Recommendations for Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices: Guidance for Industry and Food and Drug Administration Staff

Description

The Secretary of Health and Human Services has delegated to FDA the authority to determine whether particular tests are "simple" and have "an insignificant risk of an erroneous result" under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and are thus eligible for waiver categorization (69 FR 22849, April 29, 2004). The Centers for Medicare & Medicaid Services (CMS) is responsible for oversight of clinical laboratories, which includes issuing waiver certificates. CLIA requires that clinical laboratories obtain a certificate before testing materials derived from the human body. (42 U.S.C. § 263a(b)) Laboratories that perform only tests that are "simple" and that have an "insignificant risk of an erroneous result" may obtain a Certificate of Waiver. (42 U.S.C. § 263a(d)(2).)

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

1

In Vitro Diagnostic Devices

Validation of certain in vitro diagnostic devices (IVDs) for emerging pathogens; Validation of certain IVD devices for emerging pathogens

Stakeholders

7

Manufacturer

Entity responsible for submitting NDINs

trained operators

results of the candidate test in the hands of trained operators

untrained operators

Test operators in waived settings with limited or no training; Intended users in CLIA-waived settings; candidate test in the hands of untrained operators

Moderately complex laboratory user

Used as a comparator to demonstrate accuracy for waived users.

Operator

Person whose actions may cause a product to be deemed adulterated

Untrained Operator

Test operator in waived settings with limited experience; The target user for waived tests who must be able to perform the test accurately.; A test operator in waived settings with limited or no training.

Moderate Complexity Laboratory User

Trained operator meeting specific qualifications

Regulatory Context

Regulatory Activities

8

De Novo

De Novo requests for classification; Classification request pathway; De Novo classification request

Pre-Submission

Process to obtain FDA feedback on Documentation Level

CLIA Waiver Application

Manufacturers submit this to FDA to support a determination for waiver categorization.; Manufacturers of In Vitro Diagnostic Devices submitting for waiver; demonstrate that a candidate test meets the CLIA statutory criteria; Manufacturers must submit this application to request a waiver for in vitro diagnostic devices.; Recommendations for CLIA Waiver Applications for Manufacturers.

510(k)

Premarket notification submission type

Dual 510(k) and CLIA Waiver application

A concurrent submission process established under MDUFA III.

Q-Submission Program

mechanism to seek input from the Agency

CLIA Waiver Applications

Recommendations for manufacturers of IVD devices

PMA

Premarket Approval Application

Document Types

3

Quick Reference Guide

Labeling component for waived devices.; Instructions written at no higher than a 7th grade reading level; Labeling that integrates instructions for external control testing; modification of a previously waived test system where the Quick Reference Guide was not modified; Laminated instructions for accurately running the test, written at a 7th grade level.; A short version of the test instructions, preferably laminated.

Operator's Instrument Manual

instructions and training materials provided with the test kit

Package Insert

Labeling information including dosage, administration, and safety sections

Attributes

6

Insignificant risk of an erroneous result

A statutory criterion for a test to be eligible for a CLIA waiver.

Color blindness

A warning addressing color blindness when tests use color-coded reagents.

7th grade reading level

The required complexity level for labeling intended for untrained operators.

Moderate Complexity Testing

Trained operators should meet the qualifications to perform moderate complexity testing

Shelf-life stability

Unopened control material stability

Simple

A statutory criterion for laboratory examinations eligible for waiver.; Statutory requirement for CLIA waived tests

Technical Details

Substances

3

Capillary blood

Direct unprocessed specimen used in simple tests

Reagent

Component of an assay

External control material

Materials used to verify test system performance

Testing Methods

3

Flex Studies

Testing including test strip stability and system operating conditions.

External control testing

Used to ensure operator competency and reagent integrity.

Flex Study

flex study designs described in section IV

Processes

3

Flex Studies

Studies that stress operational boundaries to validate the insensitivity of the test system to variation.

Decontamination

Basic specimen manipulation step

Validation and verification studies

Studies to evaluate sensitivity of internal control reagents

Identified Hazards

Hazards

6

Erroneous result

Risk that must be insignificant for waived tests

Incorrect patient results

Hazards for patients generally involve incorrect results.

Biological Hazards

Known or reasonably foreseeable hazards requiring preventive control; Types of hazards analyzed in the food safety plan.; Pathogens or biological agents that can cause illness; Pathogens and microbial forms in animal food

Specimen integrity and handling error

Potential source of error including clotted specimens or inappropriate anticoagulants

Reagent integrity failure

Use of improperly stored, outdated, or contaminated reagents

Hardware failure

Integrity issues including power failure or physical trauma

Standards & References

External Standards

7

CLSI Harmonized Terminology Database

Reference for further details on terms.

CLSI EP17

Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures

CLSI EP05

Evaluation of Precision of Quantitative Measurement Procedures

CLSI EP12

User Protocol for Evaluation of Qualitative Test Performance; See CLSI EP12 for additional details

CLSI EP27

How to Construct and Interpret an Error Grid for Quantitative Diagnostic Assays

CLSI EP21

Evaluation of Total Analytical Error for Quantitative Medical Laboratory Measurement Procedures; as described in CLSI EP21

CLSI EP18

Risk Management Techniques to Identify and Control Laboratory Error Sources

Specifications

4

QC limits

Established limits to provide adequate assessment of test performance

Medical Decision Levels

Quantitative samples in studies should include values around these levels.

Limit of Quantitation

LOQ for nitrosamine detection

Limit of Detection

Define and document a minimum set of metrics (e.g., limit of detection (LoD))

Related CFR Sections (4)

21CFR803.10§ 803.10 Generally, what are the reporting requirements that apply to me?
(a) If you are a device user facility, you must submit reports (described in subpart C of this part ), as follows:Read full regulation →
21CFR803.18§ 803.18 What are the requirements for establishing and maintaining MDR files or records that apply to me?
(a) If you are a user facility, importer, or manufacturer, you must establish and maintain MDR event files. You must clearly identify all MDR event files and maintain them to facilitate timely access.Read full regulation →
21CFR803.17§ 803.17 What are the requirements for developing, maintaining, and implementing written MDR procedures that apply to me?
If you are a user facility, importer, or manufacturer, you must develop, maintain, and implement written MDR procedures for the following:Read full regulation →
21CFR809.10§ 809.10 Labeling for in vitro diagnostic products.
(a) The label for an in vitro diagnostic product shall state the following information, except where such information is not applicable, or as otherwise specified in a standard for a particular product class or as provided in paragraph (e) of this section. Section 201(k) of the act provides that “a Read full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to develop, maintain, and implement written Medical Device Reporting (MDR) procedures

6

Failure to obtain informed consent

5

Failure to adequately develop, maintain, and implement written MDR procedures

5

Failure to ensure that the investigation was conducted according to the investigational plan

4

Failure to establish and maintain procedures to control the design of the device

3

Adulterated under section 501(f)(1)(B)

2

Misbranded under section 502(o)

2

Unapproved Device Violation

2

Failure to adequately establish procedures for corrective and preventive action

2

Failure to identify by suitable means the acceptance status of product

2