Epidemiology Center Isotretinoin Survey Allen A. Mitchell, MD Carla M. Van Bennekom, RN, MPH Slone Epidemiology Center At Boston University For presentation.

Epidemiology Center

Isotretinoin Survey

Allen A. Mitchell, MDAllen A. Mitchell, MDCarla M. Van Bennekom, RN, MPHCarla M. Van Bennekom, RN, MPH

Slone Epidemiology CenterSlone Epidemiology CenterAt Boston UniversityAt Boston University

For presentation at FDA Advisory Committee MeetingFor presentation at FDA Advisory Committee MeetingFebruary 26,-27, 2004February 26,-27, 2004

Epidemiology Center

Isotretinoin Survey

Survey extends design SEC developed in Survey extends design SEC developed in 1989 for SEC’s Accutane Survey under 1989 for SEC’s Accutane Survey under Roche sponsorship.Roche sponsorship.

SEC conducted the Accutane Survey until SEC conducted the Accutane Survey until 7/03 (n=591,936).7/03 (n=591,936).

SEC has conducted the Isotretinoin Survey SEC has conducted the Isotretinoin Survey since 12/02 (n=8,625).since 12/02 (n=8,625).

Epidemiology Center

Objectives

Assess compliance with pregnancy prevention efforts:Assess compliance with pregnancy prevention efforts:

Awareness of the teratogenic riskAwareness of the teratogenic risk

Patient and physician behaviorsPatient and physician behaviors

Pregnancy ratePregnancy rate

Pregnancy outcomePregnancy outcome

Risk factors for pregnancyRisk factors for pregnancy

Epidemiology Center

Pregnancy Rate/1000 Person Courses by Enrollment Year

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Rat

e/10

00 c

ours

es

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

Epidemiology Center

Isotretinoin Survey

Background

In 2001, in anticipation of SMART, SEC In 2001, in anticipation of SMART, SEC modified the Survey design and questionnaires modified the Survey design and questionnaires with input from Roche and FDA.with input from Roche and FDA.

The data that follow were collected for the The data that follow were collected for the generic sponsors, post-SMART, using the generic sponsors, post-SMART, using the modified design and questionnaires.modified design and questionnaires.

Epidemiology Center

Isotretinoin Survey

EnrollmentsDecember 10, 2002 – December 31, 2003

12

1539

20932410

2571

0

500

1000

1500

2000

2500

3000

Q4 2002

Q1 2003

Q2 2003

Q3 2003

Q4 2003

Quarter of Enrollment

#

Epidemiology Center

Isotretinoin Survey

Method of Enrollment by Quarter

0102030405060708090

100

Q4 2002

Q1 2003

Q2 2003

Q3 2003

Q4 2003

%

Doctor Package

Epidemiology Center

Isotretinoin SurveyPregnancy Risk Category: DAT1*

(n=4,665)

Hysterectomy or postmenopausalHysterectomy or postmenopausal 5%5%

Not sexually active, using birth controlNot sexually active, using birth control31%31%

Not sexually active, not using birth Not sexually active, not using birth controlcontrol

23%23%

Sexually active, using birth controlSexually active, using birth control 39%39%

Sexually active, not using birth controlSexually active, not using birth control 1%1%

UnknownUnknown <1%<1%*Excludes women who had not yet started isotretinoin.*Excludes women who had not yet started isotretinoin.

Epidemiology Center

Epidemiology Center

Isotretinoin SurveyReported Source of

Informational Materials Received: DAT1(n=4,669)

Claravis (Barr)Claravis (Barr) 1%1%

Amnesteem (Bertek)Amnesteem (Bertek) 18%18%

Sotret (Ranbaxy)Sotret (Ranbaxy) 4%4%

Accutane (Roche)Accutane (Roche) 58%58%

Other MaterialsOther Materials 3%3%

>1 of above>1 of above 6%6%

NoneNone 9%9%

Epidemiology Center

Isotretinoin SurveyReport of Receipt of Medication Guide with Most

Recent Prescription Filled: DAT1*(n=4,632)

YesYes 92%92%

NoNo 2%2%

Not sureNot sure 6%6%*Excludes 37 women with missing information.*Excludes 37 women with missing information.

Epidemiology Center

Isotretinoin Survey

Information Received on Pregnancy Prevention: DAT1

(n=4,669)

%%

Told to avoid pregnancyTold to avoid pregnancy 9999

Read guide to contraceptionRead guide to contraception 8080

Read contraceptive knowledge self-assessmentRead contraceptive knowledge self-assessment 7575

Read emergency contraception informationRead emergency contraception information 6868

Watched video about pregnancy preventionWatched video about pregnancy prevention77

Epidemiology Center

Isotretinoin SurveyInformation Received on Isotretinoin/Pregnancy

Prevention: DAT1(n=4,669)

%%

Knew about isotretinoin information Knew about isotretinoin information telephone linetelephone line

4444

Knew about contraception counseling Knew about contraception counseling telephone linetelephone line

3838

Doctor discussed contraceptionDoctor discussed contraception 8282

Doctor mentioned emergency Doctor mentioned emergency contraceptioncontraception

1919

Epidemiology Center

Isotretinoin Survey

Report of Consent Forms Signed: DAT1*(n=4,657)

Signed 2 consent formsSigned 2 consent forms 79%79%

Signed 1 consent formSigned 1 consent form 6%6%

Didn’t sign any consent formsDidn’t sign any consent forms 7%7%

Not sureNot sure 8%8%

*Excludes 12 women with missing information.*Excludes 12 women with missing information.

Epidemiology Center

Isotretinoin Survey

Start of Isotretinoin Treatment Relative to Most Recent Prescription Received

We anticipated that many women would switch from We anticipated that many women would switch from Accutane to generic once generic became available.Accutane to generic once generic became available.

We also expected that many of these women would enroll We also expected that many of these women would enroll in Isotretinoin Survey during treatment prompted by the in Isotretinoin Survey during treatment prompted by the enrollment form in generic package.enrollment form in generic package.

DAT1 Questionnaire was designed to assess compliance DAT1 Questionnaire was designed to assess compliance at at onsetonset of treatment, not of treatment, not duringduring treatment. treatment.

Therefore, some questions may be confusing to those Therefore, some questions may be confusing to those enrolling during treatment, and some of their responses enrolling during treatment, and some of their responses may be inaccurate.may be inaccurate.

Epidemiology Center

Isotretinoin Survey

When, in the Past 12 Months, Did Isotretinoin Treatment Begin?

TotalTotal

(n=4669)(n=4669)

With most recent prescription With most recent prescription

(new user)(new user)53%53%

Prior to most recent prescription Prior to most recent prescription (prior user)(prior user)

47%47%

Epidemiology Center

Isotretinoin Survey

Number of Pregnancy Tests in the 4 Weeks before Starting Isotretinoin*

(n=2,294)

1 test1 test 28%28%

2 tests2 tests 41%41%

3 tests3 tests 12%12%

4 tests4 tests 4%4%

5+ tests5+ tests 5%5%

No testNo test 9%9%

* Limited to new users

Epidemiology Center

Isotretinoin Survey

Was Pre-Tx Pregnancy Test Properly Timed Relative to Prescription Receipt?*

(n=2,321)

Before/on Rx receiptBefore/on Rx receipt 82%82%

After Rx receiptAfter Rx receipt 10%10%

No testNo test 9%9%

* Limited to new users

Epidemiology Center

Isotretinoin SurveyPrimary Contraceptive Method among

Nonsurgical Contraceptors: DAT1(n=2,536)

0

20

40

60

80

100

%

Age 15-24 Age 25-34 Age 35-44

Norplant/Depo-Provera Ortho Evra/NuvaRingPill IUDCondoms Other

Epidemiology Center

Isotretinoin SurveyNumber of Contraceptive Methods Among

Women Who Were Sexually Active Since Starting Isotretinoin: DAT1 (n=1,879)

0

20

40

60

80

100

Q2 2003

Q3 2003

Q4 2003

%

No Method 1 Method 2 Methods 3+ Methods

Epidemiology Center

Qualification Sticker

Qualification criteria for female patients are:Qualification criteria for female patients are:

• MustMust have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Accutane prescriptionmIU/mL before receiving the initial Accutane prescription. The first test (a screening test) is . The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient obtained by the prescriber when the decision is made to pursue qualification of the patient for Accutane. for Accutane. The second pregnancy test (a confirmation test) should be done during the The second pregnancy test (a confirmation test) should be done during the first five days of the menstrual period immediately preceding the beginning of Accutane first five days of the menstrual period immediately preceding the beginning of Accutane therapytherapy. For patients with amenorrhea, the second test should be done at least 11 days after . For patients with amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using two effective forms of the last act of unprotected sexual intercourse (without using two effective forms of contraception.) Each month of therapy, the patient must have a negative result from a urine contraception.) Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated every month prior to the female or serum pregnancy test. A pregnancy test must be repeated every month prior to the female patient receiving each prescription.patient receiving each prescription.

• MustMust have selected and have committed to use of two forms of effective contraception have selected and have committed to use of two forms of effective contraception simultaneously, at least one of which must be a primary form, unless absolute abstinence is simultaneously, at least one of which must be a primary form, unless absolute abstinence is the chosen method, or patient has undergone a hysterectomythe chosen method, or patient has undergone a hysterectomy. Patients must use two forms . Patients must use two forms of effective contraception for at least one month prior to initiation of Accutane therapy, of effective contraception for at least one month prior to initiation of Accutane therapy, during Accutane therapy, and for one month after discontinuing Accutane therapy. during Accutane therapy, and for one month after discontinuing Accutane therapy. Counseling about contraception and behaviors associated with an increased risk of Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis.pregnancy must be repeated on a monthly basis.

Epidemiology Center

Isotretinoin SurveyReport of Qualification Sticker on Most Recent

Prescription: DAT1*(n=4,638)

Sticker on prescriptionSticker on prescription 94%94%

No sticker on prescriptionNo sticker on prescription 2%2%

Don’t know because someone else Don’t know because someone else obtained and filled prescriptionobtained and filled prescription

3%3%

Don’t know because didn’t see Don’t know because didn’t see prescriptionprescription

1%1%

*Excludes 31 women with missing information.*Excludes 31 women with missing information.

Epidemiology Center

Isotretinoin Survey

Qualification Sticker vs. Patient-Reported Behaviors*

Use of 2 Contraceptive MethodsUse of 2 Contraceptive Methods

Qualification StickerQualification Sticker 2+ (%)2+ (%) 0-1 (%)0-1 (%) (N)(N)

YESYES 6868 3232 (1783)(1783)

DNKDNK 6060 4040 (48)(48)

NONO 4949 5151 (41)(41)

(N)(N) (1258)(1258) (614)(614) (1872)(1872)

*DAT1 – Sexually active women only; Missing values excluded*DAT1 – Sexually active women only; Missing values excluded

Epidemiology Center

Isotretinoin Survey

Qualification Sticker vs. Patient-Reported Behaviors*

Pregnancy Testing and Timing RequirementsPregnancy Testing and Timing Requirements††

Qualification StickerQualification Sticker Compliant (%)Compliant (%)Noncompliant Noncompliant

(%)(%)(N)(N)

YESYES 2626 7474 (1826)(1826)

DNKDNK 2424 7676 (90)(90)

NONO 2727 7373 (60)(60)

(N)(N) (506)(506) (1470)(1470) (1976)(1976)

*DAT1 – New users who reported having a menstrual period in 4 weeks before starting; *DAT1 – New users who reported having a menstrual period in 4 weeks before starting;

Missing values excludedMissing values excluded

††Compliant = 2+ properly timed pregnancy tests before starting isotretinoinCompliant = 2+ properly timed pregnancy tests before starting isotretinoin

Epidemiology Center

Isotretinoin Survey

Qualification Sticker and Medication Guide: DAT2

Qualification sticker Qualification sticker on last prescription on last prescription (n=972)*(n=972)*

96%96%

Received Medication Received Medication Guide with last Guide with last prescription (n=975)*prescription (n=975)*

86%86%

*Missing responses excluded*Missing responses excluded

Epidemiology Center

Isotretinoin Survey

Behaviors Prompted by Information in the Medication Guide(n=840 Recipients of Medication Guide, DAT2)

Changed contraceptive methodChanged contraceptive method 12%12%

Decided not to have sexual intercourse with a Decided not to have sexual intercourse with a male partner while taking isotretinoinmale partner while taking isotretinoin

16%16%

Decided to have sexual intercourse with a Decided to have sexual intercourse with a male partner less frequently while taking male partner less frequently while taking isotretinoinisotretinoin

6%6%

Had a pregnancy test while taking isotretinoinHad a pregnancy test while taking isotretinoin 22%22%

Requested more information on isotretinoinRequested more information on isotretinoin 5%5%

Requested more information on contraceptionRequested more information on contraception 2%2%

Epidemiology Center

Isotretinoin SurveyPregnancy Risk Category at DAT1 and DAT2

DAT1DAT1

(n=4655)(n=4655)

DAT2DAT2

(n=990)(n=990)

Hysterectomy or postmenopausalHysterectomy or postmenopausal 5%5% 6%6%

Not sexually active, using birth Not sexually active, using birth controlcontrol

31%31% 25%25%

Not sexually active, not using Not sexually active, not using birth controlbirth control

23%23% 24%24%

Sexually active, using birth Sexually active, using birth controlcontrol

39%39% 42%42%

Sexually active, not using birth Sexually active, not using birth controlcontrol

1%1% 1%1%

UnknownUnknown <1%<1% 1%1%

Epidemiology Center

Isotretinoin SurveyNumber of Pregnancy Tests in the Past 2 Months Reported by Women Still Taking Isotretinoin at

DAT2(n=400)

1 test1 test 12%12%

2 tests2 tests 50%50%

3 tests3 tests 5%5%

4 tests4 tests 10%10%

5+ tests5+ tests 9%9%

No testNo test 13%13%

Epidemiology Center

Isotretinoin SurveySpecialty of Isotretinoin Prescriber (DAT2)

(n=990)

DermatologistDermatologist 93%93%

General PractitionerGeneral Practitioner 2%2%

Family PractitionerFamily Practitioner 3%3%

GynecologistGynecologist <1%<1%

InternistInternist <1%<1%

PediatricianPediatrician <1%<1%

OtherOther <1%<1%

UnknownUnknown 1%1%

Epidemiology Center

Isotretinoin SurveyPregnancies Reported through 12/31/03

Pregnant at start of isotretinoin treatmentPregnant at start of isotretinoin treatment 22

Became pregnant during treatmentBecame pregnant during treatment 44

Total pregnanciesTotal pregnancies 66

Number completing DAT1Number completing DAT1 4,6694,669

Number completing DAT2Number completing DAT2 996996