# Presentation: 491005

## 510(k) Review Examples

**Avis Danishefsky, Ph.D.**
**Scientific  Reviewer**
**Division of Chemistry and Toxicology     Devices**
**Office of  In Vitro Diagnostics****	****	**
**CDRH**

## 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATIONDECISION SUMMARY/ASSAY-ONLY TEMPLATE

**A.****	****510(k) Number:**
**B.****	****Purpose for Submission:**
**C.****	****Measurand:**
**D.****	****Type of Test:**
**E.****	****Applicant:**
**F.****	****Proprietary and Established Names:**
**G.****	****Regulatory Information:**
- 1.	_Regulation section:_
- 2.	_Classification:_
- 3.	_Product code:_
- 4.	_Panel:_
**H.****	****Intended Use:**
- 1.	_Intended use(s), 2.Indications for use:_
- 3.	_Special conditions for use statement(s):_
- 4.	_Special instrument requirements:_
**I.****	****Device Description:**
**J.****	****Substantial Equivalence Information:**
- 1.	_Predicate device name(s):_
- 2.	_Predicate 510(k) number(s):_
- 3.	_Comparison with predicate:_

**K.****	****Standard/Guidance Document ****	****Referenced (if applicable):**
**L.****	****Test Principle:**
**M.****	****Performance Characteristics:**
- 1.	_Analytical performance:_
*a.**	**Precision/Reproducibility:*
*b.**	**Linearity/assay reportable range:*
*c.**	**Traceability, Stability,(controls, **	**calibrators,  methods):*
*d.**	**Detection limit:*
*e.**	**Analytical specificity:*
*f.**	**Assay cut-off:*
- 2.	_Comparison studies:_
*a.**	**Method comparison with **	**predicate device:*
*b.**	**Matrix comparison:*
- 3.	_Clinical studies_:
*a.**	**Clinical Sensitivity:*
*b.**	**Clinical specificity****:***
- c.	Other clinical supportive data
- 4.	_Clinical cut-off__**:**_
- 5.	_Expected values/Reference range:_

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## SE Decision Summary Template: Analytical Performance Characteristics

**1**.**	**_Analytical performance:_
*a.**	****Precision/Reproducibility***
*b.****	******Linearity and assay reportable range***
*c.**	**Traceability, Stability *
*d.**	**Detection limit*
*e.**	**Analytical specificity*
*f.**	**Assay cut-off*
**2**.	_Comparison studies:_
*a.**	****Method comparison with predicate device***
*b.**	**Matrix Comparison*

## Precision  SE Decision Summary Example 1- “Ace Diagnostics”:

- 	Within-run and within-laboratory precision were determined at the manufacturer’s site, using the system’s serum-based QC materials.  The evaluation followed NCCLS EP-5A, with 2 replicates per run, two runs per day for 22 days, n=88 observations.  Within-day runs were separated by at least 2 hours.  Sample order was randomized. Calibration was performed once each week.  Results are shown below. Testing of multiple lots and instruments yielded similar results.

| sample | Mean
(g/ml) | Total N | Within-run SD (g/ml) | Within-lab SD (g/ml) |
| --- | --- | --- | --- | --- |
| Control 1 | 4.0 | 88 | 0.35 | 0.39 |
| Control 2 | 25.5 | 88 | 0.52 | 0.63 |
| Control 3 | 56.3 | 88 | 1.2 | 2.3 |

## Precision  SE Decision Summary Example 1- cont’d:

- Precision was also estimated using multiple patient serum pools across the range of approximately 3-5 g/mL.
- Standard deviations were calculated based on 8 replicates, for each of 3 reagent lots, i.e. total of 24 observations at each concentration.  (One run per lot.)
- Results: across the concentration range tested, SD’s calculated for each lot and over all lots were < 0.4 g/mL.

## Precision510(k) Example 2 -“Rival Diagnostics”  

- Between-run precision studies were done on serum-based material at 3 levels using the ***S****uper****F****ast* Instrument System.  Results are summarized below.

|  | Sample 1 | Sample 2 | Sample 3 |
| --- | --- | --- | --- |
| N | 25 | 25 | 25 |
| Mean (ug/ml) | 0.3 | 0.8 | 1.4 |
| SD | 0.03 | 0.05 | 0.05 |
| %CV | 9.8 | 4.5 | 2.7 |

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## Slide 8

## Precision 510(k) Example - 3 

**Intended use: The *****User Friendly******® Point of Care System***** is intended to quantitatively measure YF analyte in serum, plasma or whole blood samples over the range of 0.5-10.0 mg/dL.  **
**	****The clinical cutoff is 0.7mg/dL.**
-  * *

- Two samples of serum controls (low and high) containing approximately 2.0 and 8.0 mg/dL YF analyte were each assayed in 3 runs over 15 days (n=45 per level).
- The percents CV were 15.2% for the low samples and 5.3% for the high sample.

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## Precision (examples of FDA review questions)

- Outline the study design. Describe
- 		- sample origin/preparation,
- 		- number of days, runs per day, sites
- 		- types of statistical calculations.
- Specify those parameters varied and those held constant in the evaluation.
- Include samples with concentrations near medical decision points.
- Evaluate all matrices included in your intended use.
- Include pre-analytical steps in the precision evaluation.

## Linearity  SE Decision Summary Example 4- “Ace Diagnostics”

- A negative serum pool was spiked with a stock solution, to a concentration of 60 g/ml analyte (“high pool”). The stock solution was gravimetrically prepared from material traceable to USP standard.  The “high pool” was serially diluted with a negative serum pool to prepare 10 samples with concentrations evenly distributed across the assay range.
- All samples were analyzed by the *Ace Diagnostics assay* in replicates (n=5) and average values were determined.
- Expected concentrations were based on the independently quantified stock solution times dilution factors.
- For samples in the range of 2-60 g/ml, observed/expected values were within the acceptance limits of +/-15%.

## Reportable Range  SE Decision Summary Example 5 -“Ace Diagnostics” 

- The assay reportable range is 4-60g/mL.
-  Acceptance criteria for this range:
- Bias does not exceed 15%  (linearity/recovery evaluation, above).
- Within-lab CV is ≤ 20% (precision evaluation, above).

## Linearity510(k) Example 6

-      Serial dilutions of a suitable control were tested and the observed value compared to known expected or calculated expected result.  Percent deviations were calculated.  Linearity claim is based on percent deviations of  < 5% at the 2 highest analyte concentrations.
**______**   fit points 1-3
**.........****.**.  fit points 2-4

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## Slide 14

## Linearity (examples of FDA review questions)

- Describe study design: sample types/preparation; “expected” or target  concentrations and methods used to determine them; statistical approaches.
- Evaluate multiple samples distributed across the entire range of the assay.
- Describe observed biases, deviations; Use clearly labeled graphs, tables.

## Method Comparison: Study Design SE Decision Summary, Example 7

***Sites:*** Comparison studies were performed at 2 sites; a neonatal intensive care unit, and a newborn nursery.  Nurses at each site performed the measurements.
***Selection Criteria/Demographics:  ***Infants < 30 days old, and greater than 1000 g, determined by their physicians to need serum bilirubin testing, were included. The study included Caucasian and  African American infants.  Infants treated by phototherapy or exchange transfusions were excluded.
***Measurements:  ***For each of 613 patients, at 2 clinical sites, one measurement was taken at sternum and one at forehead.
***Analyses and Results:  ***Linear regression analyses, comparing to the predicate device, were performed separately for each clinical site, body site and demographic group.

## Method Comparison: Stratification, Example 7 cont’d

_**Study Site/patient population         Slope  intercept   RMSE     (r) **_
**Clinical Site A**
- Forehead, African American (n=65)    1.15      -0.5          1.59     0.91
- Sternum, African American (n=65)      1.11      -0.4          1.55     0.91
- Forehead, Caucasian  (n=399)	         1.01      -0.1          1.20     0.92
- Sternum, Caucasian (n=399)	         1.04      -0.6          0.88     0.96
**Clinical Site B**
- Forehead African American (n=48)      1.42       0.5          2.27     0.84
- Sternum African American (n=48)        1.21      -0.2         1.90     0.89
- Forehead, Caucasian  (n=35)	          1.10     -1.0          1.72     0.87
- Sternum, Caucasian (n=35)	          1.22     -1.7          1.81     0.88

## Method Comparison: Stratification510(k) Example 8

| site | n | slope (95% confidence intervals) | intercept (95% confidence intervals) | r |
| --- | --- | --- | --- | --- |
| combined | 59 | 1.02 (0.92-1.10) | -0.03 (-0.09 to 0.10) | 0.93 |

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## Method Comparison: Stratification510(k) Example 8

| site | n | Slope (95% confidence intervals) | Intercept (95% confidence intervals) | r |
| --- | --- | --- | --- | --- |
| 1 | 38 | 0.83 (0.72-0.94) | 0.02 (-0.05 to 0.09) | 0.92 |
| 2 | 21 | 1.23 (1.19-1.30) | 0.0 (-0.10 to 0.11) | 0.99 |
| both | 59 | 1.02 (0.92-1.10) | -0.03 (-0.09 to 0.10) | 0.93 |

## Common review issues

- Clear study descriptions.
- Evaluations of all matrices for which the test is intended.
- Attention to entire assay range, especially medical decision points.
- Use of intended use samples and test conditions.
- Study-appropriate statistical analyses.
- Clear presentation of results.
- Performance issues.

## Related guidelines

- Evaluation of Precision Performance of Quantitative Measurement Methods (2004), NCCLS/CLSI EP5-A2.
- Evaluation of the Linearity of Quantitative Measurement Procedures; A Statistical Approach(2003), NCCLS/CLSI EP6-A.
- User Protocol for Evaluation of Qualitative Test Performance (2002), NCCLS/CLSI EP12-A.
- Method Comparison and Bias Estimation Using Patient Samples;(2002), NCCLS/CLSI EP9-A2.
- Protocols for Determination of Limits of Detection and Limits of Quantitation (2004), NCCLS/CLSI EP17-A
- ISO 17511  In vitro Diagnostic Medical Devices – Measurement of Quantities in Biological Samples – Metrological traceability of values assigned to Calibrators and Control Material (2003), ISO 17511.