Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: CFTR Gene Mutation Detection Systems
Document issued on: October 26, 2005
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Table of Contents
Guidance for Industry and FDA Staff
Class II Special Controls Guidance Document: CFTR Gene Mutation Detection Systems
This document was developed as a special control to support the classification of CFTR (cystic fibrosis transmembrane conductance regulator) gene mutation detection systems into class II (special controls). The CFTR gene mutation detection system is a device used to simultaneously detect and identify a panel of mutations and variants in the CFTR gene. It is intended as an aid in confirmatory diagnostic testing of individuals with suspected cystic fibrosis (CF), in carrier identification, and in newborn screening. This device is not intended for stand-alone diagnostic purposes, prenatal diagnostic, pre-implantation or general population screening. CFTR gene mutation detection systems may consist of various reagents and instruments, including polymerase chain reaction (PCR) primers, hybridization matrices, thermal cyclers, sequencers, signal detection instruments, and software packages.
This guidance is issued in conjunction with a Federal Register notice announcing the classification of CFTR gene mutation detection systems. Any firm submitting a 510(k) premarket notification for a CFTR gene mutation detection system will need to address the issues covered in the special control guidance. However, the firm need only show that its device meets the recommendations of the guidance or in some other way provides equivalent assurances of safety and effectiveness.
The firm must show that its device addresses the issues of safety and effectiveness identified in this guidance, either by meeting the recommendations of this guidance or by some other means that provides equivalent assurances of safety and effectiveness.
The Least Burdensome Approach
The issues identified in this guidance document represent those that we believe should be addressed before your device can be marketed. In developing the guidance, we carefully considered the relevant statutory criteria for Agency decision-making. We also considered the burden that may be incurred in your attempt to comply with the guidance and address the issues we have identified. We believe that we have considered the least burdensome approach to resolving the issues presented in the guidance document. If, however, you believe that there is a less burdensome way to address the issues, you should follow the procedures outlined in the “A Suggested Approach to Resolving Least Burdensome Issues” document.
FDA believes that special controls, when combined with the general controls, will be sufficient to provide reasonable assurance of the safety and effectiveness of CFTR gene mutation detection systems. A manufacturer who intends to market a device of this type should (1) conform to the general controls of the Federal Food, Drug & Cosmetic Act (the Act), including the premarket notification requirements described in 21 CFR 807 Subpart E, (2) address the specific risks to health associated with CFTR gene mutation detection systems identified in this guidance and, (3) obtain a substantial equivalence determination from FDA prior to marketing the device.
This guidance document identifies the classification regulation and product code for CFTR gene mutation detection systems (Refer to Section 4 – Scope). In addition, other sections of this guidance document list the risks to health identified by FDA and describe measures that, if followed by manufacturers and combined with the general controls, will generally address the risks associated with these assays and lead to a timely premarket notification [510(k)] review and clearance. This document supplements other FDA documents regarding the specific content requirements of a premarket notification submission. You should also refer to 21 CFR 807.87 and other FDA documents on this topic, such as "Premarket Notification 510(k)".
As explained in “The New 510(k) Paradigm - Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications; Final Guidance”1 a manufacturer may submit a Traditional 510(k) or an Abbreviated 510(k). FDA believes an Abbreviated 510(k) provides the least burdensome means of demonstrating substantial equivalence for a new device, particularly once FDA has issued a guidance document that provides recommendations on what should be addressed in a submission for the device. Alternatively, manufacturers considering modifications to their own cleared devices may lessen the regulatory burden by submitting a Special 510(k).
An Abbreviated 510(k) submission must include the required elements identified in 21 CFR 807.87, including the proposed labeling for the device sufficient to describe the device, its intended use, and the directions for its use. In an Abbreviated 510(k), FDA may consider the contents of a summary report to be appropriate supporting data within the meaning of 21 CFR 807.87(f) or (g); therefore, we recommend that you include a summary report. The report should describe how this guidance document was used during the device development and testing and the methods or tests used. The report should also include a summary of the test data or description of the acceptance criteria applied to address the risks identified in this document, as well as any additional risks specific to your device. This section suggests information to fulfill some of the requirements of 21 CFR 807.87 as well as some other items that we recommend you generally include in an Abbreviated 510(k).
If it is not clear how you have addressed the risks identified by FDA or additional risks identified through your risk analysis, we may request additional information about aspects of the device's performance characteristics. We may also request additional information if we need it to assess the adequacy of your acceptance criteria. (Under 21 CFR 807.87(l), we may request any additional information that is necessary to reach a determination regarding substantial equivalence.)
As an alternative to submitting an Abbreviated 510(k), you can submit a Traditional 510(k) that provides all of the information and data required under 21 CFR 807.87 and described in this guidance. A Traditional 510(k) should include all of your methods, data, acceptance criteria, and conclusions. Manufacturers considering modifications to their own cleared devices should consider submitting Special 510(k)s.
The general discussion above applies to any device subject to a special controls guidance document. The following is a specific discussion of how you should apply this special controls guidance document to a premarket notification for CFTR gene mutation detection systems.
The scope of this document is limited to the following devices (product code NUA):
21 CFR 866.5900 Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system
The CFTR gene mutation detection system is a device used to simultaneously detect and identify a panel of mutations and variants in the CFTR gene. It is intended as an aid in confirmatory diagnostic testing of individuals with suspected cystic fibrosis (CF), carrier identification, and newborn screening. This device is not intended for stand-alone diagnostic purposes, prenatal diagnostic, pre-implantation or population screening.
Failure of the CFTR mutation detection system to perform as indicated or errors in interpretation of results may lead to improper clinical recommendations and medical patient management. In the context of an aid to carrier-screening in adults, a false-negative or false-positive result or interpretation could lead to inaccurate estimates of a couple’s risk of having a child with cystic fibrosis. In the context of assisting in the diagnosis of CF in newborns and children, a false-negative could lead to a delay in the definitive diagnosis and treatment; a false-positive could lead to unnecessary or inappropriate treatment.
Interpretation of test results depends on many factors, such as patient demographics, family history, and mutation or variants associated with infertility. To aid in a test interpretation manufacturers should recommend in their labeling that test results should be accompanied by genetic counseling. This will enable individuals and couples to receive guidance and information about risks and prognostic factors. CF has a wide clinical variability, with inconsistency of genotype-phenotype correlations for particular mutations. In addition, not all CFTR mutations cause cystic fibrosis. Possible test results that would benefit from interpretation by specialists include results for individuals who have a family history of CF, CFTR mutation carriers including couples where one or both partners are carriers, and otherwise healthy males who carry mutations associated with infertility4.
Over 1300 mutations have been identified in CFTR the gene. Therefore genotypic CFTR tests, which typically detect a limited number of mutations, should not be used alone to diagnose cystic fibrosis. Assay results should be interpreted only in the context of other laboratory findings and the total clinical status of the patient. Manufacturers should clarify these limitations in the device labeling.
In the table below, FDA has identified the risks to health generally associated with the use of CFTR gene mutation detection systems addressed in this document. The measures recommended to mitigate these identified risks are given in this guidance document, as shown in the table below. We recommend that you conduct a risk analysis, prior to submitting your premarket notification, to identify any other risks specific to your device. The premarket notification should describe the risk analysis method. If you elect to use an alternative approach to address a particular risk identified in this document, or have identified risks additional to those in this document, you should provide sufficient detail to support the approach you have used to address that risk.
The intended use should specify the mutations the test is intended to detect, the general clinical utility of detecting specified mutations, and the specific populations to which the test is targeted. The intended use should clearly specify whether detection of CFTR mutations is being performed as an aid in carrier identification, newborn screening, or confirmatory diagnostic testing of individuals with suspected cystic fibrosis (CF). References to professional society recommendations are acceptable.
You should describe in detail the methodology used by your device to detect mutations or polymorphisms. For example, you should describe the following elements, where applicable for your device:
Illustrations or photographs of non-standard equipment or methods can be helpful in understanding novel methodologies. You should describe any additional process controls that guard against the possibility of inaccurate genotype determinations (miscalls) resulting from genotypes that are not detected by your device.
We recommend that you include a description of the method and technology used in CFTR gene mutation detection, and of the system components of the kit.
You may submit a 510(k) for a CFTR gene mutation detection assay intended to be run on previously cleared instrumentation. Alternatively, the instrumentation may be a part of the new system included in your 510(k). You should analyze any instrumentation that is specific and dedicated to the device according to the “Guidance for FDA Reviewers and Industry: Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices” document. If the CFTR gene mutation detection system is (or contains) a multiplex assay, it may be run on instrumentation for clinical multiplex test systems. Guidance for such instrumentation is available in the FDA Guidance for Industry and FDA Staff "Class II Special Controls Guidance Document: Instrumentation for Clinical Multiplex Test Systems." If your device includes a CFTR gene mutation detection assay with instrumentation for clinical multiplex test systems for that assay, you may submit the information for both devices within one 510(k).
The guidance document, "Replacement Reagent and Instrument Family Policy", does not apply to CFTR gene mutation detection systems for use with instrumentation for clinical multiplex test systems.
You should include a copy of instrumentation manuals for specified instrumentation. If general purpose instrumentation is to be used, you should provide specifications for the required instruments to be used in labeling.
You should provide examples of test reports (e.g., printouts) as would be supplied to the healthcare provider. Reports should be consistent with current recommendations of genetics professional societies, and should contain adequate interpretation guidelines for the use of the ordering physician/counselor.
Where applicable, reports should include information on the mutations/polymorphisms identified and the methodology and technology used for detection. You should identify appropriate literature references to genotypic interpretations, or phenotypic predictions, if applicable, to enable users to access information about specific genotypes. We expect that for most 510(k) applications, appropriate literature references will be available. If such supporting information is not available, you should provide information based on the clinical studies you conducted to address clinical validity of your device.
In your 510(k), you should detail the study design you used to evaluate each of the performance characteristics outlined below. This should include information such as:
For each of the performance characteristics described below, you should also provide a clear description of all results and acceptance criteria in your 510(k).
The issues described below generally apply, regardless of the technology used by the device to detect the CF mutations. If you make additional claims for other performance characteristics not mentioned below, you should describe the study designs and results you used to support them.
Consideration of preanalytical factors is critical for high-quality genetic tests. If your device includes reagents for extraction and preparation of DNA for testing, you should validate each step in the preanalytical process for its effects on analytical parameters such as reproducibility, accuracy, and stability of product and describe study design and results addressing this issue in the 510(k). Your external site studies (e.g., reproducibility, method comparison) should include evaluation of the preanalytical process.
If your device does not include reagents for DNA extraction and preparation as part of the assay, you should provide specifications for the reagents needed and for assessing the quality of the assay input DNA, so that the user can select appropriate reagents. You should describe, in your 510(k), the study design and results you used to determine these specifications. In this case, we recommend that in studies establishing the performance of your device, you permit sites to use any extraction method they choose, providing that meets your specifications. In this way, you can evaluate any effect of variations in preanalytical processes on your device performance.
You should evaluate the accuracy and precision of your assay, including DNA extraction, from all the sources of DNA that you recommend for your assay (e.g., blood, peripheral blood mononuclear cells, buccal swab). You should also evaluate all sample collection and storage options you recommend (e.g., heparin-preserved vs. EDTA-preserved blood, stored vs. fresh sample). Your validation of appropriate storage conditions should include both the sample and the extracted product.
You should evaluate the stability of all of your reagents, and recommended samples.
CFTR gene mutation detection systems should include both positive and negative controls. Controls should approximate sample DNA concentration in order to adequately challenge the system.
You should describe the following concerning quality control and calibration material:
We recommend that you implement the calibration of CFTR gene mutation detection systems where appropriate.
You should perform analytical studies that demonstrate that the device detects the mutations it claims to detect, and does not detect mutations when none are present. You should describe any process controls that guard against the possibility of miscalls (e.g., inaccurate genotype determinations) resulting from genotypes that are not detected by the assay, and report this as a limitation, if applicable.
You should perform method comparison studies that demonstrate that your device detects the genotypes it claims to detect, and does not detect mutations or polymorphisms when none are present. Samples used in these studies should be patient samples derived from the intended use population, in order to show that the device will perform as claimed in a clinical setting.
Because of the abundance of technologies that could be used to detect CFTR gene mutations, assays may vary significantly in terms of methodology, instrumentation, and sample source, making direct comparison difficult. You should compare results of your device to bidirectional DNA sequence analysis.
Description of Study Results
You should describe the protocol and results of your method comparison in your 510(k). You should submit, along with your comparative sequence data, a measure of sequence quality such as a phred score or percent correct sequence calls. You can then use this information to calculate the percent correct genotype call rate of your device, relative to the bidirectional sequencing data. We recommend that you tabulate all results and indicate the percent correct calls for the various genotypes. We recommend that you resolve and explain all discrepant results in the 510(k); however, you should use original unresolved results for all performance calculations, in order to avoid bias. You should include failed assays (e.g., inability to correctly determine genotype within a sample, reporting of an incorrect result, instrument failure, or reagent failure) in your description of results. Any incorrect or absent genotype determinations should be considered disagreements for the purposes of reporting performance characteristics.
When conducting studies, samples should be masked so that operators are unaware of the sequencing results, in order to ensure that the validity of the study results is not compromised. You should report results (e.g., phred score or percent correct sequence calls) with 95% confidence intervals. Exact confidence intervals should be computed instead of standard asymptotic confidence intervals when the latter poorly approximate the former (e.g., for an observed percent of correct sequence calls near 100%).
If, in addition, you wish to provide additional data on other performance characteristics of your device, we recommend that you provide a description of the testing in your submission.
Sample selection, inclusion and exclusion criteria
While prospective samples are preferred, well-characterized samples from banks can be used in your method comparison study, if clinical utility and validity are already established in the literature. You should use clinical samples from all matrices you claim in your intended use to demonstrate that correct results can be obtained from clinical material. You should fully describe selection (inclusion/exclusion) criteria, and characterize any relevant features of the samples (whether prospective or retrospective).
You should provide clear information supporting sample integrity. We recommend that you validate statements in your labeling about sample storage and transport by assessing sample stability and recovery over the storage times and temperatures recommended to users. For example, an appropriate study may include an analysis of aliquots stored under the conditions of time, temperature, or specified number of freeze/thaw cycles. We recommend that you state your acceptance criteria for the sample stability parameters.
The following is a rough guideline for sample size calculation: If the sample size is N and the observed sensitivity is N/N or 1.0, then the exact one-sided 95% confidence interval is (N – 3)/N (Van Belle, Statistical Rules of Thumb, Wiley, 2002). For example, if N=100, the 95% lower bound is 97/100 or 0.97. Clearly for small sample sizes such as N=5, the sample size is too small because then the sensitivity lower bound is only 2/5 or 0.40.
Prospective clinical testing to determine clinical validity and utility may not be necessary for validation of CFTR gene mutation detection systems, as there may be an established scientific framework and sufficient body of evidence supporting the clinical validity and utility of your device. In this case, you should provide the relevant peer-reviewed references. These should include multiple studies that test appropriate populations. In cases where the literature does not sufficiently support your indications for use, you should conduct studies to support claims for your device. If clinical testing is performed, we recommend that you select patients prospectively in order to maximize the number of mutations detected. In either case, you should use clinical samples to demonstrate that correct results can be obtained from clinical material.
If your system includes software, you should submit software documentation detailed in accordance with the level of concern (See: Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices). You should determine the Level of Concern prior to the mitigation of hazards. In vitro diagnostic devices of this type are considered a moderate level of concern, because software flaws could indirectly affect the patient and potentially result in injury because of the action or inaction of a healthcare provider who does not get accurate information.
You should include the following points, as appropriate, in preparing software documentation for FDA review:
Below are additional references to help you develop and maintain your device under good software life cycle practices consistent with FDA regulations.
The premarket notification should include labeling in sufficient detail to satisfy the requirements of 21 CFR 807.87(e). The following suggestions are aimed at assisting you in preparing labeling that satisfies the requirements of 21 CFR 807.87(e). Although final labeling is not required for 510(k) clearance, final labeling for in vitro diagnostic devices must comply with the requirements of 21 CFR 809.10 before an in vitro diagnostic device is introduced into interstate commerce.
Standards and Guidances
The following additional standards, guidelines, and guidances may be helpful when preparing your CFTR gene mutation detection system submission:
2 Refer to Indications for Use Form for the recommended format.
3 See Required Elements for a Declaration of Conformity to a Recognized Standard (Screening Checklist for All Premarket Notification [510(K)] Submissions).
4 For references regarding evaluation of benefits and risks to health of CFTR testing, see the following: W. W. Grody et al (Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetic Services Committee, ACMG): Laboratory Standards and Guidelines for Population-based Cystic Fibrosis Carrier Screening, Genetics in Medicine, March/April 2001, 3 (2): 149-154; American College of Medical Genetics (ACMG) / American College of Obstetricians and Gynecologists; 2001, 2002, 2006 Technical Standards and Guidelines for CFTR Mutation Testing; ACMG 2006 Standards and Guidelines for Clinical Genetics Laboratories; 2004 Cystic Fibrosis Foundation (CFF) / Center for Disease Control (CDC) Recommendations on Newborn Screening for Cystic Fibrosis.
5 Some of the elements listed in this section are applicable to instrumentation. If you are submitting a separate 510(k) for your instrumentation, you can describe the elements specific for instrumentation in that 510(k).