On how to comply with labeling requirements for in vitro diagnostic products or IVDs, including laboratory developed tests or LDTs. Today, we will focus on the labeling requirements for test systems under 21 CFR 809, dot 10 B, we will not be covering labeling requirements for other types of IBDs, such as collection devices and general purpose reagents. During this webinar, I'd now like to introduce today's presenter Toby Lowe, Acting Deputy Director for the Office of Health Technology, number seven for in vitro diagnostic devices within the Office of product evaluation and quality within CDRH. We'll begin with the presentation from Toby and then address previously emailed questions about today's topic. Before I turn it over to Toby, I'd like to provide two administrative reminders. First, please make sure you've joined us through the Zoom app and not through a web browser to avoid technical issues. Second, the intended audience for this webinar is industry trade rest reporters are encouraged to consult with the CDRH trade press team at cdrhtradepress@fda.hhs.gov and members of national media may consult with FDA office of media affairs at FDA, oma@fda.hhs.gov And lastly, we have a lot of information to provide you, therefore we have extended the time for today's webinar, and I'll mention this again later as well, but a recording of today's webinar and a transcript will be posted to the webinar web page and CDRH learn within a week. Thank you all again for joining us. I'll now turn it over to Toby, you Kim,
thank you Kim for the introduction. Good afternoon everyone. Thank you all for attending our webinar today on labeling requirements for in vitro diagnostic products, including laboratory developed tests under 21 CFR 809, dot 10 B as outlined in the preamble to the LDT final rule that FDA issued on May 6, 2024 FDA is phasing out its general enforcement discretion approach for laboratory developed tests LDTs in stages. Under the second stage of the phase out policy, FDA will expect compliance with labeling requirements, including those under 21 CFR, parts 801 and 809 for most, IVDs offered as LDTs by May 6, 2026 during today's webinar, we will be providing information on labeling requirements under 21 CFR 809, dot 10, B and how IVD manufacturers have met these requirements. Today's webinar will specifically focus on labeling requirements for test systems. The learning objectives for today's webinar are to first understand the labeling requirements for in vitro diagnostic products, IVDs under 21 CFR 809, dot 10 B and second, to understand compliance with with these labeling requirements For test systems that are IVDs offered as LDTs to start, let's discuss where 21 CFR 809, dot 10 B sits relative to other labeling requirements. Labeling is defined under Section 201, subsection m of the Federal Food, Drug and Cosmetic Act as all labels and other written, printed or graphic matter upon any article or any of its containers or wrappers or accompanying such article. The Code of Federal Regulations. CFR title 21 describes specific labeling requirements for all medical devices under 21 CFR Part 801 as well as specific requirements for in vitro diagnostic products for human use under 21 CFR Part 809 21 CFR 809, dot 10 is a section within part 809 that requires IVD manufacturers to disclose basic facts about an IVD, such as the intended use, limitations and performance characteristics of the IVD. Within that section, paragraph B describes the requirements for labeling that accompanies an IVD, and this applies to all IVDs, including LDTs. The focus of that of this webinar will be on labeling requirements for test systems under 21 CFR 809, dot 10 B, and will not cover labeling requirements for other types of IVDs, such as collect. Devices and general purpose
reagent the IVD, and helping assure the safety and effectiveness of the IVD. For example, these requirements help ensure that IVD labeling describes the intended use of the IVD, how the IVD should be used. Who should use the IVD, how well the IVD performs, limitations and warnings for the IVD and under what conditions the IVD should not be used. Labeling accompanying an IVD subject to the requirements of 809, dot 10, B may include a package insert for a distributed assay kit or for LDTs, a test protocol, test menu andor test report template, as described in the preamble to the LDT final rule, we anticipate that for LDTs, the information required under 809 dot 10 might be encompassed in more than one document, such as the test protocol, test Report template and test menu under section 502 subsections A and C of the Federal Food, Drug and Cosmetic Act, labeling must prominently display all required information and be truthful and non misleading. An IVD without such labeling would be misbranded. Labeling accompanying an IVD that is developed by the manufacturer is reviewed by FDA during premarket review as applicable, kept on file by the manufacturer, and accompanies the IVD during its clinical use. The manufacturer of the IVD is responsible for developing and maintaining labeling that is compliant with applicable FDA labeling requirements, and for making this information available to FDA upon request during an FDA inspection, as noted on the prior slide, FDA reviews the labeling for some IVDs in general, IVD manufacturers submit their labeling as part of their premarket submission, and FDA reviews the labeling during the review of that submission. Therefore, for IVDs offered as LDTs that are not exempt from premarket review, IVD manufacturers will be submitting their labeling as part of their premarket review submission next for IVDs that are exempt from premarket review, FDA does not generally anticipate receiving premarket review submissions or labeling. FDA also does not generally anticipate receiving premarket review submissions for IVDs that fall within certain enforcement discretion policies described in the preamble to the LDT Final Rule, such as the policies for certain modified versions of another manufacturers 510, K cleared or de novo authorized test or for non molecular anti Sera, LDTs for rare blood rare red blood cell antigens, as noted earlier, manufacturers of such IVDs are expected To have compliant labeling and maintain it on file. Finally, as described in the preamble to the final rule for IVDs that fall within the targeted enforcement discretion policies for LDTs approved by the New York State clinical laboratory Evaluation Program, New York State CLEP LDTs for unmet needs or currently marketed IVDs offered as LDTs, ie those that were first marketed prior to may 6, 2024 where FDA is intending to exercise enforcement discretion for premarket review. FDA intends to request that manufacturers submit labeling information to the agency in connection with the listing of the IVD as provided in 21 CFR 807, dot 20 6e This information will help FDA more closely monitor these IVDs and identify those that may lack analytical validity, clinical validity or safety. FDA may take action where the labeling of an IVD offered as an LDT is in violation of applicable requirements, including where the labeling is false or misleading andor the IVD. Offered as an LDT lacks a reasonable assurance of safety and effectiveness for its intended uses as a result of any such claims that are not adequately substantiated. Turning back to 809 dot 10. B there are 15 paragraphs within 809 dot 10 B, as shown here on the screen. The link on this screen will take you to title 21 of the Code of Federal Regulations where the complete requirements under 809 B are described. Most IBD manufacturers, including laboratory manufacturers choose to include sections in their labeling that align with the paragraph under 809, dot 10, b2, through 13. For example, They do this by including an intended use section, a summary and explanation section, principles of procedure, section, etc, the location of the name of the device and name and place of business is typically at the top of the labeling, and the date of issuance of the labeling is typically found in a header or footer. Two of these paragraphs, five and six apply only to specific types of IVDs, reagents and instruments, respectively. As the focus of today's discussion is labeling for test systems. We will talk a little later in the presentation about how to comply with the requirements in paragraphs five and six for reagents and instruments in the context of labeling for a test system, the other paragraphs under 809, point 10 B apply to all IVDs, including test systems. First, we will walk through the requirements that are applicable to all IVDs. We will be using examples to walk through the requirements and show how IVD manufacturers have complied with each requirement. Today, we will be using examples of test systems approved under a PMA or a humanitarian Device Exemption, since the labeling for those IVDs are publicly available on FDA website. Labeling requirements for 510 k cleared and 510 k exempt IVDs are the same as discussed here. However, FDA does not make the labeling for such IVDs publicly available on FDA website. In other words, the labeling requirements under Part 809 apply to all IVDs, regardless of premarket review requirements. Please keep in mind that these are examples using publicly available information to show approaches manufacturers have used to meet the labeling requirements. Labeling can be presented in various formats, not limited to the examples shown here. We encourage you to review other labeling examples from FDA authorized devices, such as package inserts provided with assay kits you may use, or labeling available through the medical device PMA database on FDA website to help better understand how IVD manufacturers have met IVD labeling requirements for various IVDs. As noted earlier, we anticipate that for LDTs, the information required under 809, dot 10, B might be encompassed in more than one document, such as the test protocol, test report template and test menu. Further, as we walk through the examples, you will see that some manufacturers maintain a primary or summary labeling document that contains most of the necessary elements to meet the requirements of 809, dot 10, B, and additional documents that contain more detailed labeling information, including proprietary information that they do not want made publicly available. This is often the case with laboratory manufacturers, since a detailed test protocol may not be provided to multiple laboratories in these situations, the primary labeling document is the document that FDA might make publicly available on our website, such as for approved PMAs, whereas the detailed documents such as the test protocol would be maintained confidentially
getting started. Subsection 809, dot 10, b1 requires the proprietary and established name be stated and. And some set subsection 809, dot 10, b2 requires inclusion of the intended use or uses and the type of procedure, for example, qualitative or quantitative, the intended use is the general purpose or function of the device, while the intended use statements for IVDs have varied in detail. The intended use of an IVD, as seen in the example below, generally have included the analyte being detected or measured. The purpose of the IVD, the disease or condition the device is intended to diagnose, monitor or predict risk of etc, the test method, including the technology, specimen type and types of results reported the patient population for which the device is intended and the context of use. It is important that the intended use statement is clear and complete, so that users can understand how the IVD is used and the rest of the information in the labeling relative to the intended use. For example, having a clear understanding of the intended use is critical for users to also understand the IVDs limitations and the performance information for the IVD. In addition, during FDA review of an IVD, FDA assesses the IVDs analytical validity, clinical validity and safety based on its intended use in the premarket approval pathway. FDA assesses whether there is a reasonable assurance of safety and effectiveness, including whether the benefits outweigh the risks of the IVD based on its intended use. As you can see in this example, the intended use clearly states the analyte being measured, BRCA one and BRCA two alterations the purpose of the test system aid in identifying a patient population that is eligible for a specific treatment, the disease or condition therapeutic response. The test method, including specimen type and type of results, reported a qualitative next generation sequencing using formalin fixed paraffin embedded ovarian tumor tissue, the patient population, ovarian cancer patients for whom treatment is being considered and the context of use a single site laboratory test system, the
The next requirement, 809, dot, 10, b3, requires a summary and explanation of the test, which must include a short history of the methodology of the test with pertinent references and a balanced statement of The special merits and limitations of the method or product manufacturers generally include a description of the analyte measured and how it relates to the condition being assessed. This slide includes an example of the summary and explanation section of an AAV size total antibody test system used as a companion diagnostic for Octavian as shown on the slide, the summary and explanation section of the labeling includes a summary and explanation of the test system, including the clinical context of the test system, A description of the analyte measured, AAV, five total antibodies, and how the analyte measure relates to the condition being assessed, and a summary of the test system. This section also contains the special merits of the product. The labeling contains in a Warnings and Precautions section, important limitations of the test system. Combined this information, as well as other information in the labeling document, provides a balanced statement of the merits and limitations of the product. The next requirement, 21 CFR, 809 dot, 10, b4 requires the chemical, physical, physiological or biological principles of the procedure be stated and any chemical reactions and techniques involved to be explained concisely. This isn't the step by step instructions which are required under 809, dot, 10, b8, which we will go through in a few slides, but rather an explanation of the underlying scientific mechanisms and techniques used in this test system. This is important for providing users of the test system in. Information on the underlying scientific principles of the test system. This slide includes an example of the principles of procedure section for a polymerase chain reaction or PCR based genetic test system intended to detect kit D, 816, V, mutational status. The blue box highlights the stated biological principles of the procedure, which in this case is genomic DNA detection. The purple boxes highlight the chemical reactions and technique, which in this case is a nucleic acid amplification and detection technique that uses two separate PCR reactions and capillary electrophoresis for PCR product detection. We will cover requirements for reagents and instruments under 809, dot 10, b5 and six after we walk through the rest of the 809 dot 10 B, requirements that are applicable to all IVDs, the next requirement we will cover, applicable to all IVDs, including test systems, is 809 dot 10 b7, which requires information regarding specimen collection and preparing for analysis. 809, dot, 10, b7, requires labeling to state special precautions regarding specimen collection, including special preparation of the patient as it bears on the validity of the test, the additives, preservatives, etc, necessary to maintain the integrity of the specimen, known interfering substances and recommended storage, handling or shipping instructions for the protection and maintenance of stability of the specimen. The requirements within this section are intended to ensure that specimens are collected and prepared under conditions that have been validated as suitable specimens for the test system. These requirements help mitigate risks associated with specimen mishandling that can lead to erroneous test results, helping to ensure that the test system maintains the performance stated within the labeling over the course of its use. Today, we will use three examples to illustrate this labeling requirement. We will first use parts of the labeling for the foundation focus, CDX, BRCA as an example of how labeling requirements for specimen handling and storage have been met for a single site test system from a laboratory manufacturer. For this test system, the manufacturer chose to meet labeling requirements through the use of multiple documents. They created a primary labeling document that includes most information required under 809, dot 10, B and other accompanying documents that contain additional labeling information, as shown on this slide, the primary labeling document for this test points the user to the test requisition form, as well as a specimen preparation instructions document, which are all documents that are part of the labeling for this test system, as noted previously for laboratory developed tests, information required under 809, dot 10 B might be in multiple documents. In this example, the manufacturer provides a box for shipping samples to their laboratory. In this box they include specimen handling and preparation instructions. This document is separate from and in addition to their primary labeling document, this specimen handling document describes what is considered an acceptable sample for the test system, detailed instructions on how to prepare the samples and shipping instructions consistent with 809, dot 10, b7 romanette one. This document includes a section with Warnings and Precautions regarding specimen collection. This section states that biopsy sample collection may pose a risk to the patient when archival tissue is not available, consistent with 809, dot 10, b7, romanette two and three. This document describes how to prepare samples for this test and the additives, preservatives, etc, that are necessary to maintain the integrity of the specimen, namely, that the specimen should be formalin fixed, paraffin embedded. It also includes that other fixatives. Which may interfere with the test system should not be used. It also states that specimens should not be decalcified. And lastly, consistent with 809, dot, 10, b7, romanette, two and four. This document includes the recommended handling instructions for the protection and maintenance of the stability of the specimen. The shipping instructions include information on how to ship the samples, which, in this case, do not require any specialized conditions for shipping. This slide includes two additional examples of specimen collection and preparation sections from other test systems to illustrate different ways information regarding specimen collection and preparation for analysis could be presented. The example on the left side of the screen is for an AAV, five total antibody test system used as a companion diagnostic for ractavian where the specimen is a whole blood sample collected using a 3.2% sodium citrate blood collection tube. As you can see, the test manufacturer includes all information, including the special precautions, additives, preservatives, known interfering substances and recommended storage and shipping instructions in one section in this example, shipping conditions are specified. The samples must be frozen at negative 10 degrees Celsius or below and shipped on dry ice. The labeling on the right side of the screen for a human papilloma virus test system shows an example where the specimen collection and preparation analysis information is divided into subsections for specimen types, specimen storage, specimen shipping and preparation for analysis the process.
Now let's move on to 809, dot 10, b8 which requires statement of a step by step, outline of recommended procedures from reception of the specimen to obtaining results. These requirements are intended to help ensure that labeling accompanying an IVD has adequate instructions for performing the IVD, 809, dot 10, b8 contains six paragraphs describing the information that must be included within the step by step procedures described in the labeling for the test system. This information may be contained in one document or multiple documents, as discussed earlier. For LDTs, most information regarding the procedure is typically contained in the laboratory's test protocol, and only high level information regarding the procedure is included in the primary labeling document. In the case of LDTs with approved PMAs, FDA makes the primary labeling document publicly available through its PMA database. However, the laboratory's internal test protocol may be confidential or proprietary. We will show multiple examples in the coming slides. The first example is from a laboratory manufacturer for a single site test system, looking at the AAV five detect CDX from Arup laboratories, there is high level information on the steps for performing the test system in the principles of the test procedure section of the labeling, there is also information on the reagents and instruments used in the test system in their own section. While this publicly facing document does not have as much detail as a typical package insert for an assay kit, it does contain the basic elements required under 809, dot 10, b8 the laboratories internal test protocol contains more detailed information, but this is not publicly available. Next we will use publicly available examples of package inserts from distributed kits to walk through the detailed procedure information required in each paragraph of 809, dot 10, b8 in general, this level of detailed information is contained in a laboratories test protocol, which may be confidential and proprietary and has not typically been made public by FDA, starting at the beginning. 21 CFR 809, dot 10, b8 romanette one requires labeling accompanying an IVD to include a list of all materials provided with their instructions for. Use 21 CFR 809, dot 10, b8 romanette Two requires labeling accompanying an IVD to include a list of materials required but not provided together. These two requirements ensure that the materials used in the test system are adequately described in the labeling for the Pardo shore test example, all materials are provided, including the collection swab test strip and solvent solution by the manufacturer in a single kit for this test system, there are no materials required but not provided. Therefore 809, dot, 10, b8, romanette two is not applicable for this test system. The next example is of a procedure that lists both materials provided for the test system and materials required for the test system, but not provided. Moving on, 21 CFR 809, dot 10, b8 romanette Three requires that step by step procedures include a description of the amounts of reagents necessary times required for specific steps, proper temperatures, wavelengths, etc. This requirement helps ensure that the labeling provides adequate information for performing each step, including details that are critical to ensure the procedure is performed properly. Going back to the part of your test, example, there are seven steps which include sample collection. The procedure specifies the time The swab should be rinsed by rotating using the solvent solution. It also specifies that results should be read at five minutes and should not be read or interpreted after 10 minutes. Note that while this example includes a relatively straightforward procedure with only seven steps, some more complex test systems may have procedures that are two to three pages or longer. 21 CFR, 809, dot, 10, b8 Roman at four requires a statement describing the stability of the final reaction material to be measured and the time within which it shall be measured to assure accurate results in this part. Osure test, example, the labeling indicates that the intensity of the lines may vary and that faint or uneven lines indicate a stable final result. And as noted in the previous slide, the labeling indicates that results should not be read or interpreted after 10 minutes, to help assure accurate results. 21 CFR 809, dot 10, b8 romanette Five requires labeling accompanying an IVD to have details of calibration for the IVD, including a description of the preparation of reference samples, use of blanks, the preparation of a standard curve, etc, and a description of the range of calibration that includes the highest and the lowest values measurable by the procedure. The Pardo Shure test is a visually read test system and does not require calibration. In this case, 21 CFR 809, dot 10. B8, romanette, five is not applicable. We have included a second example on the slide for the Abbott, real time IDH one test system to show how details of calibration for a test system may be described in this example, the labeling for the Abbott, real time, IDH, one sa kit references the operations manual for the Abbott. M2 1000, RT instrument, an IVD that is required to have its own 809 compliant labeling, where more detailed information on the calibration procedure is located. This section also lists the materials that are necessary for calibration for the Abbott real time, IDH one test system, which are five calibration plates for LDTs a laboratory could similarly point to the operations manual for an instrument if that instrument is appropriately labeled for clinical diagnostic use and is being used in accordance with the intended use for which it is legally marketed, as discussed in the preamble to the final rule LDT manufacturers that use one or more components that are not appropriately labeled for clinical diagnostic use, such as. Research Use Only or Ruo components in their IVDs, offered as LDTs, are responsible for qualifying those components manufactured by another manufacturer, such as instruments, under their own quality system. Therefore adequate information on calibration for the instrument should be provided in the labeling for the LDT when using components that are appropriately labeled for clinical diagnostic use and being used in accordance with the intended use for which it is legally marketed, the manufacturer instead points to the compliant labeling provided by the manufacturer of that component.
21 CFR 809, dot 10, b8 romanette Six requires labeling accompanying an IVD to have details of the kinds of quality control procedures and materials required if there is a need for both positive and negative controls. This should be stated. It also requires that satisfactory limits of performance be stated in the Pardo Shure example, the quality control is an internal procedure control where a line appears on the test strip if the test system is functioning properly. We have included a second example on the slide to show a test system for which separate quality control procedures must be performed in the laboratory, the ADVIA Centaur anti Hepatitis B antigen assay, which is run on the ADVIA Centaur instrument, includes detailed quality control procedures, including the materials needed for performing the quality control, how often the procedure should be performed, and the satisfactory level of performance for the quality controls, which is stated on the package insert for the separately purchased Quality Control material for LDTs, FDA anticipates that quality control information, as with other labeling information, may be in multiple documents, such as a primary labeling document andor the laboratory's internal test protocol. Now we will move to the next requirement under 21 CFR 809 dot 10 b9 which requires labeling to include information on the results produced by the test system, including explaining the procedure for calculating the value of the unknown. 809 dot 10 b9 goes on to require that the labeling give an explanation for each component of the formula used for the calculation of the unknown, and include a sample calculation, step by step, explaining the answer. It also requires that values be expressed to the appropriate number of significant figures for test systems that do not provide quantitative results, 809, dot, 10, b9 requires that there be an adequate description of expected results. We are showing an example of a qualitative single site test system, the AAV detect, CDX, the results section includes descriptions of positive and negative results. The next requirement, 809, dot 10, B 10 requires that the limitations of the procedure be stated, including extrinsic factors or inter interfering substances affecting results and if further testing either more specific or more sensitive is indicated in all cases where certain results are obtained, the need for the additional test shall be stated. The limitations section often contains information on relevant populations in whom the test system is not validated, and limitations on the performance of the test system related to interfering substances, poor performance at specific parts of the claimed measuring range or types of variance where performance is poor or not validated for a genetic test system, as shown In this example, for a single site test system from a laboratory manufacturer. The limitations section includes a statement indicating that the test system is intended for in vitro diagnostic use and for prescription use only. It also includes other important limitations of the test system, for example, that the test system does not detect copy number losses, homozygous deletions in the ATM gene, 809, dot, 10, B 11, requires labeling to describe information on the. Expected values for the test system. Specifically, the range of expected values as obtained with the product from studies of various populations must be stated. How the range was established must be indicated, and the population on which the range was established must be identified. On the screen, we have shown the expected values section of the labeling from two different test systems for both, the section describes information on the expected values in different populations, how the expected values were established and the populations used to establish the expected values for quantitative test systems. This information is most commonly obtained through a reference range study in a healthy population, depending on the test system, there may be a number of different expected values. For example, as shown on the left side of the screen, there may be different reference ranges for men and women. Test systems may also include different reference ranges for pediatric individuals. For qualitative test systems, this section may describe the cutoff for the device and how patients are expected to be distributed around that cutoff, or as shown in the example on the right side of the screen, this has been demonstrated by providing information on the association between test results and different patient populations. 809, dot, 10, B, 12 requires labeling to include information on the specific performance characteristics for the test system. This must include as appropriate information describing such things as accuracy, precision, specificity and sensitivity. These must be related to a generally accepted method using biological specimens from normal and abnormal populations, a statement summarizing the data upon which the specific performance characteristics are based must be included. The specific performance characteristics required to be included in the labeling may include performance characteristics beyond accuracy, precision, sensitivity and specificity, depending on which performance characteristics are relevant for demonstrating the test systems, safety and effectiveness, for example, linearity, performance is applicable for quantitative test systems performance characteristics typically include both analytical and clinical performance. On this slide, we're showing excerpts of some of the performance characteristics in the labeling for a single site test system from a laboratory manufacturer. Each performance characteristic has its own section. The precision section, clearly and concisely describes the study design and data demonstrating the precision of the test system. In this example, the laboratory chose to perform their precision study based on the recommendations in an FDA recognized clinical laboratories, standards, Institute standard. The same is true for other analytical performance characteristics for the test system, such as specificity, which was evaluated by testing for interferences and cross reactivity to other antibodies. In addition performance characteristics relevant to the test type, such as prozone effect and carryover are also described. The last three requirements for labeling for IVD products, including test systems under 809, dot 10 B, require a bibliography of pertinent references keyed to the text the name and place of the business of manufacturer, Packer or distributor, and the date of issuance of the last revision of the labeling. Now let's jump back to 809 dot 10 b5, and 809 dot 10 b6, which include requirements specific to reagents and instruments. Reagents and instruments that are labeled for clinical diagnostic use, ie, labeled for in vitro diagnostic use and not labeled for research or Investigational Use, must have labeling accompanying the product, for example, package inserts that comply with the requirements under 809 dot 10 b5, and 809 dot 10 b6, respectively, as well as other 809 dot 10 B requirements as applicable, as you can see on the slide, which includes excerpts from the full 10. Text, there are several requirements for reagents and instruments respectively. As we move through some examples, we'll discuss the specifics of each of these requirements.
Since today's discussion is focused on the labeling for test systems, let's first look at how the reagent and instrument labeling requirements relate to test system labeling. Generally, most test systems include reagents and instruments. Therefore the test systems must comply with the labeling requirements in 809, dot 10 b5, and 809 dot 10 b6, as applicable, test systems often use reagents and instruments that are labeled for clinical diagnostic use. Some test systems, including LDTs, that use such reagents and instruments in accordance with their labeled intended use, reference the compliant reagent and instrument labeling rather than repeating the reagent and instrument labeling information in the test system labeling, these reagents and instruments are typically listed in the test system labeling as the materials that are required but not provided as required under 809, dot 10, b8, romanette two, so two. In contrast, in some cases, test systems use reagents or instruments that are not appropriately labeled for clinical diagnostic use, such as reagents and instruments intended for Research Use Only, or where the reagents and instruments are being used in the test system in a manner that is not in accordance with their labeled intended use, as discussed in the preamble to the final rule, if a laboratory chooses to use one or more Ruo components in its IVDs offered as LDTs, then the laboratory is responsible for qualifying such components in its IVDs under their own quality system. As such, the laboratory manufacturer is responsible for complying with the applicable labeling requirements, such as including information in the test system labeling to meet the requirements of 809 dot 10 b5, and 809 dot 10 b6, as discussed for other aspects of labeling. For LDTs, FDA anticipates that this information may be contained in more than one document, such as summary information in a primary labeling document, and additional details in other documents, such as a test protocol or reagent and instrument qualification document. Now let's look at a couple of examples of labeling meeting the reagent and instrument requirements. First, at the top, there is an example of labeling for a single site test system from a laboratory manufacturer where, as shown on the slide, high level information on the reagents and instruments used as part of the test system are described in a primary labeling document. In this example, the laboratory manufacturer has provided information on the primary reagents and their storage conditions additional reagents used and the instrument needed for the test system. Laboratories typically include additional detailed information required under 809 dot 10 b5, and 809 dot 10 b6, in their internal test protocol and other laboratory documents not made public by FDA. The next example is an assay kit for which all labeling information is publicly available on FDA website, the Abbott real time, IDH, one test system. The labeling accompanying the assay kit specifies the complete test system, including the instrument and other reagents that are required for the test system but are not provided with the assay kit. Under 809, dot 10, b5, romanette one, labeling for reagents is required to have a declaration of the established name, quantity, proportion or concentration of each reactive ingredient, and for biological material, the source and the measure of its activity. This information must be stated in the system, generally used and recognized by the intended user of the reagent. In the example on the slide, this is percentages, milliliters and units per microliter. Paragraph, 809, dot 10, b5, romanette one also requires a statement indicating the presence of and characterizing any catalytic or non reactive ingredients, such as buffers, preservatives, state. Lasers, for example, as shown on the slide, the labeling states that the active ingredients are in a buffered solution with preservatives, sodium azide and point one, 5% pro Quinn, 950, paragraph, 809, dot, 10, b5 romanette Two requires reagents have a statement of Warnings and Precautions for users, as established in the regulations contained in 16 CFR Part 1500 and any other warnings appropriate to the hazard presented by the product, A statement for in vitro diagnostic use, any other limiting statements appropriate to the intended use, and as applicable, a limiting statement appropriate for the intended use of a prescription IBD for reagents, statements addressing any hazards or safety precautions for handling The reagent are included in this section, this requirement is intended to help ensure user safety. Looking at the same FA kit example, the publicly available labeling includes warnings regarding reagent handling and a statement that the system is for in vitro diagnostic use. This next slide shows the remaining requirements under 809, dot, 10, b5, romanette, two limiting statements as shown here for the Abbott, real time. IDH, one test system limiting statements appropriate for the intended use of the reagents in the assay kit are included in a special precautions section, among other places, the labeling for this assay kit also states it is for prescription use only. Paragraph 809, dot 10, b5, romanette three requires adequate instructions for reconstitution, mixing, dilution, etc, for the reagents in a test system. If reconstitution mixing, diluting, or other manipulation or processing of the reagent is not needed, this requirement is not applicable, as shown in this example, the reagent does not need reconstitution, mixing or diluting, but does need to be thawed in a specific temperature range. Paragraph 809, dot 10, b5, romanette four requires labeling accompanying a reagent to have appropriate storage instructions adequate to protect the stability of those reagents for products requiring manipulation, such as reconstitution andor mixing before use, appropriate storage instructions shall be provided for the reconstituted or mixed product. This example of labeling for an assay kit includes instructions that the assay reagent kit must be stored at minus 25 to minus 15 degrees Celsius. It also includes instructions for storage of the reagents once they are thawed and mixed with other reagents to form a Master Mix. Paragraphs, 809, dot 10 b5, romanette five and 809, dot 10 b5, romanette Six require labeling accompanying a reagent to have a statement of any purification or treatment required for use and physical biological or chemical indications of instability or deterioration, respectively. In the example on the slide, the manufacturer has specified specific thawing conditions as well as indications of instability or deterioration of the reagents.
Now let's move on to requirements specific to instruments, as with other labeling information for LDTs, FDA anticipates that labeling information specifically required for instruments may be in more than one document, such as a laboratory's test protocol, the instruments, operations, manual or other laboratory documents. We will walk through the same distributed test system, example, for instruments as we did for reagents. Paragraphs, 809 dot 10 b6, romanette 1809, dot 10 b6, romanette two and 809 dot 10 b6, romanette three require statements of the instruments, use or function installation procedures and special requirements and principles of operation, respectively. In the example on the slide, the use or function is included in the intended use section. The installation procedures and special requirements are included in the instrument section, and the principles of operation are included in the biological principles of the procedure section. The FA kit labeling here specifies the instrument and other required but not provided materials to be used as part of the test system. The test system labeling refers to the labeling of the Abbott m2 1000 RT instrument which is sold separately. That instrument is intended for clinical diagnostic use, ie it is not for research or Investigational Use, so its labeling is required to comply with all applicable labeling requirements for instruments, including that its label bear a statement that the instrument is for in vitro diagnostic use, detailed information about the instrument is included in the instruments compliant labeling and is not repeated in the test system labeling, which instead refers to the instrument labeling. A similar approach has been taken for labeling for other IVDs that use instruments legally marketed and appropriately labeled for clinical diagnostic use, ie labeled for in vitro diagnostic use. Paragraph 809, dot 10 b6 Roman at four requires the performance characteristics and specifications be stated. The performance characteristics required under 809, dot 10 b6 for instruments used in a test system are the same as those described under, 809 dot 10 B 12, as described earlier. 809 point 10 B 12 requires labeling include information on the specific performance characteristics for the test system, this must include as appropriate information describing such things as accuracy, precision, specificity and sensitivity. The specific performance characteristics required to be included in the labeling may include performance characteristics beyond accuracy, precision, sensitivity and specificity, depending on which performance characteristics are relevant for demonstrating safety and effectiveness. For instruments that are already accompanied by compliant labeling, as discussed on the previous slide, the instrument specifications are described in such labeling, such as an instrument Manual Test System. Labeling using such instruments typically include the instrument labeling by reference, as described in the previous slide, as described previously, where LDT manufacturers that are qualifying an instrument that is not accompanied by compliant labeling for use as part of a test system. Under their quality system, the laboratory manufacturer is responsible for complying with the applicable labeling requirements, such as including the specifications qualified by the laboratory in the labeling for the LDT to meet the requirements of 809 dot, 10, b6, Roman at four. FDA anticipates that this information most often would be in an internal, laboratory specific document and not in a primary labeling document. Paragraph, 809, dot 10, b6, romanette five requires labeling accompanying an instrument to state the operating instructions for the instrument, as shown on the slide for the Abbott IDH one system the assay kit labeling references the operations manual for the Abbott m2 1000 RT instrument, which includes information specific to how to operate the instrument for the specific IDH one test system. Paragraph 809, dot 10. B6 romanette Six requires labeling accompanying an instrument to state the calibration procedures, including materials andor equipment to be used, as shown on the slide for the Abbott IDH one test system, the FA kit labeling references the operations manual for the Abbott m2 1000 RT instrument, which includes the calibration information. This information might look familiar as it is, the same information used in our example on slide 26 for describing the details of calibration as part of a test system procedure. So. Paragraphs, 809, dot 10, b6 romanette, seven, eight and nine require labeling accompanying an instrument to state the operational precautions and limitations, hazards and service and maintenance information, respectively. The labeling for the Abbott IDH one test system references the operations manual for the Abbott 2000 RT instrument and states that laboratory personnel must be appropriately trained and follow good laboratory practices. That concludes our walkthrough of examples of how IVD manufacturers have complied with the labeling requirements under 809 dot 10 B for labeling accompanying an IVD, we recognize that we've covered a lot of information in a short time. To summarize, it's important to keep in mind that the labeling requirements under 809, dot 10, B are intended to help ensure that IVD labeling has a consistent set of information critical to understanding IVDs and helping assure the safety and effectiveness of IVDs when considering how to develop appropriate and adequate labeling for an IVD. Manufacturers often consider the intended use of the IVD and focus on clarity and completeness for the intended user. Most IVDs offered as LVTs are generally expected to comply with FDA labeling requirements by May 6, 2026 as described in the preamble to the LDT Final Rule, there are targeted enforcement discretion policies that may apply to certain IVDs offered as LDTs. And for certain policies, FDA intends to request labeling for those IVDs at the time of device listing, there are many examples of IBD labeling publicly available on FDA website that reflect different approaches used to comply with the labeling requirements, as stated in the preamble to the LDT final rule and Throughout today's webinar, FDA anticipates that for LDTs, the required labeling information may be encompassed in more than one document, such as a primary labeling document, as well as the test protocol, test report template and test menu. And that's the end of today's presentation on labeling for IVDs, including LDTs. We hope that this has been helpful in providing an overview on how to comply with labeling requirements for test systems under 809, dot 10 B, our next webinar related to FDA final rule on LDTs will be October, 24 2024 from one to 2pm Eastern Time, and will provide an overview of FDA total product lifecycle approach to in vitro diagnostic products. We hope that you will join us for the October and future webinars. This slide and the next include resources and references mentioned during today's webinar.
Thank you for that presentation, Toby, and we apologize for the brief noise interference at the beginning of the presentation. We will now transition to address some of your previously submitted questions related to today's topic. For this segment, I'll read a question aloud, and then Toby will provide a response. We will not be taking live questions during today's webinar, therefore, please refrain from raising your hand in zoom. So Toby, let's get started. Our first question is, FDA has stated that the agency intends to request submission of labeling for certain IVDs offered as LDTs at the time of device listing. What does this mean, and what is the scope of FDA review of this labeling.
Thanks, Kim for IBDs that fall within the enforcement discretion policies for New York State. CLEP, unmet needs or currently marketed IBDs offered as LDTs, ie, those mark, those first marketed before May 6, 2024, where FDA is intending to exercise enforcement discretion for premarket review, FDA intends to request that manufacturers submit labeling information to the agency in connection with the listing of the IBD as provided in 21 CFR 807, 20 6e as described in the preamble to the LDT Final Rule. Labeling includes IVD performance information and a summary of supporting validation as applicable. In particular, this information will help FDA more closely monitor IVDs offered as LDTs under these enforcement discretion policies and identify those that may lack analytical validity, clinical validity or safety, helping with FDA post market oversight for these IBDs, for example, as part of its review of labeling for currently marketed IBDs offered as LDTs, FDA intends to look closely at claims of superior performance and whether those claims are adequately substantiated. FDA generally intends to take action where the labeling of an IVD offered as an LDT is false or misleading andor the IDD offered as an LDT lacks the appropriate assurance of safety and effectiveness for its intended uses as a result of any such claims that are not adequately substantiated.
Thanks. Toby, okay, so for our next question, that question is, Will enforcement discretion be applied to promotional materials?
As described in the preamble to the final rule, FDA expects compliance with labeling requirements for most IVDs offered as LDTs by May 6, 2026 labeling may include promotional material. The term labeling is defined in the Federal Food, Drug and Cosmetic Act as including all labels and other written, printed or graphic matter upon any article or any of its containers or wrappers or accompanying such article such materials must comply with labeling requirements, including the requirement To be truthful and non misleading labeling that is not truthful or that is misleading would result in the product being misbranded as part of its labeling review. FDA also intends to look closely at claims of superior performance and whether such claims are adequately substantiated. Such claims are of particular public health concern because in FDA experience, they have led to escalating claims from competitors that can ultimately mislead the public. FDA generally intends to take action where labeling, including promotional materials for an IVD are false or misleading, or where the test lacks appropriate assurance of safety and effectiveness for its intended uses as a result of any claims that are not adequately substantiated, as described in the preamble to the final rule, FDA generally does not expect compliance with applicable requirements, including labeling requirements for IVDs offered as LDTs under certain enforcement discretion policies, including 1976 type LDTs, HLA tests for transplantation, forensic tests and LDTs manufactured and performed within DOD and VHA.
Thanks again. Toby, so our next question is, what are the FDA expectations regarding labeling for LDTs?
Thanks, Kim again, as described in the preamble to the final rule, FDA expects compliance with labeling requirements for most IVDs offered as LDTs by May 6, 2026 the IVD labeling requirements set forth in 21 CFR 809, dot 10, B specify the information that must be included in labeling accompanying each product, such as a package insert. However, the regulations do not require that the labeling be in the form of a package insert, as described in the preamble. FDA anticipates that for LDTs, the information required under 21 CFR 809, dot 10, B might be encompassed in more than one document, such as the test protocol, test report template and test menu in FDA is experienced to date. Most, many, most laboratory manufacturers have met the requirements of 809 dot 10 b by maintaining a document summarizing the information required under 809 dot 10 B and additional documents that contain more detail, such as the test protocol, test report template and test menu, which may include proprietary information in these situations, FDA refers to the summary as the primary labeling document for PMAs. FDA makes the primary labeling document publicly available on our website, whereas other detailed documents were. Referenced in the primary labeling document, such as the test protocol, would be maintained confidential confidentially. Manufacturers are responsible for having compliant labeling and maintaining it on file, regardless of whether it is submitted to FDA for IVDs subject to premarket review, proposed labeling is generally required to be submitted as part of a pre market submission, as described in the preamble to the final rule for IBDs that fall within certain targeted enforcement discretion policies for which FDA intends to exercise enforcement discretion with respect to pre market review, specifically the targeted enforcement discretion policies for LDTs approved by the New York State clinical laboratory Evaluation Program, New York State club certain LDTs for unmet needs and currently marketed IVDs offered as LDTs, ie those that were first marketed prior to may 6, 2024 FDA intends to request that manufacturers submit labeling information to the agency in connection with the listing of the IDD as provided in 21 CFR 807, dot 20 6e.
Thanks again. Toby, that was a lot of information. Okay, so for our next question, that is, what are the labeling expectations for reagents and instruments used as part of an LDT, but not manufactured by the laboratory?
Thanks Kim, reagent and instrument specific labeling requirements can be found in 21 CFR 809 dot 10 b5, and 21 CFR 809 dot 10 b6, respectively. These requirements must be met for any test system for clinical diagnostic use that uses reagents andor instruments. Test systems often use reagents and instruments that are labeled for clinical diagnostic use. Some test systems, including LDTs, that use such reagents and instruments in accordance with their labeled intended use, reference the compliant reagent and instrument labeling rather than repeating the reagent and instrument labeling information in the test system labeling. These reagent and reagents and instruments are typically listed in the test system labeling as the materials that are required but not provided as required under 809, dot 10, b8, romanette Two. In contrast, some, in some cases, test systems use reagents or instruments that are not appropriately labeled for clinical diagnostic use, such as reagents and instruments intended for Research Use Only, or where the reagents and instruments are being used in the test system in a manner that is not in accordance with their labeled intended use, as discussed in the preamble to the LDT final rule, if a laboratory chooses to use one or more, are you, oh, components in its IVDs offered as LDTs, then the lab, then the laboratory is responsible for qualifying such components in its IVDs under their own quality system as such, the laboratory manufacturer is responsible for complying with the applicable labeling requirements, such as including information in the test system labeling to meet the requirements of 809 dot 10 b5, and 809 dot 10 b6, as discussed for other aspects of labeling. For LDTs, FDA anticipates that this information may be contained in more than one document, such as summary information in a primary labeling document and additional details in other documents, such as a test protocol or reagent and instrument qualification documentation.
Great. Thanks Toby. And we have one more question for today, and that question is, what are the labeling expectations around performance characteristics, and how does that differ from what is expected to be included in a pre market submission?
Thanks. Kim 21 CFR 809, dot 10, B 12 requires labeling to include information on the specific performance characteristics for the test system. This must include as appropriate information describing such things as accuracy, precision, specificity and sensitivity. These must be related to a generally accepted method using biological specimens from normal and abnormal populations, a statement summarizing the data upon which the specific performance characteristics are based must be included. The specific performance characteristics required to be included in the labeling may include. Performance characteristics beyond accuracy, precision, sensitivity and specificity, depending on which performance characteristics are relevant for demonstrating the test systems safety and effectiveness, for example, linearity performance is relevant for quantitative test systems. Performance characteristics typically include both analytical and clinical performance. While labeling for a test system must include a summary of the data. Additional details of the validation are generally expected in a pre market submission.
Thanks again. Toby, that will wrap up our previously submitted questions for today. I'd like to thank everyone who submitted questions in advance of today's webinar, as well as to Toby and her team for developing responses to these questions and presenting them to us today. Toby, I'd like to turn it back over to you to provide any final remarks on today's topic.
Thanks, Kim. I just want to thank everyone again for joining us today. Hopefully this has been helpful to get a better understanding of the labeling requirements for IBDs under 21 CFR 809, dot 10 B and compliance with these labeling requirements for test systems that are IVDs offered as LDTs. We look forward to future webinars, and hope you'll be able to join us for those too.
Thanks again. Toby, so for your information, printable slides of today's presentation are currently available on the CDH events page for this webinar, as well as on CDH learn at the link provided on this slide under this section titled in vitro diagnostics, as I mentioned earlier, a recording of today's webinar and a transcript will be posted to the webinar webpage and CDH learn within the following week, and a screenshot of where in CDH learn you can find these materials has been provided on this slide. If you have additional questions about today's webinar, feel free to reach out to us in dice, at dice@fda.hhs.gov and last lastly, as Toby mentioned previously, our next IBD related webinar on the topic of FDA total product lifecycle approach to IBDs will be held on october 24 from one to 2pm Eastern time. You can find information on how to attend this webinar and any of our upcoming webinars on our CDH events page, and the link to this page is provided on the bottom of the slide. Thank you all again for joining us. This concludes today's CDH webinar. Applause.
