1. Tests for Recent Infection and CDC’s Plans for the Detuned IND Bernard M. Branson, M.D. Centers for Disease Control and Prevention

2. Less Sensitive EIA Strategy Principle:  As seroconversion progresses –Antibody titers increase –Antibody “affinity” increases

3. Window Period and STARHS HIV Antibody Infection Time 1 Sensitive EIA Time 2 Less Sensitive EIA Window Period Vironostika: Mean 170 days (95% CI=162, 183)

4. Window Period Estimates: Incidence Days SOD Mean Mis- classified Long- standing Misclassified recent 170 days (95% CI=162, 183) Cutoff

5. STARHS for Individual Results Two factors:  Variability in different seroconverters  Variability in the less-sensitive assay itself

6. Distribution of Individual Window Periods

7. Proportion of persons with time from seroconversion to test longer than mean window period days since seroconversion 200400600800 0. 5 2. 0 Each line is someone’s optical density curve. The windows with SOD cut off 1.0 end at the horizontal line. The red curve is the probability density of the windows. The vertical line is at the mean window period. 183 S O D 1. 0 1. 5

8. Proportion of individuals with time from seroconversion to test greater than 1 year Each line is someone’s optical density curve. The windows with SOD cut off 1.0 end at the horizontal line. The red curve is the probability density of the windows. The vertical line is at one year from seroconversion. days since seroconversion S O D 200400600800 0. 5 1. 0 1. 5 2. 0 365

9. 0 100 200 300 400 500 600 1234567891011121314151617181920 SOD D a y s Upper95%CIMeanLower95%CI 183 Simulated 95% Confidence Interval for the window period (in days) of one person selected from a population, by standardized optical density (SOD) 0.10.20.30.40.50.60.70.80.91.01.11.21.31.41.51.61.71.81.92.0

10. Interpretation of Results 170-day window period is used in formulas to calculate incidence from aggregate data For individuals:  SOD < 1.0: probably seroconverted within 1 year  SOD 1.0 or greater: may or may not have seroconverted > 1 year ago.

11. Incidence Assays on the Horizon HIV-1 Plus O, successor to Vironostika BED antibody capture assay Avidity index IgG subclass assay

12. IgG Capture BED Assay Uses synthetic peptide that represents multiple subtypes (B, E, and D) Captures both HIV antibody and IgG antibodies Measures increase in proportion of HIV-IgG as infection progresses Avoids problem of very large dilution step

13. BED: Changes in OD-n after seroconversion Cutoff 1.0/window 160 days

14. BED Label Indication “For surveillance use only. Not for in vitro diagnostic use.” For CDC’s National Incidence Surveillance:  No IDE required  No informed consent required  No IRB review required

15. CDC’s IND for the “Detuned Assay” Began with Abbott 3A11; amended to use Vironostika BED has utility for both B and non-B subtypes CDC does not plan to continue or amend the IND because the BED accomplishes CDC’s objective of HIV incidence surveillance.

16. FDA: General Principles 1. If research (with intention to produce generalizable knowledge) is done with either an unapproved product or off-label use of an approved product, and it involves clinical management in any way (including diagnosis, prognosis, treatment decisions, eligibility for clinical trials, counseling, notification of partners, etc.) then an IND or IDE is required.

17. FDA: General Principles 2. For clinical lab testing, if done under CLIA as a laboratory practice (subject to CLIA-required validation) and does not violate FDA’s analyte-specific labeling, or as part of the practice of medicine for the management of individual patients, off-label use does not require an IND or IDE. The regulations do not allow this to be a subterfuge for a study; if the purpose is an organized effort to produce generalizable information, users cannot pretend it is clinical use.

18. FDA: General Principles 3. Accountability. The law prohibits distribution of medical products that are unapproved or used off-label for the purposes of an investigation. The sponsor that provides the material is accountable to ensure that is not misused. If a product is used in a study in a way that is not consistent with its label indication, either the distributor or end-user must apply for an IND/IDE. Proper protocols are required, and FDA has enforcement authority within the U.S. The laws mostly regulate the product, and enforcement falls upon the distributor.

19. FDA: General Principles 4. An IND is required for biologics (in the case of HIV tests, those approved for screening blood products; an IDE is required for other in vitro diagnostics. (This would apply to either the Vironostika Plus O or the BED.)

20. Q and A Is off-label use of the Vironostika Plus O (with the LS procedure), under IRB protocol with informed consent possible without IND?  An IDE is required because this use is part of an investigation.

21. Q and A How should CDC manage requests for "Surveillance Use" of the BED in surveillance activities other than CDC's national incidence surveillance; e.g., might off-label use of Vironostika offer an alternative for this in unlinked surveys with subtype-B specimens?  As long as the use is non-clinical, no IDE is required. There can be linkages between the assay results and identifiers, but only in such a way that it is not possible for the information to get to individuals or practitioners.

22. Q and A Want about use of the BED assay outside the U.S.?  If the product is used for clinical purposes outside the U.S., the manufacturer needs to apply to FDA for approval for export. The assay can be used (and distributed outside the U.S.) without export approval if used under the exemption (i.e., non- clinical use such as surveillance.)