Issues in Projecting Increased Risk of Cardiovascular Events to the Exposed Population

1

Department of Health and Human Services

Center for Drug Evaluation and Research

Issues in Projecting Increased Risk of Cardiovascular Events

to the Exposed Population

Robert T. O’Neill, Ph.D.

Director, Office of BiostatisticsFebruary 18, 2005February 18, 2005

2



Issues for Discussion• The approach we used (one of several) and why? Rofecoxib as an

example - data sets available

• What do we know from the rofecoxib randomized controlled trials

(RCTs)

• Data sources for projections of events to the exposed population

• Model assumptions

• A range of estimates for different scenarios

• Uncertainties in the projection strategies

• Concluding remarks

3



Approach to estimation of excess events

associated with exposure• Estimate the absolute difference in cumulative incidence

rates of events from the VIGOR and APPROVE studies (event definitions) at monthly intervals for 1 to 36 months of exposure - control and dose groups assumed

• Estimate from IMS data the total prescriptions (usage) for 25mg and 50 mg between years 1999 thru 2004

• Define episodes of exposure from the Caremark database and estimate approximate patient numbers with different durations of successive episodes

• Use a ratio multiplier to project up from Caremark database to IMS data base - provides U.S. estimate of number of patients with various successive episodes

4



Approach to estimation of excess events associated with exposure

(cont.)• Multiply this estimate of numbers of patients with

exposure episodes by the estimate of increased risk (incidence) to obtain number of excess events

• Add estimates from all mutually exclusive episode groups to get total excess events over the control background risk (rate)

• Discuss statistical variability of estimate (confidence interval)

• Repeat for different sets of assumptions about control rates, relative risk by duration, and risk factors

5



For chronically used drugs, the duration of person exposure and the calculated risk at that time matter

As does the appropriate estimate of risk and increased risk at defined intervals of time or durations of exposure

6



What did we learn from two Rofecoxib clinical trials?

(Studies were not prospectively designed for CV events)

Study VIGOR APPROVeEndpoint PUBs Recurrent CA

Indication Rheumatoid Arthritis Polyp prevention

Duration 1 year 3 year

Dose 50 mg 25 mg

Mean Age 58 years 59 years

Subjects 79% Female 48% Female

Comparator Naproxen Placebo

7



Replication

• Do we believe there is an effect to project?

• Is there consistency of effects in different studies on same endpoints?– Alzheimer’s Disease– Mild Cognitive Impairment

8



Event Definitions Matter !

• Event rates are a function of event definitions and how many different subtypes are included in the definition

• Blindly adjudicated vs. investigator reported events will (can) make a difference risk estimates and risk ratios

9



Event definitions in VIGOR & APPROVe

We will examine two of them:

• Confirmed thrombotic events within 14 days of last dose of study drug:

• Myocardial infarction (fatal and non-fatal), or sudden cardiac death

APTC events within 14 days of last dose of study drug

10



VIGORPatients withdraw from exposure (trial)

early !Impact on event rates and comparisonsCompleted:

rofecoxib: 2862 / 4047 ( 70.7% )naproxen: 2880 / 4029 ( 71.5% )

Discontinued (Reasons):Clinical AE’s:

rofecoxib: 563 (13. 9%); naproxen: 492 (12.2%)Lack of efficacy:

rofexocib: 256 (6.3%); naproxen: 263 (6.5%)

Other: laboratory AE’s, moved, lost, withdrew consent

11



12



RR = 2.28, P =0.0035

(1.31,3.97 )

13



Myocardial infarction contributes most to the composite endpoint in the VIGOR Study

14



(Huque)

15



Data support risk and increased risk, increases with longer duration of exposure

16



RR = 1.92 , p = 0.008)

(1.19 , 3.11)

17



18



(Merck, 2005 )

Risk and increased risk, increases with exposure duration and time

19



(Merck, 2005 )

20



Increased Incidence of MI & Sudden Cardiovascular Death for 25 mg Vioxx (APPROVe )

-0.5

0

0.5

1

1.5

2

2.5

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

in Months

Inc

reas

ed

In

cid

en

ce

in

%

Average

95% CI Upper Limit

95% CI Lower Limit

25 mg Tablet strength - Increased Risk (Difference in rates)

21



Increased Incidence of MI & Sudden Cardiovascular Death for 50 mg Vioxx (over Naproxen) (VIGOR)

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 1 2 3 4 5 6 7 8 9 10 11 12 13

in Months

Inc

rea

se

d I

nc

ide

nc

e i

n % Average

95% CI Upper Limit

95% CI Lower Limit

50 mg Tablet strength - Increased Risk (Difference in rates)

22



Increased Incidence of All Thrombotic Events for 50 mg Vioxx (with Constant Projection to 36 Mon)

-0.5

0

0.5

1

1.5

2

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

in Months

Inc

rea

se

d I

nc

ide

nc

e i

n % Average

95% CI Upper Limit

95% CI Lower Limit

Assumptions for increased risk beyond 12 months

23



Increased Incidence of MI & Sudden Cardiovascular Death for 50 mg Vioxx (with APPROVe Projection to 36 Mon)

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

4

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

in Months

Inc

rea

se

d I

nc

ide

nc

e i

n %

Average

95% CI Upper Limit

95% CI Lower Limit

Assumptions for increased risk beyond 12 months:

Using APPROVe estimates for 12 to 36 months

24



Projections to the Population

Projections to the population involve:• Estimating how many persons are exposed• For how long• To what increased risk, and• Against what background rate

We will rely on drug use prescription data – We will rely on drug use prescription data – many assumptions are mademany assumptions are made

25



National Prescription Data Sources

• IMS Health, National Prescription Audit Plus – Total number of prescriptions dispensed from U.S.

retail pharmacies– Does not provide patient demographic information

• IMS Health, National Disease and Therapeutic Index– Survey of 2000 - 3000 office-based physicians – Projections may be unstable given small sample

size

26



Total number of prescriptions dispensed for Vioxx from 1999 - 2004 in outpatient settings

14 M

20 M22 M

25 M

21 M

5 M

0

5

10

15

20

25

30

1999 2000 2001 2002 2003 2004

Year

Dis

pen

sed

Pre

scri

pti

on

s(m

illio

ns)

All Strengths

25 mg

50 mg

12.5 mg

IMS Health, National Prescription Audit Plus™, Years 1999 – 2004, Extracted January 2005, Original File: 0501viox.dvr

27



Indications for Use of Vioxx: 1999-2003

Average use of Vioxx for 1999 - 2003

OA: 18% RA : 3%

Highest use was in 1999

OA: 23% RA: 5%

Use in 2003

OA: 16% RA: 3%

28



Estimating Patient Level Duration of Rofecoxib Exposure

The Caremark Data

An attempt to estimate how many persons are exposed for how long

a duration to different tablet strengths

29



Source of Data for Defining Episodes of Vioxx Use

• Dataset obtained through Caremark™– Large pharmacy benefits manager– Covers 70+ million patient lives and ~25% of total U.S.

prescriptions

• Dataset included all Vioxx claims (n=1,969,285) from 1 January 2002 through 31 December 2004– Patients must have been in Caremark™ for entire study

time period (~25% of all claims)

30



Analytical Caremark™ Dataset

• We excluded prescriptions claims where:– Strength = 12.5 mg– Patients who were younger than 18 years – Suspension formulation

• We also removed nonsensical data– Days supply dispensed equal to zero– Patients aging more than 2 years between subsequent

prescriptions– Patients whose gender changed between prescriptions

• Final dataset included 1,736,639 claims and 403,293 patients

31



Limitations of Caremark™ Data

• Not nationally representative

• Limited to insured persons with prescription drug coverage– Under-representation of elderly persons (due to

Medicare coverage)– Poor, indigent persons underrepresented

• Quality of prescription claims data– Data not collected for research purposes

32



Definition of exposure episode

One exposure-episode

Two exposure-episodes

Caremark 36-month window) 6/1/2002

Exposure-episode included in analysis(≥ 3 months observed)

Exposure-episode excluded (< 3 months observed)

1/1/2002 12/31/2004

33



Definition of Continuous Episode of Vioxx Use

Days supply (initial Rx)

Time between prescriptions

< = 15 days 15 days

16 – 60 days 30 days

61+ days 60 days

34



Frequency of 25 mg Vioxx Exposure-Episodes (Caremark/AdvancePCS 36-mon Window)

0

50000

100000

150000

200000

250000

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35

Length in Months

# o

f E

xp

osu

re-e

pis

od

es

Vioxx exposure-episode (exclusive)

Vioxx exposure-episode (cummulative)

Total Number of Exposure-episode=489900

35



Frequency of 50 mg Vioxx Exposure-Episodes (Caremark/AdvancePCS 36-month Window)

0

10000

20000

30000

40000

50000

60000

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35

Length in Months

# o

f E

xp

osu

re-e

pis

od

es

Vioxx exposure-episode (exclusive)

Vioxx exposure-episode (cummulative)

Total Number of Exposure-episode = 78748

36



Projection Ratio R IMS Rx relative increase over Caremark™ Rx:

Assume constant multiplier

R = (Total IMS Rx’s in 1999-2004) /(Total Rx’s in Caremark)

Caremark (2002-2004)

IMS Rx's(in 1,000) R

# Exposure/episodes # Rx's

25 mg 489900 1437231 84205 58.59

50 mg 78748 190914 9601 50.29

Total 568648 1628145 93806

37



What is the increased risk in exposure sub-populations?

• By dose• By duration of exposure

• No other factors possible to examine:– Age– Gender– Indication, or– Other risk factors

38



CalculationAverage Increased Number (Events)

Attributable to Vioxx

• For each dose strength and length of exposure-episode L

NL = (# of exposures) x (Increased Incidence) x R

• To obtain the increased events for each dose strength

Sum over all exposure lengthsSum over both dose strengths to obtain total

39



Estimates of Population Increased Events: MI & Sudden Cardiovascular Deaths

(Events)

25 mg = 28,686 (95% CI upper limit = 100,159)

50 mg = 3,732 (9,256) – constant projection = 4,407 (w / APPROVe Projection )

Both 25mg and 50mg strengths combined

32,418 (109,415) events (w/constant projection) 33,093 (w/APPROVe Projection)

40



Estimates of Population Increased Events:Confirmed thrombotic events within

14 days of last study dose

25 mg = 41,406 (95% CI upper limit 145,046)

50 mg = 6304 (15,380) for constant projection = 8034 for APPROVe projection

Both 25mg and 50mg strengths combined

47,710 (160,426) events for constant projection 49,440 events for APPROVe Projection

41



Sensitivity of the Estimate

Estimates of the number of increased events are influenced by: – Validity of the assumption to use clinical trial incidence for population

incidence and comparability of populations (cross trial data)

– Relevance of observational data odds ratio to short term use, hazard rate

– The Caremark inclusion criteria for left censored exposure-episode and the

cutoff time of the first prescription

– The variability of the ratio projected from Caremark to US population

(nationwide) and its validity

– Variability of the estimates of increased incidence

– Assumption of projection from 13-month trial exposure data to 36-month of

exposure

42



Where do some of the differences in estimates come

from?• Assumption of constant hazard rate calculated as

events per 100 person years - can overestimate early 1 - 2 month hazard, underestimates later ( > 8 months, 1.5 year ) hazard

• Assumption of constant (proportional hazard ratio over exposure time)

• Estimate of very large number of people exposed for short (1-2 months) episodes - RCT vs. Caremark vs. Actual US pop

43



Exposure Length Distribution Difference

Vioxx 25 mg Exposure in APPROVe and Caremark

0.0000

10.0000

20.0000

30.0000

40.0000

50.0000

60.0000

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43

Exposure in Months

Pe

rce

nta

ge

of

Ex

po

su

re

Vioxx 25 mg Exposure in APPROVe

Vioxx 25 mg Exposure in Caremark

44



Increased Incidence of MI and Sudden Cardiovascular Death for Vioxx 25 mg over Placebo (APPROVe) - Kaplan-Meier vs. Patient-

Mon Rate

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35Month in Trial

Incr

ease

d In

cid

ence

Person-month Diff (0.0315%/patient-Month

Kaplan-Meier Rate Diff in APPROVe

45



Increased Incidence of MI & Sudden Cardiovascular Death for 50 mg Vioxx (over Naproxen) (VIGOR) - Kaplan-Meier vs.

Average Patient-month rate

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 1 2 3 4 5 6 7 8 9 10 11 12 13

in Months

Incr

ease

d In

cid

ence

in

%

Kapla-Meier-diff

Average Patient-Month rate Diff

46



Increased Incidence of MI & Sudden Cardiovascular Death by Kaplan-Meier Diff and Average Patient-Month Diff

• 25 mg– By Kaplan-Meier diff 28,686– By Patient-Month diff 39,187

• 50 mg– By Kaplan-Meier diff 7,542 (w/APPROVe

Projection) – By Patient-Month diff 5,843

• 25 mg & 50 mg Combined– By Kaplan-Meier diff 36,228– By Patient-Month diff 45,030

47



Summary• Goal of the projection effort:

– Provide a framework for considering estimates

– Provide a range of estimates to show how assumption

dependent each is - not to emphasize any one estimate

– To describe the logic, process, assumptions and

uncertainties in the estimates

– To focus attention on duration of exposure and time related

risk

– Given the data limitations and uncertainties, argue that

there is no best approach nor estimate and it is difficult to

choose an estimate without qualifying its relevance

48



Acknowledgements• ODS Team

– Laura Governale– Gerald Dal Pan– Aaron Mendelsohn– Judy Staffa

• OB Team– Joanne Zhang– Yi Tsong– Mohammad Huque

Documents

Issues in Projecting Increased Risk of Cardiovascular Events to the Exposed Population