1. Approaches to Validation of Over-the- Counter (OTC) Home-Use HIV Test Kits Blood Products Advisory Committee November 3, 2005 Elliot P. Cowan, Ph.D. Chief, Product Review Branch Division of Emerging and Transfusion Transmitted Diseases FDA/CBER/OBRR

2. Purpose of this Session u FDA seeks advice regarding the conditions necessary to support approval of a home- use HIV test kit. u In particular, we will ask 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. Introduction u Prior public discussions of home-use HIV tests u History of point-of-care testing for HIV: Rapid HIV tests u Issues to be addressed for home-use HIV test kits u Overview of this session u Questions for the Committee

4. Home-Use Tests u Tests that are used at home by untrained persons without the help of a healthcare professional u Two types –Home-use collection kits »You take your own sample, mail it to a laboratory, and get your result over the phone –Home-use test kits »You take your own sample, test the sample, and read your own result

5. Currently Approved Home-Use Collection Kits and Test Kits u Home-use collection kits –Hepatitis C virus infection –HIV u Home-use test kits –Fecal occult blood –Glucose –Cholesterol –Pregnancy –Prothrombin time u No previously approved home-use test kits for infectious diseases

6. Home-Use HIV Test Kits are Different from Home-Use HIV Collection Kits u Home-use collection kit –Specimen is collected by the test subject –Test is performed and interpreted by a trained operator in a certified laboratory –Live counseling u Home-use test kit –Specimen is collected by the test subject –Test is performed and interpreted by the test subject »Lack of a trained operator »Lack of live pre-test counseling and post-test counseling at the time the test result is provided »Lack of medical referral

7. Prior FDA Considerations of Home-Use Tests: 1986 u Companies first expressed interest in developing and marketing home-use blood collection kits for HIV testing –FDA and AIDS advocacy groups raised public health concerns about »Test accuracy in the hands of an untrained individual »The way users would be notified of test results – patient confidentiality and adequacy of telephone counseling u Effective counseling deemed critical to ensure that HIV-infected people understand what HIV infection means and receive vital information about recommended treatment and coping methods

8. Prior FDA Considerations of Home-Use Tests: March 1988 u FDA notified, by letter, manufacturers and other interested parties of requirements for approval of such systems –Based on consultation with other US public health agencies and private sector advisory groups

9. Prior FDA Considerations of Home- Use Tests: February 17, 1989 u Federal Register notice –Criteria for HIV specimen collection systems »Professional use only »Results of testing reported to professional health care provider for reporting and interpretation of test result to person requesting test, as well as counseling of individual »Use of licensed HIV test, etc. –Announcement of public meeting to discuss »Collection and shipping of blood specimens by laypersons »Return of results directly to person from whom sample collected »Counseling outside of medical health care environment »Availability of blood collection systems OTC »Kits for collection and home testing of blood for evidence of HIV- 1 infection

10. Prior FDA Considerations of Home-Use Tests: April 6, 1989 u Open Public Meeting: Blood Collection Kits Labeled for Human Immunodeficiency Virus Type 1 Antibody Testing u Agenda –Invited speakers on regulatory issues, CDRH experience in home testing, counseling, ethical issues, state experience –Public commentors u Extensive discussion on risks and benefits of blood collection kits and home-use test kits

11. Prior FDA Considerations of Home-Use Tests: July 30, 1990 u Federal Register notice –FDA considered data and comments from 4/6/89 meeting –FDA reiterated that HIV specimen collection kits should remain for professional use only –FDA stated willingness to work with manufacturers on requirements for a premarket approval application and to review data for home collection kits

12. Prior FDA Considerations of Home-Use Tests: July 1990 u BPAC considers approval of premarket approval application from Direct Access Diagnostics (University Hospital Laboratories) for its home collection system u Recommendation against approval –Application lacked sufficient data –Questions remained regarding possible problems with such issues as confirmatory testing of positive samples, adequacy of telephone counseling, and compliance with state notification requirements while maintaining patient confidentiality

13. Prior FDA Considerations of Home-Use Tests: 1990-1994 u FDA discussed OTC home specimen collection kits extensively with other US public health agencies and with product sponsors u Change in circumstances –Advances in technology = potential for improved accuracy –Change in treatment methods (availability of therapy for asymptomatic individuals) –Public’s increasing desire for greater involvement in personal health care decisions

14. Prior FDA Considerations of Home-Use Tests: June 1994 u BPAC re-examination of home-use specimen collection systems u Agreement that benefit of having alternative means of reaching previously unreachable populations for HIV testing outweighed potential risks u Concerns expressed about –Accessibility of a home-use kit for target groups –Adequacy of counseling while maintaining confidentiality –Effectiveness of education and follow-up u Recommendation for pilot studies to evaluate these issues

15. Prior FDA Considerations of Home- Use Tests: February 23, 1995 u Federal Register notice –FDA revising guidance for specimen collection kits labeled for HIV antibody testing set forth in 2/17/89 FR notice –OTC specimen collection kit systems may be approvable –Listed specific kinds of data sponsors should submit for review of safety and effectiveness –Did not address kits for home testing of specimens for evidence of HIV infection

16. What has changed since 1995? u Tests that: –Have an extremely low risk of an incorrect result (unaffected by changes in operating conditions or conditions that could affect the integrity of the specimen) –Are simple to use –Do not require special storage conditions –Results within 20 minutes –Use of oral fluid eliminates concerns about biohazardous conditions (no blood and sharps) u Experience with these tests in non-traditional testing settings u Early detection translates into better outcomes u Changes in social awareness of HIV infection

17. HIV Testing u Traditional testing for HIV requires two visits to a clinic/healthcare provider –Provide sample –Receive test result ~1 week later –CDC has estimated that each year approximately 8,000 HIV positive individuals do not return to receive their test results u Point-of-care testing –Tests that can provide a test result in a relatively short time so that only a single visit is required

18. Rapid HIV Tests u Results within 20 minutes u Few steps to perform; visual readout u No special storage conditions or instrumentation needed u Detect antibodies to HIV u Tests to be used as an aid in the diagnosis of HIV infection and not for blood donor screening u 4 FDA-approved tests at this time

19. Rapid HIV Test Approval Requirements and Standards u Performance standards and clinical trial/non-clinical requirements for rapid HIV tests: BPAC discussed/concurred on June 15, 2000 u Performance –Sensitivity: 98% (lower bound of the 95% confidence interval) –Specificity: 98% (lower bound of the 95% confidence interval)

20. Performance of Rapid HIV Tests: Sensitivity* Whole BloodPlasmaSerumOral Fluid OraQuick99.6%99.7%-99.3% Reveal-99.8% - Uni-Gold100% - Multispot-100% - *Point estimates from clinical trial data in support of product approval

21. Performance of Rapid HIV Tests: Specificity* Whole BloodPlasmaSerumOral Fluid OraQuick100%99.9%-99.8% Reveal-98.6%99.1%- Uni-Gold99.7%98.8%99.8%- Multispot-99.9% - *Point estimates from clinical trial data in support of product approval

22. Rapid HIV Tests: Interpretation u Non-reactive = Negative u Reactive = Preliminary Positive –All reactive results should be confirmed using an appropriate supplemental test –Consistent with concept that although screening test results are highly accurate, reactive test result should be confirmed by supplemental testing

23. Rapid HIV Tests are Restricted Devices u Sale restricted to clinical laboratories –that have an adequate quality assurance program and –where there is assurance that operators will receive and use the instructional materials u Approved for use only by an agent of a clinical laboratory –i.e., not for self-testing u Test subjects must receive a “Subject Information” pamphlet and pre-test counseling prior to specimen collection, and appropriate counseling when test results are provided

24. Rapid HIV Test Restrictions, cont. u Not approved for use to screen blood or tissue donors u Customer letter included with all kits –“By purchasing this device, you are doing so as an agent of a clinical laboratory and agree that you or any of your consignees will abide by the…restrictions on the sale, distribution, and use of the device…”

25. Access to Rapid HIV Tests u Who is permitted to use rapid HIV tests? u Device classification –Clinical Laboratory Improvement Amendments of 1988 (CLIA) –Classifies devices according to complexity »High »Moderate »Waived

26. CLIA Waiver u To perform CLIA-waived tests, entities must: Enroll in CLIA program Obtain a Certificate of Waiver Pay a biennial fee Follow manufacturers’ instructions Meet state requirements u Sponsor must apply for CLIA waiver –Application is made after initial approval –Studies to demonstrate that device is simple and accurate in the hands of intended users

27. CLIA Waiver Expands Access to Rapid HIV Tests u Impact of CLIA waiver –Use of rapid tests permits notification of preliminary test results without the need for the subject to be re-contacted –Fewer laboratory restrictions permits wider use u June 14, 2001 BPAC discussion on CLIA waiver for rapid HIV tests –CLIA Criteria for In Vitro Diagnostic Tests: FDA Perspectives on Applicability of Waivers to HIV Rapid Tests

28. Rapid HIV Tests Waived under CLIA u Tests that are waived under CLIA –OraQuick ® for use with whole blood (1/31/03) –OraQuick ® for use with oral fluid (6/25/04) –Uni-Gold TM for use with venipuncture whole blood (6/23/04) –Uni-Gold TM for use with fingerstick whole blood (11/5/04) u Sales and use restrictions apply to waived rapid HIV tests

29. 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

30. Recurring Themes for Home-Use HIV Test Kits, cont. u Risks –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

31. Recurring Themes for Home- Use HIV Test Kits, cont. u Additional issues –Obtaining a test result without a supplemental test »False positive rate significant in low prevalence populations –Availability for those who need the test most –Potential conflict with state and/or federal health reporting requirements

32. Information to be Discussed at this Meeting u Proposal by OraSure Technologies, Inc. for an OTC claim for the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test for use with oral fluid specimens –Proposed studies to validate adequate performance in the hands of intended users »Populations to be studied reflecting intended users? –Ability of informational materials to provide counseling and other information in a comprehensible manner by intended users »Accuracy of testing »Correct test interpretation »Management of psychological and social issues »Medical referral

33. Information to be Discussed at this Meeting, cont. u Discussion of changes in HIV testing practices and counseling recommendations –Dr. Bernard Branson, CDC u Role of quality systems for diagnostic tests –Dr. Devery Howerton, CDC u Psychological and social issues associated with HIV testing and OTC home-use tests –Dr. Joseph Inungu, Central Michigan University u Overview of the OTC review process and human factors considerations –Arleen Pinkos, FDA/CDRH/OIVD

34. Questions for the Committee 1.Are FDA’s previously established criteria for sensitivity and specificity for rapid HIV tests also appropriate to support OTC use for home-use HIV test kits? 2.Please comment on the design of clinical studies necessary to validate the safety and effectiveness of an OTC home-use HIV test kit.

35. Questions for the Committee 3.Please comment on the proposed content of the informational materials and the steps that should be taken to validate the adequacy of the 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