# Presentation: 660635

## Isotretinoin Pregnancy Prevention Program Evaluation

- Prescription Compliance Survey
- and
- Patient Surveys
- Allen Brinker, MD, MS
- February 26, 2004

## Isotretinoin Pregnancy Prevention Program Evaluation

- 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

## Isotretinoin Pregnancy Prevention Program Evaluation

- Order of topics:
- Prescription Compliance Program (PCS)
- Patient Survey

## Prescription Compliance Survey (PCS)Overview

- Survey Design
- Survey Results
- Methodological Issues
- Response Rate
- Number of Prescriptions Captured
- Participation by Stores
- Survey Audit
- Recruiting Strategy/Response Rate
- Conclusions

## PCS 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

## PCS 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

## PCS 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

## Methodological 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** **

## Methodological IssuesPCS Prescriptions Captured

| Number of Prescriptions: | Estimated | Actual |
| --- | --- | --- |
| Average no. per QTR | 2.55 | 0.84 |
| Total per QTR | 1,150 | 268 |

## PCS AuditRecruiting

- 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 Conclusions

- High rate of compliance with Qualification stickers
- not the same as high rate of compliance with SMART program in total

## PCS 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

## Patient Surveys Overview

- Purpose of Patient Survey
- Methods
- Limitations
- Survey Population
- Representativeness / Generalizability
- Results
- Summary Conclusions
**	**

## Patient 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.”
**	**

## Patient Survey - Reports and Analysis Overview

- 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 - 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

## Patient Survey - Methods

- 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 - MethodsSelected Limitations

- Mailed survey
- some are surveyed by telephone
- Follow-up survey
- cannot be anonymous
- Generalizability limited due to
- low enrollment rate
- voluntary survey participation
**	****	****	****	**

## Patient Survey - MethodsSelected Limitations

- Important issues - continued
- Measurement errors
- Recall bias
- Social desirability bias
- Poor questionnaire design
- complex questions and question skip patterns to be followed	**	**

## ResultsSurvey 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
**	****	****	****	**

## Trends in Enrollment in Isotretinoin Patient Surveys

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

## ResultsSurvey Population

**	****	**
**	****	****	****	**

## ResultsSurvey Population

- 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 *Plus**TM*  (3 Dec 2003)

## Results - Initiation of TherapyConsent 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

## Results - Initiation of TherapyQualification sticker

- Analyses of Degge/SI cohort:
- 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 TherapyPregnancy 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 Trends 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 TherapyTrends in ANY Pregnancy Testing in Slone Survey

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

## Results - Initiation of TherapyContraception 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**

## Results - Initiation of TherapySexual 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 TherapyBivariate 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 TherapyQualification Sticker and Pregnancy Testingn=4400

## Results - Initiation of TherapyQualification Sticker and Birth Control (any)n=1788

## ResultsDuring Therapy

- Analyses of Degge/SI participants during therapy:
- 95% report use of a Qualification sticker
- 81% report monthly pregnancy testing

## Results - During Therapy Trends 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

## Results - During TherapyTrends in ANY Pregnancy Testing in Slone Survey

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

## Pregnancy 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

## AddendumGeneric 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%**

## Overall 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

## Overall Summary

- Despite their wide utilization, Qualification stickers have been issued to patients who have not undergone pregnancy testing

## Overall Summary

- 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 implementation of the current RMP