# Presentation: 335283

## The Approval Process for Clinical Laboratory Devices

- Sousan S. Altaie, Ph.D.
- Center for Devices & Radiological Health, Division of Clinical Laboratory Devices

## CDRH Mission  Statement

- ....responsible for ensuring that medical devices are safe and effective.....
- Two pronged approach
- promote public health
- protect public health

## Background

- Federal Food, Drug, and Cosmetic Act of 1938 (The Act)
- Medical Device Amendments of May 28, 1976
- Safe Medical Devices Act of 1990
- FDA Modernization Act (FDAMA) of 1997

## Device Classification

- Class I
- devices needing the lowest level of regulation
- subject to the general controls
- requirements sufficient to assure safety and effectiveness for their intended use.

## General controls

- registration and listing
- Good Manufacturing Practices (GMPs)
- premarket notification (510(k))
- prohibition of adulterated, misbranded, or                      banned devices
- record keeping
- reporting of device failures

## Device Classification (cont’d)

- Class II
- devices subject to special controls in addition to general control requirements.

## Special controls

-   performance standards
-   postmarket surveillance
-   patient registries
-   guidelines/guidances
-   design control
-   tracking requirements

## Device Classification (cont’d)

- Class III
- devices with high risk
- have no established predicates, or
- new device raises new types of questions about safety and effectiveness.

## Pathways to Market

- IVD may be exempt
- Premarket notification - 510(k)
- Premarket approval - PMA
- “significant risk” devices require an Investigational Device Exemption - IDE
- Product development protocol - PDP
- Humanitarian device exemption - HDE
- Analyte specific reagent - ASR

## 510(k) Process

- Section 510(k) of the FD&C Act
- Demonstrates “substantially equivalent”
- same intended use
- similar technological characteristics
- does not raise new issues of safety and effectiveness
- 90-day review clock

## PMA Process

- Class III devices are subject to premarket approval requirements
- Reasonable assurance of safety and effectiveness
- 180 day review timeframe

## PMA Process (cont’d)

- The review of a PMA is a 4-step process consisting of:
- Filing review
- In-depth review
- Panel review (if necessary)
- Final Decision

## Limitations in Review

- Paper review
- Lack of performance standards
- Lack of “gold standards”
- Bias

## Major Elements of a Submission

- Intended use/indications for use
- Performance characteristics
- Labeling (package insert)

## Performance Characteristics  Non-clinical Studies

- Characterization of components
- Antigens/antibodies
- Controls/calibrators
- Cut-off determination
- Equivocal zone

## Performance Characteristics  Non-clinical Studies (cont’d)

- Accuracy
- performance of test vs. analytical standard (bias)
- Analytical sensitivity
- lowest detectable level of analyte
- Analytical specificity
- interference, cross-reactivity

## Performance Characteristics  Non-clinical Studies (cont’d)

- Specimen handling
- fresh, frozen, centrifugation, etc
- Linearity
- range where there’s direct relationship between analyte and target
- reportable range

## Performance Characteristics  Non-clinical Studies (cont’d)

- Precision-reproducibility of a test when it is run several times (CV)
- Intra-assay
- Inter-assay
- Inter-laboratory
- Lot-to-lot
- Inter-technician (POC)

## Clinical Protocol

- Objectives
- Developed in advance
- Patient recruitment procedures
- Patient / specimen  inclusion / exclusion criteria
- Sample size
- End points
- Gold standard

## Performance CharacteristicsClinical Studies

- Clinical sensitivity--the ability of the test to correctly identify the presence of disease.
- Clinical specificity--the ability of the test to correctly identify the absence of disease.

## Simple Model

- Clinical Truth
**2 outcomes**
- 	“**Diseased**”		 	       “**Non-Diseased**”
- Condition/Analyte Present	        **OR**	           Condition/Analyte Absent
- 	   Case +				 Case  –
- Clinical “Truth”** **
- “gold standard” or 100% accurate method
- clearly defined clinical criteria, signs & symptoms
- some combination

## Example

- 					  TRUTH
- 				Diseased	Non-diseased
- 				       +	     	        
-               ________________________________________________
- 	New		+	      44	        	         1
- 	Test		 	        7		     168
-               ________________________________________________
- 	total			      51		     169
**estimated sensitivity** = 44/51 or 86.3%
**estimated specificity** = 168/169 or 99.4%

## Same Example

- 			                     Imperfect Standard
- 				       +	     	        
-               __________________________________________
- 	New		+	      40	        	         5
- 	Test		 	        4		     171
-               __________________________________________
- 	total			      44		     176
*Can’t get sensitivity and specificity (no truth)*
**overall agreement** = (40+171)/220 = 211/220 or 95.9%

## Problem with Agreement

- AGREEMENT  CORRECT

## Concrete Example

- Cystatin C
- compared to creatinine as a predicate for “substantial equivalence”
- BUT
- had to compare to iothalamate clearance /GFR (clinical truth) to compute sensitivity and specificity

## Statistical Comparison of Cystatin C and Creatinine

## Another Example

|  | New PSA test |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|     Established  PSA test | ≥ 4 | <4 | Total |  |  |
| ≥ 4 | 349 | 22 | 371 |  | 70.4% ± 1.99% |
| <4 | 8 | 148 | 156 |  |  |
| Total | 357 | 170 | 527 |  |  |
|  | 67.7% ± 2.0% |  |  |  |  |
| Observed Agreement | 94.3% | Chance agreement  | 57.2% |  |  |
| Difference in test positivity |  | -2.7% | ± 1.0% |  |  |

- Agreement of PSA results at a cutoff of 4 ng/ml

**Notes:**
From data maintained on file (JPR)

## Statistical Comparison of a New and Established PSA test

- Agreement when clinical status is known: Cancer Subjects

|  | New PSA test |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|     Established PSA test | ≥ 4 | <4 | Total |  |  |  |
| ≥ 4 | 208 | 11 | 219 |  |  | 94.8% ± 1.46% |
| <4 | 2 | 10 | 12 |  |  |  |
| Total | 210 | 21 | 231 |  |  |  |
|  | 90.9% ± 1.9% |  |  |  |  |  |
| Observed Agreement  | 94.4% | Chance agreement |  |  | 86.7% |  |
| Difference in Sensitivity | -3.9% | ± 1.5% |  |  |  | p = 0.011 of Equal Se |

- Difference in Specificity 	-3.5% ± 2.3%	p > 0.05 of Equal Sp

## Another Example

- Cyclosporine Assays
- - due to variability of immunoassays, discourage comparison to each other
- - encourage comparison to HPLC or tandem mass spectroscopy
- 		i.e., clinical truth is parent compound

## Another Example

- Monitoring overall immune status
- - currently no single test for adequate comparison, therefore:
- 		- need to compare to patients clinical state: rejecting (undersuppressed), infected (overly suppressed), good allograft function
- 		- would values change quickly enough to be useful for clinical monitoring

## Some Key Statistical Points

- You can compute estimated sensitivity and specificity of the new test only if you know _truth_ and the new test results for _all_ patients.
- Don’t use the terms sensitivity and specificity to describe the comparison of a new test to an imperfect standard.  Instead, report the agreement between the two methods.

## Key Statistical Points (cont’d)

- Don’t revise results based on discrepant resolution alone  - misleading and biased
- There are valid statistical alternatives to discrepant resolution for estimating sensitivity and specificity when a perfect standard exists (FDA guidance document pending).
- There are no simple statistical solutions for obtaining unbiased sensitivity and specificity estimates when no perfect standard exists - more research is needed.

## Safety & Efficacy

- Risk : Benefit
- impact of an erroneous result?
- false positive
- false negative
- screening vs. diagnosis
- stand alone vs. adjunct

## Labeling of IVDs (21 CFR 809.10(b))

- Proprietary and established names
- Intended Use(s)
- Summary and explanation of test
- Principle of procedures
- Information on reagents
- Information  on instruments
- Specimen collection and preparation
- Warnings and limitations

## Partnerships

- Encourage partnerships with CDC, NIH, WHO etc. and sponsors
- Need for a panel of well-characterized specimens
- Encourage early collaboration
- Evaluate protocols
- Develop guidance and standards documents

## Impact on Patient Care

- Ensure device performance meets a minimum threshold
- ensure truth in labeling
- ensure accountability for consistent manufacturing in conformance with labeling claims
- ensure adverse events are reported, tracked and corrective action taken

## Acknowledgements

- Steven Gutman, M.D., M.B.A.
- Kristen Meier, Ph.D.
- Marva Moxey-Mims, MD
- James P. Reeves, Ph.D.

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