Interim Report OTIS – North American Isotretinoin Information and Survey Line Toll-Free Number: 1-866-626-6847 Website: FDA Advisory

Interim Report Interim Report OTIS – North American Isotretinoin OTIS – North American Isotretinoin

Information and Survey Line Information and Survey Line

Toll-Free Number: 1-866-626-6847Toll-Free Number: 1-866-626-6847 Website: Website: www.otispregnancy.orgwww.otispregnancy.org

FDA Advisory Committee MeetingFDA Advisory Committee MeetingAccutane Risk Management ProgramAccutane Risk Management Program

Gaithersburg, MarylandGaithersburg, MarylandFebruary 26, 2004February 26, 2004

Funded by the Centers for Disease Control and Prevention in Funded by the Centers for Disease Control and Prevention in partnership with the Association of American Medical Collegespartnership with the Association of American Medical Colleges

OTIS Survey Team:OTIS Survey Team:Principal Investigator:Principal Investigator:

John Carey (University of Utah)John Carey (University of Utah)Coordinator: Coordinator:

Julia Robertson (Utah Department of Health) Julia Robertson (Utah Department of Health) OTIS Development and Review Teams:OTIS Development and Review Teams:

Tina Chambers (University of California San Diego)Tina Chambers (University of California San Diego)Gideon Koren (Toronto Hospital for Sick Children)Gideon Koren (Toronto Hospital for Sick Children)Sharon Lavigne (University of Connecticut)Sharon Lavigne (University of Connecticut)Richard Miller (University of Rochester)Richard Miller (University of Rochester)Janine Polifka (University of Washington)Janine Polifka (University of Washington)Cynthia Moore (CDC, Technical Monitor)Cynthia Moore (CDC, Technical Monitor)

AcknowledgemeAcknowledgementsnts

North American Isotretinoin Information & Survey Line

Non-profit, North American network of 19 state or Non-profit, North American network of 19 state or regional Teratology Information Services (TIS) regional Teratology Information Services (TIS)

Provides up-to-date information regarding the effects Provides up-to-date information regarding the effects of drugs and chemicals on the human embryo and of drugs and chemicals on the human embryo and fetus via free-of-charge telephone consultations fetus via free-of-charge telephone consultations

Receives approximately 100,000 calls per year--half Receives approximately 100,000 calls per year--half of the calls received initiated by patients (or the of the calls received initiated by patients (or the general public), half from health care professionalsgeneral public), half from health care professionals

Organization of Organization of Teratology Information Teratology Information Services (OTIS)Services (OTIS)


OTIS is organized exclusively OTIS is organized exclusively

– to stimulate and encourage research, to stimulate and encourage research, education, and the dissemination of knowledge education, and the dissemination of knowledge in the field of Teratologyin the field of Teratology

– to improve the abilities of TIS’s to provide to improve the abilities of TIS’s to provide accurate and timely information about prenatal accurate and timely information about prenatal exposures, with the overall objective of exposures, with the overall objective of preventing birth defects and improving the preventing birth defects and improving the public health public health



Increased regulatory safeguards using the thalidomide Increased regulatory safeguards using the thalidomide S.T.E.P.S. program as a template to include:S.T.E.P.S. program as a template to include:

– Mandatory enrollment and compliance of physicians, Mandatory enrollment and compliance of physicians, pharmacists and patients in the program pharmacists and patients in the program

– Mandatory participation of patients, prescribing Mandatory participation of patients, prescribing physicians, and pharmacies in a single, independent and physicians, and pharmacies in a single, independent and uniform registry uniform registry

– Increased patient accessibility to the use of two reliable Increased patient accessibility to the use of two reliable forms of contraceptionforms of contraception

– Continued educational activities provided for physicians, Continued educational activities provided for physicians, pharmacists and patientspharmacists and patients

OTIS Recommendations OTIS Recommendations for Use of Isotretinoin, for Use of Isotretinoin,

20022002


Availability strictly limited to women who meet the Availability strictly limited to women who meet the clinical criteria for severe recalcitrant cystic acneclinical criteria for severe recalcitrant cystic acne

Prescribing strictly limited to dermatologists who have Prescribing strictly limited to dermatologists who have enrolled in and agreed to comply with the S.M.A.R.T. enrolled in and agreed to comply with the S.M.A.R.T. program program

More effective and comprehensive contraceptive More effective and comprehensive contraceptive counseling counseling

Toll–free number and website on all packaging for Toll–free number and website on all packaging for direct access to risk assessment and counseling direct access to risk assessment and counseling

Continued evaluation of the effectiveness of this Continued evaluation of the effectiveness of this program and modification if necessary program and modification if necessary

The Subcommittee on Oversight and Investigations,The Committee on Energy and Commerce, United States House of Representative, 12/11/02


20022002


http://energycommerce.house.gov/107/hearings/12112002Hearing755

Previous Accutane Previous Accutane Research OTISResearch OTIS


In 2000, the California TIS contributed In 2000, the California TIS contributed to a study of 14 women whose to a study of 14 women whose pregnancy was inadvertently exposed pregnancy was inadvertently exposed to isotretinoin, reflecting a failure of to isotretinoin, reflecting a failure of the pregnancy prevention program the pregnancy prevention program

(Chambers, C., et al., Accutane-Exposed (Chambers, C., et al., Accutane-Exposed Pregnancies – California, 1999. MMWR 49: 28-Pregnancies – California, 1999. MMWR 49: 28-

31, 2000).31, 2000).

OTIS Experience with Isotretinoin Exposures OTIS Experience with Isotretinoin Exposures during Pregnancy, 2001 - 2003during Pregnancy, 2001 - 2003

YearYear

Total # of Total # of IsotretinoiIsotretinoin Callersn Callers

Isotretinoin Isotretinoin Exposed Exposed Callers Callers

(US)(US)

# of TIS # of TIS ReportinReportin

gg

IsotretinoiIsotretinoin n

Exposed Exposed Callers Callers

(Canada)(Canada)


gg

20032003 3737 2929 1111 88 22

20022002 3232 2424 1616 88 22

20012001 3939 2424 2020 1515 22


OTIS Experience with Isotretinoin Exposures OTIS Experience with Isotretinoin Exposures during Pregnancy, 2001 - 2003during Pregnancy, 2001 - 2003

YearYear

Total # of Total # of IsotretinoiIsotretinoin Callersn Callers

Isotretinoin Isotretinoin Exposed Exposed Callers Callers

(US)(US)


gg

IsotretinoiIsotretinoin n

Exposed Exposed Callers Callers

(Canada)(Canada)


gg

20032003 3737 2929 1111 88 22

20022002 3232 2424 1616 88 22

20012001 3939 2424 2020 1515 22


Enrollment Enrollment

Women who called a TIS about an isotretinoin exposure Women who called a TIS about an isotretinoin exposure during pregnancy; enrolling through Sept. 2004during pregnancy; enrolling through Sept. 2004

MethodsMethods

Detailed, structured interview by a research specialist; Detailed, structured interview by a research specialist; participant followed until the outcome is knownparticipant followed until the outcome is known

Study ObjectiveStudy Objective

To identify barriers to the successful implementation of the To identify barriers to the successful implementation of the components of the pregnancy risk management programcomponents of the pregnancy risk management program

OTIS Isotretinoin SurveyOTIS Isotretinoin Survey


Goals of the S.M.A.R.T. Program Goals of the S.M.A.R.T. Program

– To prevent pregnancy in women who are To prevent pregnancy in women who are taking isotretinointaking isotretinoin

– To prevent embryonic exposure to To prevent embryonic exposure to isotretinoin in women who are already isotretinoin in women who are already pregnantpregnant

Case histories from the OTIS surveyCase histories from the OTIS survey

OTIS Isotretinoin OTIS Isotretinoin Survey: Assessing the Survey: Assessing the

GoalsGoals


Goal: Goal: To prevent pregnancy in women who are taking isotretinoinTo prevent pregnancy in women who are taking isotretinoin

Ms. A., 30’s, reported taking isotretinoin samples Ms. A., 30’s, reported taking isotretinoin samples

– Exposure during weeks 3 to 7 of gestationExposure during weeks 3 to 7 of gestation

– Birth control method discontinued one month prior to starting Birth control method discontinued one month prior to starting isotretinoin and misinterpreted OB-GYN’s statement about ability to isotretinoin and misinterpreted OB-GYN’s statement about ability to conceive afterwards conceive afterwards

– Prescribing dermatologist did not order pregnancy tests or confirm two Prescribing dermatologist did not order pregnancy tests or confirm two forms of contraception forms of contraception

– Pregnancy continuing; fetal status unknown Pregnancy continuing; fetal status unknown

Case History Case History Pregnancy Pregnancy ExposureExposure


Goal: Goal: To prevent embryonic exposure to isotretinoin in women who To prevent embryonic exposure to isotretinoin in women who

are already pregnantare already pregnant

Ms. Z., teenager, reported taking isotretinoin Ms. Z., teenager, reported taking isotretinoin

– Exposure during weeks 5 to 6 of gestationExposure during weeks 5 to 6 of gestation

– Denied possibility of pregnancy to dermatologist despite positive Denied possibility of pregnancy to dermatologist despite positive pregnancy testpregnancy test

– Given prescription by dermatologist without additional pregnancy Given prescription by dermatologist without additional pregnancy testingtesting

– Pregnancy continuing; fetal status unknown Pregnancy continuing; fetal status unknown


Case History Case History Pregnancy Pregnancy ExposureExposure

Case histories illustrate several missed opportunities Case histories illustrate several missed opportunities for prevention of exposure to isotretinoin during for prevention of exposure to isotretinoin during pregnancypregnancy

Errors arise from multiple sources such as Errors arise from multiple sources such as miscommunication between the health care provider miscommunication between the health care provider and patient, misinterpretation of information by the and patient, misinterpretation of information by the health care provider, and denial of risk by the patient health care provider, and denial of risk by the patient

Lack of adherence to required components of the risk Lack of adherence to required components of the risk management program removed safeguards that management program removed safeguards that might have prevented these exposuresmight have prevented these exposures

Case History SummaryCase History Summary


EnrollmentEnrollment

– United StatesUnited States 11 women (Apr. 2003 - Feb. 11 women (Apr. 2003 - Feb. 2004)2004)

– CanadaCanada 12 women (Feb. 2001 -12 women (Feb. 2001 - Feb. 2004) Feb. 2004)

Key differences in isotretinoin risk Key differences in isotretinoin risk management programs in the United States management programs in the United States and Canada and Canada

– United StatesUnited States S.M.A.R.T. program begun Apr. S.M.A.R.T. program begun Apr. 20022002

– CanadaCanada P.P.P. continued P.P.P. continued

OTIS Isotretinoin SurveyOTIS Isotretinoin SurveyInterim ResultsInterim Results


In response to several questions about use of isotretinoin, In response to several questions about use of isotretinoin, survey participants:survey participants:– Described their skin problem as cystic or nodular acne Described their skin problem as cystic or nodular acne

S.M.A.R.T. (36%)S.M.A.R.T. (36%) P.P.P. (33%)P.P.P. (33%)– Recalled that their doctor had diagnosed their condition as Recalled that their doctor had diagnosed their condition as

cystic or nodular acne cystic or nodular acne

S.M.A.R.T. (20%)S.M.A.R.T. (20%) P.P.P. (9%) P.P.P. (9%) – Recalled treatment with oral antibiotics before isotretinoin Recalled treatment with oral antibiotics before isotretinoin

was prescribed was prescribed

S.M.A.R.T. (82%)S.M.A.R.T. (82%) P.P.P. (57%) P.P.P. (57%)

Use of IsotretinoinUse of IsotretinoinInterim ResultsInterim Results


Women must have two negative pregnancy tests before receiving a prescription Women must have two negative pregnancy tests before receiving a prescription

Women must use two forms of birth control simultaneously, starting one month before receiving a Women must use two forms of birth control simultaneously, starting one month before receiving a prescription prescription

Women must receive a pregnancy test each month before refilling their prescriptionWomen must receive a pregnancy test each month before refilling their prescription

Pharmacists must only fill prescriptions that bear a yellow qualification stickerPharmacists must only fill prescriptions that bear a yellow qualification sticker

S.M.A.R.T. ElementsS.M.A.R.T. Elements


Women must have two negative pregnancy tests Women must have two negative pregnancy tests

before receiving a prescriptionbefore receiving a prescription

RESPONSES FROM OTIS SURVEY:RESPONSES FROM OTIS SURVEY:

Women reporting that they had a second pregnancy Women reporting that they had a second pregnancy test during their menstrual period before beginning test during their menstrual period before beginning isotretinoin:isotretinoin:

S.M.A.R.T. (27%)S.M.A.R.T. (27%) P.P.P. (33%)P.P.P. (33%)

CONCLUSION:CONCLUSION:

For the S.M.A.R.T. program, it appears that For the S.M.A.R.T. program, it appears that 73%73% of of women surveyed were not screened using two women surveyed were not screened using two pregnancy tests as requiredpregnancy tests as required

S.M.A.R.T. Elements – 1S.M.A.R.T. Elements – 1 Interim ResultsInterim Results


Women must use two forms of birth control Women must use two forms of birth control

simultaneously, starting one month before receiving a simultaneously, starting one month before receiving a prescriptionprescription


Women surveyed who said they were using two forms of Women surveyed who said they were using two forms of birth control:birth control:

S.M.A.R.T. (36%)S.M.A.R.T. (36%) P.P.P. (8%)P.P.P. (8%)


64%64% of the women surveyed indicated they were not of the women surveyed indicated they were not following the S.M.A.R.T. requirement to use two forms of following the S.M.A.R.T. requirement to use two forms of birth controlbirth control



Women must receive a pregnancy test each month Women must receive a pregnancy test each month before refilling their prescriptionbefore refilling their prescription

RESPONSES FROM OTIS SURVEY:RESPONSES FROM OTIS SURVEY: Women in the study reporting that they had monthly Women in the study reporting that they had monthly pregnancy testing during the course of therapy:pregnancy testing during the course of therapy:

S.M.A.R.T. (36%)S.M.A.R.T. (36%) P.P.P. (83%) P.P.P. (83%)


For the S.M.A.R.T program, it appears that For the S.M.A.R.T program, it appears that 64%64% of of women were not screened for pregnancy monthly as women were not screened for pregnancy monthly as requiredrequired



Pharmacists must only fill prescriptions that bear a Pharmacists must only fill prescriptions that bear a yellow qualification stickeryellow qualification sticker


U.S. women who recalled seeing a yellow sticker on U.S. women who recalled seeing a yellow sticker on the prescription they took to the pharmacy:the prescription they took to the pharmacy:

S.M.A.R.T. (30%)S.M.A.R.T. (30%)


For more than For more than two-thirdstwo-thirds of the women surveyed, of the women surveyed, there is doubt about compliance with use of the there is doubt about compliance with use of the S.M.A.R.T. program yellow qualification stickerS.M.A.R.T. program yellow qualification sticker



In response to participation in any of the In response to participation in any of the manufacturers’ surveys, for the U.S. and Canada manufacturers’ surveys, for the U.S. and Canada combinedcombined

– 13%13% of women surveyed reported that they had of women surveyed reported that they had participated in the Accutane Surveyparticipated in the Accutane Survey

– 65%65% reported that they did not participate in any of reported that they did not participate in any of the manufacturers’ surveysthe manufacturers’ surveys

– 18%18% did not know if they had participated did not know if they had participated


Monitoring Compliance Monitoring Compliance Interim ResultsInterim Results

StrengthsStrengths

– OTIS has extensive experience in communicating with women about OTIS has extensive experience in communicating with women about their reproductive concerns their reproductive concerns

– Survey used a detailed, structured interview instrument Survey used a detailed, structured interview instrument

– Most U.S. interviews were completed within 3 months of exposure Most U.S. interviews were completed within 3 months of exposure and before the status of the fetus was known and before the status of the fetus was known

LimitationsLimitations

– Small numbers limit interpretation Small numbers limit interpretation

– Estimates based on women’s recall of eventsEstimates based on women’s recall of events

– Women who call a TIS and agree to participate in a survey might not Women who call a TIS and agree to participate in a survey might not be representativebe representative

Survey Strengths and LimitationsSurvey Strengths and Limitations


Consistent with U.S. data reported prior to institution of the Consistent with U.S. data reported prior to institution of the S.M.A.R.T. program S.M.A.R.T. program

Show similar rates of non-compliance in the U.S. with the Show similar rates of non-compliance in the U.S. with the S.M.A.R.T. program and in Canada with the P.P.P.S.M.A.R.T. program and in Canada with the P.P.P.

Demonstrate that preventable exposures continue to occur due to Demonstrate that preventable exposures continue to occur due to non-compliance with current requirements of the S.M.A.R.T. non-compliance with current requirements of the S.M.A.R.T. program program

Provide important qualitative data that may identify risk factors for Provide important qualitative data that may identify risk factors for exposure and help design more effective prevention strategies exposure and help design more effective prevention strategies

Preliminary ConclusionsPreliminary Conclusions


Interim Report Interim Report OTIS – North American Isotretinoin OTIS – North American Isotretinoin

Information and Survey Line Information and Survey Line

Toll-Free Number: 1-866-626-6847Toll-Free Number: 1-866-626-6847 Website: Website: www.otispregnancy.orgwww.otispregnancy.org

FDA Advisory Committee MeetingFDA Advisory Committee MeetingAccutane Risk Management ProgramAccutane Risk Management Program

Gaithersburg, MarylandGaithersburg, MarylandFebruary 26, 2004February 26, 2004

The Subcommittee on Oversight and Investigations,The Committee on Energy and Commerce,

United States House of Representative, 12/11/02


20022002


http://energycommerce.house.gov/

107/hearings/12112002Hearing755



Documents

Interim Report OTIS – North American Isotretinoin Information and Survey Line Toll-Free Number: 1-866-626-6847 Website: FDA Advisory