, 6.60)
1.28 (0.97, 1.69)
1.36 (0.98, 1.89)
1.37 (1.07, 1.75)
1.39 (1.05, 1.84)
1.41 (0.80, 2.49)
1.50 (0.96, 2.34)
1.53 (0.65, 3.61)
1.56 (0.42, 5.79)
1.58 (0.32, 7.82)
1.68 (0.66, 4.29)
1.69 (0.76, 3.75)
1.80 (0.53, 6.12)
1.84 (1.01, 3.35)
2.70 (1.17, 6.23)
4.54 (0.40, 51.20)
7.39 (0.15, 366.10)
1.09 (1.00, 1.18)
0.01
0.04
0.01
0.45
0.15
0.17
0.08
0.07
0.22
0.62
1.12
0.56
5.27
5.08
1.35
1.29
1.47
10.32
0.15
2.22
1.08
0.56
1.73
5.16
0.20
6.69
0.66
5.00
2.88
4.71
1.83
0.20
4.85
3.84
5.65
4.79
1.56
2.38
0.73
0.32
0.22
0.62
0.84
0.37
1.42
0.77
0.10
0.04
89.82
Heterogeneity between groups: p = 0.186
Overall (I-squared = 17.1%, p = 0.145)
1.09 (1.01, 1.18)
100.00
NOTE: Weights are from random effects analysis
VTE
Meta-analysis
Meta-analysis of
VTE rates in 38
phase III trials with
8,172 patients for
ESAs versus
placebo or control
HR= 1.57 (1.31,1.87)
Study ID
RR (95% CI)
%
Weight
Bamias_2003
Smith_2003
Case_1993
Henry_1995
Wright_2007 (EPO-CAN-20)
N93-004_2004 (Grote)
Chang_2007 (EPO-CAN-17)
Littlewood_2001
Vansteenkiste_2002
INT-1_2004
Leyland-Jones_2005 (INT-76)
Witzig_2005
Osterborg_1996b
DA 145_2007
Henke_2003
Ten Bokkel_1998a
EPO-GER22_2007
Charu_2007
Rose_1994
Thatcher1999b
Osterborg_1996a
Abels_1993
Throuvalas_2000
GOG-191_2007
Italian_1998
Razzouk_2004
Welch_1995
Osterborg_2005
Gordon_2006
Ten Bokkel_1998b
Vadhan-Raj_2004 (PR0003-006)
INT-3_2004
Wilkinson_2006
Savonije_2004
Machtay_2004 (RTOG99-03)
EPO-GBR-7_2004
Dammacco_2001
EPO-CAN-15_2004
Rosenzweig_2004
Cascinu_1994
P-174_2004
Thatcher_1999a
Overall (I-squared = 0.0%, p = 0.901)
0.33 (0.01, 8.05)
0.34 (0.02, 5.27)
0.63 (0.11, 3.64)
0.73 (0.27, 1.98)
0.75 (0.13, 4.20)
0.97 (0.60, 1.59)
1.36 (0.70, 2.62)
1.38 (0.51, 3.75)
1.44 (0.47, 4.43)
1.46 (0.15, 13.85)
1.47 (0.89, 2.40)
1.47 (0.54, 4.05)
1.53 (0.06, 36.23)
1.53 (1.08, 2.18)
1.58 (0.59, 4.26)
1.96 (0.10, 38.79)
1.98 (0.97, 4.03)
2.36 (0.13, 43.20)
2.50 (0.55, 11.30)
2.56 (0.13, 51.05)
2.71 (0.14, 54.32)
2.73 (0.11, 65.68)
2.79 (0.12, 65.66)
2.84 (0.81, 9.96)
2.93 (0.12, 70.08)
2.95 (0.61, 14.28)
3.00 (0.13, 68.26)
3.05 (0.13, 74.41)
3.15 (0.17, 57.55)
3.56 (0.20, 62.58)
3.74 (0.85, 16.56)
3.85 (0.49, 30.15)
4.09 (0.54, 30.80)
4.44 (0.57, 34.55)
4.93 (0.24, 100.89)
4.93 (0.58, 41.73)
5.51 (0.66, 45.98)
8.00 (1.93, 33.09)
8.40 (0.50, 142.27)
. (., .)
. (., .)
. (., .)
1.57 (1.31, 1.87)
0.31
0.42
1.01
3.13
1.06
13.16
7.27
3.16
2.48
0.62
12.93
3.08
0.31
25.84
3.21
0.35
6.23
0.37
1.38
0.35
0.35
0.31
0.32
2.00
0.31
1.26
0.32
0.31
0.37
0.38
1.42
0.74
0.77
0.75
0.35
0.69
0.70
1.56
0.39
0.00
0.00
0.00
100.00
NOTE: Weights are from random effects analysis
.1 .2
ESA better
.5 1 2
5 10 20 50
Control better
Bohlius et al,
J Clin Onc 2006
Wilson et al,
Health Tech 2007
Seidenfeld et al,
BCBS 2006
Bennett et al,
JAMA 2008
Bohlius et al,
Lancet 2009
No. of
trials
(No. of
patients)
42 (8,167)
28 (5,308)
35 (6,918)
51 (13,611)
53 (13,933)
HR for
mortality
(95% CI)
1.08 (0.99-1.18)
1.03 (0.92-1.16)
1.11 (0.99-1.23)
1.10 (1.01-1.20)
1.17 (1.06-1.30)
KDOQI 2007
guideline
(non-dialysis
patients)
KDOQI 2007
guideline
(dialysis
patients)
Phrommintikul
2007
RADAR report
(unpublished)
No. of
trials
(No. of
patients)
8 (3,038)
4 (2,391)
9 (5,143)
3 (3,300)
HR for
mortality
(95% CI)
1.01 (0.63,1.61)
1.12 (0.91,1.37)
1.17 (1.01, 1.35)
1.25 (1.071.45)
Conflicts of Interest in Basic Science Studies:
Evaluating Erythropoietin Effects
of Solid Tumor Cell Lines
Bennett CL, et al. Association between pharmaceutical support and basic science research on
erythropoiesis-stimulating agents. Arch Intern Med, 2009; 170(16): 1490-1498.
•
Senator Charles Grassley (R-IA)
recently initiated conflict of interest
probes against physicians at
Harvard Medical School, Columbia
University, and Emory University.
•
Physician Payments Sunshine Act:
requires transparency in
relationships between physicians
and pharmaceutical companies.
•
Clinical studies have demonstrated that when
investigators have financial relationships with
pharmaceutical manufacturers, they are less likely
to criticize the safety, efficacy, or costeffectiveness of agents supplied by the
manufacturers.
•
No study has evaluated the effects of these
financial relationships in the basic science setting.
We investigated the relationship between
manufacturer involvement and laboratory results in
studies of erythropoietin receptors (EpoRs) in
cancer cells.
Erythropoietin Stimulating Agents (ESAs)
•
ESAs were approved in 1993 for use in the treatment of
chemotherapy-associated anemia.
•
Concerns were raised that the off-target effects might
include stimulation of erythropoietin receptors (EpoRs) on
cancer cells.
•
Early adverse clinical evidence for ESA use:
- BEST 2003 (breast cancer)
- ENHANCE 2003 (head and neck cancer)
•
A MEDLINE database search was conducted (1988-June
2008).
•
Studies investigating EpoR presence and ESA-induced
signaling and/or changes in cellular function, in solid
tumors, were evaluated.
•
Conflicts of interest, laboratory results, funding sources,
and affiliations were extracted.
•
Academic studies without funding from ESA
manufacturers; n=64
•
Studies led by academic investigators who had
received funding from ESA manufacturers; n=7
•
Investigators employed by ESA manufacturers; n=3
Gene
Protein
Signal transduction
Function / Activity
Erythropoietin Receptors in Solid Tumors:
Gene Level
Gene
Protein
Signal transduction
Function / Activity
•
EpoR mRNA is detected in a wide variety of
solid tumors.
•
Studies have demonstrated an increase in
EpoR mRNA levels upon stimulation with Epo.
Erythropoietin Receptors in Solid Tumors:
Protein Level
Gene
Protein
Signal transduction
Function / Activity
•
Cell surface expression of EpoR in solid
tumors detected by immunohistochemistry,
immunocytochemistry, immunoblot, etc.
Erythropoietin Receptors in Solid Tumors:
Signaling
Gene
•
EpoR stimulation by Epo induces the
phosphorylation of signaling proteins
involved in critical pathways regulating cell
growth, apoptosis and angiogenesis.
•
Signal transduction is detected in the PI3KAKT, JAK-STAT and/or NF-kB pathways and
varies among tumor types.
Protein
Signal
transduction
Function / Activity
Erythropoietin Receptors in Solid Tumors:
Cellular Function and Activity
Gene
Protein
Signal transduction
•
Function /
Activity
Activation of the Epo/EpoR-signaling axis by
Epo administration results in changes in
proliferation, apoptosis, invasion, and
chemosensitivity.
Percent of Studies Identifying Conclusion (%)
No COI
Academics with COIs
Investigators employed by ESA manufacturers
100
80
60
p= 0.009
p= 0.001
40
20
0
Presence of the EpoR
Erythropoietin-Induced
Signaling Events
Conclusion Identified
Erythropoietin-Induced
Changes in Cellular
Function
p= 0.007
Percent of Studies Identifying Conclusion (%)
70
NO COI
Academics with COIs
Investigators employed by ESA manufacturers
60
50
40
p= 0.008
30
20
10
0
Qualitative Conclusions “ESAs
Harmful”
Qualitative Conclusions “ESAs
Beneficial”
Conclusion Indentified
p< 0.04
No COI
Percent of Presenters Identifying Conclusions (%)
100
Investigators employed by ESA
manufacturers
80
60
40
p<0.01
p<0.04
p<0.01
20
0
EpoR Presence
Erythropoietin-Induced Signaling
Events
Conclusions Identified
Erythropoietin-Induced Changes in
Cellular function
 Association
between pharmaceutical
support and basic science research
findings on ESAs: Comparison of
findings before and after an NCI
workshop on this subject was
convened





Prior study evaluated associations between pharmaceuticalindustry funding and preclinical research
Study of erythropoiesis stimulating agents (ESAs) found
academic researchers without industry support were more
likely than others to identify detrimental effects of ESAs on
tumor cells
Concurrently, a meta-analysis identified mortality risks when
cancer patients received ESAs
2007 - the National Cancer Institute convened a workshop
reviewing research of preclinical effects of ESAs on tumor
growth
We updated our analyses of associations between funding
source and ESA research findings following the workshop


Articles identified in MEDLINE and EMBASE
databases (2008-2012) investigating preclinical
findings for ESAs in the cancer setting were reviewed.
Possible outcomes:
◦
◦
◦
◦
EPO receptor detection
Signaling events
Cellular function
Qualitative conclusions

Outcomes were reported for the current and the earlier
time-period according to funding source
◦ investigators without ESA manufacturer funding [27 and 64
studies, respectively]
◦ investigators with funding from manufacturers or who held an
ESA patent [5 and 7 studies, respectively]
◦ investigators employed by ESA manufacturers [2 and 3
studies, respectively]
EpoR(s), Epo Receptor(s),
OR Erythropoietin
Receptor(s)
+
Cancer, Tumor,
Malignancy, OR Carcinoma
Performed all combinations and used the search with
most results
280 Total Articles
29 Included
Articles
Erythropoietin Receptor +
Cancer
For each of the tumor types identified in the above searches, additional searches
were run with “tumor type” + “EpoR” variant:
EpoR(s)
AN
D
Erythropoietin
Receptor(s)
Breast
Lung
Prostate
Cervical
Endometrial
Ovarian
Glioma
Head and Neck
Neuroblastoma
Renal
Pancreatic
Melanoma
Mesothelioma
Colorectal
Colon
Ewing’s Sarcoma Family of
Tumors
The first and last author of each previous
article were searched for more recent
publications
280 Total Articles
251 Articles were excluded:
• Hematologic malignancies
• Single case reports
• Investigators employed
contrived systems
• Investigation did not
involve cancer
• Experiments involved tumor
types for which evidence of
changes in signaling upon
Epo administration was not
investigated in the literature
• Article was a review
33 Total
Articles
Erythropoietin
+
First OR Last
Author (from
prior study)
4
Included
Articles
Effect of Impact Factor (</> 4)
on Studies
120
100
Percent of Studies
80
60
0-4.00
4.0+
40
20
0
Academic Investigators without conflicts of
interest
Investigative teams comprised primarily of
Investigative teams comprised primarily of ESA
academic investigators, one or more authors has a
manufacturer employees
conflict of interest
Academic Investigators without conflicts of interest: 16/24 and 8/24, respectively
Investigative teams comprised of primarily academic investigators, one or more authors
has a conflict of interest: 0/3 and 3/3, respectively
Investigative teams comprised primarily of ESA manufacturer employees: 1/2 and 1/2,
respectively
Percent of New Studies Identifying Varying Conclusion
120
100
80
60
40
20
0
Presence of the EpoR
Erythropoietin-Induced
Signaling Events
Erythropoietin-Induced
Changes in Cellular
Function
Qualitative Conclusions
*ESAs Harmful*
Qualitative Conclusions
*ESAs Beneficial*
Academic Investigators without conflicts of interest
Investigative teams comprised primarily of academic investigators, one or more authors has a conflict of interest
Investigative teams comprised primarily of ESA manufacturer employees
Presence of the EpoR: 25/26, 5/5, and 2/2, respectively
Erythropoietin-induced signaling events: 19/22, 2/2, and 0/2, respectively
Erythropoietin-induced chances in cellular function: 19/22, 2/3, and 0/2, respectively
Qualitative conclusions that ESAs were harmful: 20/26, 2/5, and 0/2, respectively
Qualitative conclusions that ESAs were beneficial: 0/26, 0/5, and 0/2, respectively
Qualitative conclusions that ESAs were neutral/no statement: 6/26, 3/5, and 2/2 respectively
Qualitative Conclusions
*ESAs Neutral/No
Statement*
Academic Investigators without conflicts of interest
Investigative teams comprised primarily of academic investigators, one or more authors has a conflict of interest
Investigative teams comprised primarily of ESA manufacturer employees
Percent of Studies Identifying Conclusion (%)
120
100
80
60
40
20
0
Presence of the EpoR
Erythropoietin-Induced
Signaling Events
Erythropoietin-Induced Changes Qualitative Conclusions *ESAs Qualitative Conclusions *ESAs
in Cellular Function
Harmful*
Beneficial*
Conclusion Identified
Presence of the EpoR: 82/83, 8/10, and 3/5, respectively
Erythropoietin-induced signaling events: 50/55, 2/4, and 0/3, respectively
Erythropoietin-induced chances in cellular function: 49/61, 2/9, and 0/3, respectively
Qualitative conclusions that ESAs were harmful: 44/91, 2/12, and 0/5, respectively
Qualitative conclusions that ESAs were beneficial: 6/91, 3/12, and 0/5, respectively


Academic researchers with or without financial
conflicts increasingly report detrimental effects of
ESAs.
Concerns over potential financial conflicts of interest
affecting basic science research are less apparent in
academic versus pharmaceutical-owned laboratories.
•
Antibody specificity
•
Choice of controls; proprietary versus nonproprietary carrier protein
•
Differences in biological threshold for identifying
changes in cellular function of erythropoietinexposed cancer cells
In these basic science studies, pharmaceutical
sponsorship is associated with a decreased
likelihood of identifying:

Presence of EpoR on solid cancer cell lines

Unfavorable signaling events upon ESA
administration

Unfavorable changes in cellular function upon
ESA administration
•
These findings are counter to the belief that basic
science studies are not subject to variable
interpretation.
•
The observed relationship may extend to other
basic science research studies.
•
Only further analyses can confirm or deny these
preliminary findings, but the implications are
significant and additional studies in this area are
warranted.
Rituximab-associated Progressive multifocal
leukoencephalopathy (PML)
Carson KR, Bennett CL, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in
HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports
project. Blood, 2009; 113(20). 4834-4840.
 Etiology
 JC polyomavirus infection
 >80% of cases seen in patients with HIV
 Latent JC virus in up to 80% of population
 Reactivation of JC virus not well understood
 Non-HIV PML
 Hematologic malignancy
 B-cell lymphoproliferative disorders
 Possible association with stem cell transplant and purine analog therapy
 Chronic inflammatory diseases, solid organ transplant, sarcoidosis, advanced age
 June 2004
 Warning about Hepatitis B reactivation added to package insert
 February 2006
 Warning about other viral infections added to package insert
 December 2006
 Letter to health professionals from manufacturer and FDA warning: PML seen
in two patients with lupus
 February 2007
 Black box warning added to package insert
Cases were identified among rituximab-treated patients by clinicians from 12
cancer centers or academic hospitals (22 cases) or by reviewing FDA reports
(11 cases), the manufacturer’s database (30 cases), and publications (18 cases;
MeSH search terms: leukoencephalopathy, rituximab, immunosuppressed,
lymphoma, and leukemia)
 Unique data sources

 Clinical observation (n=7)
 Medical literature (n=14)
 FDA MEDWatch (n=14)
 Manufacturer (n= 23)
 Inclusion criteria: Rituximab treatment AND
 Brain biopsy confirmation of PML OR
 Autopsy confirmation OR
 MRI evidence AND JC virus in CSF by PCR
 Exclusion
 Diagnosis of HIV


15 excluded for inadequate evidence of PML, 2 for diagnosis of HIV
Patient Information (n=57)
Median Age (Years)
61 (range 30-89)
Sex (%)
M: 48.3 F: 56.2
Median Doses Rituximab
6 (range 1-28)
Purine Analogue
26 patients
Stem Cell Transplant
6 (4 Auto, 2 Allo)
Carson, Blood 2009
 Median
time course (All patients, n=57)
1st rituximab to PML
16 months (range 1.0-90.0)
Last rituximab to PML
5.5 months (range 0.3-66.0)
PML diagnosis to death
2.0 months (0.4-122)
Previous and concomitant
chemotherapy treatments
(range)
4 (1-14)
Carson, Blood 2009
 Mental
status changes
or confusion
 Focal motor weakness
 Loss of coordination
 Difficulty speaking
 Vision changes
Carson, Blood 2009
54.4%
33.3%
24.6%
21.2%
17.5%
Carson, Lancet Oncology 2009 (In press)
T- Lymphocyte
Selective adhesion molecule inhibitors
LFA-1
Mucin
VLA-4
BLOOD FLOW
Selectins
VCAM-1
ICAM-1
Endothelial Basal lamina
BRAIN
TISSUE
Molecules
not to scale.
Carson, Lancet Oncology 2009 (In press)
Myelin internode
Node of Ranvier
Case No.
Rituximab Indication
Transplant
CD4/CD8
CD4+
Purine analog
exposure
CD8+
1
Diffuse large B-cell lymphoma
None
N/A
68
N/A
N
2
Systemic lupus erythematosus
None
1.25
71
57
N
3
Non-Hodgkin lymphoma
Autologous
2.17
89
41
N
4
Diffuse large B-cell lymphoma
None
0.39
94
243
N
5
Mantle cell lymphoma
None
0.35
110
310
N
6
Follicular lymphoma
None
0.29
152
532
N
7
Follicular lymphoma
Autologous
0.23
234
1015
N
8
Chronic lymphocytic leukemia
None
0.92
287
311
N
9
Mantle cell lymphoma
Allogeneic
0.31
403
1309
N
10
Marginal zone B-cell lymphoma
Autologous
0.21
551
2596
N
11
Autoimmune hemolytic anemia
None
1.47
562
382
N
12
Follicular lymphoma
None
0.30
570
1871
N
13
Autoimmune hemolytic anemia
Allogenie
0.31
1059
3453
N
14
Waldenstrom
macroglobulinemia
None
0.34
2100
6200
Y
Carson, Blood 2009
 Nine
of ten with severe CD4 lymphopenia or low
CD4/CD8 ratio
 Abnormal CD4 counts or CD4/CD8 ratio possibly due to
cytotoxic chemotherapy and not rituximab, based on
clinical trial data
 What about T-cell function after rituximab?
 Response
in ITP associated with changes in T-cell
compartment (Stasi et al, Blood 2007)
 Modification of T-cell phenotype and cytokine profiles in
patients with SLE and Evans’ syndrome (Tamimoto et al,
Rheumatology Advanced Access 4/8/2008)
 Rapid
effect in multiple sclerosis suggests rituximab
targets a process thought to be T-cell mediated (McFarland
HF, NEJM 2/14/08)
 Through
inhibition of T- and B-lymphocyte interactions,
rituximab is contributing to viral reactivation and PML.
 Criticism- Latent site of JC virus is in hematopoietic
cells and likely B-lymphocytes. This may be how
natalizumab causes PML
 5/5
bone marrow samples tested for JC in patients with
PML, positive
 2/86 bone marrow samples from MSD at NIH with no
PML, positive
 Odds-ratio not calculable
 Rituximab
+ chemotherapy increases risk of JC
reactivation and PML
◦ JC latent in CD34+ cells and early B-cells
◦ Chemotherapy
mobilizes stem cells from bone marrow
Causes quantitative T-cell depletion
◦ Rituximab
Reduces qualitative T-cell response
B-cell depletion results in expansion of progenitor cells containing
latent JC
 Retrospective
Case-series
 Hypothesis is speculative and not verified in laboratory
model
 T-cell findings not yet shown to be significant in casecontrol study
 Case-control
study of T-cell markers after exposure to
R-chemo and chemo without rituximab
 Case-control study of marrow specimens from disease
and treatment matched controls
 Cohort study using large EMR or government database
(VA, Kaiser, and/or Medicare)
 Using
methods of SONAR project, important
hypotheses can be explored
 Subsequent investigations allow clarification of issues
raised by SONAR
 Rituximab may be associated with multiple viral
reactivation syndromes, screening and early detection
could be helpful in prevention.
Ticlopidine- and clopidogrel-associated Thrombotic
Thrombocytopenia Purpura (TTP)
Thrombotic Thrombocytopenic
Purpura (TTP)
Clinical features
• Microangiopathic hemolytic anemia
• Thrombocytopenia
• Microvascular thrombosis
• Renal Failure
• Neurological abnormalities
Epidemiology
•Incidence may be rising
 Increased awareness & diagnosis
 Increased exposure to TTP-associated agents
(ticlopidine, clopidogrel & prasugrel)
Drug-Associated Thrombotic
Thrombocytopenic Purpura
Among all clinically diagnosed TTP, 20% are drug-associated
Of all drug-associated TTP
• Most frequent: ticlopidine
Ticlopidine
• Next frequent: clopidogrel
Clopidogrel
•1991: association of TTP with ticlopidine
•2000: association of TTP with clopidogrel
Drug-Associated Thrombotic
Thrombocytopenic Purpura
Incidence & significance of thienopyridine-associated TTP
•Ticlopidine
•Coronary artery stent: 1 in 1,500 to 1 in 5,000 patients
•Cerebrovascular disease: 1 in 100,000 patients
•5 cases per year before development of stent procedures
•Stents: important contributing factor to occurrence of TTP
Used by 100,000 in the U.S.
• Clopidogrel
•1 in 100,000 to 1 in 250,000 patients
Used by 6 million in the U.S.
Bennett CL, Davidson CD, et al. 1999. Thrombotic thrombocytopenic purpura associated with
Ticlopidine in the setting of coronary artery stents and stroke prevention. Arch Intern Med 159: 2524-2528
Of the 11 patients, 10 received clopidogrel <14 days before TTP onset.
Bennett et al. 2000. Thrombotic Thrombocytopenia Purpura Associated with Clopidogrel. NEJM,
342 (24): 1773-77.

Study Objectives
◦ To describe clinical and laboratory findings for a large cohort of patients
with thienopyridine-associated thrombotic thrombocytopenic purpura
(TTP).

Methods
◦ Clinical reports of TTP associated with clopidogrel and ticlopidine were
identified from medical records, published case reports, and FDA case
reports (n=128).
◦ Duration of thienopyridine exposure, clinical and laboratory findings, and
survival were recorded.
◦ ADAMTS13 activity and inhibitor were measured for a subset of
individuals.
Bennett CL, Kim B, Zakarija A, et al. Two mechanistic pathways of thienopyridine-associated thrombotic thrombocytopenia purpura:
Results from the SERF-TTP Research Group and the RADAR Project. J Am Coll Cardiol 2007; 50 (12): 1138-43.
279 articles identified in MEDLINE,
EMBASE, the public website of the FDA
and abstracts from national scientific
conferences from 1991 to 2010 using
terms: TTP, ticlopidine, clopidogrel, TTP
215 articles reviewed
138 articles on ticlopidineassociated TTP
Articles were excluded if
they were in a language
other than English and if
there were duplicates (N=64)
67 articles on clopidogrelassociated TTP
29 articles reviewed
Articles were excluded if
they did not include details
on pharmacology,
epidemiology, laboratory or
basic science studies
(N=176)
Time on Onset Differences in thienopyridine-associated TTP
Time to Onset
70
60
50
40
30
30
40
ADAMTS13 deficient n=26
Clopidogrel n=35
Ticlopidine n=93
0
0
10
10
20
Percentage of patients with TTP
70
60
50
ADAMTS13 Non deficient n=13
20
Percentage of patients with TTP
80
80
90
90
Time to Onset
0
5
10
15
20
25
30
35
40
45
50
0
5
10
days
15
20
25
30
35
40
45
50
days
▲Figure 1. Left
▲Figure 1. Right
Thienopyridine-Associated TTP Onset: ADAMTS13 Deficient versus
ADAMTS13 Non-Deficient (p>0.05).
Thienopyridine-Associated TTP Onset: Ticlopidine versus Clopidogrel
(p=0.0016).
Bennett CL, Kim B, Zakarija A, et al. Two mechanistic pathways of thienopyridine-associated thrombotic thrombocytopenia purpura:
Results from the SERF-TTP Research Group and the RADAR Project. J Am Coll Cardiol 2007; 50 (12): 1138-43.
Outcomes for Thienopyridine-Associated
TTP Cases Based on Access to Therapeutic
Plasma Exchange therapy (TPE).
Survival with TPE
Survival without
TPE
All Patients (N=128)*
81.6 %
50.0 %
Ticlopidine (N=93) *
85.5 %
45.8 %
Ticlopidine Rx < 14 days (N=9)
100.0 %
100.0 %
Ticlopidine Rx > 14 days (N=84)
84.1 %*
38.1 %*
Clopidogrel (N=35)
72.4 %
66.7 %
Clopidogrel Rx < 14 days (N=26)
70.0 %
66.7 %
Clopidogrel Rx > 14 days (N=9)
77.8 %
Thienopyridine Rx < 14 days (N=35)
76.9 %
77.8 %
Thienopyridine Rx > 14 days (N=93)
83.3 %*
38.1 %*
Bennett CL, Kim B, Zakarija A, et al. Two mechanistic pathways of thienopyridine-associated thrombotic thrombocytopenia
purpura: Results from the SERF-TTP Research Group and the RADAR Project. J Am Coll Cardiol 2007; 50 (12): 1138-43.
ADAMTS13 activity and clinical characteristics of idiopathic and
thienopyridine-associated TTP cases
ADAMTS13 Activity (≤10%)
Normal ADAMTS13 Activity
(>10%)
Idiopathic
(n=30)
Thienopyridine
(n=26)
Idiopathic
(n=24)
Thienopyridine
(n=14)
Age (years)
40**
67**
46**
62**
Sex (%female)
83%*
54%*
96%**
43%**
20,900**
9,269**
51,458
37,000
60%**
96%**
29%
36%
1.4**
2.2**
3.7
2.9
Creatinine >2.5 mg/dl
7%
19%
48%
36%
Neurologic Dysfunction
53%
69%
52%
43%
Total IgG autoantibodies to
ADAMTS13 (prior to TPE)
100%
N/A
65% (n=23)
N/A
Platelet count (mean)
Platelet count <20,000/mm3
Creatinine (mean)
*p<0.05; **p< 0.001 for comparisons between idiopathic and thienopyridine associated TTP in each ADAMTS13 cohort. Note: Total numbers
of patients (n) are provided where information are not available for the entire cohort.
Idiopathic vs. Thienopyridine Associated TTP
ADAMTS13 Activity (≤10%)
Idiopathic
(n=30)
Thienopyridine
(n=26)
Normal ADAMTS13 Activity
(>10%)
Idiopathic
(n=24)
Thienopyridine
(n=14)
Neutralizing autoantibodies to
ADAMTS13 (prior to TPE)
Ticlopidine
Clopidogrel
79%*
39%
Neutralizing autoantibodies to
ADAMTS 13 (measured at
remission)
46%
N/A
29%
N/A
% cases ADAMTS13 level 1150%
0%
0%
33%
79%
30-day survival
97%
85%
96%
57%
1-year relapse
33%
8%
13%
0%
100%* (n=23)
100% (n=2)
N/A
0% (n=6)
*p<0.05; **p< 0.001 for comparisons between idiopathic and thienopyridine associated TTP in each ADAMTS13 cohort. Note: Total numbers
of patients (n) are provided where information are not available for the entire cohort.
Clinical characteristics of ticlopidine vs clopidogrel associated TTP Cases
Ticlopidine (n=30)
Clopidogrel no relapse (n=8)
Age (years)
68
58
Platelet count <20,000/mm3
90%
13%
Creatinine >2.5 mg/dl
20%
50%
Neurologic Dysfunction
60%
50%
Neutralizing autoantibodies to ADAMTS 13 (at
presentation)
100%
0%
% cases ADAMTS13 ≤10%
80%
0%
% cases ADAMTS13 level 11-50%
20%
63%
Percent < 2 weeks
0%
50%
Percent 2-12 weeks
100%
25%
Percent > 12 weeks
0%
25%
Percent received TPE
83%
100%
Survival after TPE
85% (n=26)
50% (n=8)
30-day survival
80%
50%
1-year relapse
0%
0%
Duration of Thienopyridine Use:
ADAMTS13 Activity (≤10%)
ADAMTS13 Activity (>10%)
Neutralizing Antibody at
Presentation
Present
(n=23)
Not Present
(n=6)
Present (n=10)
Not Present
(n=14)
Age (years)
38
43
48
45
Sex (%female)
87%
67%
100.0%
92.3%
Platelet count (mean)
19,261
24,000
38,400
60,786
Platelet count <20,000/mm3
65%
50%
30.0%
28.6%
Creatinine (mean)
1.27
1.70
3.66
10.49
Creatinine >2.5 mg/dl
4%
20%
50.0%
42.9%
Neurologic Dysfunction
52%
67%
40.0%
61.5%
Neutralizing autoantibodies
to ADAMTS 13
(measured at remission)
60%* (n=20)
0%*
50.0%
18.2%
% cases ADAMTS13 level
11-50%
0%
0%
50.0%
21.4%
30-day survival
95%(n=22)
100%
100.0%
92.9%
1-year relapse
57%
17%
25.0%
0.0%

Most ticlopidine-associated TTP cases”
- occur after 2 weeks of drug exposure,
- ADAMTS13 deficient,
- 100% have ADAMTS13 autoantibodies at presentation but do not
relapse
- immune-mediated involving neutralizing antibodies to ADAMTS-13.

Clopidogrel-associated TTP cases:
- occur within days of drug exposure,
- do not exhibit ADAMTS13 deficiency,
- does not have ADAMTS13 autoantibodies at presentation but do not
relapse
- less responsive to TPE
- may be a direct result of endothelial damage,
Bennett CL, Kim B, Zakarija A, et al. Two mechanistic pathways of thienopyridine-associated thrombotic thrombocytopenia purpura:
Results from the SERF-TTP Research Group and the RADAR Project. J Am Coll Cardiol 2007; 50 (12): 1138-43.
Bennett CL, Georgantopoulos P, Matsumoto M, Rock G, Fujimura Y, et al. Thrombotic
thrombocytopenic purpura (TTP) patients associated with ticlopidine: A review of 22 cases in Japan.
(Under Review).
Matsumoto
(n= 186)
Bennett (n=22) Bennett
this paper
(n= 98)
Tsai (n=7)
Steinhubl
(n=19)
Country
Japan
Japan
United States
United States
United States
% female
55.1%
45.50%
46.6%
70.0%
30.0%
Median Age
(yrs)*
54 (8 mos87)*
69 (41- 89)*
64.2 (11.1=
SD)
57 (42-89)
62 (38-75)
96.0% (23/24)
71.9%
100.0%
89.4%
Plt < 20k/mm3 100.0%
Hgb < 9 g/dl
75.0%
72.7%
26.9%
42.3%
66.7%
Cr > 2.5
mg/dl*
Neurologic
abnormality
75.8%
18.1%
30.1%
NA
47.0%
79.0%
63.6%
73.1%
70.0%
73.7%
Median days
ticlopidine
(range)
Not applicable 27.5 (14 -36)
21 (7-112)
21 (14-56)
21 (14-28)
*p<0.05 for comparison between acquired idiopathic TTP
Matsumoto
(n= 186)
Bennett (n=22) Bennett
this paper
(n= 98)
Tsai (n=7) Steinhubl
(n=19)
Survival
84.3%
91.03%
84.9%
100.0%
78.9%
% Therapeutic
plasma
exchange (TPE)
Not available
63.6%
74.2%
100.0%
68.4%
Survival w/o TPE Not available
66.70%
42.1%
Not
available
33.3%
Survival w/ TPE*
83.9%*
100.0%*
81.7%
100.0%
100.0%
% w/
ADAMTS13:AC
deficiency
(<10%)
100.0%
100.0%
100.0%
83.3%
Not available
% with
ADAMTS13
inhibitors
97.8%
100.0%
Not
available
100.0%
Not available
*p<0.05 for comparison between acquired idiopathic TTP

Idiopathic TTP and thienopyridine-associated TTP
represent distinct clinical syndromes.

Ticlopidine- and clopidogrel-associated TTP are also
distinct clinical syndromes.

Measurement of ADAMTS13 activity as well as
ADAMTS13 auto-antibodies provides important
information that characterizes the two different
mechanistic pathways for thienopyridine-associated
TTP syndromes.
Gadolinium-Associated
Nephrogenic Systemic Fibrosis
Bennett CL, Qureshi ZP, Sartor AO, Norris LB, Murday A, Xirasagar S, Thomsen HS. Gadolinium
Induced Nephrogrenic Systemic Fibrosis, the Rise and Fall of an Iatrogenic Disease. Clinical Kidney
Journal, 2012; 5: 82-88.
 Overview:
◦ The first cases of nephrogenic systemic sclerosis were
initially identified by Cowper et al. in 1997 and
published in 2000.
◦ Fifteen patients on hemodialysis presented with
thickening and hardening of the skin and
scleromyxedema-like features.
◦ This condition can be quite disabling because the skin
tightening and musculo-tendinous involvement result in
joint contractures that can reduce the range of motion of
joints.
Subtype
Description
1
New-onset acute renal failure or acute
decompensation in CKD
Pneumonia like disorder, followed by
acute renal failure
Surgical procedure (often vascular) or
acute blood loss, followed by acute
renal failure
Kidney transplant
2
3
4
5
6
7
Chronic kidney disease, unknown
trigger
Thrombotic event, renal failure may
prewdate or follow the event
Brain tumor
Percentage of
previously reported
patients (n=100)
25
6
18
34
3
12
1
NFD
progression
May be
transient
Usually
transient
May be
transient
May be
transient
Usually chronic
May be
transient
Unknown
Number of Cases
* Indicates a linear chelating agent
Key Events (US):
•Grobner’s report (2005)
•First FDA report: summarizes Danish findings and
indicates that the FDA is investigating (2006)
•FDA advisory warns of GBCA administration to
persons with CKD stage 4-5 (2007)
•Black-box warnings issued (2008)

Swift but uncoordinated efforts led to identifying and
disseminating information GBCA-associated NSF

Nearly a 70% drop in US cases from 1997 to 1998
◦ The US still accounts for the vast majority of NSF
cases worldwide

The absence of a centralized registry of NSF cases
resulted in variable quality and quantity of case reports

The individual safety databases in this study will be
derived from:
◦ FDA’s MedWatch: European Medicines Agency ;
Published case reports and case series
◦ International Registry maintained at the Yale
University School of Medicine
◦ Medical record reviews
◦ Safety reports collated by 23 product safety law firms
◦ Safety reports obtained from two of the manufacturers
of GCCAs


Report on the long-term outcome of persons with NSF.
We hope to adjudicate weather NSF is a class- or product-specific
toxicity (as we did with Epo-associeated PRCA)
Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004; 351:1403-8.