1. Proposed Studies to Support the Approval of Over-the-Counter (OTC) Home-Use HIV Test Kits Blood Products Advisory Committee March 10, 2006 Elliot P. Cowan, Ph.D. Chief, Product Review Branch Division of Emerging and Transfusion Transmitted Diseases FDA/CBER/OBRR

2. November 3, 2005 u FDA sought advice from BPAC regarding the conditions necessary to support approval of a home- use HIV test kit. u In particular, we asked the Committee to consider what studies are needed to validate test accuracy test interpretation and medical follow-up based on the provision of informational material in place of a trained test operator and counselor.

3. Summary of 11/3/05 Meeting u Proposal by OraSure Technologies u Discussion of changes in HIV testing practices and counseling recommendations u Role of quality systems for diagnostic tests u Psychological and social issues associated with HIV testing and OTC home-use tests u Overview of OTC review process at FDA

4. Recurring Themes for Home- Use HIV Test Kits u Benefits –Anonymous testing potentially leads to more people knowing their HIV status –Earlier diagnosis and therefore earlier intervention –Empowerment of consumers in healthcare decisions –Potential impact on behavior and public health

5. Recurring Themes for Home-Use HIV Test Kits, cont. u Risks –Incorrect test results due to improper performance of the test or incorrect test interpretation has the potential for significant risk of harm to patients and public health –Inappropriate use of test or test result »Misinterpretation (relying on test to provide accurate result after a very recent exposure) –Potential adverse outcomes after obtaining a test result without live counseling –Inability to reach individuals for follow-up and to perform partner notification –Coercive testing –Testing by minors

6. Summary of BPAC Comments, 11/3/05 u A home-use HIV test kit should be no less accurate than tests approved for use under CLIA waiver –Home-use HIV test kits should have high analytical sensitivity and specificity –FDA could be flexible on performance levels in the intended use population –If requirements for performance are unattainable, then the availability of a home use test kit would be jeopardized

7. Summary of BPAC Comments, 11/3/05, cont. u Clinical trial could be performed in two phases (observed and unobserved) u The clinical trial should look not only at performance of test, but also at the effectiveness of the instructions for use u Critical for users to understand limitations of test, especially concerning window period u Linkage to counseling and medical follow-up is critical

8. Purpose of this Session u FDA seeks the advice of the Committee on proposed studies that would be needed to validate a home-use HIV test kit with regard to – test accuracy – test interpretation – medical follow-up based on the provision of informational material in place of a trained test operator and counselor.

9. Overview of Proposed Studies u Studies to identify potential users of the test u Phase I studies u Phase II studies u Phase III studies u Additional recommendations on informational materials, counseling, testing, and referral

10. Studies to Identify Potential Users of the Test u Potential users of the test should be identified by means of qualitative research u Clinical trial study populations should reflect the demographics of those users identified in these studies

11. Phase I Studies u Objectives –To establish the inherent sensitivity and specificity of the test –To demonstrate that the test is capable of withstanding operational stress u Performed by individuals trained in the use of the test

12. Phase I Analytical Sensitivity and Specificity u Studies similar to those required for HIV tests for professional use u Expected results: comparable to approved professional use tests u Additional analytical studies not necessary for previously FDA approved test

13. Phase I Operational Stress (“Flex”) Studies u Conduct thorough hazard analysis u Evaluate ability of test to withstand potential sources of error u Device should be designed with procedural control that is sensitive to all applicable system errors

14. Phase II Studies u Objective: To evaluate in a controlled setting –Effectiveness and safety of sample collection by untrained potential users –Ability of untrained potential users to perform test properly –Ability of untrained potential users to read and interpret test results –Performance of test in hands of untrained potential users –Reactions to test results by untrained potential users

15. Phase II Format u Observational studies –Untrained users perform test by themselves while being observed by individuals trained in the use of the test –Actual testing setting should be simulated as closely as possible, physically separating the trained tester from the test subject

16. Phase II: Safety and Effectiveness of Sample Collection u Monitor the ability of study participants to properly collect a test specimen u Note any deviations from the procedure described in the test kit, along with impact on the test result

17. Phase II: Ability to Perform Test Properly u Monitor study participants for their ability to follow the instructional materials on the running of the test after the specimen is collected u Note any deviation from the instructional materials

18. Phase II: Read and Interpret Test Results u Interpretation of self-testing u Interpretation of testing of weak reactive and negative specimens u Interpretation of examples of test results

19. Phase II: Read and Interpret Test Results, cont. u Interpretation of self-testing –Ability to correctly interpret own test results and identify any follow-up actions that should be taken consistent with the informational materials provided with test kit –Compare results of testing by untrained potential users to results of testing by trained personnel using appropriate statistical methods

20. Phase II: Read and Interpret Test Results, cont. u Interpretation of testing of weak reactive and negative specimens –120 aliquots of weak reactive and 120 aliquots of negative specimen, evaluated by 240 study participants –Expected performance is a point estimate of at least 95% for the weak reactive specimen and 99% for the negative specimen

21. Phase II: Read and Interpret Test Results, cont. u Interpretation of examples of test results –Study participants, whose HIV status was not known prior to testing, will be evaluated for their ability to correctly interpret a set of test results (non-reactive, strongly reactive, weakly reactive, invalid) –Expected lower bound of 95% CI for % agreement »>98% for non-reactive, strongly reactive, and invalid »95% for weakly reactive

22. Phase II: Performance u The number of untrained users participating in these studies should be sufficient to demonstrate that the lower bound of the two- sided 95% confidence interval is at least 95% for both sensitivity and specificity u At least three geographically diverse clinical trial sites with a high prevalence of HIV infection u Known HIV-positive individuals may be included in this part of the clinical trial, but we propose that at least 10 HIV-positive individuals will be identified from testing by/of the untrained potential users who are unaware of their HIV status

23. Phase II: Reactions to Test Results u Objective: Validation of adequacy of informational materials to: –Inform the study participant about the limitations of the test –Inform the study participant about the need to confirm a reactive test result –Inform the study participant about the availability of resources for counseling and medical follow-up –Have the study participant properly dispose of test-related waste

24. Phase II: Reactions to Test Results, cont. u Monitor untrained potential users of the test for their reactions following interpretation of the test result –E.g., interview, questionnaire –Assess likelihood of appropriate follow-up by study participant –Use cognitive evaluation to assess responses –Note adverse reactions and take appropriate action

25. Phase II: Additional Notes u Phase II will include reference testing by trained users u Collect follow-up specimen from individuals with reactive test results for confirmatory testing u Informed consent should indicate that study participant may or may not be observed

26. Phase III Studies u Objective: –To evaluate the home-use HIV test kit in an unobserved and uncontrolled (intended use) setting u Multiple options for the conduct of Phase III studies

27. Phase III: Option 1 u Objectives: –Evaluate test performance of the test (sensitivity and specificity) in the hands of untrained potential users –Evaluate reactions of study participants to their test results –Validate ability of informational materials to: »Communicate the proper use of the test »Communicate test limitations »Have study participant seek follow-up testing and referral to care »Effectively provide a route to counseling –Validate the counseling system

28. Phase III: Option 1 Performance Expectations u The number of untrained users participating in these studies should be sufficient to demonstrate that the lower bound of the two- sided 95% confidence interval is at least 95% for both sensitivity and specificity u At least three geographically diverse clinical trial sites with a high prevalence of HIV infection u Known HIV-positive individuals may be included in this part of the clinical trial, but propose that at least 10 HIV-positive individuals will be identified from testing by/of the untrained potential users who are unaware of their HIV status

29. Phase III: Option 2 u Limited to evaluating the ability of the informational materials to communicate –Proper use of the test –Test limitations –Have the test subject seek follow-up testing and referral to care –Effectively provide a route to counseling –Validate the counseling system u Sensitivity and specificity would be determined from the Phase II studies u Assumes that test performance derived from Phase II studies reflects test performance in potential use settings

30. Phase III: Option 3 u Phase III studies not necessary u Assumes that Phase II studies will be sufficient to establish test performance in potential use settings and validate effectiveness of the informational materials

31. Additional Recommendations u Labeling to clearly communicate need to read informational materials prior to conducting test u The informational materials should be easy to comprehend by potential users of test u Informational materials must clearly communicate expected performance of test kit based on clinical studies, including number of false positive and false negative results observed

32. Additional Recommendations, cont. u Informational materials must clearly communicate the limitations of window period testing u Test manufacturer should be prepared to offer users advice and referral mechanisms to obtain proper medical follow-up of test results u Informational materials must clearly communicate actions to be taken in the event of a reactive test result

33. Additional Recommendations, cont. u Clear and convenient methods for follow-up testing and referral must be established and communicated in informational materials u Counseling must be accessible by means appropriate to potential desired users, be available at any time, and counseling information must be clearly communicated in informational materials

34. Questions for the Committee 1.Does the Committee concur with FDA’s proposed criteria for test performance (analytical and clinical sensitivity and specificity) for home- use HIV test kits? 2.Does the Committee concur with FDA’s proposal for the Phase II study? 3.For Phase III studies, which of the options presented does the committee recommend?

35. Questions for the Committee, cont. 4.Does the Committee concur with FDA’s proposed content needed for informational materials provided with home-use HIV test kits and the steps that should be taken to validate the adequacy of those informational materials to communicate or provide pathways to adequately address issues including: a.Accuracy of testing b.Correct test interpretation c.The importance of supplemental testing for confirmation of positive results d.Management of psychological and social issues e.Availability of counseling f.Medical referral

36. Questions for the Committee, cont. 5.If the Committee does not concur with any of the proposals in Questions 1-4, what additional information/modification would be needed to support approval of a home-use HIV test kit?