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

ProjectCharles 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 sADRPresentations/

Abstracts Publications

RADAR Communication with Company Company Alerts FDA Alerts

Additional Outcomes by Regulating Agencies and Others

Epoetin/ Darbepoetin

Venous thromboembolism

ASCO Abstract (2007)

J Natl Cancer Inst (2006) 2007

DHP Letter (2005); Boxed

Warning (2006); DHP Letter (2007)

FDA alert (2006/7)

ODAC meeting (2007) on drug misuse

Epoetin/ Darbepoetin Death

ASCO Abstract (2007) N/A 2007

DHP Letter (2005); Warning (2005); Warning

(2007); DHP Letter (2007)

FDA alert (2006/7)

ODAC meeting (2007) on drug misuse

EpoetinPure Red-Cell

Aplasia

Scientific Program in the Developmental Therapeutics – Immunotherapy

Presentation (2004)

N Engl J of Med (2004); Blood (2005); Best

Pract Res Clin Haematol

(2005); Best Pract Res Clin

Haematol (2005) 2003

Boxed warning (2002); DHP Letter (2005) 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

Ticlopidine

Thrombotic thrombocytopenic

purpura (TTP)ASH Abstract

(2002)

Ann Intern Med (1998); Lancet (1998); Arch Intern Med

(1999); JAMA (1999) 1998

DHP Letter (1998); Boxed

Warning (1999) N/A

Clopidogrel adopted as standard antiplatelet for patients with

cerebrovascular or cardiovascular disease

Clopidogrel

Thrombotic thrombocytopenic

purpura (TTP)ASH Abstract

(2002)

N Engl J of Med (2000);

Transplantation (2002); Stroke

(2004) 1999Warning (2000); Warning (2006) N/A N/A

Report Completeness: RADAR vs. FDA

*P < .005 for completeness of RADAR vs. FDA

History/Physical examination (%)

Laboratory/ Radiology (%)

Basic science correlative (%)

RADAR FDA RADAR FDA RADAR FDA

Overall mean completeness 92* 45 54 46 34 4

Bennett CL, Nebeker JR, Yarnold PR, et al. Evaluation of Serious Adverse Drug Reactions: A proactive pharmacovigilanceprogram (RADAR) vs. safety activities conducted by the Food and Drug Administration and pharmaceutical manufacturers. Arch Int Med. 2007; 167: 1041-49.

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.

Incidence Rate Outcome Treatment/ prophylaxis

References included in report

RADAR Supplier RADAR Supplier RADAR Supplier RADAR Supplier

Number of reports that contain information

14/15 6/15 15/15 1/15 14/15 3/15 12/15 1/15

Report Completeness: RADAR vs. Supplier

Bennett CL, Nebeker JR, Yarnold PR, et al. Evaluation of Serious Adverse Drug Reactions: A proactive pharmacovigilanceprogram (RADAR) vs. safety activities conducted by the Food and Drug Administration and pharmaceutical manufacturers. Arch Int Med. 2007; 167: 1041-49.

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.

Major RADAR PublicationsDrug ADR N Publication

Sirolimus/paclitaxel coated cardiac stents Thrombotic events 139 JAMA 2007

G-CSF/ GM-CSF Acute myeloid leukemia and myelodisplastic syndrome 16 J Natl Cancer Inst

2007

Epoetin/ darbepoetin Venous thromboembolism Meta-analysis

J Natl Cancer Inst 2006

Sirolimus/paclitaxel coated cardiac stents Hypersensitivity reactions 6 J Am Coll Cardiol

2006

Thalidomide/ lenalidomide Venous thromboembolism Meta-

analysis JAMA 2006

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

Clopidogrel Thrombotic thrombocytopenic purpura 13 N Engl J Med 2000

Ticlopidine Thrombotic thrombocytopenic purpura 21 Lancet 1998

Postmarket Pharmacovigilance

Hampton, T. Postmarket “Pharmacovigilance” Program on Alert for Adverse Events from Drugs. JAMA, August 22/292007, 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 & Johnson- 170 cases

Science Antibodies None Each company had its own test

TimelinessFirst 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)

0

10

20

30

40

50

60

70

80

90

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Year

TTP

case

s re

port

ed

Total TTP cases for top ten reported drugsto the FDA's Medw atch Program

Ticlopidine

Clopidogrel

Cyclosporine

Tacrolimus

Gemcitibine

Clopidogrel/Ticlopidine and TTP

Ticlopidine

Clopidogrel

days

Perc

enta

ge o

f pat

ient

s w

ith T

TP

0 5 10 15 20 25 30 35 40 45 50

010

2030

4050

6070

8090

0Time to Onset

ADAMTS13 Non deficient n=13

ADAMTS13 deficient n=26

Thienopyridine-Associated TTP Onset

Thienopyridine-Associated TTP Onset: ADAMTS13 Deficient versus near normal levels of ADAMTS13 activity (p>0.05).

Thienopyridine-Associated TTP Onset

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

Clopidogrel n=35

Ticlopidine n=93

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 Ticlopidine*-associated TTP

Clopidogrel**-associated TTP

Basic Science

Probable underlying pathophysiology

Antibody mediated toxicity and microvascular endothelial cell damage

Microvascular 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 Ticlopidine-associated TTP

Clopidogrel-associated TTP

Clinical

Usual time-period for onset Two to 12 weeks after drug initiation

Within two weeks of drug initiation

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

Comparison of findings for ticlopidine- versus clopidogrel-associated TTP

Category Ticlopidine-associated TTP

Clopidogrel-associated TTP

Epidemiologic

Epidemiologic studies identifying an association of thienopyridine administration with TTP

Surveys Case-control studies

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 Ticlopidine-associated TTP

Clopidogrel-associated TTP

Pharmacovigilance

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 case-control study

Science Antibody test; Plasma test None Not known

Timeliness 1 year Used academic data Used academic data

Dissemination N Engl J Med 2000; JACC (in press) Package insert Dear Doctor letter

Network International Internal Internal

Funding R01 Internal Internal

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

22

78

58

42

4.5

0

17

83

33

67

47

33

Treatment withoutChemotherapy

High dose >4000U/wk

Low dose ≤40000U/wk*

Hematologic Cancer

Mixed Cancer

Solid Cancer

Target hb ≤12.5

Target hb > 12.5

HR <1

HR >1

Overall Survival as1° or 2° endpoint

PFS, DFS, RFS as1° or 2° endpoint

Pre-2003 % studies Post-2003 % studies

Number of Patients (Pre-2003)

Number of Patients (Post-2003)

PFS, DFS, RFS as 1° or 2° endpoint 0/3217 2025/7517

Overall Survival as 1° or 2° endpoint 375/2885 3556/7517

HR >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

Effect of ESA on survival: studies before 2003 vs. after 2003

0

21

79

32

18

50

21

12

88

7

15

78

Treatment withoutChemotherapy

High dose >4000U/wk

Low dose ≤40000U/wk*

Hematologic Cancer

Mixed Cancer

Solid Cancer

Target hb ≤12.5

Target hb > 12.5

HR <1

HR >1

Overall Survival as1° or 2° endpoint

PFS, DFS, RFS as1° or 2° endpoint

Number of Pati ents

(Pre-2003)

Number of Patients (Post-2003)

Solid Cancer 3124/4902 5619/6516

Mixed Cancer 695/4902 508/6516

Hematologic Cancer 1083/4902 389/6516

Low dose ≤ 40000U/wk 2046/2885 6021/7172

High dose > 4000U/wk 839/2885 1151/7172

Treatment without Chemotherapy 0/3217 2649/7010

Treatment withoutChemotherapy

High dose >4000U/wk

Low dose ≤40000U/wk*

Hematologic Cancer

Mixed Cancer

Solid Cancer

Target hb ≤12.5

Target hb > 12.5

HR <1

HR >1

Overall Survival as1° or 2° endpoint

PFS, DFS, RFS as1° or 2° endpoint

Pre-2003 % studies Post-2003 % studies

Effect of ESA on survival: studies with and without survival endpoint

Comparing Studies with and without Survival Endpoint

0

0

52

24

24

86

14

63

94

93

7

0

80

20

PFS, DFS, RFS as1° or 2° endpoint

Overall Survival as1° or 2° endpoint

Solid Cancer

Hematologic Cancer

Mixed Cancer

Low Dose ≤40000U/wk*

High Dose >4000U/wk*

HR >1

HR <1

Studies before 2003

Studies post 2003

Target hb● ≤12.5

Target hb● > 12.5

% Non-survival studies % of survival studies  Category

Number of patients (non-survival)

Number of patients (survival)

PFS, DFS, RFS as 1° or 2° endpoint 0/7212 2835/4080

Overall Survival as 1° or 2° endpoint 0/7212 3857/4080

Solid Cancer3097/6113 3961/4006

Hematologic Cancer 1427/6113 45/4006

Mixed Cancer

1589/6113 0/4006

Low Dose ≤ 40000U/wk*

4981/5645 2680/4006

High Dose > 4000U/wk*

664/5645 1326/4006

Effect of ESA on survival: studies with and without survival endpoint

55

45

57

43

25

75

63

37

6

94

7

93

PFS, DFS, RFS as1° or 2° endpoint

Overall Survival as1° or 2° endpoint

Solid Cancer

Hematologic Cancer

Mixed Cancer

Low Dose ≤40000U/wk*

High Dose >4000U/wk*

HR >1

HR <1

Studies before 2003

Studies post 2003

Target hb● ≤12.5

Target hb● > 12.5

PFS, DFS, RFS as1° or 2° endpoint

Overall Survival as1° or 2° endpoint

Solid Cancer

Hematologic Cancer

Mixed Cancer

Low Dose ≤40000U/wk*

High Dose >4000U/wk*

HR >1

HR <1

Studies before 2003

Studies post 2003

Target hb● ≤12.5

Target hb● > 12.5

% Non-survival studies % of survival studies Category

Number of patients (non-survival)

Number of patients (survival)

HR >1 4175/7011 2739/4080

HR <1

2836/7011 1341/4080

Studies before 2003

2842/7212 375/4080

Studies post 2003

4370/7212 3705/4080

Target hb● ≤12.5 1900/5934 215/3631

Target hb● > 12.5 4034/5934 3416/3631

Pharmacovigilance Chart: Erythropoietin/darbepoetin

in cancer

Academic Organizations FDA Pharmaceutical

Manufacturers

DataPublished 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

NOTE: Weights are from random effects analysis

Heterogeneity between groups: p = 0.057

Overall (I-squared = 25.4%, p = 0.195)

Parfrey

Subtotal (I-squared = .%, p = .)

Singh AK 2006

Bahalman J 1991

Furuland H 2003

Foley RN 2000

Gouva C 2004

yes - High vs Low Epo

no - High vs Low Epo

Roger SD 2004

Kuriyama S 1977

Subtotal (I-squared = 35.9%, p = 0.182)

Rossert J 2006

Revicki 1995

Besarab 1998

Study ID

no - Epo vs No

Subtotal (I-squared = 0.0%, p = 0.941)

Levin A 2005

yes - Epo vs No

Subtotal (I-squared = 0.0%, p = 0.808)

Drueke 2006

1.12 (0.88, 1.42)

0.45 (0.23, 0.92)

1.15 (0.17, 7.86)

1.45 (0.96, 2.19)

1.15 (0.17, 7.86)

0.99 (0.61, 1.62)

1.33 (0.31, 5.75)

1.40 (0.33, 5.87)

. (., .)

2.71 (0.26, 28.56)

0.67 (0.37, 1.19)

0.17 (0.02, 1.37)

3.14 (0.13, 75.02)

1.21 (1.01, 1.46)

RR (95% CI)

2.86 (0.43, 18.93)

0.35 (0.04, 3.30)

1.27 (1.08, 1.49)

1.49 (0.87, 2.53)

322/2823

12/396

2/46

52/715

2/46

29/216

Events,

4/73

4/43

0/75

2/31

47/1029

1/195

1/41

183/618

Exp

3/72

1/74

270/1676

31/300

272/2742

20/300

2/53

36/717

2/53

27/200

Events,

3/73

3/45

0/79

1/42

59/925

6/195

0/43

150/615

Control

1/85

3/78

210/1679

21/302

100.00

9.08

1.49

18.52

1.49

15.17

%

2.51

2.59

0.00

1.00

29.11

1.24

0.56

33.14

Weight

1.56

1.10

67.84

13.60

1.12 (0.88, 1.42)

0.45 (0.23, 0.92)

1.15 (0.17, 7.86)

1.45 (0.96, 2.19)

1.15 (0.17, 7.86)

0.99 (0.61, 1.62)

1.33 (0.31, 5.75)

1.40 (0.33, 5.87)

. (., .)

2.71 (0.26, 28.56)

0.67 (0.37, 1.19)

0.17 (0.02, 1.37)

3.14 (0.13, 75.02)

1.21 (1.01, 1.46)

RR (95% CI)

2.86 (0.43, 18.93)

0.35 (0.04, 3.30)

1.27 (1.08, 1.49)

1.49 (0.87, 2.53)

322/2823

12/396

2/46

52/715

2/46

29/216

Events,

4/73

4/43

0/75

2/31

47/1029

1/195

1/41

183/618

Exp

3/72

1/74

270/1676

31/300

Experimental better Standard better

1.0133 1 75

Safety:

0.67(0.37, 1.19)

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

Registries

Databases

Clinical Trials

Referral CentersCase Reports

Independent Pharmacovigilance Center

Information Synthesis; Epidemiology; Basic Science; Immunology; Pathology

Presentations/Abstracts at National

Medical ConferencesPublications in Peer-Reviewed

Medical Journals

Cochrane Collaboration

Academic FDA

Company Alerts,Including Dear

HCP Letters and Package Insert Updates

Company Communication

w/RADAR

Company

Evidence-Based PracticeCenter Reports

DEcIDE Centers

Eisenberg Center-Consumer Union Reports

CERTs

VA MedSafe

Other

FDA Alerts

MedWatch Reports

Dissemination

New Paradigm for Pharmacovigilance

Future Pharmacovigilance

Efforts

CERT Data Coordinating Center

Physicians

Nurses

Pharmacists

Acute Liver FailureTexas: UT Southwestern

Dallas

Hematology and OncologyRADAR

GI Vanderbilt CERT

SERF-TTPChicago

CERT CommunicationCenter

CardiovascularDuke CERT

Q-T Cardiac ArrhythmiaArizona CERT

Ocular ToxicitiesOregon Health and

Sciences

FDA

Cleveland ClinicCleveland

Pediatric University of North

Carolina CERT

Cardiology/GI/Peds/IDUniversity of Pennsylvania

Philadelphia

R-0

1 Fu

nded

U-0

1 Fu

nded

No

Fund

ing

CER

T Fu

nded

FDA Funded (20%)

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