Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: RNA Preanalytical Systems (RNA Collection, Stabilization and Purification Systems for RT-PCR used in Molecular Diagnostic Testing)
Document issued on: August 25, 2005
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Table of Contents
Guidance for Industry and FDA Staff
Class II Special Controls Guidance Document: RNA Preanalytical Systems (RNA Collection, Stabilization and Purification Systems for RT-PCR used in Molecular Diagnostic Testing)
This guidance document was developed as a special controls guidance to support the classification of RNA preanalytical systems (RNA collection, stabilization and purification systems) into class II (special controls). RNA preanalytical systems are devices intended to collect, store, and transport patient specimens, and stabilize intracellular RNA from the specimens, for subsequent isolation and purification of the intracellular RNA for RT-PCR (real-time polymerase chain reaction) used in in vitro molecular diagnostic testing. The device may consist of sample collection devices, nucleic acid isolation and purification reagents, and processing reagents/equipment (tubes, columns, etc.). It also may contain instruments for automation of the nucleic acid isolation and purification steps.
This guidance is issued in conjunction with a Federal Register notice announcing the classification of RNA preanalytical systems. Any firm submitting a premarket notification (510(k)) for a RNA preanalytical system will need to address the issues covered in this special controls guidance document. 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 need to 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 follow the statutory and regulatory criteria in the manner suggested by the guidance and in your attempt to 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 document, “A Suggested Approach to Resolving Least Burdensome Issues.”.
FDA believes that special controls, when combined with the general controls, will be sufficient to provide reasonable assurance of the safety and effectiveness of a RNA preanalytical system. A manufacturer who intends to market a device of this generic type should (1) conform to the general controls of the Federal Food, Drug, and 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 the device identified in this guidance, and (3) obtain a substantial equivalence determination from FDA before marketing the device.
This guidance document identifies the classification regulation and product code for RNA collection, stabilization, and purification systems. (Refer to Section 4 – Scope). In addition, other sections of this guidance document identify the risks to health and describe measures that, if followed by manufacturers and combined with the general controls, will generally address the risks associated with these RNA preanalytical systems 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 Guidance1 ,” a manufacturer may submit either 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 when 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 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 scope of this document is limited to the following device as described in 21 CFR 866.4070 (product code NTW):
21 CFR 866.4070 RNA Preanalytical Systems.
These devices may consist of sample collection devices, nucleic acid isolation and purification reagents, and processing reagents/equipment. The system may also contain instruments for automation of the nucleic acid isolation and purification steps.
Failure of the system during specimen collection, or during RNA stabilization or purification could yield an RNA sample of low quality and quantity. Low quality RNA, when tested, could result in falsely low or falsely high RNA transcript signal levels leading to inaccurate diagnosis and/or improper patient management. Low quantity of RNA could render the samples unusable for downstream RT-PCR applications; specimens would need to be recollected, causing possible delay in diagnosis. In addition, depending on specimen type, recollection could pose additional patient risk (e.g., tissue biopsy). The degree of risk varies depending on the disease or condition/stage being diagnosed or managed. Results of RNA testing should always be considered in conjunction with other clinical factors.
In the table below, FDA has identified the risks to health generally associated with the use of a RNA preanalytical system addressed in this document. The measures recommended to mitigate the identified risks are described in this guidance document, as shown in the table below. You should 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 the risks 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.
In your 510(k), you should identify the regulation, the product code, and a legally marketed predicate device. In order to help FDA efficiently review all the aspects of your device compared with the predicate, you should include a table that outlines the similarities and differences between the predicate and your device.
Key issues in the review of a new device are the specific intended use, the type of specimens tested, and the technology utilized. You may submit appropriate peer-reviewed literature references relevant to the technology of the device in addition to the descriptive information to adequately describe the new instrumentation. You should include the following descriptive information to adequately characterize RNA preanalytical systems.
You should clearly describe the intended use of the device. The intended use should specify the components of the device (e.g. tubes, purification reagents), the type of specimen the device is used for, the intended application (e.g., collection, storage, transport, stabilization) and the analyte processed (e.g., intracellular or viral RNA). You should also list the type of molecular diagnostic test (RT-PCR, bDNA, etc.) used in conjunction with the device.
Description of Methodology
We recommend that you provide a thorough explanation of all aspects of the system methodology. This could include, but is not limited to, the following:
The quality of extracted RNA is essential for high-quality RT-PCR diagnostic assays. You should conduct statistically-based studies using clinical samples to demonstrate RNA stability, purity, integrity, yield, repeatability, reproducibility, and suitability for use in RT-PCR assays according to claims stated in the product labeling.
Specific Study Recommendations
RNA quality assessment:
We recommend that you include device stability testing to support the shelf life claim (e.g., reagents and other components). [See EN 13640 - 2002 Stability testing of in vitro diagnostic reagents.]
You should fully examine the reproducibility of your RNA collection, stabilization and purification system. “Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline” (2004) CLSI Document EP5-A2, “User Protocol for Evaluation of Qualitative Test Performance; Approved Guideline” (2002), CLSI Document EP12-A, and “Protocols for Determination of Limits of Detection of Quantitation: Approved Guideline” (2004), CLSI Document EP17-A include guidelines for experimental design, computations, and a format for stating performance claims. You should include the following in your study design:
In the study design description in your 510(k), you should identify which factors (e.g., reagent lots, operators) were held constant and which were varied during the evaluation, and describe the computational methods and statistical analyses used to evaluate the data.
Instrumentation and software (if applicable)
If the system includes instrument(s) that are used to automate the RNA isolation and purification steps, the submission should include all required information as detailed in the FDA/CDRH “Guidance for FDA Reviewers and Industry: Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices” document. You should include a copy of the instrument manual for specified instrumentation. All of the analytical performance data, including the repeatability and reproducibility data, should be generated using the automated system.
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 proposed labeling that satisfies the requirements of 21 CFR 807.87(e). Although final labeling is not required for 510(k) clearance, final labeling must comply with the requirements of 21 CFR 809.10 before an in vitro diagnostic device is introduced into interstate commerce.
Directions for use
You should provide clear and concise instructions on the use of the system from specimen collection (e.g. blood) to RNA isolation and purification. You should include work-flow recommendations for the RNA isolation and purification steps. You should include pictograms and flow diagrams, wherever appropriate.
We recommend that you address the limitations of your system with statements in the labeling, such as the following:
We recommend that you include product storage conditions and sample stability information in the labeling.
We recommend that you provide product performance information such as RNA purity, yield, repeatability, reproducibility, and stability of gene transcript levels in the labeling. We recommend that you describe all relevant aspects of the protocols used to establish your performance characteristics, including materials used and results. We also recommend that you provide graphic representations of the results.
If software is a component of your device, we recommend that you provide a user manual that addresses all components of the instrumentation for RNA pre-analytical systems. Your user manual should provide an adequate description of the role of the software, the user interface with the software, as well as results of performance testing to demonstrate that the software functions as designed. We recommend pictorial representations of computer screens, graphical user interfaces (GUIs), and other elements that aid the user in correctly using the software.
The user manual, where possible, should also include descriptions of how the user can recognize incorrect operation or failure of the instrumentation, and a troubleshooting guide.
2Refer to Indications for Use Form (PDF File Size: 1.03MB) for the recommended format.
3If FDA makes a substantial equivalence determination based on acceptance criteria, the subject device should be tested and shown to meet these acceptance criteria before being introduced into interstate commerce.
4See Required Elements for a Declaration of Conformity to a Recognized Standard (Screening Checklist for All Premarket Notification [510(K)] Submissions).