1. Hemoglobin Device Regulation Josephine Bautista, M.S., MT (ASCP) Senior Advisor for IVD Regulation DRB/DBA/OBRR/CBER Workshop: Hemoglobin standards and maintaining adequate iron stores in blood donors Bethesda, Maryland November 8, 2011

2. 2 Overview The regulatory clearance process The regulatory clearance process ♦ Regulatory submission ♦ Regulatory route ♦ Statistical analysis Cleared CBER devices Cleared CBER devices Future device submissions Future device submissions

3. 3 Regulatory Process Regulatory submission Intended Use Statement Describes how the device is to be used. Describes how the device is to be used. ♦ Analyte to be measured. ♦ Whether the test is quantitative, semi-quantitative, and/or qualitative; ♦ Specimen type(s) or matrix(-ces), e.g. blood (include collection method) ♦ Conditions for use.

4. 4 Regulatory Process cont’d The Indications for use describes for what or for whom the device is to be used (e.g., disease, condition, or population). The Indications for use describes for what or for whom the device is to be used (e.g., disease, condition, or population). The following are some examples of information included in the indications for use: The following are some examples of information included in the indications for use: ♦ The condition(s) or disease(s) to be screened, monitored, treated or diagnosed (e.g. diabetes, hepatitis) ♦ Target population (e.g. blood donor) ♦ Frequency of use (e.g. prior to blood donation); ♦ Physiological purpose (e.g. determine hemoglobin level).

5. 5 Regulatory Process cont’d 510 (k) 510 (k) Under section 510(k) of the Federal Food, Drug, and Cosmetic Act, a person who intends to introduce a device into commercial distribution is required to submit a premarket notification, or 510(k), to FDA at least 90 days before commercial distribution is to begin. Section 513(i) of the Act states that FDA may issue an order of substantial equivalence to the predicate device.

6. 6 Statistical Analysis Under 21 CFR 807.87 and 21 CFR 809.10, FDA established the content requirements for premarket notifications to be submitted by device manufacturers in support of the substantial equivalence decision. Under 21 CFR 807.87 and 21 CFR 809.10, FDA established the content requirements for premarket notifications to be submitted by device manufacturers in support of the substantial equivalence decision. Analytical studies Precision studies: 1. Precision studies is conducted with specimens at the cutoff (e.g., control(s) diluted to extinction). 2. Reproducibility is calculated similarly to precision above, using test results assayed between users/sites, and over time (e.g., day to day) where those variables have the potential to contribute significantly to total error in the system. 3.Normal Range/Cut-off The normal range or cut-off value is usually determined in both a healthy, asymptomatic population and/or in a population with similar signs or symptoms as the target population for the device.

7. 7 Statistical Analysis cont’d 4.Analytical Specificity Assessing specificity includes a determination of any potentially cross-reacting or interfering substances that may be encountered in specific specimen types or under specific assay conditions. 5.Matrix studies Used to verify relevant performance characteristics (e.g., correlation, precision) for each matrix claimed in the intended use. The comparison is usually performed using samples with both high and low values of the analyte being measured, and/or within the dynamic range of the assay. 6. Linearity studies To determine if the assay is linear over the reportable range.

8. 8 Statistical Analysis cont’d Clinical studies Correlation studies 1. Comparison to a predicate device The device is compared to the performance of the predicate device. 2.Comparison to a reference method. The difference between a method comparison to a predicate device and comparison to a reference method is that the reference method is recognized by the general laboratory, the medical community, or as a gold standard.

9. 9 Statistical Analysis cont’d Demographic characteristics of the study population Describe the clinical status (diagnosis, stage of illness, signs/symptoms), sex, ethnic origin, and the prevalence of disease, condition, signs/symptoms.

10. 10 Devices Cleared by CBER HemoCue Devices: HemoCue Devices: HemoCue Hb 301 System Donor Hemoglobin Checker System Separation Technology: Separation Technology: UltraCrit TM Hematocrit Measurement Device

11. 11 Future Devices CBER continues to receive device submissions for hemoglobin measurement. CBER continues to receive device submissions for hemoglobin measurement. ♦ Current technologies ♦ Newer technologies e.g. non-invasive