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U.S. Department of Health and Human Services

Recognized Consensus Standards: Medical Devices

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Part B: Supplementary Information Sheet (SIS)
FR Recognition List Number 061 Date of Entry 12/18/2023 
FR Recognition Number 7-320
CLSI  H62 1st Edition
Validation of Assays Performed by Flow Cytometry
This guideline focuses on the unique requirements for the analytical validation of cell-based assays performed by flow cytometry, which are not covered in other CLSI documents. Although flow cytometry can be used for a wide variety of applications other than cellular analysis, this guideline focuses on cellular analysis; however, the general principles are also applicable to noncellular particles. Recommendations and practical instructions are provided for preexamination phase activities such as sample requirements, reagent optimization evaluation, instrument qualification and standardization, and assay optimization and validation. Guidance for examination phase activities such as instrument monitoring and QC are described, as are recommended practices for postexamination activities, including data review, reporting, storage, and retention. This guideline is intended for use in a flow cytometry environment in which preclinical (or nonclinical) and clinical assessments are conducted, including but not limited to:
- Research laboratories (academic and nonacademic)
- Medical laboratories
- Drug discovery, development, and manufacturing companies
- Reagent, assay, and instrument manufacturers
- Regulatory agencies

Extent of Recognition
Partial recognition. The following part(s) of the standard is (are) not recognized:
Chapter 1: Subchapter 1.3.1 Definitions
Chapter 3: Subchapter 3.1.1 Bioanalytical Data Categories
Chapter 3: Subchapter 3.2 Application of Standard Validation Parameters for Flow Cytometric Methods
Chapter 3: Subchapter 3.2.2 Linearity
Chapter 3: Subchapter 3.3 Validation: Definition of Risk
Chapter 4: Subchapter 4.2.5 Carryover
Chapter 5: Subchapter 5.3.2 Assay Sensitivity including Table 13
Chapter 6: Subchapter Acceptance Criteria
Chapter 6: Subchapter Accuracy
Chapter 6: Subchapter Detection Capability
Chapter 6: Subchapters Specimen Stability
Chapter 6: Subchapter Assay Carryover
Chapter 6: Subchapter Accuracy/Diagnostic Concordance
Chapter 6: Subchapter Assay Carryover (Instrument)
Appendix A: Tables A1 - A8
Appendix G
Rationale for Recognition
This standard is relevant to medical devices and is recognized on its scientific and technical merit and/or because it supports existing regulatory policies.

This standard is recognized in part because:

Chapter 1 Subchapter 1.3.1 and Chapter 3 Subchapter 3.1.1: The definition of the term "quasiquantitative" is in conflict with existing terms such as "quantitative", "semi-quantitative", and "qualitative", which are ubiquitous in 21 CFR 864 and many FDA-recognized standards, including CLSI EP06 2nd Edition (Ref#3) and CLSI EP17-A2 (Ref#6) listed below.

Chapter 3 Subchapter 3.2, Chapter 5 Subchapter 5.3.2, and Chapter 6 Subchapters,,, and do not specify analytical study requirements for assay developers and therefore do not satisfy the requirement for analytical performance characteristics under 21 CFR 809.10(b)(12) (Ref#1) listed below for submitters of premarket submissions.

Chapter 3 Subchapter 3.2.2 is in conflict with FDA recognized standard CLSI EP06 2nd Edition (Ref#3) Section 1.4.2. Section 2.4, and Chapter 3 listed below.

Chapter 3 Subchapter 3.3's approach used to evaluate risk assessment is not consistent with Section IV of FDA guidance (Ref#2) listed below.

Chapter 4 Subchapter 4.2.5 and Chapter 6 Subchapters and Formula (7) on Page 48 may underestimate the expected carryover. The described approach to carryover may also cause reporting of an incorrect result to a patient.

Chapter 5 Subchapters 5.3 and 5.4.1 are in conflict with the recommendations in FDA recognized standards CLSI EP17-A2 Chapters 4.5, 5, and 6 (Ref#6), and CLSI EP25-A Chapters 4, 5, and 6 (Ref#7) listed below.

Chapter 6 Subchapter does not describe the requirement for submitters of premarket submissions to establish acceptance criteria in conflict with 21 CFR 820.30 (Ref#4) listed below.

Chapter 6 Subchapter is in conflict with FDA recognized standard CLSI Guideline EP39 1st Edition Chapters 3 and 4 (Ref#8) listed below.

Chapter 6 Subchapters and are in conflict with FDA recognized standard CLSI EP25-A (Ref#7) listed below.

Chapter 6 Subchapter is in conflict with FDA recognized standard CLSI EP17-A2 Chapter 5 (Ref#6) listed below.

Chapter 6 Subchapter is in conflict with FDA recognized standards CLSI EP12-A2 (Ref#4) and CLSI EP12 3rd Edition (Ref#5) listed below.

Appendix A Tables A1-A8: Tables A1 through A6 state they are not for regulatory validation purposes. Tables A7 and A8 contain study outlines that may not support a premarket submission and/or are in conflict with FDA recognized standards, regulations, and FDA guidances listed below.

Appendix G is in conflict with FDA guidance (Ref#9) and FDA recognized standard CLSI EP12-3rd Edition (Ref#5) listed below.
Public Law, CFR Citation(s) and Procode(s)*
21 CFR 864 Hematology and pathology devices
Relevant FDA Guidance and/or Supportive Publications*
1. 21 CFR 809.10(b)(12) Specific Performance Characteristics.
2. Factors to Consider Regarding Benefit Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions - Guidance for Industry and Food and Drug Administration Staff, issued December 2016.
3. CLSI EP06 2nd Edition Evaluation of Linearity of Quantitative Measurement Procedures. (FR Recognition Number 7-306)
4. 21 CFR 820.30 Design controls.
5. CLSI EP12 3rd Edition Evaluation of Qualitative, Binary Output Examination Performance. (FR Recognition Number 7-315)
6. CLSI EP17-A2 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline-Second Edition. (FR Recognition Number 7-233)
7. CLSI EP25-A Evaluation of Stability of In Vitro Diagnostic Reagents. (FR Recognition Number 7-235)
8. CLSI EP39 1st Edition A Hierarchical Approach to Selecting Surrogate Samples for the Evaluation of In Vitro Medical Laboratory Tests. (FR Recognition Number 7-311)
9. Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests - Guidance for Industry and FDA Staff, issued March 2007.

Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical Devices - Guidance for Industry and Food and Drug Administration Staff, issued September 2018.

FDA Technical Contact
 Elizabeth Stafford
Standards Development Organization
CLSI Clinical Laboratory Standards Institute https://clsi.org/
FDA Specialty Task Group (STG)
InVitro Diagnostics
*These are provided as examples and others may be applicable.