Charles L. Bennett MD PhD MPP. Limited size of clinical trials Undetected toxicities at time of...

Charles L. Bennett MD PhD MPP

Planes, cars, oil spills, and pharmaceuticals-- common lessons for

preventing major safety tragedies

Limited size of clinical trials

Undetected toxicities at time of FDA approval

Many AEs identified after several years on the market

Barriers to Identifying Adverse Events

Postmarket Pharmacovigilance

Hampton, T. Postmarket “Pharmacovigilance” Program on Alert for Adverse Events from Drugs. JAMA, August 22/292007, 298 (8): 851-2.

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

Detect ADR signals

Investigate possible ADR occurrence

Analyze data

Disseminate results

Lessons Learned: The RADAR method

Bennett CL, Nebeker JR, Lyons EA, et al. The Research on Adverse Drug Events and Reports (RADAR) Project. JAMA 2005, 293:17, 2131-40.

Major RADAR Publications

Drug ADR N Publication

Bisphosphonates Osteonecrosis of the JawReview of

case series

Lancet Oncology 2008

Epoetin/ darbepoetin VTE and MortalityMeta-

analysisJAMA 2008

Sirolimus/paclitaxel coated cardiac stents

Thrombotic events 139 JAMA 2007

G-CSF/ GM-CSFAcute myeloid leukemia and myelodisplastic syndrome

16J Natl Cancer Inst

2007

Epoetin/ darbepoetin Venous thromboembolismMeta-

analysisJ Natl Cancer Inst

2006

Sirolimus/paclitaxel coated cardiac stents

Hypersensitivity reactions 6J Am Coll Cardiol

2006

Thalidomide/ lenalidomide

Venous thromboembolismMeta-

analysisJAMA 2006

Epoetin Pure Red-Cell Aplasia 9 N Engl J Med 2004

Clopidogrel Thrombotic thrombocytopenic

purpura13 N Engl J Med 2000

TiclopidineThrombotic thrombocytopenic

purpura21 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.

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)

NOTE: Weights are from random effects analysis

Heterogeneity between groups: p = 0.133Overall (I-squared = 19.5%, p = 0.114)

Subtotal (I-squared = 0.0%, p = 0.536)

Cazzola_1995


Chang_2007 (EPO-CAN-17)

N93-004_2004 (Grote)

P-174-2004

Dammacco_2001

Savonije_2004

Witzig_2005

Ten Bokkel_1998

Razzouk_2004

Vansteenkiste_2002

Henry_1995

EPO-CAN-15_2004

DAHANCA-10-2007

TRA

DA 232_2005 (Taylor)

DA 145_2007

Machtay_2004 (RTOG99-03)

EPO-GER22-2007

Thatcher b_1999

Ables_1993

Wright_2007 (EPO-CAN-20)

Hedenus_2003

Throuvalas_2000

Study ID

Coiff ier_2001

Gordon_2006

Mystakidou_2005

EPO-GBR-7_2004

Bamias_2003

WILKINSON_2006

Del Mastro_1997

Amgen 200010103_2007

INT-3_2004

Rose_1994

Osterborg_2005

BLOHMER_2007 (AGO/NOGG)

PREPARE-2007

Henke_2003

INT-1_2004

Oberhoff_1998

Case_1993

Osterborg_1996

Charu_2004

GOG-191_2007

MOEBUS_2007

Smith_2003

Vadhan-Raj_2004 (PR0003-006)

STRAUSS_2005

Kotasek_2003

Littlewood_2001

O'Shaughnessy_2005

Thatcher a_1999

Dunphy_1999

Leyland-Jones_2005 (INT-76)

AOC

1.10 (1.01, 1.20)

1.29 (1.00, 1.67)

0.37 (0.06, 2.27)

1.09 (0.99, 1.19)

0.88 (0.49, 1.59)

1.53 (0.65, 3.61)

0.41 (0.03, 5.76)

0.32 (0.11, 0.95)

0.98 (0.36, 2.67)

1.09 (0.83, 1.43)

1.01 (0.19, 5.31)

0.98 (0.14, 6.90)

0.78 (0.60, 1.01)

0.75 (0.28, 2.01)

2.70 (1.17, 6.23)

1.28 (0.97, 1.69)

0.85 (0.45, 1.60)

0.93 (0.82, 1.05)

1.41 (0.80, 2.49)

1.02 (0.60, 1.74)

1.26 (0.24, 6.60)

0.89 (0.41, 1.93)

1.84 (1.01, 3.35)

1.36 (0.98, 1.89)

0.13 (0.00, 332.66)

HR(mortality) (95% CI)

1.02 (0.38, 2.73)

0.67 (0.23, 2.00)

0.50 (0.05, 4.99)

1.07 (0.73, 1.57)

1.80 (0.53, 6.12)

4.54 (0.40, 51.20)

0.36 (0.05, 2.56)

1.43 (1.06, 1.92)

1.56 (0.42, 5.79)

1.68 (0.66, 4.29)

1.04 (0.80, 1.35)

0.67 (0.34, 1.33)

1.50 (0.96, 2.34)

1.39 (1.05, 1.84)

1.58 (0.32, 7.82)

0.61 (0.24, 1.55)

1.08 (0.44, 2.66)

1.02 (0.51, 2.04)

1.38 (0.44, 4.33)

1.25 (0.65, 2.41)

1.14 (0.77, 1.69)

3.96 (0.29, 54.12)

0.15 (0.00, 415.90)

1.16 (0.69, 1.95)

0.55 (0.11, 2.71)

0.81 (0.62, 1.06)

7.39 (0.15, 366.10)

0.49 (0.03, 8.71)

0.14 (0.00, 6.88)

1.37 (1.07, 1.75)

100.00

7.72

0.22

92.28

1.85

0.94

0.11

0.59

0.70

5.74

0.26

0.19

6.01

0.72

0.99

5.59

1.64

10.44

1.97

2.17

0.27

1.13

1.79

4.54

0.01

Weight

0.73

0.60

0.14

3.67

0.48

0.13

0.19

5.19

0.42

0.80

5.91

1.43

2.92

5.53

0.28

0.80

0.86

1.38

0.54

1.54

3.50

0.11

0.01

2.28

0.29

5.82

0.05

0.09

0.05

6.39

%

1.10 (1.01, 1.20)

1.29 (1.00, 1.67)

0.37 (0.06, 2.27)

1.09 (0.99, 1.19)

0.88 (0.49, 1.59)

1.53 (0.65, 3.61)

0.41 (0.03, 5.76)

0.32 (0.11, 0.95)

0.98 (0.36, 2.67)

1.09 (0.83, 1.43)

1.01 (0.19, 5.31)

0.98 (0.14, 6.90)

0.78 (0.60, 1.01)

0.75 (0.28, 2.01)

2.70 (1.17, 6.23)

1.28 (0.97, 1.69)

0.85 (0.45, 1.60)

0.93 (0.82, 1.05)

1.41 (0.80, 2.49)

1.02 (0.60, 1.74)

1.26 (0.24, 6.60)

0.89 (0.41, 1.93)

1.84 (1.01, 3.35)

1.36 (0.98, 1.89)

0.13 (0.00, 332.66)


1.02 (0.38, 2.73)

0.67 (0.23, 2.00)

0.50 (0.05, 4.99)

1.07 (0.73, 1.57)

1.80 (0.53, 6.12)

4.54 (0.40, 51.20)

0.36 (0.05, 2.56)

1.43 (1.06, 1.92)

1.56 (0.42, 5.79)

1.68 (0.66, 4.29)

1.04 (0.80, 1.35)

0.67 (0.34, 1.33)

1.50 (0.96, 2.34)

1.39 (1.05, 1.84)

1.58 (0.32, 7.82)

0.61 (0.24, 1.55)

1.08 (0.44, 2.66)

1.02 (0.51, 2.04)

1.38 (0.44, 4.33)

1.25 (0.65, 2.41)

1.14 (0.77, 1.69)

3.96 (0.29, 54.12)

0.15 (0.00, 415.90)

1.16 (0.69, 1.95)

0.55 (0.11, 2.71)

0.81 (0.62, 1.06)

7.39 (0.15, 366.10)

0.49 (0.03, 8.71)

0.14 (0.00, 6.88)

1.37 (1.07, 1.75)

100.00

7.72

0.22

92.28

1.85

0.94

0.11

0.59

0.70

5.74

0.26

0.19

6.01

0.72

0.99

5.59

1.64

10.44

1.97

2.17

0.27

1.13

1.79

4.54

0.01

Weight

0.73

0.60

0.14

3.67

0.48

0.13

0.19

5.19

0.42

0.80

5.91

1.43

2.92

5.53

0.28

0.80

0.86

1.38

0.54

1.54

3.50

0.11

0.01

2.28

0.29

5.82

0.05

0.09

0.05

6.39

%

ESA better Control better

15.1e-05 1 19684

MortalityMeta-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)

Updated MortalityMeta-analysis


Heterogeneity between groups: p = 0.186

Overall (I-squared = 17.1%, p = 0.145)

Charu_2007

INT-1_2004

Leyland-Jones_2005 (INT-76)


Study ID

O'Shaughnessy_2005

Henry_1995

PREPARE_2007

DAHANCA-10_2007

Thomas(GOG-191_2007)

EPO-GBR-7_2004

Rose_1994

Debus_2007 (EPO-GER22)

N93-004_2004 (Grote)

Glaspy_2007 (Amgen 200010103)

Vansteenkiste_2002

EPO-CAN-15_2004

Thatcher_1999b

Machtay_2004 (RTOG99-03)

Hedenus_2003

ten Bokkel Huinink_1998 (Reed_2005)

Strauss_2005

Gordon_2006

Vadhan-Raj_2004 (PR0003-006)

Littlewood_2001

DA 232_2005 (Taylor)

Kotasek_2003

INT-3_2004

Aapro_2008 (BRAVE)

Moebus_2007

Razzouk_2004

Osterborg_1996

TRA

Mystakidou_2005

Oberhoff_1998

Smith_2003



Ables_1993

Throuvalas_2000

Blohmer_2007 (AGO/NOGG)

DA 145_2007

Coiff ier_2001

Bamias_2003

P-174_2004

Henke_2003

Del Mastro_1997Dammacco_2001

Witzig_2005

Dunphy_1999


AOC

Osterborg_2005

Case_1993

Cazzola_1995

Savonije_2005

Wilkinson_2006

Thatcher_1999a

Rosen_2003(phase II RCT)

1.09 (1.01, 1.18)

1.38 (0.44, 4.33)

1.58 (0.32, 7.82)

1.37 (1.07, 1.75)

1.09 (1.00, 1.18)


7.39 (0.15, 366.10)

0.75 (0.28, 2.01)

1.50 (0.96, 2.34)

1.28 (0.97, 1.69)

1.69 (0.76, 3.75)

0.98 (0.62, 1.56)

1.68 (0.66, 4.29)

1.02 (0.60, 1.74)

1.53 (0.65, 3.61)

1.22 (1.03, 1.45)

0.78 (0.60, 1.01)

2.70 (1.17, 6.23)

1.26 (0.24, 6.60)

1.41 (0.80, 2.49)

1.36 (0.98, 1.89)

1.06 (0.20, 5.53)

1.16 (0.69, 1.95)

0.67 (0.23, 2.00)

0.15 (0.00, 415.90)

0.81 (0.62, 1.06)

0.85 (0.45, 1.60)

0.55 (0.11, 2.71)

1.56 (0.42, 5.79)

1.07 (0.87, 1.32)

1.14 (0.77, 1.69)

0.98 (0.14, 6.90)

1.02 (0.51, 2.04)

0.51 (0.05, 4.99)

0.61 (0.24, 1.55)

3.96 (0.29, 54.12)

0.88 (0.49, 1.59)

1.84 (1.01, 3.35)

0.89 (0.41, 1.93)

0.13 (0.00, 332.66)

0.67 (0.34, 1.33)

0.93 (0.82, 1.05)

1.02 (0.38, 2.73)

1.80 (0.53, 6.12)

0.41 (0.03, 5.76)

1.39 (1.05, 1.84)

0.36 (0.05, 2.56)0.32 (0.11, 0.95)

1.09 (0.83, 1.43)

0.14 (0.00, 6.88)

1.19 (1.01, 1.40)

1.04 (0.80, 1.35)

1.08 (0.44, 2.66)

0.37 (0.06, 2.27)

1.15 (0.87, 1.53)

4.54 (0.40, 51.20)

0.49 (0.03, 8.71)

0.84 (0.45, 1.55)

100.00

0.42

0.22

5.65

89.82

Weight

0.04

0.56

2.38

4.85

0.84

2.22

0.62

1.73

0.73

8.23

5.27

0.77

0.20

1.56

3.84

0.20

1.83

0.46

0.01

5.08

1.29

0.22

0.32

6.69

2.88

0.15

1.08

0.11

0.62

0.08

1.47

1.42

0.88

%

0.01

1.12

10.32

0.56

0.37

0.08

4.79

0.150.45

5.00

0.04

10.18

5.16

0.66

0.17

4.71

0.10

0.07

1.35

1.09 (1.01, 1.18)

1.38 (0.44, 4.33)

1.58 (0.32, 7.82)

1.37 (1.07, 1.75)

1.09 (1.00, 1.18)


7.39 (0.15, 366.10)

0.75 (0.28, 2.01)

1.50 (0.96, 2.34)

1.28 (0.97, 1.69)

1.69 (0.76, 3.75)

0.98 (0.62, 1.56)

1.68 (0.66, 4.29)

1.02 (0.60, 1.74)

1.53 (0.65, 3.61)

1.22 (1.03, 1.45)

0.78 (0.60, 1.01)

2.70 (1.17, 6.23)

1.26 (0.24, 6.60)

1.41 (0.80, 2.49)

1.36 (0.98, 1.89)

1.06 (0.20, 5.53)

1.16 (0.69, 1.95)

0.67 (0.23, 2.00)

0.15 (0.00, 415.90)

0.81 (0.62, 1.06)

0.85 (0.45, 1.60)

0.55 (0.11, 2.71)

1.56 (0.42, 5.79)

1.07 (0.87, 1.32)

1.14 (0.77, 1.69)

0.98 (0.14, 6.90)

1.02 (0.51, 2.04)

0.51 (0.05, 4.99)

0.61 (0.24, 1.55)

3.96 (0.29, 54.12)

0.88 (0.49, 1.59)

1.84 (1.01, 3.35)

0.89 (0.41, 1.93)

0.13 (0.00, 332.66)

0.67 (0.34, 1.33)

0.93 (0.82, 1.05)

1.02 (0.38, 2.73)

1.80 (0.53, 6.12)

0.41 (0.03, 5.76)

1.39 (1.05, 1.84)

0.36 (0.05, 2.56)0.32 (0.11, 0.95)

1.09 (0.83, 1.43)

0.14 (0.00, 6.88)

1.19 (1.01, 1.40)

1.04 (0.80, 1.35)

1.08 (0.44, 2.66)

0.37 (0.06, 2.27)

1.15 (0.87, 1.53)

4.54 (0.40, 51.20)

0.49 (0.03, 8.71)

0.84 (0.45, 1.55)

100.00

0.42

0.22

5.65

89.82

Weight

0.04

0.56

2.38

4.85

0.84

2.22

0.62

1.73

0.73

8.23

5.27

0.77

0.20

1.56

3.84

0.20

1.83

0.46

0.01

5.08

1.29

0.22

0.32

6.69

2.88

0.15

1.08

0.11

0.62

0.08

1.47

1.42

0.88

%

0.01

1.12

10.32

0.56

0.37

0.08

4.79

0.150.45

5.00

0.04

10.18

5.16

0.66

0.17

4.71

0.10

0.07

1.35


15.1e-05 1 19684

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)

VTEMeta-analysis


Overall (I-squared = 0.0%, p = 0.901)

Ten Bokkel_1998a

Welch_1995

DA 145_2007

Smith_2003

Vadhan-Raj_2004 (PR0003-006)

EPO-CAN-15_2004

Bamias_2003

Henke_2003


INT-3_2004

EPO-GBR-7_2004Machtay_2004 (RTOG99-03)

Wilkinson_2006

Cascinu_1994

Throuvalas_2000

Thatcher_1999a

Italian_1998GOG-191_2007

N93-004_2004 (Grote)

Charu_2007Rose_1994

Littlewood_2001

P-174_2004

Gordon_2006

Rosenzweig_2004

EPO-GER22_2007

Osterborg_1996a

Savonije_2004

Thatcher1999b

Study ID

Witzig_2005Leyland-Jones_2005 (INT-76)

Osterborg_2005

Osterborg_1996b

Abels_1993

Ten Bokkel_1998b

INT-1_2004

Razzouk_2004

Henry_1995

Dammacco_2001

Vansteenkiste_2002


Case_1993

1.57 (1.31, 1.87)

1.96 (0.10, 38.79)

3.00 (0.13, 68.26)

1.53 (1.08, 2.18)

0.34 (0.02, 5.27)

3.74 (0.85, 16.56)

8.00 (1.93, 33.09)

0.33 (0.01, 8.05)

1.58 (0.59, 4.26)

0.75 (0.13, 4.20)

3.85 (0.49, 30.15)

4.93 (0.58, 41.73)4.93 (0.24, 100.89)

4.09 (0.54, 30.80)

. (., .)

2.79 (0.12, 65.66)

. (., .)

2.93 (0.12, 70.08)2.84 (0.81, 9.96)

0.97 (0.60, 1.59)

2.36 (0.13, 43.20)2.50 (0.55, 11.30)

1.38 (0.51, 3.75)

. (., .)

3.15 (0.17, 57.55)

8.40 (0.50, 142.27)

1.98 (0.97, 4.03)

2.71 (0.14, 54.32)

4.44 (0.57, 34.55)

2.56 (0.13, 51.05)

RR (95% CI)

1.47 (0.54, 4.05)1.47 (0.89, 2.40)

3.05 (0.13, 74.41)

1.53 (0.06, 36.23)

2.73 (0.11, 65.68)

3.56 (0.20, 62.58)

1.46 (0.15, 13.85)

2.95 (0.61, 14.28)

0.73 (0.27, 1.98)

5.51 (0.66, 45.98)

1.44 (0.47, 4.43)

1.36 (0.70, 2.62)

0.63 (0.11, 3.64)

100.00

0.35

0.32

25.84

0.42

1.42

1.56

0.31

3.21

1.06

0.74

0.690.35

%

0.77

0.00

0.32

0.00

0.312.00

13.16

0.371.38

3.16

0.00

0.37

0.39

6.23

0.35

0.75

0.35

Weight

3.0812.93

0.31

0.31

0.31

0.38

0.62

1.26

3.13

0.70

2.48

7.27

1.01

1.57 (1.31, 1.87)

1.96 (0.10, 38.79)

3.00 (0.13, 68.26)

1.53 (1.08, 2.18)

0.34 (0.02, 5.27)

3.74 (0.85, 16.56)

8.00 (1.93, 33.09)

0.33 (0.01, 8.05)

1.58 (0.59, 4.26)

0.75 (0.13, 4.20)

3.85 (0.49, 30.15)

4.93 (0.58, 41.73)4.93 (0.24, 100.89)

4.09 (0.54, 30.80)

. (., .)

2.79 (0.12, 65.66)

. (., .)

2.93 (0.12, 70.08)2.84 (0.81, 9.96)

0.97 (0.60, 1.59)

2.36 (0.13, 43.20)2.50 (0.55, 11.30)

1.38 (0.51, 3.75)

. (., .)

3.15 (0.17, 57.55)

8.40 (0.50, 142.27)

1.98 (0.97, 4.03)

2.71 (0.14, 54.32)

4.44 (0.57, 34.55)

2.56 (0.13, 51.05)

RR (95% CI)

1.47 (0.54, 4.05)1.47 (0.89, 2.40)

3.05 (0.13, 74.41)

1.53 (0.06, 36.23)

2.73 (0.11, 65.68)

3.56 (0.20, 62.58)

1.46 (0.15, 13.85)

2.95 (0.61, 14.28)

0.73 (0.27, 1.98)

5.51 (0.66, 45.98)

1.44 (0.47, 4.43)

1.36 (0.70, 2.62)

0.63 (0.11, 3.64)

100.00

0.35

0.32

25.84

0.42

1.42

1.56

0.31

3.21

1.06

0.74

0.690.35

%

0.77

0.00

0.32

0.00

0.312.00

13.16

0.371.38

3.16

0.00

0.37

0.39

6.23

0.35

0.75

0.35

Weight

3.0812.93

0.31

0.31

0.31

0.38

0.62

1.26

3.13

0.70

2.48

7.27

1.01


1.1 .2 .5 1 2 5 10 20 50

Summary of Mortality Hazard Ratios from Various Published Meta-analyses: Cancer Setting

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 (1.07-1.45)

Summary of Mortality Rates from Various Meta-analyses: Chronic Kidney Disease Setting

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.

Prominent Conflict of Interest Cases

• Clinical studies have demonstrated that when investigators have financial relationships with pharmaceutical manufacturers, they are less likely to criticize the safety, efficacy, or cost-effectiveness of agents supplied by the manufacturers.

• No study has evaluated the effects of these financial relationships in the basic science setting.

Background

We investigated the relationship between manufacturer involvement and laboratory results in

studies of erythropoietin receptors (EpoRs) in cancer cells.

Study Objectives

• 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)

Erythropoietin Stimulating Agents (ESAs)

• 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.

Methods

• 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

Study Groups

Erythropoietin Receptors in Solid Tumors:Methods of Detection

Gene

Protein

Signal transduction

Function / Activity

Erythropoietin Receptors in Solid Tumors:Gene Level

• EpoR mRNA is detected in a wide variety of solid tumors.

• Studies have demonstrated an increase in EpoR mRNA levels upon stimulation with Epo.

Gene

Protein

Signal transduction

Function / Activity

Erythropoietin Receptors in Solid Tumors:Protein Level

• Cell surface expression of EpoR in solid tumors detected by immunohistochemistry, immunocytochemistry, immunoblot, etc.

Gene

Protein

Signal transduction

Function / Activity

Erythropoietin Receptors in Solid Tumors:Signaling

• 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 PI3K-AKT, JAK-STAT and/or NF-kB pathways and varies among tumor types.

Gene

Protein

Signal transduction

Function / Activity

Erythropoietin Receptors in Solid Tumors:Cellular Function and Activity

• Activation of the Epo/EpoR-signaling axis by Epo administration results in changes in proliferation, apoptosis, invasion, and chemosensitivity.

Gene

Protein

Signal transduction

Function / Activity

0

20

40

60

80

100

Presence of the EpoR Erythropoietin-InducedSignaling Events

Erythropoietin-InducedChanges in Cellular

Function

Conclusion Identified

Per

cen

t o

f S

tud

ies

Iden

tify

ing

Co

ncl

usi

on

(%

) No COIAcademics with COIsInvestigators employed by ESA manufacturers

Comparison of Scientific Conclusions in Publications According to Funding Type

p= 0.009

p= 0.001

p= 0.007

0

10

20

30

40

50

60

70

Qualitative Conclusions “ESAsHarmful”

Qualitative Conclusions “ESAsBeneficial”

Conclusion Indentified

Per

cen

t o

f S

tud

ies

Iden

tify

ing

Co

ncl

usi

on

(%

) NO COIAcademics with COIsInvestigators employed by ESA manufacturers

Comparison of Scientific Conclusions in Publications According to Funding Type

p= 0.008

p< 0.04

Comparison of Scientific Conclusions in Presentations at Two National Meetings According to Funding Type

0

20

40

60

80

100

EpoR Presence Erythropoietin-Induced SignalingEvents

Erythropoietin-Induced Changes inCellular function

Conclusions Identified

Perc

ent

of P

rese

nter

s Id

enti

fyin

g Co

nclu

sion

s (%

)

No COI

Investigators employed by ESAmanufacturers

p<0.01 p<0.01 p<0.04

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

Background Prior study evaluated associations between pharmaceutical-

industry 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

Methods

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+

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

Performed all combinations and used the search with most results

Erythropoietin Receptor + Cancer

280 Total Articles29 Included Articles

For each of the tumor types identified in the above searches, additional searches were run with “tumor type” + “EpoR” variant:

EpoR(s)

Erythropoietin Receptor(s)

BreastLung

ProstateCervical

EndometrialOvarianGlioma

Head and NeckNeuroblastoma

RenalPancreaticMelanoma

MesotheliomaColorectal

ColonEwing’s Sarcoma Family of

Tumors

AND

Erythropoietin+

First OR Last Author (from prior study)

4 Include

d ArticlesThe first and last author of each

previous article were searched for more recent publications

33 Total Articles

0

20

40

60

80

100

120

Effect of Impact Factor (</> 4) on Studies

0-4.00

4.0+

Per

cen

t o

f S

tud

ies

Academic Investigators without conflicts of interest: 16/24 and 8/24, respectivelyInvestigative teams comprised of primarily academic investigators, one or more authors has a conflict of interest: 0/3 and 3/3, respectivelyInvestigative teams comprised primarily of ESA manufacturer employees: 1/2 and 1/2, respectively

Old Results

Pres

ence

of th

e Epo

R

Eryth

ropo

ietin

-Indu

ced S

igna

ling E

vent

s

Eryth

ropo

ietin

-Indu

ced C

hang

es in

Cell

ular

Func

tion

Qualit

ative

Con

clusio

ns *E

SAs H

armfu

l*

Qualit

ative

Con

clusio

ns *E

SAs B

enefi

cial*

Qualit

ative

Con

clusio

ns *E

SAs N

eutra

l/No S

tatem

ent*

0

20

40

60

80

100

120

Percent of New Studies Identifying Varying Conclusion

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

Basic Science Results Qualitative Conclusions

Presence of the EpoR: 25/26, 5/5, and 2/2, respectivelyErythropoietin-induced signaling events: 19/22, 2/2, and 0/2, respectivelyErythropoietin-induced chances in cellular function: 19/22, 2/3, and 0/2, respectivelyQualitative conclusions that ESAs were harmful: 20/26, 2/5, and 0/2, respectivelyQualitative conclusions that ESAs were beneficial: 0/26, 0/5, and 0/2, respectivelyQualitative conclusions that ESAs were neutral/no statement: 6/26, 3/5, and 2/2 respectively

Total

Presence of the EpoR Erythropoietin-Induced Signaling Events

Erythropoietin-Induced Changes in Cellular Function

Qualitative Conclusions *ESAs Harmful*

Qualitative Conclusions *ESAs Beneficial*

0

20

40

60

80

100

120

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

Conclusion Identified

Per

cent

of S

tudi

es I

dent

ifyi

ng C

oncl

usio

n (%

) Qualitative ConclusionsBasic Science Results

Presence of the EpoR: 82/83, 8/10, and 3/5, respectivelyErythropoietin-induced signaling events: 50/55, 2/4, and 0/3, respectivelyErythropoietin-induced chances in cellular function: 49/61, 2/9, and 0/3, respectivelyQualitative conclusions that ESAs were harmful: 44/91, 2/12, and 0/5, respectivelyQualitative 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.

Conclusions

• Antibody specificity

• Choice of controls; proprietary versus non-proprietary carrier protein

• Differences in biological threshold for identifying changes in cellular function of erythropoietin-exposed cancer cells

Criticisms of Findings Suggesting Harmful Effects of ESAs

In these basic science studies, pharmaceuticalsponsorship is associated with a decreasedlikelihood of identifying:

Presence of EpoR on solid cancer cell lines

Unfavorable signaling events upon ESA administration

Unfavorable changes in cellular function upon ESA administration

Summary of Results

• 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.

Future Implications of COI Study

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.

EtiologyJC polyomavirus infection>80% of cases seen in patients with HIVLatent JC virus in up to 80% of populationReactivation of JC virus not well understood

Non-HIV PMLHematologic malignancy

B-cell lymphoproliferative disorders Possible association with stem cell transplant and purine analog therapy

Chronic inflammatory diseases, solid organ transplant, sarcoidosis, advanced age

Progressive Multifocal Leukoencephalopathy (PML)

June 2004Warning about Hepatitis B reactivation added to package insert

February 2006Warning about other viral infections added to package insert

December 2006Letter to health professionals from manufacturer and FDA warning: PML seen

in two patients with lupusFebruary 2007

Black box warning added to package insert

Rituximab and viral reactivation(United States)

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

Case Reports, Inclusion/Exclusion

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)

Findings

15 excluded for inadequate evidence of PML, 2 for diagnosis of HIV Patient Information (n=57)

Carson, Blood 2009

Additional Findings

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 54.4% Focal motor weakness 33.3% Loss of coordination 24.6% Difficulty speaking 21.2% Vision changes 17.5%

Symptoms at diagnosis

Carson, Blood 2009

MRI Findings

Carson, Lancet Oncology 2009 (In press)

Inhibition of T-lymphocyte Trafficking by natalizumab and efalizumab

T- Lymphocyte

ICAM-1VCAM-1Selectins

Mucin

LFA-1

BLOOD FLOW

Selective adhesion molecule inhibitors

Node of RanvierMyelin internode

BRAIN TISSUE

Molecules not to scale.

Endothelial Basal lamina

VLA-4

Carson, Lancet Oncology 2009 (In press)

T-Lymphocyte count at PML diagnosis

Case No. Rituximab Indication Transplant CD4/CD8 CD4+ CD8+Purine analog exposure

1Diffuse large B-cell

lymphoma None N/A 68 N/A N

2Systemic lupus erythematosus None 1.25 71 57 N

3 Non-Hodgkin lymphoma Autologous 2.17 89 41 N

4Diffuse 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

8Chronic lymphocytic

leukemia None 0.92 287 311 N

9 Mantle cell lymphoma Allogeneic 0.31 403 1309 N

10Marginal zone B-cell

lymphoma Autologous 0.21 551 2596 N

11Autoimmune hemolytic

anemia None 1.47 562 382 N

12 Follicular lymphoma None 0.30 570 1871 N

13Autoimmune hemolytic

anemia Allogenie 0.31 1059 3453 N

14Waldenstrom

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?

Summary of T-cell findings

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)

Rituximab in autoimmune disorders

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

Hypothesis

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

Epidemiology

Rituximab + chemotherapy increases risk of JC reactivation and PML◦ JC latent in CD34+ cells and early B-cells◦ Chemotherapy

mobilizes stem cells from bone marrowCauses quantitative T-cell depletion

◦ RituximabReduces qualitative T-cell responseB-cell depletion results in expansion of progenitor cells containing

latent JC

Revised Hypothesis

Retrospective Case-series Hypothesis is speculative and not verified in laboratory

model T-cell findings not yet shown to be significant in case-

control study

Limitations

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)

Future Directions

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.

Conclusions

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)

Among all clinically diagnosed TTP, 20% are drug-associated

Of all drug-associated TTP• Most frequent: ticlopidine • Next frequent: clopidogrel

• 1991: association of TTP with ticlopidine• 2000: association of TTP with clopidogrel

Drug-Associated Thrombotic Thrombocytopenic Purpura

Ticlopidine

Clopidogrel

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.

Drug-Associated Thrombotic Thrombocytopenic Purpura

Ticlopidine-associated TTP in Coronary Stent Setting (Arch Intern Med, 1999)

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

Clopidogrel-Associated TTP (NEJM, 2000)

Bennett et al. 2000. Thrombotic Thrombocytopenia Purpura Associated with Clopidogrel. NEJM, 342 (24): 1773-77.

Of the 11 patients, 10 received clopidogrel <14 days before TTP onset.

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.

Thienopyridine-associated TTP

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 ticlopidine-associated TTP

67 articles on clopidogrel-associated TTP

Articles were excluded if they were in a language other than English and if there were duplicates (N=64)

29 articles reviewed

Articles were excluded if they did not include details on pharmacology, epidemiology, laboratory or basic science studies (N=176)

Latency difference of Thienopyridine-Associated TTP

days

Per

cent

age

of p

atie

nts

with

TTP

0 5 10 15 20 25 30 35 40 45 50

010

2030

4050

6070

8090

0

Time to Onset

ADAMTS13 Non deficient n=13

ADAMTS13 deficient n=26

▲Figure 1. LeftThienopyridine-Associated TTP Onset: ADAMTS13 Deficient versus ADAMTS13 Non-Deficient (p>0.05).

days

Per

cent

age

of p

atie

nts

with

TT

P

0 5 10 15 20 25 30 35 40 45 50

010

2030

4050

6070

8090

0

Time to Onset

Clopidogrel n=35

Ticlopidine n=93

▲Figure 1. RightThienopyridine-Associated TTP Onset: Ticlopidine versus Clopidogrel (p=0.0016).


Time on Onset Differences in thienopyridine-associated TTP

Survival rates were associated with access to TPE and duration of thienopyridine exposure.

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.

Outcomes for Thienopyridine-Associated TTP Cases Based on Access to Therapeutic Plasma Exchange therapy (TPE).

Idiopathic vs. Thienopyridine Associated TTP

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)


Age (years) 40** 67** 46** 62**

Sex (%female) 83%* 54%* 96%** 43%**

Platelet count (mean) 20,900** 9,269** 51,458 37,000

Platelet count <20,000/mm3

60%** 96%** 29% 36%

Creatinine (mean) 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

*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.

ADAMTS13 activity, neutralizing autoantibodies, and outcomes of idiopathic and thienopyridine-associated TTP cases

ADAMTS13 Activity (≤10%) Normal ADAMTS13 Activity (>10%)

Idiopathic (n=30)


Idiopathic (n=24)


Neutralizing autoantibodies to ADAMTS13 (prior to TPE) Ticlopidine Clopidogrel

79%*

100%* (n=23)

100% (n=2)

39%

N/A0% (n=6)

Neutralizing autoantibodies to ADAMTS 13 (measured at remission)

46% N/A 29% N/A

% cases ADAMTS13 level 11-50%

0% 0% 33% 79%

30-day survival 97% 85% 96% 57%

1-year relapse 33% 8% 13% 0%

*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

Ticlopidine vs. ClopidogrelClinical characteristics of ticlopidine vs clopidogrel associated TTP

CasesTiclopidine (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%

Duration of Thienopyridine Use:

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%

Characteristics of Idiopathic TTP Cases by ADAMTS13 Activity and Presence of Neutralizing Antibody to ADAMTS13

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,

Ticlopidine- vs. Clopidogrel-associated TTP


Thrombotic Thrombocytopenic Purpura (TTP) Patients Associated

with Ticlopidine

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) this paper

Bennett (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 mos-87)*

69 (41- 89)* 64.2 (11.1= SD)

57 (42-89) 62 (38-75)

Plt < 20k/mm3 100.0% 96.0% (23/24) 71.9% 100.0% 89.4%

Hgb < 9 g/dl 75.0% 72.7% 26.9% 42.3% 66.7%

Cr > 2.5 mg/dl*

75.8% 18.1% 30.1% NA 47.0%

Neurologic abnormality

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)

Characteristics of ticlopidine-associated TTP in Japan and the United States

*p<0.05 for comparison between acquired idiopathic TTP

Matsumoto (n= 186)

Bennett (n=22) this paper

Bennett (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

Characteristics of ticlopidine-associated TTP in Japan and the United States

*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.

TTP: Conclusions

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.

Nephrogenic Systemic Fibrosis: Introduction

Clinical Appearance of NSF

Systemic Involvement in NSF

Clinical Subtypes of Nephrogenic Systemic Fibrosis: a proposed classification scheme

Subtype Description Percentage of previously reported patients (n=100)

NFD progression

1 New-onset acute renal failure or acute decompensation in CKD

25 May be transient

2 Pneumonia like disorder, followed by acute renal failure

6 Usually transient

3 Surgical procedure (often vascular) or acute blood loss, followed by acute renal failure

18 May be transient

4 Kidney transplant 34 May be transient

5 Chronic kidney disease, unknown trigger

3 Usually chronic

6 Thrombotic event, renal failure may prewdate or follow the event

12 May be transient

7 Brain tumor 1 Unknown

Number of Cases in FDA database of GBCA-associated NSF by Year (With Confirmed Event Date)

Num

ber

of C

ases

• 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)

* Indicates a linear chelating agent

Key Events (US):

Results of Advisories

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

Data Sources

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

Methodology

Project Objectives regarding GBCA- associated NSF

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.

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