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수정일 2017년 09월 02일.

A series of articles that describe how different types of laboratory tests are developed, validated, and made available for use by patients and their healthcare providers.

Accordion Title
새로운 검사법의 적용(Putting New Laboratory Tests into Practice) Part I
  • Overview

    This is the first in a series of articles that describe how different types of laboratory tests are developed, validated, and made available for use by patients and their health care providers. This section looks at the reasons new tests are developed and how they may eventually reach the patients they are meant to help.

    Part II: Commercial Tests and FDA Approval
    Part III: Laboratory-Developed Tests (LDTs)
    Part IV: Exceptions: Humanitarian Use
    Part V: Tests Used in Clinical Trials
    Sources

    Introduction

    So often we see and hear in the news about new laboratory tests that have been developed to detect or manage conditions or diseases that affect our life or that of someone we know. As with other products and services, new laboratory tests are meant to satisfy a need: to help us and our health care providers screen for, diagnose, or monitor conditions faster, easier, and with more confidence. But how does a particular test that shows promise in the research stages actually get to the point where it is available for use at our doctor's office, clinic, or hospital? What does it mean for you, the health care consumer, when a new test is announced or when headlines tout the latest research? How are your health care needs met with the advancement of new tests and how is your health protected from new tests that might misinform or mislead your doctor? Becoming familiar with how laboratory tests are navigated through the development, validation, and approval stages and get put into practice may help you to understand the answers to these questions and put the latest headline news into appropriate context.

    It may take years for a new test to pass through the many phases - research, testing, clinical evaluation, development of manufacturing processes, and review by regulatory authorities before the test is available for use. It is an intensive process with no assurance that the test, once developed and validated, will actually be adopted by health care providers. That is why the first step is usually determining whether the proposed test will be useful for patients and their doctors.

  • Purpose for new tests: The Search for a Solution

    Putting Laboratory Tests into Practice: Part I II III IV V

    Researchers continually look for new ways to improve early detection and diagnosis of diseases, more accurately monitor conditions, and better predict outcomes (prognosis). The goals of improving and advancing patient care often provide the incentive for the development and use of new or improved laboratory tests.

    One of the most common ways a new test gets developed is through the recognition of a need for an accurate test to diagnose or monitor a particular disease or condition. An example is the test for troponins. After years of looking for a better way to diagnose heart attacks or acute coronary syndrome (ACS), it was realized that the protein troponin is released into the bloodstream when heart muscle is damaged. Measurement of troponin levels in the blood has now gained acceptance in the medical community as a test for evaluating patients with chest pain to help determine if they have had a heart attack.

    Often, researchers look to improve the way in which a condition is detected or a substance of interest is measured. Their goal is to improve upon the accuracy, precision, sensitivity and/or specificity of an existing test. (For more on these, see the article How Reliable is Laboratory Testing?: Key Concepts.) This can sometimes be accomplished by developing and employing a new way (methodology) of testing. An example is the development of a molecular method that detects genetic material, such as polymerase chain reaction or PCR, to detect infections as a replacement for an immunoassay method that may be less sensitive or specific. Sometimes the decision to use new tests for established analytes is based on whether a new method offers faster results, moving from a slower, more labor-intensive method to an automated method that generates many more patient results in a shorter amount of time.

    In some cases, an existing test may evolve to have a new clinical use. A test may have been developed for one purpose, but over time, a new use for the test becomes apparent. This is how the high-sensitivity C-reactive protein (hs-CRP) test was added as a marker for predicting the risk of heart disease. The original purpose of the CRP test was to detect significantly increased levels to identify infection or inflammation associated with disease, but researchers found a new use: measuring it with highly sensitive tests that can detect slight increases within the "normal range" to help predict cardiovascular risk.

    There are several questions that can be considered when evaluating the merits of developing a new test:

    • Is the new test more accurate? That is, can it detect disease when it is present and rule it out when it is not present?
    • Is it less invasive? Is the sample required easier to obtain and/or does the procedure cause less discomfort for the patient?
    • Is the new test faster? Does it provide results more quickly so that treatment can begin sooner?
  • Government and Professional Approval and Oversight

    Putting Laboratory Tests into Practice: Part I II III IV V

    Though the reasons for developing new tests or methods may vary, it is important to note that the development of all new tests is highly regulated. Each new test must meet certain criteria before it is allowed to be used on patient samples. To understand this process of validation, it is helpful, first, to understand that there are essentially two main kinds of tests:

    • Commercial tests are those that are manufactured and sold in volume as kits to laboratories or other health care facilities. The majority of lab tests fall into this category. In the U.S., commercial tests must be approved by the Food and Drug Administration (FDA) before they are marketed to labs. The specific approval process can vary with the type and complexity of the test. For more on these, see Part II.
    • Laboratory-developed tests (LDTs) are those that are developed within a particular laboratory (sometimes called home-brewed). In general, the evaluation, validation, and use are confined to the laboratory that develops the test. Typically, these tests are developed because there is no commercial test available. For more on these, see Part III.

    These two types of tests take somewhat different paths for validation and approval, but in each case, their development and use on patient samples is governed by sets of rules that ensure their accuracy and reliability. The Clinical Laboratory Improvement Amendment (CLIA 88) is part of federal law that regulates laboratory tests and the quality assurance programs that oversee their validation and use. Professional accrediting organizations such as the Joint Commission and College of American Pathologists (CAP) also provide continuing oversight of laboratories and laboratory testing.

  • Gaining Acceptance from Health Care Providers

    Putting Laboratory Tests into Practice: Part I II III IV V

    There is no assurance that once a test is developed, approved, and available for use it will ever be adopted for use by doctors. A new test must gain acceptance by doctors, a process that can take years. A crucial element in this process is publication of study findings and other reporting on the new test in the peer-reviewed medical literature. Over time, exposure to the test and data supporting its clinical usefulness from these sources will increase doctors' confidence and comfort with the new test and the interpretation of test results.

    Adoption rates are highest among doctors who keep up with the medical literature. These doctors may read about a particular new test in a medical journal and then ask the laboratory if the test is available.

    Because doctors regard the scientific literature as the gold standard for information about new tests, researchers seek to have their findings about a newly approved test published in one of the leading journals, as the test is ready for regulatory review or for commercial distribution.

    But not all doctors are "early adopters." Some are slower to change their practice patterns. While publication is bound to generate interest, educational seminars offered by professional societies or the manufacturers also provide important information to health care professionals. For these doctors, education and information is essential in their decision-making process whether to use the new test.

    Manufacturers of commercial tests provide educational programs for doctors, insurance companies, and opinion leaders. However, professional societies like AACC also play an important role in educating doctors by hosting conferences and seminars, publishing articles in member publications, distributing pamphlets, sending email updates, and other mechanisms that can bring a new test to their members' attention. The laboratories themselves are also involved in promoting newly available tests by providing doctors with educational materials in bulletins or newsletters.

    Gaining Acceptance from Insurers

    Another factor that affects use by doctors is whether the new test will be paid for by insurers. Coverage determinations are made by insurers, such as private insurance companies as well as Medicare and Medicaid, indicating whether and to what extent a particular test will be paid for by that company. Doctors try to order tests that are covered by insurance, recognizing that most patients cannot afford to pay out-of-pocket for these tests.

    As a general rule, tests or the process a test performs are assigned a current procedural terminology (CPT) code by the American Medical Association (AMA). Government payers (Medicare and Medicaid) and private insurance companies have adopted CPT codes to identify the service provided for a patient. The AMA publishes a list of such codes annually in the CPT Manual, which is used by health insurers to determine reimbursement for medical technology and practices.

    The next step is a coverage determination by private and government insurers. Private insurers include those used by companies for their employee health insurance plans and policies that individuals can purchase for themselves or their families. Government insurers include Medicare, the federal health insurance program for 39 million elderly and disabled Americans, and Medicaid, which are administered by the Centers for Medicare and Medicaid Services (CMS). Coverage by Medicare is critical for determining whether and at what level a test will be paid, inasmuch as private insurers often follow Medicare's standards. However, many tests are covered by private payers that are not recognized by Medicare; tests for which Medicare coverage precedes private payment are typically those that impact elderly populations.

    The criteria that insurers use in coverage decisions vary. For example, Medicare uses a different standard than the FDA for evaluating new technologies. While the FDA uses a "safe and effective" standard, Congress requires that Medicare employ "reasonable and necessary" criteria in deciding whether the program will pay for a treatment, drug, procedure, or device. In addition, the process can vary in cases where local insurance carriers differ in how – or whether – a device meets the "reasonable and necessary" criteria.

    So even though a new laboratory test has traveled the long road from research and development through validation of its safety and efficacy, there is still the issue of getting the test reimbursed by insurers so that when it is ordered by a doctor, the patient's health insurance will pay the laboratory performing the test. Acceptance by insurers can be one final, important step in putting a new test into practice.

     

  • Process with a Purpose

    Putting Laboratory Tests into Practice: Part I II III IV V

    The development of new laboratory tests give patients and doctors reason to anticipate and expect advancements in the tools used to diagnose and monitor a range of conditions and diseases. If a new test is to become a commonly-used, safe, and effective clinical tool, it will proceed from concept through development, validation, approval, and favorable coverage decisions to acceptance and use by doctors. While the process has many steps and does take time, it ensures that the tests we as patients rely on for accurate information about our health are effective and have earned the confidence of regulators and our health care providers. The process helps to ensure that new laboratory tests successfully balance the need for medical advancements with patient safety.

     

    Continue to the next article in the series: Part II: Commercial Tests and FDA Approval

Article Sources

Putting Laboratory Tests into Practice: Part I II III IV V

NOTE: This article is based on research that utilizes the sources cited here as well as the collective experience of the Lab Tests Online Editorial Review Board. This article is periodically reviewed by the Editorial Board and may be updated as a result of the review. Any new sources cited will be added to the list and distinguished from the original sources used.

Sources Used in Current Review

CLIA Regulations. Subpart K, Sec. 493.1253. Available online at http://wwwn.cdc.gov/clia/regs/subpart_k.aspx#493.1250 and Subpart E available online at http://wwwn.cdc.gov/clia/regs/subpart_e.aspx through http://wwwn.cdc.gov. Accessed August 2009.

American Association for Clinical Chemistry Resource Library. Genetic and Laboratory-Developed Tests. Available online at http://www.aacc.org/resourcecenters/resource_topics/tests/Pages/default.aspx through http://www.aacc.org. Accessed August 2009.

U.S. Food and Drug Administration. Draft Guidance for Industry, Clinical Laboratories and FDA Staff. In Vitro Diagnostic Multivariate Index Assays, Issued July 26, 2007. Available online at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm079148.htm through http://www.fda.gov. Accessed August 2009.

College of American Pathologists. About the CAP Accreditation Program. Available online at http://www.cap.org/apps/cap.portal?_nfpb=true&_pageLabel=accreditation through http://www.cap.org. Accessed August 2009.

Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Burtis CA, Ashwood ER and Bruns DE, eds. 4th ed. St. Louis, Missouri: Elsevier Saunders; 2006 Pp 353-356.

Clarke, W. and Dufour, D. R., Editors (2006). Contemporary Practice in Clinical Chemistry, AACC Press, Washington, DC, Pp 51-60.

U.S. Food and Drug Administration. Medical Devices, Device Advice: Device Regulation and Guidance, Overview (Updated August 31, 2009). Available online at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/default.htm through http://www.fda.gov. Accessed September 2009.

U.S. Food and Drug Administration, Center for Devices and Radiological Health (June 30, 2009 Updated). New Humanitarian Device Approval: Mesomark ™ - H060004. Available online at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm077034.htm through http://www.fda.gov. Accessed August 2009.

U.S. Food and Drug Administration, Center for Devices and Radiological Health Guidance for Industry and FDA Staff: Humanitarian Device Exemption (HDE) Regulation: Questions and Answers (July 18, 2006, Issued). Available online at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071473.htm through http://www.fda.gov. Accessed August 2009.

National Cancer Institute. Mesothelioma: Questions and Answers. Available online at http://www.cancer.gov/cancertopics/factsheet/sites-types/mesothelioma through http://www.cancer.gov. Accessed August 2009.

Hammerschmidt, D. Humanitarian Use Devices: A Brief Guide for Clinicians, Investigators, and IRB Members (October 2002, issued). PDF available for download at http://www.research.umn.edu/irb/members/education/HUDs.pdf through http://www.research.umn.edu. Accessed August 2009.

Fujirebio Diagnostics. Managing Mesothelioma. Available online at http://www.fdi.com/mesomark/world/patients/managing_mesothelioma.html through http://www.fdi.com. Accessed August 2009.

Pacific Hearth & Blood Institute. Mesomark. (Dec 12, 2008). Available online at http://www.phlbi.org/phlbi/mesomark-blood-test-may-help-doctors-measure-a-patients-response-to-therapy/ through http://www.phlbi.org. Accessed August 2009.

(September 9, 2007) Clinical Trials.gov. Understanding Clinical Trials. Available online at http://www.clinicaltrials.gov/ct2/info/understand through http://www.clinicaltrials.gov. Accessed August 2009.

Clinical Laboratory Standards Institute. About CLSI (2009), Frequently Asked Questions. Available online at http://www.clsi.org/Content/NavigationMenu/AboutCLSI/FAQ/FAQ.htm through http://www.clsi.org. Accessed August 2009.

US Department of Health and Human Services. Centers for Medicare and Medicaid Services. Accrediting Organizations/Exempt States. Available online at https://www.cms.hhs.gov/CLIA/13_Accreditation_Organizations_and_Exempt_States.asp#TopOfPage through https://www.cms.hhs.gov. Accessed September 2009.

College of American Pathologists. Accreditation and Laboratory Improvement. Available online at http://www.cap.org/apps/cap.portal?_nfpb=true&_pageLabel=accreditation through http://www.cap.org. Accessed August 2009.

The Joint Commission. Accreditation, Laboratory Services. Available online at http://www.jointcommission.org/AccreditationPrograms/LaboratoryServices/HTBA/ through http://www.jointcommission.org. Accessed August 2009.

National Human Genome Research Institute. Promoting Safe and Effective Genetic Testing In the United States (April 2006). Available online at http://www.genome.gov/10002393 through http://www.genome.gov. Accessed August 2009.

US Food and Drug Administration. Medical Devices, Learn if a Medical Device Has been Cleared by the FDA for Marketing (June 18, 2009). Available online at http://www.fda.gov/MedicalDevices/ResourcesforYou/Consumers/ucm142523.htm through http://www.fda.gov. Accessed August 2009.

Sources Used in Previous Reviews

The original article was written by Cathy Tokarski with additional contributions from:

Fred Lasky, PhD, formerly Director of Diagnostics Compliance for Ortho-Clinical Diagnostics, a division of Johnson & Johnson, Rochester, NY.

Robert Murray, PhD, formerly Technical Director for Midwest Diagnostic Pathology at Lutheran General Hospital, Park Ridge, IL.

Sue Evans PhD, formerly Vice President of Product Development for Caliper Technologies Corporation.

Steven Gutman, MD, formerly Director - Division of Clinical Laboratory Devices, US Food and Drug Administration.

David Sundwall, formerly President of the American Clinical Laboratory Association.

Elissa Passiment, EdM, CLS(NCA), Executive Vice President,of the American Society for Clinical Laboratory Science.

US Food and Drug Administration: Premarket Approval Applications for In Vitro Diagnostic Devices Pertaining to Hepatitis C Viruses; CDRH Consumer Information, Learn if a Medical Device Has Been Cleared by FDA for Marketing; Device Advice, Class I/II Exemptions. Available online through http://www.fda.gov.