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,

Approaches to Validation of Over-the-Counter (OTC) Home-Use HIV Test Kits

Blood Products Advisory CommitteeNovember 3, 2005

Elliot P. Cowan, Ph.D.Chief, Product Review Branch

Division of Emerging and Transfusion Transmitted DiseasesFDA/CBER/OBRR

Purpose of this Session FDA seeks advice regarding the conditions

necessary to support approval of a home-use HIV test kit.

In particular, we will ask the Committee to consider what studies are needed to validate

test accuracytest interpretation andmedical follow-up

based on the provision of informational material in place of a trained test operator and counselor.

Introduction Prior public discussions of home-use

HIV tests History of point-of-care testing for HIV:

Rapid HIV tests Issues to be addressed for home-use

HIV test kits Overview of this session Questions for the Committee

Home-Use Tests Tests that are used at home by

untrained persons without the help of a healthcare professional

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

Currently Approved Home-Use Collection Kits and Test Kits

Home-use collection kits– Hepatitis C virus infection– HIV

Home-use test kits– Fecal occult blood– Glucose– Cholesterol– Pregnancy– Prothrombin time

No previously approved home-use test kits for infectious diseases

Home-Use HIV Test Kits are Different from Home-Use HIV Collection Kits 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

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

Prior FDA Considerations of Home-Use Tests: 1986

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 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

Prior FDA Considerations of Home-Use Tests: March 1988

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

Prior FDA Considerations of Home-Use Tests: February 17, 1989

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

Prior FDA Considerations of Home-Use Tests: April 6, 1989

Open Public Meeting: Blood Collection Kits Labeled for Human Immunodeficiency Virus Type 1 Antibody Testing

Agenda– Invited speakers on regulatory issues, CDRH

experience in home testing, counseling, ethical issues, state experience

– Public commentors

Extensive discussion on risks and benefits of blood collection kits and home-use test kits

Prior FDA Considerations of Home-Use Tests: July 30, 1990

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

Prior FDA Considerations of Home-Use Tests: July 1990

BPAC considers approval of premarket approval application from Direct Access Diagnostics (University Hospital Laboratories) for its home collection system

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

Prior FDA Considerations of Home-Use Tests: 1990-1994

FDA discussed OTC home specimen collection kits extensively with other US public health agencies and with product sponsors

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

Prior FDA Considerations of Home-Use Tests: June 1994

BPAC re-examination of home-use specimen collection systems

Agreement that benefit of having alternative means of reaching previously unreachable populations for HIV testing outweighed potential risks

Concerns expressed about– Accessibility of a home-use kit for target groups– Adequacy of counseling while maintaining

confidentiality– Effectiveness of education and follow-up

Recommendation for pilot studies to evaluate these issues

Prior FDA Considerations of Home-Use Tests: February 23, 1995

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

What has changed since 1995? 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)

Experience with these tests in non-traditional testing settings

Early detection translates into better outcomes

Changes in social awareness of HIV infection

HIV Testing 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

Point-of-care testing– Tests that can provide a test result in a

relatively short time so that only a single visit is required

Rapid HIV Tests Results within 20 minutes

Few steps to perform; visual readout

No special storage conditions or instrumentation needed

Detect antibodies to HIV

Tests to be used as an aid in the diagnosis of HIV infection and not for blood donor screening

4 FDA-approved tests at this time

Rapid HIV Test Approval Requirements and Standards

Performance standards and clinical trial/non-clinical requirements for rapid HIV tests: BPAC discussed/concurred on June 15, 2000

Performance– Sensitivity: 98% (lower bound of the 95%

confidence interval)– Specificity: 98% (lower bound of the 95%

confidence interval)

Performance of Rapid HIV Tests: Sensitivity*

Whole Blood Plasma Serum Oral Fluid

OraQuick 99.6% 99.7% - 99.3%

Reveal - 99.8% 99.8% -

Uni-Gold 100% 100% 100% -

Multispot - 100% 100% -

*Point estimates from clinical trial data in support of product approval

Performance of Rapid HIV Tests: Specificity*

Whole Blood Plasma Serum Oral Fluid

OraQuick 100% 99.9% - 99.8%

Reveal - 98.6% 99.1% -

Uni-Gold 99.7% 98.8% 99.8% -

Multispot - 99.9% 99.9% -

*Point estimates from clinical trial data in support of product approval

Rapid HIV Tests: Interpretation Non-reactive = Negative

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

Rapid HIV Tests are Restricted Devices 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

Approved for use only by an agent of a clinical laboratory– i.e., not for self-testing

Test subjects must receive a “Subject Information” pamphlet and pre-test counseling prior to specimen collection, and appropriate counseling when test results are provided

Rapid HIV Test Restrictions, cont.

Not approved for use to screen blood or tissue donors

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…”

Access to Rapid HIV Tests

Who is permitted to use rapid HIV tests?

Device classification– Clinical Laboratory Improvement

Amendments of 1988 (CLIA)– Classifies devices according to complexity

» High» Moderate» Waived

CLIA Waiver 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

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

CLIA Waiver Expands Access to Rapid HIV Tests

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

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

Rapid HIV Tests Waived under CLIA

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-GoldTM for use with venipuncture whole

blood (6/23/04)– Uni-GoldTM for use with fingerstick whole blood

(11/5/04)

Sales and use restrictions apply to waived rapid HIV tests

Recurring Themes for Home-Use HIV Test Kits

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

Recurring Themes for Home-Use HIV Test Kits, cont.

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

Recurring Themes for Home-Use HIV Test Kits, cont.

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

Information to be Discussed at this Meeting

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

Information to be Discussed at this Meeting, cont.

Discussion of changes in HIV testing practices and counseling recommendations– Dr. Bernard Branson, CDC

Role of quality systems for diagnostic tests– Dr. Devery Howerton, CDC

Psychological and social issues associated with HIV testing and OTC home-use tests– Dr. Joseph Inungu, Central Michigan University

Overview of the OTC review process and human factors considerations– Arleen Pinkos, FDA/CDRH/OIVD

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.

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 interpretationc. The importance of supplemental testing for

confirmation of positive results d. Management of psychological and social issuese. Availability of counselingf. Medical referral