In Vitro Diagnostic Devices: Guidance for the Preparation of 510(k) Submissions - Appendix C - Points To Consider Regarding Labeling And Premarket Submissions For Home-Use In Vitro Diagnostic Devices

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APPENDIX C - POINTS TO CONSIDER REGARDING LABELING AND PREMARKET SUBMISSIONS FOR HOME-USE IN VITRO DIAGNOSTIC DEVICES

1. Purpose
   The purpose of this document is to assist prospective manufacturers, producers, and marketers (hereinafter called manufacturers) of home-use in vitro diagnostic devices (IVDs) in complying with existing labeling regulations, e.g., 21 CFR 801 and 809.10; premarket clearance requirements e.g., Sections 510(k) and 515 of the Federal Food, Drug, and Cosmetic Act (the Act); and other regulations, including 21 CFR 814.
   CDRH believes that both prospective manufacturers of home-use IVDs and CDRH reviewers will be better able to evaluate the safety and effectiveness of these devices when supporting information based on the following considerations is submitted to CDRH in an appropriate premarket submission. Moreover, CDRH believes that as a result of these considerations the general public health will be better served by the availability of meaningful and reliable home-use IVDs.
2. Background
   In vitro diagnostic devices (IVDs) as defines in 21 CFR 809.3(a) are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. These products are intended for use in the collection, preparation, and examination of specimens taken from the human body. This document, therefore, addresses home-use testing kits as well as home-use mail-in specimen collection kits.
   Traditionally, IVDs have been used primarily by hospitals, clinical laboratories and physicians' offices. In recent years, however, there has been increasing interest in home-use IVDs. Because of this growing interest, FDA's Center for Devices and Radiological health (CDRH) anticipates receiving an increasing number of premarket product submissions, i.e., premarket notifications of premarket approval applications, for these devices. Consequently, CDRH believes that uniform evaluation criteria for home-use IVDs are needed to better ensure that these devices are regulated in a consistent fashion and that consumers are provided with reliable, useful, and adequately labeled products. To this end, CDRH, over the past year, has solicited views from various industry, consumer, and health professional organizations to help identify the issues to be resolved by CDRH in developing evaluation criteria for home-use IVDs. In addition, on September 9, 1985, CDRH convened a public meeting of the chairpersons, the consumer representatives, and the industry representatives of the Immunology Devices Panel, the Microbiology Devices Panel, the Hematology and Pathology Devices Panel. The purpose of this meeting was to solicit the views of these individuals and other interested persons regarding general issues of the safety and effectiveness of home-use IVDs.
   The present document reflects CDRH's views on key points to be considered by prospective manufacturers of home-use IVDs in establishing the safe and effective use of home-use IVDs. These views are significantly based on the input CDRH has received from the aforementioned outreach activities.

3. Factors CDRH Will Consider in Evaluating the Safety and Effectiveness of Home-Use IVDs

   1. Risk/Benefit Considerations
      In terms of function, home-use-IVDs are essentially the same as other clinical laboratory devices in that they are intended to detect and/or measure particular analytes, e.g., antigens, antibodies, hormones, or drugs, in human specimens. The significance of the test results will depend on the analyte's relationship to other medical patient data. Home-use IVDs are different from clinical laboratory devices in three important ways: (1) the person performing the test likely lacks the necessary medical training to evaluate other related medical information, such as pertinent personal or family medical history, other analyte levels, and the results of a complete physical examination; (2) the person performing the test may lack the technical training of laboratory technologists who usually perform laboratory tests, and may not interpret directions carefully; and (3) the person performing the test may or may not carry out necessary follow up actions on the basis of test results. Hence, a major factor CDRH must consider in evaluating the safety and effectiveness of home-use IVDs is the probable health benefit(s) to be gained by lay persons in the use of such devices compared to the probable risks associated with their use. Consequently, CDRH will consider the following questions relative to assessing risk/benefit factors:
      Benefits

      1. What is the clinical benefit of the test to the patient or society (public health) in terms of screening, diagnosing, or monitoring a particular disease, condition, or risk factor?
      2. What are the benefits to the patient or society of having the test available for home-use as opposed to having the test performed by health care professionals?

      Risks

      1. What is the impact on the user or to society of a false-positive or false-negative test result, e.g., in terms of user follow up of adverse medical conditions?
      2. What are the risks to the user or society in terms of delay in obtaining a professional examination if a proposed home-use IVD that is intended for use on symptomatic subjects gives a false or equivocal result?

      CDRH encourages prospective manufacturers of home-use IVDs to assist CDRH in assessing risk/benefit factors by addressing the above questions in an appropriate premarketing submission.

      CDRH recognizes that, for evaluation purposes, responses to these questions can vary based on the type of product being considered. Hence, an acceptable risk/benefit ratio is not based on uniform answers to the questions posed.

   2. Performance Considerations
      Another key factor CDRH must consider in assessing the safety and effectiveness (risk/benefit) of home-use IVDs is test performance. Because the great majority of proposed home-use IVDs are likely to be derived from professional use IVDs, it is expected that there will be a clear and established relationship between the analyte to be tested using the home-use IVD and a specific medical disorder or condition. Because home-use IVDs function essentially the same as professional-use IVDs, their performance characteristics can be defined in terms of traditional performance parameters such as sensitivity, specificity, accuracy, and reproducibility of test results. Nevertheless, the performance of the device in the hands of skilled users may not reflect the device's performance in the hands of lay users. Consequently, CDRH recommends that manufacturers of home-use IVDs focus their attention on the following performance considerations:

      1. For a given intended use, home-use IVDs should perform as well as their professional-use IVD equivalents, i.e., the ability of the home-use IVD to detect and/or measure a particular analyte of interest (analytical performance) should compare favorably with IVDs used in clinical settings that are intended for the same purpose;
      2. Home-use IVDs should be designed with a view to ensuring that the device's performance will not be appreciably affected by anticipated variation in user technique; and
      3. Home-use IVDs should include a simple method by which the user can reasonably verify that the product's performance meets its design specifications throughout the shelf-life of the product. That is, a user quality control test should be provided or "built into" each home-use IVD (see 21 CFR 809.10(a)(b)(6).) Omission of such a test should be justified based on scientific merit.

   3. Labeling Considerations
      Acceptability of home-use IVD labeling will depend upon whether such labeling meets the criteria for "adequate directions for use" as provided for in section 502(F)(1) of the Act and 21 CFR 801.5. In addition, 21 CFR 801.119 provides that all IVDs (including home-use IVDs) shall be deemed to be in compliance with the requirements for adequate directions for use if they meet the requirements of 21 CFR 809.10-Labeling for In Vitro Diagnostic Products.
      Inherent in the concept of "adequate directions for use" is the need for the labeling of home-use IVDs to be simple, concise, easy to understand, make liberal use of illustrations and drawings, use bold print or other methods to highlight warnings and precautions, and provide color coding of reagent containers whenever practicable.
      Although CDRH believes that the labeling requirements as provided for in 21 CFR 809.10 are generally adequate for home-use IVDs, these regulations have been promulgated primarily to address professional-use IVDs and some qualification of these requirements for home-use IVDs may be useful as follows:

      Labeling information must comply with the requirements of 21 CFR Part 801, subpart C - Labeling requirements for over-the-counter devices and 21 CFR Part 809, Subpart B, section 809.10 - Labeling for In Vitro Diagnostic Products unless specifically addressed by the following:

      Section 809.10(a)

      1. The intended use statement (section 809.10(a)(2)) should clearly indicate on the outside packaging container the type of procedure that is offered, i.e., screening, monitoring, or diagnostic, and the specific disorder, condition, or risk factor of interest for which the test is intended. In addition, a statement also should be presented indicating who should use the test and the conditions for its use, followed by a contraindication statement(s), if necessary.
      2. The quantity, proportion, concentration, or activity of each reactive ingredient included with the test kit need only be presented as specified by section 809.13(a)(3) when information is necessary for proper lay use of the test.

      Section 809.10(b)

      The order and scope of the information specified by this section should be as follows:

      1. The intended use statement should reiterate the information required under section 809.10(a).
      2. Section 809.10(b)(3), summary and explanation of the test, may be combined with section 809.10(b)(4), principles of the procedure. This combined section should include a discussion of both the medical benefits and limitations of the test with respect to its intended use in addition to providing a simple explanation of how the test works. Presentation of chemical reactions or formulas is not necessary, but they may be referenced in the bibliography (section 809.10(b)(13)).
      3. A separate information section, interpretation of test results, should be presented and should include information specified by section 809.10(b)(10), limitations of the procedure. Thus, this section should indicate the significance of the test results in light of the test's intended use and provide specific information as to what appropriate follow-up action should be taken by the user. Additionally, this section should explain the meaning of false-positive and false-negative test results and cite possible sources and implications of false results.
      4. A separate information section should be presented which discusses/lists any foods, medications, or other possible interfering substances that would affect test results. Such information should specify what substances should be avoided and for how long prior to testing.

      5. Information specified in sections 809.10(b)(5),(6),(7), and (8) may be combined into a single information section, i.e., test procedure. All information specified by these individual sections should be presented in the combined section if applicable, in addition to the following:

         1. As previously stated, the quantity, proportion, concentration, or activity of each reactive ingredient included in the test kit need not be presented unless this information is necessary for proper use of the test. However, such information should be presented elsewhere in a premarket submission for CDRH review.
         2. Discussion of specimen collection, preparation, and analysis steps should be enhanced by the use of pictures and illustrations, preferably in color.
      6. Information specified by section 809.10(b)(9), test results, should be presented. This section also should include troubleshooting information.
      7. Information specified by sections 809.10(b)(11) and (12) may be combined into a single information section, i.e., test performance characteristics. This section should summarize the data (separately) from both the laboratory evaluation and the consumer field evaluation (see III above) and should include a concise discussion and/or presentation of data relative to the test's accuracy should be presented and should include false-positive and false-negative levels. Such information should be presented for both the laboratory and the consumer field evaluations.
      8. Sections 809.10(b)(13), (14) and (15) should be addressed in the same manner as other IVDs.
         In addition, CDRH recommends that manufacturers provide users with a toll-free telephone number or an address to write to should questions occur concerning the use of the device.
         Finally, CDRH is concerned that consumers be aware of significant changes in home-use IVD labeling, particularly labeling accompanying frequently used devices such as home-use glucose test devices. CDRH advises manufacturers to alert consumers of significant labeling changes by including special inserts with device packaging which highlight key labeling changes. Moreover, CDRH advises manufacturers that labeling changes that significantly impact on a device's safe and effective use may require premarket review and clearance by CDRH before commercial distribution of devices bearing such labeling.

   4. Premarket Evaluation Considerations
      
      Given the above considerations, CDRH recommends that prospective manufactures of home-use IVDs conduct the following performance studies and submit results to CDRH for review in an appropriate premarket submission:

      1. A laboratory evaluation of the analytical performance of the device, e.g., analytical sensitivity, analytical specificity, accuracy, and reproducibility, should be done by performing standard laboratory measurements using appropriate reference tests. The purpose of this evaluation is to establish the "true" performance characteristics of the device as determined under controlled laboratory conditions. Also,

      2. A consumer field evaluation of the device should be conducted to determine the device's performance when used by lay users, unassisted, following instructions provided in the labeling.
         CDRH places considerable importance on the outcome of the consumer field evaluation (item 2 above) in assessing the safety and effectiveness of home-use IVDs. Consequently, the following additional suggestions are offered with respect to the goals, conduct, and analysis of such studies.

         1. The primary goal of the consumer field evaluation should be to establish comparable levels of test performance for a particular home-use IVD when comparison-tested by both intended users and trained laboratory personnel. It is suggested that split clinical samples be tested by both lay users and trained laboratory personnel with both groups using the home-use IVD. Such testing will simultaneously validate the technical performance characteristics of the device and the device's labeling based on user experience.
         2. In order to assess the ability of lay users to properly perform and interpret test results, CDRH recommends that manufacturers provide simple questionnaires to study participants as part of the consumer field evaluation to determine if lay users can read and understand the labeling. For example, a questionnaire could be used to determine if the user understands the purpose of the test, the conditions for its use, the test's limitations, the meaning of the results and appropriate follow up.
            It is recommended that samples of such questionnaires be included in a premarket submission, as well as a tabulation of all study participants' responses to each question.
         3. Lay users selected for the study should be representative of target users for which a test is intended. A representative study population may require the selection of individuals of varies background, education levels, and age groups. Consequently, subjects should be selected for testing based on carefully developed selection criteria. The basis for establishing the selection criteria should be submitted to CDRH along with the study protocol and test results.
         4. The number of subjects selected for testing should be sufficient to substantiate that all targeted lay user populations can perform and interpret the test. It is highly recommended that the number of subjects selected for study be based on a statistically valid sampling of relevant lay users and should take into account appropriate demographic factors. Moreover, test results should be analyzed using appropriate statistical methods to demonstrate correlation between lay users and trained technologists performing the test.
         5. To avoid potential problems of bias during data collection and evaluation, the consumer field study, ideally, should have double blind design. However, in studies where such a design is impossible or impractical, a single blind approach and other measures to reduce potential bias may be acceptable