1. DODAC and DSaRM Advisory Committee August 1, 2007 Pregnancy Registry and Root Cause Analysis Cynthia Kornegay, Ph.D. Division of Drug Risk Evaluation Office of Surveillance and Epidemiology Center for Drug Evaluation and Research Food and Drug Administration Cynthia Kornegay, Ph.D. Division of Drug Risk Evaluation Office of Surveillance and Epidemiology Center for Drug Evaluation and Research Food and Drug Administration

2. DODAC and DSaRM Advisory Committee August 1, 2007 2 OutlineOutline Challenges –Pregnancy Registry and Root Cause Analysis Background Possible Barriers Considerations –Knowledge and Behavior Assessment Background Possible Barriers Considerations Comparison Group Preliminary Observations Challenges –Pregnancy Registry and Root Cause Analysis Background Possible Barriers Considerations –Knowledge and Behavior Assessment Background Possible Barriers Considerations Comparison Group Preliminary Observations

3. DODAC and DSaRM Advisory Committee August 1, 2007 Pregnancy Registry and Root Cause Analysis (RCA)

4. DODAC and DSaRM Advisory Committee August 1, 2007 4 Background – Pregnancy Registry and RCA Root Cause Analysis (RCA) proposed by 2004 AC committee –Purpose is to gather detailed information on all reported isotretinoin-exposed pregnancies and use aggregate data to improve iPLEDGE program Root Cause Analysis (RCA) proposed by 2004 AC committee –Purpose is to gather detailed information on all reported isotretinoin-exposed pregnancies and use aggregate data to improve iPLEDGE program

5. DODAC and DSaRM Advisory Committee August 1, 2007 5 Background – Pregnancy Registry and RCA All women who become pregnant are asked to participate in the Registry –Initial data collected at time pregnancy reported with quarterly follow-up until infant is up to 1 year old The RCA is administered as part of the Registry All women who become pregnant are asked to participate in the Registry –Initial data collected at time pregnancy reported with quarterly follow-up until infant is up to 1 year old The RCA is administered as part of the Registry

6. DODAC and DSaRM Advisory Committee August 1, 2007 6 Background – Pregnancy Registry and RCA For the first year of iPLEDGE, the RCA participation rate was approximately 10% the total number of eligible pregnancies* –Insufficient enrollment to use data for improving iPLEDGE For the first year of iPLEDGE, the RCA participation rate was approximately 10% the total number of eligible pregnancies* –Insufficient enrollment to use data for improving iPLEDGE *Data derived from iPLEDGE Quarterly Reports from January 1, 2006 through March 31, 2007.

7. DODAC and DSaRM Advisory Committee August 1, 2007 7 Possible Participation Barriers – Pregnancy Registry and RCA Reasons for low participation are not known, but several possible barriers may exist –Significant time element involved in participation –Additional informed consent and lengthy questionnaires –Intrusive nature of RCA Reasons for low participation are not known, but several possible barriers may exist –Significant time element involved in participation –Additional informed consent and lengthy questionnaires –Intrusive nature of RCA

8. DODAC and DSaRM Advisory Committee August 1, 2007 8 Possible Participation Barriers – Pregnancy Registry and RCA Possible barriers (cont.) –iPLEDGE prescriber may not have further contact with participant –Registry is not widely promoted –RCA is administered only after introductory reporting forms have been completed Possible barriers (cont.) –iPLEDGE prescriber may not have further contact with participant –Registry is not widely promoted –RCA is administered only after introductory reporting forms have been completed

9. DODAC and DSaRM Advisory Committee August 1, 2007 9 Considerations – Pregnancy Registry and RCA To help increase participation: –Streamline informed consent process and questionnaires –Continue to ensure interviewers present questionnaire in non-judgmental manner –Increase awareness –Collect RCA information as soon as possible after pregnancy is reported To help increase participation: –Streamline informed consent process and questionnaires –Continue to ensure interviewers present questionnaire in non-judgmental manner –Increase awareness –Collect RCA information as soon as possible after pregnancy is reported

10. DODAC and DSaRM Advisory Committee August 1, 2007 Knowledge and Behavior Assessment

11. DODAC and DSaRM Advisory Committee August 1, 2007 11 Background – Knowledge and Behavior Assessment Patient education is primary method of risk communication in iPLEDGE –Brochures, workbooks, and videos are available for patients and prescribers –All patients receive basic materials, but females of childbearing potential also get additional brochures targeted specifically for them Patient education is primary method of risk communication in iPLEDGE –Brochures, workbooks, and videos are available for patients and prescribers –All patients receive basic materials, but females of childbearing potential also get additional brochures targeted specifically for them

12. DODAC and DSaRM Advisory Committee August 1, 2007 12 Background – Knowledge and Behavior Assessment iPLEDGE makes effort to provide adequate contraceptive counseling –iPLEDGE prescribers are required to provide contraceptive counseling as part of the program –Health care providers can refer patients to contraceptive counselors –Initial contraceptive counseling is provided free of charge if requested iPLEDGE makes effort to provide adequate contraceptive counseling –iPLEDGE prescribers are required to provide contraceptive counseling as part of the program –Health care providers can refer patients to contraceptive counselors –Initial contraceptive counseling is provided free of charge if requested

13. DODAC and DSaRM Advisory Committee August 1, 2007 13 Background – Knowledge and Behavior Assessment Females of childbearing potential must answer a series of questions every month of therapy to assess knowledge of iPLEDGE –At start, questions focus on receipt of iPLEDGE materials –During therapy, questions assess contraceptive practices –Must be answered prior to receiving each prescription Females of childbearing potential must answer a series of questions every month of therapy to assess knowledge of iPLEDGE –At start, questions focus on receipt of iPLEDGE materials –During therapy, questions assess contraceptive practices –Must be answered prior to receiving each prescription

14. DODAC and DSaRM Advisory Committee August 1, 2007 14 Possible Barriers – Knowledge and Behavior Assessment Possible information overload –Females of childbearing potential receive over 50 pages of materials at the start of therapy –Research suggests that even when more information is available, patients may still not understand the risks associated with isotretinoin* Possible information overload –Females of childbearing potential receive over 50 pages of materials at the start of therapy –Research suggests that even when more information is available, patients may still not understand the risks associated with isotretinoin* *Allen LaPointe et al. Patient receipt and understanding of written information provided with isotretinoin and estrogen prescriptions. J Gen Intern Med 2007 Jan;22(1):98-101

15. DODAC and DSaRM Advisory Committee August 1, 2007 15 Possible Barriers – Knowledge and Behavior Assessment Inconsistencies regarding initial counseling by females of childbearing potential –Patient informed consent states that they have received counseling from their iPLEDGE prescriber –About 13% of patients reported not receiving contraceptive counseling when starting isotretinoin therapy* Inconsistencies regarding initial counseling by females of childbearing potential –Patient informed consent states that they have received counseling from their iPLEDGE prescriber –About 13% of patients reported not receiving contraceptive counseling when starting isotretinoin therapy* *iPLEDGE Year 1 Report, Table 7, March 30, 2007

16. DODAC and DSaRM Advisory Committee August 1, 2007 16 Possible Barriers – Knowledge and Behavior Assessment Possible disconnect between reading and comprehension of program materials –Although response rates indicate that over 95% of women had read the materials*: 38% of women answered the question “ You can use any forms of birth control for iPLEDGE” incorrectly** Possible disconnect between reading and comprehension of program materials –Although response rates indicate that over 95% of women had read the materials*: 38% of women answered the question “ You can use any forms of birth control for iPLEDGE” incorrectly** *iPLEDGE 4 th Quarter 2006 Report, Table B.1, January 31, 2007 **iPLEDGE 4 th Quarter 2006 Report, Table B.1.5, January 31, 2007

17. DODAC and DSaRM Advisory Committee August 1, 2007 17 Possible Barriers – Knowledge and Behavior Assessment Monthly questions may need to be revised –Depending on the birth control method chosen, between 21% and 62% of women answered a key birth control question incorrectly* –Wording has been improved in recent changes proposed by Sponsors Monthly questions may need to be revised –Depending on the birth control method chosen, between 21% and 62% of women answered a key birth control question incorrectly* –Wording has been improved in recent changes proposed by Sponsors *iPLEDGE 4 th Quarter 2006 Report, Table B.1.5, January 31, 2007

18. DODAC and DSaRM Advisory Committee August 1, 2007 18 Considerations – Knowledge and Behavior Assessment Reduce length of materials Streamline message on essentials of iPLEDGE Review materials to ensure clear, consistent and patient-friendly language Changes to materials should be tested prior to distributing as part of iPLEDGE Reduce length of materials Streamline message on essentials of iPLEDGE Review materials to ensure clear, consistent and patient-friendly language Changes to materials should be tested prior to distributing as part of iPLEDGE

19. DODAC and DSaRM Advisory Committee August 1, 2007 19 Considerations – Knowledge and Behavior Assessment Although patients may receive their contraception from other healthcare providers, isotretinoin prescribers still need to review iPLEDGE’s additional contraceptive requirements with females of child- bearing potential –Two forms of birth control must be emphasized Although patients may receive their contraception from other healthcare providers, isotretinoin prescribers still need to review iPLEDGE’s additional contraceptive requirements with females of child- bearing potential –Two forms of birth control must be emphasized

20. DODAC and DSaRM Advisory Committee August 1, 2007 20 Considerations – Knowledge and Behavior Assessment Ongoing review of questions should continue to ensure that: –They are focused on demonstrating knowledge of the iPLEDGE program –They are clearly worded –Correct answers pertain to iPLEDGE –They provide an accurate assessment of knowledge Ongoing review of questions should continue to ensure that: –They are focused on demonstrating knowledge of the iPLEDGE program –They are clearly worded –Correct answers pertain to iPLEDGE –They provide an accurate assessment of knowledge

21. DODAC and DSaRM Advisory Committee August 1, 2007 Comparison Group

22. DODAC and DSaRM Advisory Committee August 1, 2007 22 Comparison Group RCA gathers retrospective data on actual contraceptive use Comparable information is not available for women who did not get pregnant This comparison will help place RCA data in context RCA gathers retrospective data on actual contraceptive use Comparable information is not available for women who did not get pregnant This comparison will help place RCA data in context

23. DODAC and DSaRM Advisory Committee August 1, 2007 23 Comparison Group The Agency and Sponsors need to –Consider additional studies to provide data on non-pregnant females’ contraceptive behaviors for comparison Random sample of non-pregnant females (age matched) –Should help make evaluation of iPLEDGE more informative The Agency and Sponsors need to –Consider additional studies to provide data on non-pregnant females’ contraceptive behaviors for comparison Random sample of non-pregnant females (age matched) –Should help make evaluation of iPLEDGE more informative

24. DODAC and DSaRM Advisory Committee August 1, 2007 Preliminary Observations

25. DODAC and DSaRM Advisory Committee August 1, 2007 25 Preliminary Observations Concerns: –RCA participation rate –Patient understanding of risks associated with isotretinoin –Evaluation of patient knowledge Needs to be valid assessment Consideration for minor program adjustments might be helpful –Concerns about program disruption Concerns: –RCA participation rate –Patient understanding of risks associated with isotretinoin –Evaluation of patient knowledge Needs to be valid assessment Consideration for minor program adjustments might be helpful –Concerns about program disruption

26. DODAC and DSaRM Advisory Committee August 1, 2007 26 Preliminary Observations Evaluation goal is to determine if there are areas of iPLEDGE that can be enhanced to improve the program’s overall effectiveness –Behavior change can be difficult to achieve –iPLEDGE program effectiveness may be limited by non-program factors (motivation, perception of risk) Evaluation goal is to determine if there are areas of iPLEDGE that can be enhanced to improve the program’s overall effectiveness –Behavior change can be difficult to achieve –iPLEDGE program effectiveness may be limited by non-program factors (motivation, perception of risk)