# Presentation: 761537

## CBER's policies on assay regulation: Definitions of assay performance characteristics

- Andrew I. Dayton, M.D., Ph.D.
- CBER

## Regulation of In-Vitro Diagnostics (IVD)

- Center for Devices and Radiological Health (CDRH)
- Center for Biologics Evaluation and Research

## IVDs in CBER

- Blood borne pathogen tests
- Hepatitis B
- HIV
- Hepatitis C
- Syphilis

## Statutes for IVD Regulation 

- Public Health Service Act: Biologics Regulation 21 CFR 600-699
- Food, Drug and Cosmetic Act
- Medical Device Amendments of 1976
- Inter-center agreements

## Regulatory Jurisdiction

- Inter-Center Agreement: 1991
- 	-	CBER:
- 	For all blood donation and all HIV diagnostic applications
- 	-	CDRH:
- 	IVDs for all other applications

## CBER/FDA licensed/approved HIV tests 

- HIV antibodies by EIA/IFA for screening/diagnosis
- HIV antibodies by Western blot or IFA for confirmation of screening results
- HIV p24 antigen for screening/prognosis
- HIV-1 RNA for prognosis, management

## General Regulatory Requirements for HIV Tests 

- Manufacturing consistency
- Sensitivity
- Specificity
- Reproducibility
- Clinical utility

## Manufacturing consistency means:

- Full description of the manufacturing process
- Demonstration that the manufacturing process is adequately controlled.
- QC tests & specifications with supporting data
- Data on consistency over time
- Assurance of long term availability

## Sensitivity (general)

- Show the assay measures the analyte
- Range of measurable analyte
- Interfering substances/conditions

## Specificity (general)

- False positives
- Under ideal circumstances
- Interfering substances/conditions

## Reproducibility

- Run-run
- Site-site
- Operator-operator
- Day-day

## Specific concerns for regulation of HIV drug resistance genotype tests

- Sensitivity
- Viral burden & Mutant proportion
- Reproducibility
- Particularly under challenging conditions.
- Clinical Utility
- Predicate device
- Reference to “special controls.”

## Special Controls for HIV Drug Resistance Genotype Tests

- For class II devices special controls can obviate the need for a predicate device if the knowledge of the field is such that adherence to the special controls can adequately ensure that a device is safe and effective.

## Special Controls for HIV Drug Resistance Genotype Tests

- One type of special control can be a guidance document.
- The BPAC has recommended that HIV Drug Resistance Genotype Assays be regulated as Class II medical devices.
- In this case, the special control would be a guidance document currently under development.

## Concepts being Entertained for the Guidance Document for Resistance Tests

- May list several well documented loci with the expectation that the intended use will be limited to the listed mutations. Extension to other mutations may require additional data (cited literature ? new studies ?) and may be handled at a later time by amendments.
- e.g. AZT(215,41); 3TC(184); Sustiva & NNRTIs(103); Nevirapine (181)

## Concepts being Entertained for the Guidance Document for Resistance Tests

- Clinical Utility can be demonstrated (pre-market) by correlating virus responses to assay predictions during trials. (Sufficient but not necessary?)
- Clinical Utility may be established by certain *in vitro* studies. (E.g. a mutation that confers >8-fold increase in IC50/IC90.)

## Public Contributions to the Guidance Document

- A draft guidance document on HIV Drug Resistance Genotype Assays, currently under development, will be released for public comment. At that time, we expect significant input from the scientific community. We encourage a vigorous debate and we will incorporate the results of the debate into the document.

## Summary

**FDA’s CBER regulates all HIV tests**
**HIV Drug Resistance assays pose unique interpretations of some regulatory criteria, but these interpretations are not counterintuitive.**
**Absent a predicate device, HIV drug resistance tests may possibly be allowed to go to market with identifiable special controls instead of extensive Class III (PMA) level clinical trials.**