1

Postmarketing Drug Safety and Risk Intervention Studies

Evelyn M Rodriguez MD, MPH

Director, DDREII, OPDRA

2

Topics for Today’s Discussion• Postmarketing Drug Safety• Two Risk Intervention Case Studies

– Review of the Labeling History– Study Objective, Methods, Results

and Conclusions

• Summary / Considerations• Future Directions

3

Why Post-Marketing Surveillance?

• Limitations of Phase 3 Trials

– Too few, too simple, too median

aged, too narrow, too brief

• Population of Users Expands After

Drug Approval

– Age, Sex, Race/Ethnicity, Use in

pregnancy

• Rare Events

4

Postmarketing Safety Surveillance

• Database reporting system:

Adverse Event Reporting System

(AERS)• Cost effective• Signal generation• Receives > 250,000 reports per year

5

Postmarketing Causality Assessment

• Temporal Relationship

• Biological Plausibility

• Known Class Effect

• Previous Pre-marketing Findings

• Dose-related Effect

6

Postmarketing Causality Assessment

• Onset Time and Progression

• Confirmed Diagnosis

• Dechallenge - discontinue drug

• Rechallenge - restart drug

• Underlying Disease

• Concomitant Drugs

7

Use of Cases Identified in AERS

• Case definition - reporter’s clinical

diagnosis or one from the literature

• Develop Case Series

– Causality Assessment

– Conditions of exposure

– Risk Factors and Confounders

8

Underreporting:Barriers to Reporting

• Voluntary System

• Recognize , Attribute , and Establish

Adverse Event to Drug

• Labeled adverse events less likely

reported

• Constraints, Litigation Fear, Desire to

Publish Findings, Privacy Concerns

9

Underreporting of Adverse Drug Reactions From the Literature

Country Drug Reaction Reporting Rate

UK Practolol Oculocutaneous syn << 2%

UK NSAIDS Aplastic anemia 11%

UK OCs TE death in women 15%

US Digitalis Hosp for toxicity 0.3%

US Isoniazid Fatal hepatitis 10%

US DPT SIDS 10-20%

US RI survey Serious << 3%

US MD survey Medically serious < 8-13%

10

Lotronex

• Pre-marketing cases of ischemic colitis and constipation

• Postmarketing reports of serious cases – Ischemic colitis

– Serious complications of Constipation

• Early in marketing (3 months)

11

Possible Next Steps

• Incidence Study for Serious Outcomes–Ischemic Colitis and

Constipation difficult to ascertain in automated databases (ICD-9 codes and underreporting)

12

Possible Next Steps

• Risk Factor Study– Risk factor identification may be

feasible for Ischemic Colitis IF complete ascertainment is assured

– Constipation as a risk factor for serious GI outcomes hard to evaluate because it is associated with IBS, the indication for the drug

13

Possible Next Steps

• Implement Risk Interventions (e.g. Education, Labeling change)

• Evaluate whether the Risk

Interventions are achieving

desired goals

14

First Drug History

Risk Intervention Study

15

First Case History• Approved in January 1997• Marketed in March 1997• Seven months after marketing, first

Acute Liver Failure death• Several Re-labelings and Dear

Healthcare Practitioner letters including recommendations for Liver Transaminase (LT) testing

16

Risk Intervention Study Objective

• To assess the impact of the labeling changes regarding LT monitoring in a large managed care organization automated claims database using ICD-9 and CPT codes

17

Risk Intervention Study Objective

• Recommended LT monitoring varied slightly with each labeling change

• Last labeling change recommended a baseline test with monthly monitoring for first 8 months, data presented to AC 3/99

18

Overview of Study in the United HealthGroup Database

Cohort 1n = 2307

Cohort 2n = 2823

Cohort 3n = 1411

25 Oct 97 1 Dec 97 30 Jun 98 1 Aug 98 31 Dec 9825 Oct 97 1 Dec 97 30 Jun 98 1 Aug 98

Cohort 3n = 1411

31 Dec 98Mar 97 25 Oct 97* 1 Dec 97* 30 Jun 98 1 Aug 98*

19

LT Monitoring at Baseline after the First Prescription by Cohort

% with Baseline Test

Cohort 1(n=2307)

24.5

Cohort 2(n=2823)

37.0

Cohort 3(n=1411)

45.1

20

Full Compliance with Monthly LT Monitoring by Cohort among Drug Users

Month*

1 2 3 4 5 6

Cohort 1 2.6 0.8 0.3 0 0 0

Cohort 2 7.3 2.5 1.0 0.7 0.6 0.8

Cohort 3 9.3 4.2 2.7 0.5

4.3

*Data Shown as Percentage of Eligible Subjects at Each Time Period

21

Conclusion

• Poor compliance with full LT

monitoring scheme recommended by

labeling

• Better compliance with baseline LT

testing that improved with each

labeling change to a maximum of

45%

22

Investigators

FDA Dave Graham MD, MPH Evelyn M Rodriguez MD,

MPH

FDA Cooperative Agreement Program

UHG Carol Drinkard, PhD Deborah Shatin, PhD

23

Second Drug History

Risk Intervention Study

24

Second Drug History

• Approved in July 1993 • First reports of Ventricular Arrhythmia

with an antifungal drug 12/94• Multiple Dear Healthcare Practitioner

letters that described new contraindications and warnings for specific drugs and conditions

25

Second Drug History

• Black Box Warning with Contraindication for QT interval prolonging drugs and Cardiovascular and Medical Conditions, 2nd line indication & DHPL 6/98

26

Study Objective

• To describe the impact of the labeling changes through 6/98–CYP P450 3A4 Enzyme Inhibitor

Drugs

–QT Prolonging Drugs

–Contraindicated Comorbidities

27

Methods• Automated Databases:

–Sites A, B, and C

• Time Periods–Before DHPL: 7/97 - 6/98

–After DHPL: 7/98 - 6/99

28

Study Sites

Model N, Millions

A IPA 3.2

B Medicaid Managed 1.4

C HMO 2.2N based on calendar 1998; no material change for any of databases in 1999.

29

Cohorts Before and After Labeling Changes through

6/98Pre Post

Site N

A 16,934 15,088

B 4,823 4,924

C 8,271 7,508

30

Results: Contraindicated Drug or Disease

Pre Post

Site % of Cohort

A 29.4 26.6

B 59.7 57.5

C 29.6 27.5

31

Conclusion

• No reduction in

contraindicated use was

found following labeling

changes and DHPL of 6/98

32

Study GroupFDA Investigators

Diane Wysowski Ph.D., Evelyn M. Rodriguez, Dave Graham M.D., M.P.H.

United Health Group (Site A)

Deborah Shatin, Ph.D., Stephanie D. Schech, Ph.D.

Tennessee Medicaid (Site B)Walter Smalley, M.D., M.P.H., Jim Daugherty, M.S., Wayne Ray, Ph.D.

Harvard Consortium (Site C)Jerry Gurwitz, M.D, Susan Andrade, D.Sc., Jackie Cernieux, M.P.H. (Meyers Primary Care Institute, Fallon Healthcare System); Richard Platt, M.D., M.S., Arnold Chan, M.D., Dr.P.H. (Harvard Pilgrim Healthcare, Michael Goodman, Ph.D. (HealthPartners)

33

Summary / Considerations• Risk Intervention studies are useful to

assess the effect of labeling and DHPL• These two studies suggest labeling

fatigue phenomenon• Other strategies, such as Education

targeting Prescribers and Patients, may be useful to encourage the implementation of recommended risk management efforts

34

Future Directions• Determine

–How prescribers interpret information from DHPL & other educational materials

–Best format to inform prescribers and patients of drug safety concerns -- PPI, Med Guide, company sales materials, CME courses

35

Future Directions

• Determine –How information,

contraindications, and monitoring recommendations are used

• Feasibility of constipation as contraindication

36

Future Directions

• Conduct risk intervention studies in

multiple databases that reflect the

range of health care services

delivery systems

• Validate the findings in databases

with medical record review

37

Back Up Slides

38

Sample Size of Study Population, UHG

Ever received drug 9,369

Total person-years 4,873

90 day prior enrollment 7,568

Included in LT

monitoring study 6,541

39

Criteria for Inclusion in the Study Cohort for LT Monitoring

• Enrollment Date 90 days prior to 1st troglitazone prescription

40

Study Method for Measuring Liver Transaminase Monitoring in UHG

Baseline Month 1

…….. Last Rx.

-30d 30d1st Rx. 60d

-30d - + 7d +/- 7d +/- 7d

Month 2

41

Cohorts

7/97 6/98 7/98 6/99

PostPre

Pre and post cohorts included persons with any cisapride use in that study period.Zero time (t

0) date first dispensed prescription in study period.

42

0

10

20

30

40

50

0

10

20

30

40

<3 3-19 20-39 40- 59 60-79 80+0

10

20

30

40

Site A

Site B

Site C

Age in Years

Age Distribution (%) of Cisapride Users, Pre Year

% Female:

Site A: 60.3

Site B: 67.2

Site C: 62.8

%

43

Contraindicated Drugs

P450-3A4 QT-Label QT-ClassClarithromycinErythromycinTroleandomycinNefazodoneFluconazoleItraconazoleKetoconazoleIndinavirRitonavir

QuinidineProcainamideSotalolAmitriptylineMaprotilineAstemizoleBepridilSparfloxacinTerodiline

Antiarrhythmics, IA or IIICyclic AntidepressantsAntipsychotics

(At least 1 day of use concurrent with cisapride use)

Antiarrhythmics: procainamide, quinadine, sotalol, amiodarone, disopyramide

Antipsychotics: chlorpromazine, mesoridazine, thioridazine, trifluoperazine, thiothixene, haloperidol, fluphenazine, triflupromazine, pimozide, risperidone, perphenazine

Cyclic antidepressants: amitriptyline, clomipramine, imipramine, doxepin, trimiprramine, amoxapine, desipramine, nortriptyline, protiptyline, maprotiline

44

Pre (%) Post (%)Site A: Any 14.4 12.6 P450 3A4 7.4 5.5 QT-Label 4.0 4.1 QT-Class 8.1 7.9

Site B: Any 33.8 33.6 P450 3A4 10.4 9.8 QT-Label 11.4 12.0 QT-Class 26.5 26.4

Site C: Any 18.3 16.1 P450 3A4 9.3 7.5 QT-Label 5.4 5.2 QT-Class 10.4 9.7

Contra-indicatedDrugs

45

Contraindicated Comorbidity

• Heart Failure

• Other Ischemic Heart Disease

• Electrolyte Disorder

• Ventricular Arrhythmia

• Renal Failure

• Respiratory Failure

Any diagnosis in the 180 days preceding t0. Restricted to cohort members with 180+ days prior enrollment

46

Contraindicated Comorbidity

Pre PostSite %

A 14.9 14.0

B 41.3 38.8

C 15.3 14.5

Based on (pre/post) persons with 180+ days of enrollment: Site A: 13613/12418; B: 4379/4229; C: 6848/5812

47

<3 3-19 20-39 40-59 60-79 80+

Age, years

0

20

40

60

80

100%

Cis

aprid

e U

sers

Contraindicated Drug or Comorbidity, By Age

Site B only

48

Future Directions

• Conduct studies among prescribers to identify the “best communication practices” that will enhance timely and useful communication by industry and FDA

• Assess the impact of the health care services delivery system on prescribing and medical practice in the context of safer drug use

49

Future Directions• Form industry-government partnerships

& interagency collaborations to conduct further studies to identify effective risk intervention strategies

• Using the results from these studies, implement strategies and evaluate success