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8.3: Regulation of Clinical Tests

  • Page ID
    39521
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    In Vitro Diagnostics (IVDs)

    In vitro diagnostics are tests done on samples such as blood or tissue that have been taken from the human body. In vitro diagnostics can detect diseases or other conditions and can be used to monitor a person’s overall health to help cure, treat, or prevent diseases. In vitro diagnostics may also be used in precision medicine to identify patients who are likely to benefit from specific treatments or therapies. These in vitro diagnostics can include next-generation sequencing tests, which scan a person’s DNA to detect genomic variations. Some tests are used in laboratory or other health professional settings and other tests are for consumers to use at home.

    IVD Oversight

    Under the inter-center agreement, both CDRH and CBER oversee IVDs. The Office of Blood Research and Review (OBRR) within CBER manages the pre-market review and post-market surveillance for IVDs assigned to CBER, whereas the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) within CDRH administers the pre-market review and post-market surveillance for IVDs assigned to CDRH. OIVD is also responsible for CLIA waivers (see below). Manufacturers apply for the CLIA determination during the pre-market review process.

    IVD Classification

    IVDs can be classified I, II, or III depending on their application, diagnosis, monitoring, patient population, type of specimen, and the consequence of a false test result. For example, if the false test results in the amputation of a leg due to suspected cancer, this would be classified as a Class III IVD. Approximately 8% of IVDs on the market are Class III. This classification determines the regulatory pathway for the device. www.fda.gov/medical-devices/ivd-regulatory-assistance/overview-ivdregulation

    There are 11 types of IVDs listed on the FDA website. Click here and explore them (panel on the left side): https://www.fda.gov/medical-devices/products-and-medical-procedures/vitro-diagnostics. Here are five interesting and relevant ones:

    1. Companion Diagnostics: A companion diagnostic is a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product. The test helps a health care professional determine whether a therapeutic product's benefits to patients will outweigh any potentially serious side effects or risks. If the diagnostic test is inaccurate, then the treatment decision based on that test may not be optimal. https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm407297.htm
      Companion diagnostics can:
      • Identify patients who are most likely to benefit from a therapeutic product;
      • identify patients likely to be at increased risk for serious side effects as a result of treatment with a therapeutic product, or
      • monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness" (FDA.gov)
    2. Direct-To-Consumer: In vitro diagnostics (IVDs) that are marketed directly to consumers without the involvement of a health care provider are called direct-to-consumer tests (also referred to as DTC). These tests generally request the consumer collect a specimen, such as a saliva or urine, and send it to the company for testing and analysis. www.fda.gov/medical-devices/vitrodiagnostics/direct-consumer-tests
      Companion diagnostics can:
      • Direct-to-consumer testing is expanding the number of people who can get genetic testing of their DNA (or genome). Some variants have clinical significance and may give consumers insight into monitoring their health, or about potential disease or conditions.
      • Not all direct-to-consumer tests are genetic tests, though the majority on the market today are. Some measure other things, such as types of bacterial flora (referred to as a "microbiome").
      • Direct-to-consumer tests have varying levels of evidence that support their claims. Some direct-to-consumer tests have a lot of scientific and clinical data to support the information they are providing, while other tests do not have as much supporting data
    3. Nucleic-Acid Based Tests: tests analyze variations in the sequence, structure, or expression of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) to diagnose disease or medical conditions, infection with an identifiable pathogen, or determine genetic carrier status. https://www.fda.gov/medical-devices/vitro-diagnostics/nucleic-acid-based-tests
    4. Laboratory Developed Test (LDT): A laboratory-developed test (LDT) is a type of in vitro diagnostic test designed, manufactured, and used within a single laboratory. LDTs can be used to measure or detect a wide variety of analytes (substances such as proteins, chemical compounds like glucose or cholesterol, or DNA), in a sample taken from a human body" (FDA.gov). https://www.fda.gov/medical-devices/vitro-diagnostics/laboratory-developed-tests
    5. Precision Medicine: Most medical treatments are designed for the "average patient" as a one-size-fits-all-approach, which may be successful for some patients but not for others. Precision medicine, sometimes known as "personalized medicine," is an innovative approach to tailoring disease prevention and treatment that considers differences in people's genes, environments, and lifestyles. The goal of precision medicine is to target the right treatments to the right patients at the right time. https://www.fda.gov/medical-devices/vitro-diagnostics/precision-medicine
    Flowchart for Next Generation Sequencing-based genetic tests. Databases flows into bioinformatic tools which flows into standards which flows back into databases. Databases: Would allow developers to use data from FDA-recognized public databases of genetic variants to support a test's clinical validity. Bioinformatics tools: a cloud-based community research and development portal that engages users across the world to experiment, share data and tools, and test new bioinformatics approaches for NGS. Standards: the FDA offers recommendations for designing, developing, and validating NGS tests that could also form the basis for community-developed consensus standards.
    Figure \(\PageIndex{1}\): The FDA's Role in Precision Medicine using NGS. Image FDA, public domain.

    Advances in precision medicine have already led to powerful discoveries and FDA-approved treatments that are tailored to specific characteristics of individuals, such as a person's genetic makeup, or the genetic profile of an individual's tumor. Patients with a variety of cancers routinely undergo molecular testing as part of patient care, enabling physicians to select treatments that improve chances of survival and reduce exposure to adverse effects.

    Next-Generation Sequencing (NGS) Tests

    Precision care will only be as good as the tests that guide diagnosis and treatment. Next-Generation Sequencing (NGS) tests are capable of rapidly identifying or 'sequencing' large sections of a person's genome and are important advances in the clinical applications of precision medicine. Patients, physicians, and researchers can use these tests to find genetic variants that help them diagnose, treat, and understand more about human disease.

    FDA's Bioinformatics Platform

    The FDA created https://precision.fda.gov/, cloud-based community research, and development portal that engages users across the world to share data and tools to test, pilot, and validate existing and new bioinformatics approach NGS processing. Individuals and organizations in the genomics community can find more information and sign up to participate at http://precision.fda.gov.

    Research Use Only (RUO) & Investigational Use Only (IUO)

    Both IVDs are considered to be pre-commercial since they are not used for diagnostic purposes and do not have to follow the strict labeling requirements that apply to commercial diagnostic IVDs. The labeling needs of these are found in 21 CFR 809.10. The difference between RUO and IUO is that RUO is for research only, but IUO may be pre-shipped and may be evaluated for future use as an IVD.

    General Purpose Reagents (GPR) & Analyte Specific Reagents (ASR)

    GPR has a general laboratory application and is a Class I device. As such, Class I devices are exempt from PMN. ASR is a little more complicated in that it can be used as a Class I, II, or III device depending on its application. ASR devices can range from antibodies to nucleic acid binding proteins used for diagnostics in blood banking samples (class II) to a test for Ebola (Class III).

    Clinical Laboratory Improvement Amendments (CLIA)

    Diagnostic testing helps health care providers screen for or monitor specific diseases or conditions. It also helps assess patient health to make clinical decisions for patient care. The Clinical Laboratory Improvement Amendments (CLIA) regulate laboratory testing and require clinical laboratories to be certificated by their state as well as the Center for Medicare and Medicaid Services (CMS) before they can accept human samples for diagnostic testing. Laboratories can obtain multiple types of CLIA certificates, based on the kinds of diagnostic tests they conduct. www.fda.gov/medical-devices/ivd-regulatoryassistance/clinical-laboratory-improvement-amendments-clia

    In 1988, the Clinical Laboratory Improvement Amendments (CLIA) was established to define quality standards for all laboratory testing to ensure accuracy, reliability, and timeliness of patient test results regardless of where the test was performed. Final regulations were established in 1992. Three federal agencies are responsible for CLIA: The Food and Drug Administration (FDA), Center for Medicaid Services (CMS), and the Center for Disease Control (CDC). Each agency has a unique role in assuring quality laboratory testing. www.cms.gov/Regulations-andGuidance/Legislation/CLIA/Program_Descriptions_Projects.html

    CLIA AND THE FDA, CMS, CDC

    Three federal agencies are responsible for CLIA: The Food and Drug Administration (FDA), Center for Medicaid Services (CMS), and the Center for Disease Control (CDC). Each agency has a unique role in assuring quality laboratory testing.

    CLIA Categorizations

    The FDA categorizes diagnostic tests by their complexity—from the least to the most complex: waived tests, moderate complexity tests, and high complexity tests. Diagnostic tests are categorized as waived based on the premise that they are simple to use, and there is little chance the test will provide wrong information or cause harm if it is done incorrectly. Tests that are cleared by the FDA for home or over-the-counter use are automatically assigned a waived categorization.

    CLIA categorization is determined after the FDA has cleared or approved a marketing submission. The FDA determines the test’s complexity by reviewing the package insert test instructions and using a criteria “scorecard” to categorize a test as moderate or high complexity. Each test is graded for level of complexity by assigning scores of 1, 2, or 3 for each of the seven criteria on the scorecard.

    A score of 1 indicates the lowest level of complexity, and the score of 3 indicates the highest level. The 7 scores are added together and the tests with a score of 12 or less are categorized as moderate complexity, and those with a score above 12 are categorized as high complexity. The FDA will notify the sponsor—usually within two weeks of the marketing clearance or approval of their CLIA categorization.

    Learn more here: https://www.fda.gov/medical-devices/ivd-regulatory-assistance/clia-categorizations

    CLIA Waiver Application

    Under CLIA, FDA categorizes in vitro diagnostic (IVD) tests by their degree of complexity: waived, moderate complexity, and high complexity. Tests that are waived by regulation under 42 CFR 493.15(c), or cleared or approved for home use or for over-the-counter use, are automatically categorized as waived following clearance or approval. Otherwise, following clearance or approval, tests may be categorized either as moderate or high complexity according to the CLIA categorization criteria listed in 42 CFR 493.17.

    The statute states that: The examinations and procedures that may be performed by a laboratory with a Certificate of Waiver are laboratory examinations and procedures that have been approved by the Food and Drug Administration for home use or that are simple laboratory examinations and procedures that have an insignificant risk of an erroneous result, including those that — (A) employ methodologies that are so simple and accurate as to render the likelihood of erroneous results by the user negligible, or (B) the Secretary has determined pose no unreasonable risk of harm to the patient if performed incorrectly.

    Explore!

    There are three ways to find out what categorization a laboratory test has received. Take a look at these three databases.

    1. CLIA Database
    2. Waived Analytes
    3. Over the Counter Database

    This page titled 8.3: Regulation of Clinical Tests is shared under a CC BY license and was authored, remixed, and/or curated by Jack O'Grady.

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