Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee...

Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee Advisory Committee February 26 & 27, 2004February 26 & 27, 2004

Isotretinoin Pregnancy Prevention Isotretinoin Pregnancy Prevention Program EvaluationProgram Evaluation


Prescription Compliance Surveyand

Patient Surveys

Allen Brinker, MD, MSFebruary 26, 2004

Prescription Compliance Surveyand

Patient Surveys

Allen Brinker, MD, MSFebruary 26, 2004




Collaborators -Cynthia Kornegay, Ph.D.

Primary reviewer for prescription compliance survey

Parivash Nourjah, Ph.D.Primary analyst for a patient survey dataset supplied by Hoffmann-LaRoche

Collaborators -Cynthia Kornegay, Ph.D.

Primary reviewer for prescription compliance survey

Parivash Nourjah, Ph.D.Primary analyst for a patient survey dataset supplied by Hoffmann-LaRoche




Order of topics:

Prescription Compliance Program (PCS)

Patient Survey

Order of topics:

Prescription Compliance Program (PCS)

Patient Survey

4Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee Advisory Committee February 26 & 27, 2004February 26 & 27, 2004

Prescription Compliance Survey (PCS)Prescription Compliance Survey (PCS)OverviewOverview

Prescription Compliance Survey (PCS)Prescription Compliance Survey (PCS)OverviewOverview

• Survey Design• Survey Results• Methodological Issues

– Response Rate– Number of Prescriptions Captured– Participation by Stores

• Survey Audit– Recruiting Strategy/Response Rate

• Conclusions

• Survey Design• Survey Results• Methodological Issues

– Response Rate– Number of Prescriptions Captured– Participation by Stores

• Survey Audit– Recruiting Strategy/Response Rate

• Conclusions


PCS GoalsPCS GoalsPCS GoalsPCS Goals

• Primary Outcome: Compliance with

Qualification sticker use

• Secondary Outcomes: Completeness and

correctness of Qualification stickers

• Inference

– presence of a Qualification sticker does not

imply adherence to all parts of the current

RMP

• Primary Outcome: Compliance with

Qualification sticker use

• Secondary Outcomes: Completeness and

correctness of Qualification stickers

• Inference

– presence of a Qualification sticker does not

imply adherence to all parts of the current

RMP


PCS DesignPCS DesignPCS DesignPCS Design

• Retrospective, repeated-measures survey

• 6,000 selected U.S. pharmacies

• Stratified, random sample

• Data collected in March, June, September,

and December for 2 years

• 750 Stores selected for each collection period

• Stores can only be included once

• Retrospective, repeated-measures survey

• 6,000 selected U.S. pharmacies

• Stratified, random sample

• Data collected in March, June, September,

and December for 2 years

• 750 Stores selected for each collection period

• Stores can only be included once


PCS ResultsPCS ResultsPCS ResultsPCS Results

• High rate of compliance (>90%) across all survey waves for both PCS and audit

• Results consistent across age, gender, and payer type

• Some differences across prescription volume and population density– both high volume and rural pharmacies more

likely to receive prescriptions with incomplete stickers

• High rate of compliance (>90%) across all survey waves for both PCS and audit

• Results consistent across age, gender, and payer type

• Some differences across prescription volume and population density– both high volume and rural pharmacies more

likely to receive prescriptions with incomplete stickers


Methodological IssuesMethodological IssuesMethodological IssuesMethodological Issues

• Minimum necessary response rate for each wave

was 60% of the sample, or 450 stores

– response rates ranged from 25% to 59%

• In December 2002, CVS, Eckerd, Rite Aid,

Walgreens and Wal-Mart asked and were removed

from the survey pool

– 33% of stores, or 15,200

– probably represented more than 33% of Rxs

• Minimum necessary response rate for each wave

was 60% of the sample, or 450 stores

– response rates ranged from 25% to 59%

• In December 2002, CVS, Eckerd, Rite Aid,

Walgreens and Wal-Mart asked and were removed

from the survey pool

– 33% of stores, or 15,200

– probably represented more than 33% of Rxs


Methodological IssuesMethodological IssuesPCS Prescriptions CapturedPCS Prescriptions Captured

Methodological IssuesMethodological IssuesPCS Prescriptions CapturedPCS Prescriptions Captured

Number of Prescriptions: Estimated Actual

Average no. per QTR 2.55 0.84

Total per QTR 1,150 268


PCS AuditPCS AuditRecruitingRecruitingPCS AuditPCS AuditRecruitingRecruiting

• Proposed strategy: random sample of

15% of PCS respondents– does not appear to have been implemented

as proposed

– consistently high response rates (>20%)• recruiting strategy may not be random

– utility and/or applicability of audit results is

questionable

• Proposed strategy: random sample of

15% of PCS respondents– does not appear to have been implemented

as proposed

– consistently high response rates (>20%)• recruiting strategy may not be random

– utility and/or applicability of audit results is

questionable


PCS Overall ConclusionsPCS Overall ConclusionsPCS Overall ConclusionsPCS Overall Conclusions

• High rate of compliance with

Qualification stickers

– not the same as high rate of compliance

with SMART program in total

• High rate of compliance with

Qualification stickers

– not the same as high rate of compliance

with SMART program in total


PCS Overall ConclusionsPCS Overall ConclusionsPCS Overall ConclusionsPCS Overall Conclusions

• Insufficient pharmacy sample size

• Generalizability compromised

– low pharmacy response rate

– 23% of expected prescriptions captured

– five largest U.S. chains dropped out

• Alternate study designs should be considered

for future studies with similar goals

• Insufficient pharmacy sample size

• Generalizability compromised

– low pharmacy response rate

– 23% of expected prescriptions captured

– five largest U.S. chains dropped out

• Alternate study designs should be considered

for future studies with similar goals


Patient Surveys Patient Surveys OverviewOverview

Patient Surveys Patient Surveys OverviewOverview

• Purpose of Patient Survey

• Methods

– Limitations

• Survey Population

– Representativeness / Generalizability

• Results

• Summary Conclusions

• Purpose of Patient Survey

• Methods

– Limitations

• Survey Population

– Representativeness / Generalizability

• Results

• Summary Conclusions


Patient Survey - PurposePatient Survey - PurposePatient Survey - PurposePatient Survey - Purpose

• Isotretinoin Patient Surveys

– Implemented in 1989 to “assess the

compliance of physicians and patients with

the Accutane Pregnancy Prevention

Program and to identify the rate of

pregnancy during treatment with isotretinoin.”

• Isotretinoin Patient Surveys

– Implemented in 1989 to “assess the

compliance of physicians and patients with

the Accutane Pregnancy Prevention

Program and to identify the rate of

pregnancy during treatment with isotretinoin.”


Patient Survey - Reports and Analysis Patient Survey - Reports and Analysis OverviewOverview

Patient Survey - Reports and Analysis Patient Survey - Reports and Analysis OverviewOverview

• FDA data include:

– Slone Epidemiology Group Quarterly

Reports

• year prior and continuing in year following

– Primary FDA analysis of an Accutane-

brand patient survey• started in 3rd QTR following implementation of

the current RMP

• FDA data include:

– Slone Epidemiology Group Quarterly

Reports

• year prior and continuing in year following

– Primary FDA analysis of an Accutane-

brand patient survey• started in 3rd QTR following implementation of

the current RMP


Patient Survey - MethodsPatient Survey - MethodsPatient Survey - MethodsPatient Survey - Methods

Two versions of survey instrument:

–Old survey instrument–no questions on Qualification sticker

–no questions related to MedGuide

–pregnancy test question limited to

whether a pregnancy test was

performed

Two versions of survey instrument:

–Old survey instrument–no questions on Qualification sticker

–no questions related to MedGuide

–pregnancy test question limited to

whether a pregnancy test was

performed


Patient Survey - MethodsPatient Survey - MethodsPatient Survey - MethodsPatient Survey - MethodsNew survey instrument

• Current RMP-specific questions–Qualification sticker present on Rx ?–date and number of pregnancy tests

performed

• Not introduced until 3rd QTR following implementation of the current RMP

–enrolled ~6,000 participants through the end of first year

New survey instrument• Current RMP-specific questions

–Qualification sticker present on Rx ?–date and number of pregnancy tests

performed

• Not introduced until 3rd QTR following implementation of the current RMP

–enrolled ~6,000 participants through the end of first year


Patient Survey - MethodsPatient Survey - MethodsSelected LimitationsSelected Limitations


•Mailed survey–some are surveyed by telephone

•Follow-up survey–cannot be anonymous

•Generalizability limited due to–low enrollment rate–voluntary survey participation

•Mailed survey–some are surveyed by telephone

•Follow-up survey–cannot be anonymous

•Generalizability limited due to–low enrollment rate–voluntary survey participation




•Important issues - continued

•Measurement errors• Recall bias

• Social desirability bias

• Poor questionnaire design– complex questions and question skip

patterns to be followed

•Important issues - continued

•Measurement errors• Recall bias

• Social desirability bias

• Poor questionnaire design– complex questions and question skip

patterns to be followed


ResultsResultsSurvey PopulationSurvey Population


• Absolute participation in Isotretinoin Patient

Surveys based on FDA models:

–16% to 19% in year before current RMP

–22% to 26% in the first year current RMP

• Absolute participation in Isotretinoin Patient

Surveys based on FDA models:

–16% to 19% in year before current RMP

–22% to 26% in the first year current RMP

Trends in Enrollment in Isotretinoin Trends in Enrollment in Isotretinoin Patient SurveysPatient Surveys

Trends in Enrollment in Isotretinoin Trends in Enrollment in Isotretinoin Patient SurveysPatient Surveys

15.5 17.3 15.418.6

21.4 22.626 23.4

0

20

40

60

80

100

QTR1 QTR2 QTR3 QTR4 QTR5 QTR6 QTR7 QTR8

pe

rce

nt e

nro

llme

nt

Arrow separates the 4 QTR’s before implementation of the current RMP and the 4 QTR's following its implementation




Age group

(years)

Degge/SI

cohort*

(as submitted)

AdvancePC

S*

(4/02-3/03)

IMS Health

NDTI™***

(4/02-3/03)

Up to age 19 1917 (35%) 43% 45%

20-29 2092 (38%) 28% 30%

30-39 918 (17%) 16% 16%

40+ 536 (10%) 13% 9%

Total 5463 100% 100%

*excludes 6 records where age was missing + 432 records on generic isotretinoin **Advance PCS™ Dimension Rx, accessed 11 December 2003 ***IMS Health, IMS National Disease and Therapeutic IndexTM, 4/2002-3/2003, accessed 15 December 2003; FDA custom calculations were based on IMS Health data




• Prescriber

–94% of isotretinoin recipients within Degge/SI

cohort indicated prescriber was a dermatologist

–80% of recent isotretinoin prescriptions*

associated with a dermatologist

*Source: IMS Health National Prescription Audit PlusTM (3 Dec 2003)

• Prescriber

–94% of isotretinoin recipients within Degge/SI

cohort indicated prescriber was a dermatologist

–80% of recent isotretinoin prescriptions*

associated with a dermatologist

*Source: IMS Health National Prescription Audit PlusTM (3 Dec 2003)


Results - Initiation of TherapyResults - Initiation of TherapyConsent formConsent form

Results - Initiation of TherapyResults - Initiation of TherapyConsent formConsent form

• Analyses of Degge/SI cohort:

– 76% signed two consent forms (as required)

– 4% signed only one form

– 9% reported signing no consent forms

– 11% were uncertain / did not answer


– 76% signed two consent forms (as required)

– 4% signed only one form

– 9% reported signing no consent forms

– 11% were uncertain / did not answer


Results - Initiation of TherapyResults - Initiation of TherapyQualification stickerQualification sticker

Results - Initiation of TherapyResults - Initiation of TherapyQualification stickerQualification sticker


– 92% reported Rx with Qualification Sticker

• Consistent with findings from the PCS

– 2.5% reported no sticker

– 5.5% did not know / did not answer


– 92% reported Rx with Qualification Sticker

• Consistent with findings from the PCS

– 2.5% reported no sticker

– 5.5% did not know / did not answer


Results - Initiation of TherapyResults - Initiation of TherapyPregnancy TestingPregnancy Testing

Results - Initiation of TherapyResults - Initiation of TherapyPregnancy TestingPregnancy Testing

•Analyses of apparently fertile, 15-45

year-old participants in Degge/SI cohort:•91% reported at least one pregnancy test

•66% reported two tests

•Performance increased only slightly with restriction to sexually active

•Performance decreased only slightly with restriction to sexually INactive


Results - Initiation of Therapy Results - Initiation of Therapy Trends in Pregnancy TestingTrends in Pregnancy Testing

Results - Initiation of Therapy Results - Initiation of Therapy Trends in Pregnancy TestingTrends in Pregnancy Testing

•Slone Epi Group Quarterly reports

•ANY pregnancy testing

•77%-85% for year prior to the current RMP

•91%-92% in first year of current RMP

Results - Initiation of TherapyResults - Initiation of TherapyTrends in ANY Pregnancy Testing in Slone SurveyTrends in ANY Pregnancy Testing in Slone Survey

Results - Initiation of TherapyResults - Initiation of TherapyTrends in ANY Pregnancy Testing in Slone SurveyTrends in ANY Pregnancy Testing in Slone Survey

0

20

40

60

80

100


pe

rce

nt

Arrow separates the 4 QTRs before implementation of the current RMP and the 4 QTRs following its implementation


Results - Initiation of TherapyResults - Initiation of TherapyContraception PracticesContraception Practices

Results - Initiation of TherapyResults - Initiation of TherapyContraception PracticesContraception Practices

• Analyses of apparently fertile and sexually

active women among the Degge/SI cohort:– 95.4% reported use of some form of

birth control– 48.9% reported use of appropriate birth

control per the revised RMP• one primary and one secondary birth

control method

• Analyses of apparently fertile and sexually

active women among the Degge/SI cohort:– 95.4% reported use of some form of

birth control– 48.9% reported use of appropriate birth

control per the revised RMP• one primary and one secondary birth

control method


Results - Initiation of TherapyResults - Initiation of TherapySexual Activity - Univariate FocusSexual Activity - Univariate Focus

Results - Initiation of TherapyResults - Initiation of TherapySexual Activity - Univariate FocusSexual Activity - Univariate Focus

N

Total 4596

Sexually active since starting Accutane therapy

1806

Sexually active before but not during Accutane therapy

993

Not sexually active before or during Accutane therapy

1797


Results - Initiation of TherapyResults - Initiation of TherapyBivariate AnalysesBivariate Analyses

Results - Initiation of TherapyResults - Initiation of TherapyBivariate AnalysesBivariate Analyses

• Conducted to address the relationship

between the presence or absence of a

Qualification sticker and

•any pregnancy testing

•any birth control


Results - Initiation of TherapyResults - Initiation of TherapyQualification Sticker and Pregnancy TestingQualification Sticker and Pregnancy Testing

n=4400n=4400

Results - Initiation of TherapyResults - Initiation of TherapyQualification Sticker and Pregnancy TestingQualification Sticker and Pregnancy Testing

n=4400n=4400

NoYesPregnancy

Test

Qualification Sticker

90(90%)

3908(91%) Yes

10(10%)

392(9%)No


Results - Initiation of TherapyResults - Initiation of TherapyQualification Sticker and Birth Control (any)Qualification Sticker and Birth Control (any)

n=1788n=1788

Results - Initiation of TherapyResults - Initiation of TherapyQualification Sticker and Birth Control (any)Qualification Sticker and Birth Control (any)

n=1788n=1788

NoYesAny Birth Control

Use

Qualification Sticker

70(96%)

1671(97%) Yes

3(4%)

44(3%) No


ResultsResultsDuring TherapyDuring Therapy

ResultsResultsDuring TherapyDuring Therapy

• Analyses of Degge/SI participants

during therapy:

– 95% report use of a Qualification

sticker

– 81% report monthly pregnancy testing

• Analyses of Degge/SI participants

during therapy:

– 95% report use of a Qualification

sticker

– 81% report monthly pregnancy testing


Results - During Therapy Results - During Therapy Trends in Report of Pregnancy TestingTrends in Report of Pregnancy Testing

Results - During Therapy Results - During Therapy Trends in Report of Pregnancy TestingTrends in Report of Pregnancy Testing

• Slone Epi Group Quarterly reports

• ANY pregnancy testing during therapy with isotretinoin

• ~70% in year prior to revised RMP

• ~85% in first year of revised RMP

• Slone Epi Group Quarterly reports

• ANY pregnancy testing during therapy with isotretinoin

• ~70% in year prior to revised RMP

• ~85% in first year of revised RMP

Results - During TherapyResults - During TherapyTrends in ANY Pregnancy Testing in Slone SurveyTrends in ANY Pregnancy Testing in Slone Survey

Results - During TherapyResults - During TherapyTrends in ANY Pregnancy Testing in Slone SurveyTrends in ANY Pregnancy Testing in Slone Survey

0

20

40

60

80

100


perc

ent

Arrow separates the 4 QTRs before implementation of the current RMP and the 4 QTRs following its implementation


Pregnancy RatePregnancy RatePregnancy RatePregnancy Rate

• 15 pregnancies were identified among 4277

first-time users within the Degge/Si cohort

– pregnancy rate: 3.5/1000 women

– the rate is likely an underestimate as it is

censored as of the data lock date

• Similar to that reported for participants in the

Slone Survey of Accutane recipients

• 15 pregnancies were identified among 4277

first-time users within the Degge/Si cohort

– pregnancy rate: 3.5/1000 women

– the rate is likely an underestimate as it is

censored as of the data lock date

• Similar to that reported for participants in the

Slone Survey of Accutane recipients


AddendumAddendumGeneric Isotretinoin DataGeneric Isotretinoin Data

AddendumAddendumGeneric Isotretinoin DataGeneric Isotretinoin Data

• Any pregnancy testing prior to initiation: ~90%

• Two pregnancy tests prior to initiation: ~65%

• NO birth control among apparently fertile,

sexually active respondents: ~3%

• Any pregnancy testing during therapy: ~82%

• Any pregnancy testing prior to initiation: ~90%

• Two pregnancy tests prior to initiation: ~65%

• NO birth control among apparently fertile,

sexually active respondents: ~3%

• Any pregnancy testing during therapy: ~82%


Overall SummaryOverall SummaryOverall SummaryOverall Summary

• Isotretinoin-exposed pregnancies continue to

occur after implementation of the current RMP

• Enrollment in isotretinoin patient surveys

increased only modestly after implementation of

the current RMP

• Isotretinoin-exposed pregnancies continue to

occur after implementation of the current RMP

• Enrollment in isotretinoin patient surveys

increased only modestly after implementation of

the current RMP



• Despite their wide utilization,

Qualification stickers have been

issued to patients who have not

undergone pregnancy testing

• Despite their wide utilization,

Qualification stickers have been

issued to patients who have not

undergone pregnancy testing



• The observed pregnancy rate for the

Degge/SI cohort recruited following

implementation of the current RMP

appears similar to that reported for

cohorts recruited before


• The observed pregnancy rate for the

Degge/SI cohort recruited following


appears similar to that reported for

cohorts recruited before


Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee...

Documents

Transcript of Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee...