Phenylpropanolamine & Risk of Hemorrhagic Stroke

Phenylpropanolamine & Risk of

Hemorrhagic Stroke

Lois La Grenade, M.D., M.P.H.Office of Postmarketing Drug Risk Assessment

Center for Drug Evaluation and ResearchFood and Drug Administration

2

Plan

• Historical Background• Case Reviews• Review HSP/Yale Study

– Highlight important aspects– Address CHPA’s concerns– Summarize results– Assess Public Health Impact

• Overall Conclusions

3

Background

• Pre 1984: Case reports of PPA & hemorrhagic stroke

• 1984: O’Neill and Van de Carr’s case-control study– Medicaid data - Michigan & Minnesota

• 1991: Review of FDA’s spontaneous reporting system (SRS 1969-1991)

• 1991 -2000: Continued receipt of hemorrhagic stroke case reports

4

Background 1984• O’Neill and Van de Carr 1984

– association between PPA & hemorrhagic stroke, compared with other adrenergic decongestants

Study Limitations– retrospective study, automated databases– Rx only (not OTC)– 60-day exposure window– misclassification

5

Background 1991: ADRs reported with CVA

Drug% with CVA

reported

PPA (appetite &cough/cold)

14

All other drugs 0.8

6

Background 1991

• 1991 SRS Review– 1969 - Jan 1991

• 29 US cases CVA, 22 hemorrhagic stroke• 16 (73%) appetite suppressant• 6 (27%) cough/cold preparation• Young age (median 27, 35); female gender• 55% occurred with first use of PPA

7

Background 1991

Hypothesis: PPA containing products (appetite

suppressant & cough/cold), especially first use, are associated with an increased

risk of hemorrhagic stroke in young women

8

Case Review 2000

• 2000 AERS Review– Feb 1, 1991 - Jul 17, 2000– 22 US cases, 4 deaths (all female)– 19 (86%) cough/cold preparations– 3 (14%) appetite suppressants– Females 18 (86%) – Median age 35 years

9

Case Review 2000

• Median time to onset after last dose = 4 hours• Median duration of use = 24 hours

– 82% of events < 3 days of PPA use• All cases occurred with preparations

containing 75 mg (sustained release)• Shift in demographics - more cough/cold users but median age same (35 years)

10

Typical Case Report

• Young person, otherwise healthy• Develops cough/cold/ ”flu”• Takes PPA product• Within a few days, with no warning develops

catastrophic event - hemorrhagic stroke• Hospitalized • Permanently disabled or dies

11

Underreporting of Cases

• Substantial underreporting for Rx drugs, possibly as low as 1%

• No legal requirement for manufacturers to report non-monograph drug adverse events

• No learned intermediary who is aware of the PPA exposure

• Underreporting for OTC products >> Rx products

12

The Hemorrhagic Stroke Project (HSP)

• Phenylpropanolamine & Risk of Hemorrhagic Stroke

• Sponsored by CHPA, designed & conducted by Yale

• Protocol reviewed by Yale, CHPA & FDA• Designed to test hypotheses generated by

FDA 1991, 1984 reviews

13

HSP Case-control Study - PPA & Hemorrhagic Stroke

• Objectives1. Among men and women aged 18 – 49 years,

to estimate the association between PPA and hemorrhagic stroke generally, and

2. by type of PPA exposure

14

Objectives contd.

3. Among women aged 18-49 years to estimate (a) the association between first use of PPA and

hemorrhagic stroke and (b) PPA in appetite suppressants and hemorrhagic stroke.

Most important from FDA viewpoint as this was generated from our reviews

15

Study Design

• Case-control method - suited to rare events such as hemorrhagic stroke in young people– Captures all cases in a specified time-period– Results available more quickly than with

cohort studies– Less expensive

16

Design Strengths• Targeted to test specific hypotheses• Prospective• Carefully designed to minimize bias• Conducted with great attention to detail• Careful analysis

– Internal consistency shown across the various strata that were analyzed

• Largest hemorrhagic stroke study to date

17

Design Limitations

• Sample size & power borderline• Powered to detect OR of 5 or greater

– for practical, not scientific/public health considerations

• Study duration was 5+ years

18

Small Sample Size (CHPA)

• Low statistical power• May be subject to exposure misclassification• May introduce important biases• Results may not be robust

19

Small Sample Size (FDA)• Largest study ever of hemorrhagic stroke • Low power reduces probability of showing a

difference if one exists – major difference observed despite low power

• Bias is a product of poor study design/conduct – HSP well designed, internal safeguards, QA

• Internal consistency in subset analyses underscores robustness of data

20

Potential Confounders

– Aphasia– Smoking– Hypertension– Race– Education

• Each adjusted for in analysis• Not necessary to match for all - too long,

too complex

21

Odds Ratios for Hemorrhagic Stroke with PPA Use in Subjects without Hypertension

& without Aphasia

AllSubjects

Subsetw/o HTN

Subsetw/o

AphasiaAppetite

suppressant15.9

p=.01>10

p=.01>16

p=.01

Cough/cold 3.1p=.03

4.0p=.03

4.6p=.015

22

Misclassification (CHPA)

• Errors in classification could skew results -participant recall -product identification

23

Misclassification (FDA)

• Subjects blinded to exposure of interest• Structured interview & exposure verification

process• Recall bias minimized by short interval between

event & interview for both cases & controls• No data suggesting differential misclassification

that would generate spurious association• Misclassification typically biases OR towards 1

24

Surrogate Responders (CHPA)

• Exclusion of fatal & severely aphasic cases was inappropriate

• Excluded cases could differ in their exposure to PPA & other risk factors

• Analysis based on survivors may introduce survival bias

25

Surrogate Responders (FDA)

• Modest use of surrogate responders would introduce overwhelming misclassification error– verified by FDA & HSP investigators in

planning stage, and agreed to by CHPA– would remove all possibility of detecting an

association between PPA and hemorrhagic stroke

26

Surrogate Responders (FDA) contd

• Aphasic subjects may underreport PPA exposure (given the increased OR for non-aphasic subjects)

• No data to suggest that PPA exposure is related to the severity of the stroke

• Several epidemiologic studies show that use of surrogate interviews is a major source of bias*

*Armstrong, White & Saracci, 1992

27

FDA Analyses

• Confirmed the major findings by conducting its own analyses on data submitted by Yale

• Explored dose response relationship• Conducted sensitivity analyses to

examine sparse data bias due to small sample size

28

HSP Study Results

• The Yale study supported an increased risk of hemorrhagic stroke associated with PPA use.

• Findings were statistically significant among appetite suppressant users and first day users of PPA as a cough/cold remedy.

29

Public Health Impact

Attributable Risk*:1. How much of a disease that occurs can be

attributed to a certain exposure?2. How much of the risk (incidence) of disease

can we hope to prevent if we are able to eliminate exposure to the agent in question?

*Gordis, 1996

30

Total Number of PPA dose units sold annually by OTC status

1995 1996 1997 1998 1999Total 8.8 8.4 6.0 6.2 6.0OTC 6.8 6.6 6.0 4.7 4.5Non-OTC 2.0 1.8 1.6 1.5 1.5

Numbers in billions

*IMS HEALTH, Retail & Provider PerspectiveTM

31

Total Number PPA dose units sold annually by indication*

1995 1996 1997 1998 1999Total 8.8 8.4 6.0 6.2 6.0C/C (%) 97 98 98 98 98Diet (%) 3 2 2 2 2

Numbers in billions

*IMS HEALTH, Retail & Provider PerspectiveTM

32


• Study population similar to US population – Whites slightly overrepresented in study

population– Blacks & Hispanics slightly

underrepresented• Therefore study results generalizable to

US population.

33


• Study results projected to US population to estimate public health impact

• Summary of study results– Total # hemorrhagic strokes 1714– Total cases 702– 8 cases: 1st use PPA cough/cold remedy– 6 cases: PPA appetite suppressant

34


US population 18-49 years:• August 2000 US population estimate =

130 million• Background incidence of hemorrhagic

stroke = 8/100,000*• Estimated 10,400 hemorrhagic

strokes/year*Sacco, 1998, 2000; Petitti, 1997

35

Annual Public Health Impact18 - 49 years

OR Risk Period

Casesattributable

to PPA

Cough/cold 3.1 1st day 120-290

Appetitesuppressant

15.9 1st 3 days 90-220

Total cases/year in 18-49 age groupattributable to PPA

210-510

36


• Attributable risk in 18-49 age group:200- 500 hemorrhagic strokes/year

• Attributable risk in 50 age group: ??• Attributable risk for the entire US population

is therefore likely to be greater than for 18-49 age group

37

Criteria for Causal Association

• Temporal Relationship• Strength of the association• Dose response relationship• Biological plausibility• Consistency with other knowledge• Replication of the findings

38

Strength of Association

• PPA appetite suppressant (1st 3 days): – OR = 15.9 (95% LCL 2)

• PPA cough/cold (1st day):– OR = 3.1 (95% LCL 1.2)

39

Dose Response

• Yale study: Increased risk of hemorrhagic stroke with doses of PPA above 75 mg/day

• FDA exploratory analysis: Increased risk of hemorrhagic stroke with PPA doses above 75 mg/day

• Case review 2000: All 22 reports were with 75 mg preparations

40

Biological Plausibility

• PPA = sympathomimetic amine• Demonstrated pressor effects• Clear cut tachyphylaxis• Pressor effect greater for sustained

release

41

Blood Pressure Response to PPA Challenge in a Large Population

Blood Pressure Increase

% o

f Po p

ulat

ion

4mmHg

42

Consistency with Other Knowledge

• Numerous case reports in the literature– Kase, 1987; Lake, 1990– Lake - largest series, 24 cases ICH, 15

hypertensive encephalopathy/seizure, all with onset <24 hrs, most at 75 mg/day

• O’Neill and Van de Carr Study• Case reviews 1984, 1991, 2000

43

Summary

• Hypothesis of increased risk of hemorrhagic stroke with early PPA use generated from case reports

• Well designed prospective case control study strongly supports FDA hypothesis

• Criteria for causality largely fulfilled• Estimated 200-500 strokes/yr in young

people potentially preventable

44

Conclusions• The use of PPA as treatment for cough/cold

symptoms & as an appetite suppressant confers an increased risk of hemorrhagic stroke in young people.

• Substantial public health burden: in excess of 200-500 hemorrhagic strokes/year attributable to PPA

• There is evidence to suggest that the risk of hemorrhagic stroke may be higher with PPA doses at or above 75 mg/day.

45

Team: OPDRA/ Office of Biostatistics

• Parivash Nourjah, PhD• David Graham, MD, MPH• Anne Trontell, MD, MPH• Julie Beitz, MD• Joslyn Swann, RPh• Yi Tsong, PhD• Stella Machado PhD• Robert O’Neill, PhD

47

Back-up slides

48

Pseudoephedrine (PSE) Hemorrhagic Stroke cases

• 1969 - August 2000• 9 possible, 6 with PSE alone• cases reported 1987 - 1998• F: 6 M: 3 Age: Mean 57 (45 - 67) • Median time to onset - 2 hours• Dose unknown

49

Time Dependent Relationship between PPA and Hemorrhagic StrokeTi

me-

Spec

ific

Haz

ard

Time

True Hazard or Risk

)

50

Relationship between the Time Contour of PPA Risk and Relative Risk

Tim

e-Sp

ecifi

c H

azar

d

Time

True Hazard or Risk

Observed RR(Short Time Period)

Observed RR(Longer Time Period)

51


• Attributable risk = % of strokes attributable to PPA exposure & which could be prevented by removing exposure

• Pc { (RRa - 1)/RRa}*Pc = % cases exposedRRa = adjusted relative risk (adjusted OR)

*Greenland, 1999

52

Public Health Impact contd

Attributable risk estimates:• PPA first use (cough/cold) = 1%

– 104 cases/year • PPA appetite suppressant = 1%

– 90 cases/year

53

Public Health Impact -Attributable Risk Calculation

• {8/702} x 130 million = PPA first use cough cold AR = 120

• {6/702} x 130 million = PPA appetite suppressant use AR = 90

• Correction factor for excluded cases 702/1714 =0.41

54

Case DefinitionHemorrhagic Stroke

• Strict diagnostic criteria– clinical: signs/symptoms of hem. stroke– diagnostic: CT/ MRI/LP

• Medical records of suspected cases reviewed by investigator, blinded to exposure status

• Minimizes misclassification of cases

55

Exposure Definition/Ascertainment

• Exposure = PPA use– exposure defined, “first use”, “any use”– exposure window identified– exposure confirmed by “PI book”

• Interviewer bias minimized– blinded to exposure drug– randomly assigned to cases/controls

56

Strategies for Reducing Recall Bias

• Cases with stroke more likely to remember event surrounding stroke than controls (no stroke)– controls identified/interviewed within short

time– focal time matched to case’s time of stroke– data collected on all medicines used– date prompts e.g birthdays

57

Total Number PPA dose units sold annually*

1995 1996 1997 1998 1999 8.8 8.4 6.0 6.2 6.0

Numbers in billions*IMS HEALTH combined data from Provider

PerspectiveTM & Retail PerspectiveTM

58

YALE HEMORRHAGIC STROKEPROJECT

STATISTICAL REVIEW

Yi Tsong, Quantitative MethodResearch Staff, Office of Biostatistics

Parivash Nourjah, Ofice ofPostmarketing Drug Risk Assessment

59

SUBCOMMITTEE ON REGULATION, BUSINESS OPPERTUNITIES, AND ENERGY Hearing on PPA, September 24, 1990

Number of ADR reported to FDA and Through PCC Contact, Single-ingredient adult formation 1980-1989 (per billion dosing-episode) (Report of Subcommittee Technical Advisor Dr. Paul Radford)

FDA PCCYearPPA ASA ADAP PPA ASA ADAP

1980 865 20.7 52.1 - - -1981 2120 25.2 55.2 - - -1982 2760 47.1 65.7 - - -1983 2930 32.6 72.5 412 26.4 37.51984 2380 80.3 73.9 3890 93.8 1391985 427 24.5 61.9 2380 93.9 2151986 542 49.9 131 3820 117 4001987 844 51.6 198 2720 111 2681988 294 54.8 146 2340 119 3111989 671 77.2 94.0 2770 136 311

60

Direct Domestic Reports of CVA in Women Aged 10-59Received by the FDA (1977- Jan. 1991)

Product Category CVAReports

% of TotalReports

PPA-Diet 19 26%Oral Contraceptive 15 20%Thrombolytic Agent 7 10%

Lactation Suppressive 6 8%Chemotherapeutic 5 7%

Radiocontrast 4 5%Anticoagulant 3 4%

PPA-Cough/Cold 3 4%Miscellaneous 11 15%

Total 73 100%

61

EXPECTATION OF HSP FOR EACH OBJECTIVE

EXPECTATION Statistical Evidence Samplesize

Demonstrate PPA is safe Upper CI < tolerable riske.g.Obj #1: Upper CI < 2Obj #2: Cough/cold Upper CI < 2 App Supp Upper CI < 3Obj #3(a): Upper CI < 2 (b): Upper CI < 3

Large

Demonstrate PPA is risk Significant p-value (<0.10)And odds ratio > tolerable limit(say, 1.5)

Large/Moderate

Demonstrate PPA is risk Moderate p-valueConsistency in adjusted analysis,stratified analysis and subsetanalysis

Small toModerate

62

REVIEW OF CHPA’s COMMENTS ON HSP REPORT (CONTD)The findings of the HSP must be considered in the context of existingsafety data on PPA. This evidence overwhelmingly supports the safetyand effectiveness of PPA when used according to label directions.

Carefully designed, conducted and analyzed Study

Blessed with joint effort Industry sponsored

FDA reviewed (> 10 meetings and communications) Academia conducted

HSP results support and confirm the hypothesesgenerated by FDA Spontaneous Reports

Unique instead of to-be-pooled

63

REVIEW OF CHPA’s COMMENTS ON HSP REPORT (CONTD)

“findings of an apparent ‘association’ should not be relied upon asconclusive. Important biases and inadequate controlling forconfounding factors (see below) could account for the reportedassociation. A more appropriate conclusion is that the data arederived from too few cases and controls to allow an unbiasedassessment of any relationship between exposure and stroke.”

Small Size Compromised powerSmall Size Sensitive to misclassificationSmall Size Bias only if poor design or conductSmall Size Not Robust

Strength of Association of a Small Size Observational Study is in“consistency” not on size of p-value

Internal consistency: confounder control, subset analysesExternal consistency: confirming the hypotheses generated fromFDA spontaneous reports

64

REVIEW OF CHPA’s COMMENTS ON HSP REPORT(CONTD)

For Objectives #2 and #3 (b) Appetite Suppressant# Exposures % Odds Ratio p-value

3-day WindowCaseControl

6/664 0.91/1310 0.1

11.98 Unadj15.92 Adj 0.013

FemaleCaseControl

6/383 1.61/750 0.1

12.1916.58 0.011

Presence of Sentinel SymptomsNo SymptomsCaseControl

4/548 0.71/1075 0.1

7.0812.10 0.029

Yes SymptomsCaseControl

2/154 1.30 /301 0.0

4.83 (p=0.111) - -

65


For Objective #3 (a) First Use# Exposures % Odds Ratio p-value

First Use (M & F)CaseControl

8/664 1.15/1310 0.4

3.20 Unadj3.14 Adj 0.029

No Sentinel SymptomsCaseControl

6/548 1.14/1075 0.4

3.003.34 0.040

Sentinel Symptoms PresentCaseControl

2/154 1.31 /301 0.3

4.00 2.70 0.215

66


For Objective #2 Cough/Cold# Exposures % Odds Ratio p-value

Use in 3-day WindowCaseControl

22/664 3.132/1310 2.3

1.38 Unadj1.23 Adj 0.245

FemaleCaseControl

16/383 4.219/750 2.3

1.701.54 0.116

MaleCaseControl

6/319 1.913/626 2.1

0.900.62 0.203


17/548 3.125/1075 2.3

1.351.12 0.371

Yes Sentinel SymptomsCaseControl

5/154 3.17 /301 2.3

1.481.71 0.206

67

REVIEW COF CHPA’s COMMENTS ON HSP REPORT (CONTD)

For Objective #1 All Products Male+Female# Exposures % Odds Ratio p-value

Use in 3-day WindowCaseControl

27/664 3.833/1310 2.4

1.67 Unadj1.49 Adj 0.084

FemaleCaseControl

21/383 5.520/750 2.7

2.151.98 0.024

MaleCaseControl

6/319 1.913/626 2.1

0.900.62 0.203


20/548 3.626/1075 2.4

1.551.33 0.194

Yes Sentinel SymptomsCaseControl

7/154 4.67/301 2.3

2.132.19 0.099

68

REVIEW OF CHPA’s COMMENTS ON HSP REPORT (CONTD)Conclusions from the study should be based on overall PPAexposure, which is the study’s first objective (i.e., “Do PPAuses have an increased risk?”). The overall analysis based onthis endpoint resulted in an odds ratio that does notdemonstrate increased risk [i.e., OR=1.49, p=0.084] of PPA useand hemorrhagic stroke.

Objectives on first use (Objective # 3 (a)) and appetitesuppressant (objective #3(b) and part of Objective #2) weredata generated. Objective #1 is sample size compromisedobjective

Strength of the association of “sample size compromised”objectives are in internal and external consistency

69


Confounding factors, include lifestyle habits and pre-existingmedical conditions such as hypertension and cigarette smoking,were not controlled for in the study analyses.

Cases and controls were not adequately matched for confoundingfactors, which is the deviation from the study protocol.

The protocol of this project was fully discussed betweensponsor and Yale investigators before submission fordiscussion with the FDA.

The most serious and common confounding risks ofhemorrhagic stroke, namely smoking, hypertension, raceand education, were studied and included in the logisticregression adjustment of the association.

70

REVIEW OF CHPA’s COMMENTS ON HSP (CONTD)

Subjects with hypertension history among PPA usersAll subjects Cases ControlsHypertension

History Unexpo Expo Unexpo Expo Unexpo Expo3-day exposure windowYes 26% 28% 39% 33% 20% 24%No 74% 72% 61% 67% 80% 76%Total 2087 60 375 27 1342 33Cough/cold PPA UsersYes 27% 30% 39% 36% 20% 25%No 73% 70% 61% 64% 80% 75%Total 2023 54 680 22 1343 32Appetite suppressant PPA UsersYes 27% 29% 40% 33% 20% 0%No 73% 71% 60% 67% 80% 100%Total 2070 7 716 6 1374 11st UsersYes 27% 8% 39% 15% 21% 0%No 73% 92% 61% 85% 79% 100%Total 2064 13 694 8 1370 5

71


CONSISTENCY!

Analyses in patients without a hypertension historyCaseNo. %

ControlNo. %

OR LC p-val /UC

Adj OR LC p-val /UC

3-day Exposure WindowYes 18 3.0 25 2.3 No 482 97.0 1069 97.7

1.934 1.08 0.03 3.47

2.05 1.10 0.03 3.82

Cough/Cold PPA UsersYes 14 3.3 24 2.2No 416 96.7 1070 97.8

1.461 0.79 0.15 2.69

1.643 0.87 0.10 3.10

Appetite PPA UsersYes 4 0.9 1 0.1No 426 99.1 1093 99.9

10.26a 1.75 0.01 60.34

-- -- -- --

72


CONSISTENCY!

Analyses in patients without a hypertension historyCaseNo. %

ControlNo. %

OR LC p-val /UC

Adj LC p-val OR /UC

1st UsesYes 7 1.6 5 1.4No 423 98.4 1089 98.6

4.130 1.32 0.02 12.95

3.997 1.21 0.03 13.25

Non 1st UsersYes 7 1.6 10 0.9No 423 98.4 1084 99.1

1.749 0.72 0.15 4.26

1.746 0.67 0.17 4.57

Current UsersYes 14 3.3 15 1.4No 416 96.7 1079 98.6

2.424 1.22 0.02 4.82

2.422 1.17 0.023 5.04

a: Unmatched odds ratio. The only exposed control has an exposed case for match.

73


small number of cases of hemorrhagic stroke reportedlyassociated with PPA use identified in this five-year study

errors in classification of exposure could easily andsignificantly skew the results of the study.

This could be caused by errors in participant recalland/or product misclassification.

Patients were blinded from knowing the drug of interest

Structured setup of verification (picture identification)

Verification of each reported medication was done after theinterview with the help of a Product Identification Bookwith photographs

74


The apparent association between PPA appetitesuppressant use and hemorrhagic stroke wouldbe apparent if only four controls weremisclassified as unexposed to PPA.

CHPA PPA Working Group suggested a highly unlikely80% (4/5) misclassification rate of exposed controls (withno misclassification of exposed cases).

75


True Odds Ratio Corrected for Exposure Misclassification(hypothetical)

Pr(case misclassified ascase-unexpo)

Pr(control misclassifiedas control-unexp)

CorrectedOR

0% 20% 9.4710% 20% 10.5320% 20% 11.860% 30% 8.2810% 30% 9.2120% 30% 10.3830% 30% 11.880% 40% 7.1010% 40% 7.9020% 40% 8.8930% 40% 10.1840% 40% 11.90

76


Forty percent of the interviewed cases had a degree ofaphasia. The proportion of aphasia cases could haveaffected accurate identification of a case reported tohave used PPA products.

Consistency!No Aphasia Present: Rating 1-3

Case(n=603)

Control(n=1184)

OR(p-value)

AdjustedOR LCL p-value

No. % No. %No use 567 94.0% 1129 95.3%Any PPA 26 4.3% 27 2.3% 1.98 p=0.013 1.65 1.00 0.050Cough/cold 21 3.5% 26 2.2% 1.63 p=0.07 1.35 0.80 0.175Appetite 6 1.0% 1 0.1% 12.1 p=0.007 15.50 2.04 0.013Current use 20 3.3% 18 1.5% 2.23 p=0.012 1.70 0.95 0.066First use 8 1.3% 4 0.3% 4.00 p=0.019 3.59 1.26 0.023Not 1st use 12 2.0% 14 1.2% 1.73 p=0.123 1.20 0.59 0.334Prior use 6 1.0% 9 0.8% 1.63 p=0.368 1.45 0.57 0.257

77


No Aphasia Present: Rating 1Case(n=388)

Controls(n=759)

OR AdjustedOR LCL p-value

No. % No. %No use 363 93.6% 726 95.6%Any PPA 17 4.4% 13 1.7% 2.60 p=0.008 2.07 1.10 0.029Cough/cold 14 3.6% 13 1.7% 2.16 p=0.035 1.80 0.93 0.070Appetite 4 1.0% 0 0.0% >16* p=0.013 -C users 16 4.1% 10 1.3% 3.17 p=0.003 2.66 1.34 0.0091st use 8 2.1% 3 0.4% 5.33 p=0.009 4.60 1.45 0.015Not 1st use 8 2.1% 7 0.9% 2.33 p=0.082 1.93 0.80 0.110Prior use 1 0.3% 3 0.4% 0.67 p=0.593 0.25 -- 0.158* Unmatched OR

78

REVIEW OF CHPA’s COMMENTS ON HSP (CONTD)Cases who died before interview and those who were unable to communicatewithin 30 days (i.e. 34%) were excluded. Studies based on prevalent casescould be misleading.

A higher apparent risk of hemorrhagic stroke among PPA users might be dueto a lengthening of their survival rather than an increase in diseaseincidence, and excluded cases may differ in their exposure to PPA and otherrisk factors for hemorrhagic stroke that would likely be confounder of theassociation of interest.

Epidemiologic studies reported that surrogate interviews ofpatients who were unable to communicate were the major sourceof bias.

Concern was verified by the Yale investigators with pilotinformation.

Exposure difference between the excluded cases and study caseswas not found in either the literature or in this study for support.

79


The large differential in participation rates between cases and controls couldaffect the findings and is not adequately explained in the report. Likely,inadequate data are provided to allow independent verification of the findingsor to verify that sensitivity analyses do not alter the confidence limits or p-values for the findings.

Difference in participation rates does not bias the study findings. Participation associated with exposure status or with the confounders

of exposure may bias the findings. 82% of non-enrolled cases were not contacted within the 30 days

window non-enrollment of cases is independent of exposure status However, non-enrolled controls were not informed of the drug of

interest independent of exposure status

80

REVIEW OF CHPA’s COMMENTS ON HSP (CONTD)Choice of analytical methodology is of concern. Inappropriatestatistical methods were used, given the small numbers of exposedcases. Likewise, inappropriate and/or inadequate methods were usedto control for confoundings.

The issue on the criterion between asymptotic method and exactmethod is over emphasized.

It was shown in a published simulation study that theasymptotic method controls type I error rate even with aminimum expected cell frequency as small as two. On the otherhand, the exact method is still conservative at this level for it hasa type I error rate less than 5%.

The minimum cell frequency is 2.5 for cases exposed to PPA-appetite suppressants in this study.

81

REVIEW OF CHPA’s COMMENTS ON HSP (CONTD)A reflection of the inappropriateness of the asymptoticstatistical analysis is the fact that the strength of theassociation between exposure and disease increased whenconfounders were “controlled”. This is contrary to what isusually observed in control of confounding variables, where theadjusted odds ratio is expected to be smaller than the unadjustedodds ratio.

The statement is incorrect when the covariate is a trulycorrelated to outcome . It is often observed in clinicaltrials that the treatment effect may be greater and withmore statistical significance when the confounder such asbaseline measurement is adjusted. It is often alsohappens in epidemiological studies that the odds ratiosincrease in the analysis with stratified tables when theassociation is consistent across stratum.

82

CHPA’s COMMENTS ON HSP REPORT (CONTD)

The findings cannot be entirely generalized to the U.S.population, as the controlled cases and controls were notadequately population-based and differ in sociodemographiccharacteristics from typical U.S. consumers who use PPA drugproducts.

The ability to generalize the study findings was neveran issue when the protocol was proposed andsponsored by NDMA and when it was reviewed byFDA.

The strength of an epidemiological study is incontrolling the potential confounding factors and inminimizing the bias in the conduct and datagathering phase. Hence results of regionalepidemiological studies such as Framingham Studycan be generalized to U.S. population.

83

CONCLUSION

EXPECTATION Statistical Evidence Samplesize

Demonstrate PPA is safe

FAILED!

Upper CI < tolerable riske.g.Obj #1: Upper CI < 2Obj #2: Cough/cold Upper CI < 2 App Supp Upper CI < 3Obj #3(a): Upper CI < 2 (b): Upper CI < 3

Large

Demonstrate PPA is anindependent risk

Significant p-value (<0.10)And odds ratio > tolerable limit(say, 1.5)

Large/Moderate

Demonstrate PPA is anindependent risk

Moderate p-valueConsistency in adjusted analysis,stratified analysis and subsetanalysis

Small toModerate

84

Sensitivity Analysis for Addressing Bias due to Sparse Data

1st Time PPA UsersOR and 95% CI

AppetiteSuppressants

OR and 95% CI

From original study report 3.14 (0.96 – 10.28) 15.92 (1.37 – 184.12)

One case subject moved fromnon-exposed to exposed whilehis/her matched controlremained non-exposed

3.45 (1.09 – 10.96) 20.31 (1.95 – 212.26)

One control subject movedfrom non-exposed to exposedwhile his/her matched caseremained exposed

2.07 (0.93 – 10.15) 14.42 (1.16 – 178.09)

One control subject movedfrom non-exposed to exposedwhile his/her matched caseremained non-exposed

2.27 (0.73 – 7.15)* 7.29 (1.14 – 46.31)**

*Repeated 10 times, avg point estimate = 2.6**Repeated 10 times, avg point estimate = 6.9

Phenylpropanolamine & Risk of Hemorrhagic Stroke

Documents

Transcript of Phenylpropanolamine & Risk of Hemorrhagic Stroke