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Assessing the Safety and Effectiveness of Home-Use In Vitro Diagnostic Devices (IVDs): Draft Points to Consider Regarding Labeling and Premarket Submissions (Text Only)

This guidance was written prior to the February 27, 1997 implementation of FDA’s Good Guidance Practices, GGP’s. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be updated in the next revision to include the standard elements of GGP’s.

Assessing the Safety and Effectiveness of Home-Use
                    In Vitro Diagnostic Devices (IVDs):
                         Draft Points to Consider 
               Regarding Labeling and Premarket Submissions
                         
                  Center for Devices and Radiological Health
                               October 1988
                                                
                                     
                                     
I.   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 801.5, 809.3(a) and 809.10, and premarket
     clearance requirements, e.g., Sections 510(k) and 515 of the
     Federal Food, Drug, and Cosmetic Act (the Act), and
     regulations including 21 CFR Parts 807 and 814.  This
     document addresses home-use testing kits and home-use
     mail-in specimen collection kits.


II.  Background

     In vitro diagnostic devices (IVDs) as defined 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.

     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, where no physician is involved to interpret
     the test results.

     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 or 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, in
     the spring of 1985, CDRH 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, and the Clinical Chemistry and
     Clinical Toxicology 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 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.


III. Factors CDRH will Consider in Evaluating the Safety and
     Effectiveness of Home-use IVDs


     A.   Performance Considerations

          A key factor CDRH must consider in assessing the safety
          and effectiveness 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,
          manufacturers of home-use IVDs should focus their
          attention on the following performance considerations:

          1.   For a given intended use, the ability of the
               home-use IVD to detect and/or measure a particular
               analyte of interest (analytical performance)
               should be comparable to the performance of IVDs
               intended for the same purpose that are used by
               professionals in clinical settings;

          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 at the time of use.  Ideally, a
               user quality control test should be provided or
               "built into" each home-use IVD (see 21 CFR
               809.10(a)(6).)  Omission of such a test or other
               reasonable means of verifying product performance
               should be justified based on scientific merit.


     B.   Risk/Benefit Considerations

          Home-use IVDs are different from clinical laboratory
          devices in four important ways:  (1) the person
          performing the test or reviewing the results returned
          from a clinical laboratory 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 traditionally have
          performed laboratory tests and may not interpret
          directions carefully; (3) the person performing the
          test may or may not carry out necessary follow-up
          actions on the basis of test results; and (4) the
          person collecting a sample of a body specimen and
          mailing it to a clinical laboratory generally lacks the
          technical training of persons who traditionally have
          collected or supervised the collection of body
          specimens, and supervised the transport of the
          specimens to the test laboratory.  Thus the person may
          not ensure that the specimen that arrives at the
          clinical laboratory is in the same condition as it was
          when it was collected (e.g. ensuring that the analyte
          to be measured does not degrade because of passage of a
          long period of time from specimen collection until
          analysis, or ensuring that a specimen is not exposed to
          extremes of hot or cold temperatures or other
          environmental hazards that may affect the test
          results).

          Hence, in evaluating home-use IVDs, CDRH must consider
          probable health benefits to be gained in the use of
          such devices compared to the probable risks associated
          with their use.  In this context, consideration of
          benefit and risk is inherent in the evaluation of
          safety and effectiveness.

          When the use of an in-home IVD can be demonstrated to
          be substantially equivalent, in terms of safety and
          effectiveness, to a clinical laboratory device when
          used by a health professional, and the device meets all
          labeling and other regulatory and statutory
          requirements, it will generally satisfy requirements
          for market clearance.  When unique issues of safety and
          effectiveness arise and substantial equivalence cannot
          be demonstrated, CDRH will nonetheless evaluate benefit
          and risk factors in making determinations with respect
          to the marketability of in-home IVDs.  For purpose of
          assessing these benefit and risk factors CDRH will
          consider the following questions and encourage
          applicants to provide relevant information in their
          submissions.


          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 only 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 or 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 recognizes that for evaluation purposes, responses
          to these questions can vary based on the type of
          product being considered.


     C.   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 defined by 21 CFR 801.5, and
          the requirements of Subpart C of 21 CFR Part 801.  In 
          addition, home-use IVDs will 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.

          Labeling for IVDs intended for home and professional
          use are covered by 21 CFR 809.10.  The following
          elaborates on the application of the regulation to the
          home-use situation and suggests means of accomplishing
          compliance:


     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 statements), 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 809.10(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
               combination of sections 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 are not
               necessary but may be referenced in the
               bibliography (section 809.10(b)(13)).


          3.   A separate information section relating to
               interpretation of test results, should be
               presented and include information specified by
               section 809.10(b)(10), limitations of the
               procedure.  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 identifies 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:

               a.   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.

               b.   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 trouble-shooting information
               where applicable.

          7.   Information specified by sections 809.10(b)(11)
               and (12) may be combined into a single information
               section, i.e., test performance characteristics. 
               m is section should summarize the data
               (separately) from both the laboratory evaluation
               and the consumer field evaluation (see III
               Premarket Evaluation Considerations) and should
               include a concise discussion of the study
               protocols used to evaluate the test's performance. 
               Also, discussion and/or presentation of data
               relative to the test's accuracy should be
               presented and 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 high frequency use 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.


     D.   Premarket Evaluation Considerations

          Given the above considerations CDRH recommends that
          prospective manufacturers of home-use IVDs conduct the
          following performance studies and submit results to
          CDRH for review in an appropriate premarket submission:

          A.   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; and,

               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 B 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 study should be
               representative of target users for which a test is
               intended.  A representative study population may
               require the selection of individuals of varied
               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.   Ideally, to avoid potential problems of bias
               during data collection and evaluation of the
               consumer field study, a double blind design should
               be used.  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.  The manufacturer should
               be careful to select the appropriate type of study
               to ensure that the study will provide appropriate
               information.


     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 above 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.



10/5/88