CLIA’88 FDA 08版本

1、Guidance for Industry and FDA Staff:Recommendations for Clinical Laboratory Improvement Amendments of 1988 (CLIA)Waiver Applications for Manufacturers of In Vitro Diagnostic DevicesDocument issued on: January 30, 2008The draft of this guidance document was released on September 7, 2005.For questions

2、 regarding this document contact Carol Benson, 240-276-0396 or by email OMB control number: 0910-0598Expiration Date: 07/31/2016See additional PRA statement in Section VIII of this guidanceU.S. Department of Health and Human Services Food and Drug Administration Center for D

3、evices and Radiological Health Office of In Vitro Diagnostic Device Evaluation and SafetyContains Nonbinding RecommendationsPrefacePublic CommentWritten comments and suggestions may be submitted at any time for Agency consideration to the Division of Dockets Management, Food and Drug Administration,

4、 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD, 20852. Alternatively, electronic comments may be submitted to /dockets/ecomments. When submitting comments, please refer to Docket No. 2008D-0031. Comments may not be acted upon by the Agency until the document is next revised

5、 or updated.Additional CopiesAdditional copies are available from the Internet /cdrh/oivd/guidance/1171.pdf. You may also send an email request to to receive an electronic copy of the guidance, or send a FAX request to 240-276-3151 to receive a hard copy. Please us

6、e the document number 1171 to identify the guidance you are requesting.2Contains Nonbinding RecommendationsTABLE OF CONTENTSI.INTRODUCTION.5The Least Burdensome Approach.7II.COMPONENTS OF A CLIA WAIVER APPLICATION.7III.DEMONSTRATING SIMPLE.8IV.DEMONSTRATING INSIGNIFICANT RISK OF AN ERRONEOUS RESULT

7、Failure Alerts and Fail-Safe Mechanisms.9A. Tier 1: Risk Analysis and Flex Studies.11B. Tier 2: Fail-Safe and Failure Alert Mechanisms.131.Points to consider for designing fail-safe and failure alert mechanisms.132.External control materials .143.Additional points concerning control materials.15C. V

8、alidating Fail-Safe and Failure Alert Mechanisms, including External ControlProcedures .15V. DEMONSTRATING INSIGNIFICANT RISK OF AN ERRONEOUS RESULT “ACCURACY”16A. Clinical Study Sites and Participants171.Testing sites172.Clinical study participants173.Clinical study reports19B. Clinical Studies for

9、 Tests with Quantitative Results191.Selection of the Comparative Method (CM)202. Establishing Allowable Total Error Zones and Zones for Erroneous Results. 203.Clinical Study Design22C. Clinical Studies for Tests with Qualitative Results261.Selection of the Comparative Method (CM)262.Clinical Study D

10、esign273.Performance Criteria for Qualitative Tests31VI.LABELING FOR WAIVED DEVICES32A. Quick Reference Instructions (QRI)33B. Quality Control (QC) Labeling Recommendations33C. Educational Information343Contains Nonbinding RecommendationsVII.SAFEGUARDS FOR WAIVED TESTS35VIII.Paperwork Reduction Act

11、of 199535REFERENCES36Appendix A: Statistical Notes38Appendix B: Labeling40Appendix C: Definition of Terms as Used in this Document424Contains Nonbinding RecommendationsGuidance for Industry and FDA Staff:Recommendations for Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver Application

12、s for Manufacturers of In Vitro Diagnostic DevicesThis guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic. It does not create or confer any rights for, or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the

13、 approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of

14、 this guidance.I. INTRODUCTIONThe 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 CLIA and thus eligible for waiver categorization (69 FR 22849, April 29, 2004). The

15、 Centers for Medicare & and Medicaid Services (CMS) is responsible for oversight of clinical laboratories, which includes issuing waiver certificates. CLIA requires that clinical laboratories obtain a certificate before accepting materials derived from the human body for laboratory tests. 42 U.S.C.

16、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).CLIA, 42 U.S.C. 263a(d)(3) Examinations and Procedures, as modified by the Food and Drug Administration Modernization Act

17、(FDAMA), reads as follows regarding tests that may be performed by laboratories with a Certificate of Waiver:The examinations and procedures that may be performed by a laboratory with a Certificate of Waiver are laboratory examinations and procedures that have been approved by the Food and Drug Admi

18、nistration for home use or that, as determined by the Secretary, are simple laboratory examinations and procedures that have an insignificant risk of an erroneous result, including those that - (A) employ methodologies that are so simple and accurate as to render the likelihood of erroneous results

19、by the user negligible, or (B) the5Contains Nonbinding RecommendationsSecretary has determined pose no unreasonable risk of harm to the patient if performed incorrectly.This guidance describes recommendations for device manufacturers seeking to submit information through a CLIA waiver application to

20、 FDA to support a determination whether the device meets CLIA statutory criteria for waiver.In this document, FDA (we) recommends an approach for you to use to demonstrate that your device is simple and has an insignificant risk of an erroneous result. As part of demonstrating the latter, we recomme

21、nd studies you can conduct to demonstrate the test is accurate. While we recommend you adopt the approach we have outlined in this guidance for waiver applications, you may use another approach that you believe would be appropriate for your devices waiver application if it meets the CLIA statutory r

22、equirements. (See Least Burdensome Approach, below.)We based the recommendations in this document on our interpretation of the law, experience with CLIA complexity determinations, and interactions with stakeholders. Interactions included an open public workshop on August 14-15, 2000, a proposal pres

23、ented by AdvaMed (Advanced Medical Technology Association) at the September 2003 Clinical Laboratory Improvement Advisory Committee (CLIAC) meeting, and recommendations proposed by CLIAC during the February 2004 meeting. In addition, we considered the comments received in response to a 2001 draft gu

24、idance and the 2005 draft guidance document, and incorporated revisions based on these comments as appropriate. 1Some of the changes reflected in this document (as well as in the 2005 draft guidance document) from the earlier 2001 draft guidance document entitled “Guidance for CLIA 1988 Criteria for

25、 Waiver,” include the following: Greater emphasis on scientifically-based flex studies2 and validation and/or verification studies, linked to the risk assessment for each device. Recognition that reference methods may not be available for every device type. (However, devices should be traceable to t

26、rue reference methods of known accuracy, when such methods are available.) Additional emphasis on use of quality control procedures. Greater emphasis on intended users (which may include medical assistants, nurses or doctors, and lay people, as appropriate) during studies testing the device. Updated

27、 study recommendations with emphasis on use of patient specimens, in an intended use environment, over time.1 The draft document of September 7, 2005, entitled “Recommendations for Clinical Laboratory Improvement Amendments of 1988 Waiver Applications” (70 FR 53231) replaced the draft “Guidance for

28、Clinical Laboratory Improvement Amendments of 1998 (CLIA) Criteria for Waiver,” March 1, 2001 (66 FR 12939).2 For the definition of this term and other technical terms, as they are used in this document, see Appendix C.6Contains Nonbinding RecommendationsThis document does not address test systems c

29、leared or approved by FDA for over-the-counter or prescription home use since these automatically qualify for CLIA waiver. 42 U.S.C. 263a(d)(3). This guidance document also does not address use of the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)s replacement reagent and instrume

30、nt family policy3 for waived devices; that policy does not currently apply to CLIA waiver applications.The draft of this document was issued September 7, 2005. We have also issued a draft guidance entitled Guidance for Administrative Procedures for CLIA Categorization, /cdrh/ode/guidance/

31、1143.html. In it, we propose recommendations to device manufacturers on FDAs administrative procedures for CLIA categorization.FDAs guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agencys current thinking on a topic

32、and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.The Least Burdensome ApproachWe believe we should consider the least burdens

33、ome approach in all areas of medical device regulation. This guidance reflects our careful review of the relevant scientific and legal requirements and what we believe is the least burdensome way for you to comply with those requirements. However, if you believe that an alternative approach would be

34、 less burdensome, please contact us so we can consider your point of view. You may send your written comments to the contact person listed in the preface to this guidance or to the CDRH Ombudsman. Comprehensive information on CDRHs Ombudsman, including ways to contact him, can be found on the Intern

35、et at /cdrh/ombudsman/.II.COMPONENTS OF A CLIA WAIVER APPLICATIONThis guidance discusses the following components that we recommend you include in a CLIA waiver application: A description of your device that demonstrates it is simple to use. (Section III.) The results of risk analys

36、is including the identification of potential sources of error for your device. (Section IV.) The results of flex studies demonstrating insensitivity of the test system to environmental and usage variations under conditions of stress. (Section IV.) The results of risk evaluation and control including

37、 a description of (1) measures you have implemented to mitigate the risk of errors, and (2) validation and/or verification studies demonstrating the ability of failure alert, fail-safe mechanisms, and other control3 For a description of this policy, see Guidance for Industry and FDA Staff; Replaceme

38、nt Reagent and Instrument Family Policy, /cdrh/oivd/guidance/950.html7Contains Nonbinding Recommendationsmeasures that you have incorporated into your device to mitigate the risk of errors, even under conditions of stress. (Section IV.) A description of the design and results of cli

39、nical studies you conducted to demonstrate that the device has an insignificant risk of erroneous result in the hands of the intended user (hereinafter operator). (Section V.) Proposed labeling with instructions for use consistent with a device that is “simple.” (Section VI.)III. DEMONSTRATING SIMPL

40、ECLIA requires that tests performed by laboratories with a Certificate of Waiver be simple. 42 U.S.C. 263a(d)(2), (3). We recommend that, as a first step in the process of deciding whether your device could be a candidate for waiver, you determine whether your device is simple.Under the approach rec

41、ommended in this guidance, FDA believes that a simple test should have characteristics such as the following: Is a fully automated instrument or a unitized or self-contained test. Uses direct unprocessed specimens, such as capillary blood (fingerstick), venous whole blood, nasal swabs, throat swabs,

42、 or urine. Needs only basic, non-technique-dependent specimen manipulation, including any for decontamination. Needs only basic, non-technique-dependent reagent manipulation, such as “mix reagent A and reagent B.” Needs no operator intervention during the analysis steps. Needs no technical or specia

43、lized training with respect to troubleshooting or interpretation of multiple or complex error codes. Needs no electronic or mechanical maintenance beyond simple tasks, e.g., changing a battery or power cord. Produces results that require no operator calibration, interpretation, or calculation. Produ

44、ces results that are easy to determine, such as positive or negative, a direct readout of numerical values, the clear presence or absence of a line, or obvious color gradations. Provides instructions in the package insert for obtaining and shipping specimens for confirmation testing in cases where s

45、uch testing is clinically advisable. Has test performance comparable to a traceable reference method as demonstrated by studies in which intended operators4 perform the test. If a reference method is not4 In this guidance, intended operator refers to a test operator with limited or no training or ha

46、nds-on experience in conducting laboratory testing. Laboratory professional refers to a person who8Contains Nonbinding Recommendationsavailable for a test you are proposing for waiver, please contact OIVD to discuss your proposed plan prior to submitting your application. Contains a quick reference

47、instruction sheet that is written at no higher than a 7th grade reading level.We believe a test that is simple should not have the following characteristics: Sample manipulation is required to perform the assay. (For example, tests that use plasma or serum are not considered simple.) Sample manipula

48、tion includes processes such as centrifugation, complex mixing steps, or evaluation of the sample by the operator for conditions such as hemolysis or lipemia. Measurement of an analyte could be affected by conditions such as sample turbidity or cell lysis.After you consider whether your device is “s

49、imple” based on the items listed above, it may be helpful for you to contact OIVD for feedback on this issue prior to conducting clinical studies to support waiver. In your waiver application, you should describe features of your device that address the issues listed above. Whenever possible (for ex

50、ample, if your test system consists of a unitized device), you should include sample(s) of the device with your waiver application to aid FDA in its determination of whether your device is “simple.” You may also schedule a meeting to bring your device to FDA to aid FDA in making this determination.I

51、V. DEMONSTRATING INSIGNIFICANT RISK OF ANERRONEOUS RESULT Failure Alerts and Fail-SafeMechanismsGenerally, the risk of an erroneous result should be far less for waived tests than non-waived tests. You should demonstrate in your CLIA waiver application that (1) the test system design is robust, e.g.

52、, insensitive to environmental and usage variation, and (2) that all known sources of error are effectively controlled. In general, flex studies should be used to demonstrate robust design while risk management should be used to demonstrate identification and effective control of error sources, alth

53、ough the two are not mutually exclusive.Most risk control measures should be fail-safe measures or failure alert mechanisms. Appropriate fail- safe mechanisms and failure alert mechanisms help assure that a test has “an insignificant risk of an erroneous result.” Examples of fail-safe mechanisms are

54、 lock-out functions to ensure that a test system does not provide a result when test conditions are inappropriate, such when there is a component malfunction or operator error. Other examples are measures within the system to prevent operator error, such as guides or channels that prevent improper strip placement. We recommend that test system design incorporate fail-safe mechanisms whenever it is technically practicabl