Putting New Laboratory Tests into Practice
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 healthcare 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 healthcare consumer, when a new test is announced or when headlines tout the latest research? How are your healthcare needs met with the advancement of new tests and how is your health protected from new tests that might misinform or mislead your healthcare provider? Becoming familiar with how laboratory tests are navigated through the development, validation, and approval stages and placed into practice may help you 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 healthcare providers. That is why the first step is usually determining whether the proposed test will be useful for patients and healthcare practitioners.
About New Laboratory Tests
Why develop new tests: the search for a solution
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 troponin. 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 blood when heart muscle is damaged. Measurement of troponin levels in the blood is routinely used by 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?.) 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 (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 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. This can directly impact how quickly a diagnosis can be obtained, how long a patient stays in the hospital, or alter any medications taken.
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 that occur with an infection or inflammation that is often associated with disease. Researchers, however, found a new use: measuring it with a highly sensitive testing method that can detect slight increases even when they are within the “normal range” to help determine a cardiovascular event.
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?
Regulation: Government and Professional Approval and Oversight
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 healthcare 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 the article on Commercial Laboratory Tests.
- Laboratory-developed tests (LDTs) are those that are developed within a particular laboratory (sometimes called home-brewed tests). 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 the article on Lab Developed Tests.
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 testing and the quality assurance programs that oversee their validation and use. Professional accrediting organizations such as the Joint Commission and the College of American Pathologists (CAP) also provide continuing oversight of laboratories and laboratory testing.
Gaining Acceptance from Healthcare Practitioners
There is no assurance that once a test is developed, approved, and available that it will be immediately used by a healthcare practitioner. A new test generally gains acceptance by the practitioner through various continuing educational venues. This is often accomplished through peer-reviewed medical publications, continuing medical education programs, and other reporting media that tout the advantages of the new test. Over time, exposure to the test and data supporting its clinical usefulness will increase the practitioner’s confidence and comfort in ordering the new test and the interpretation of the results.
Adoption rates are highest among healthcare practitioners who keep up with the medical literature. They may read about a particular new test in a medical journal and then ask the laboratory if the test is available. Because healthcare practitioners regard the scientific literature as the gold standard for information about new tests, researchers seek to have their findings published in one of the leading journals as the test is prepared for regulatory review or for commercial distribution.
It is commonplace for manufacturers of commercial tests to provide educational programs for healthcare practitioners, insurance companies, and laboratory leaders. However, professional societies like AACC also play an important role in educating healthcare practitioners 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 practitioners with educational materials through in-service education programs, in bulletins, or newsletters.
Gaining Acceptance from Insurers
Another factor that may affect how and when a new test will be ordered is dependent on healthcare 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. Healthcare practitioners do their best to try to order tests that are covered by most insurance plans, recognizing that some patients may have to pay out-of-pocket for these tests. Non-FDA approved tests are often denied payment by the insurance company, with payment responsibility falling on the patient. This is particularly true for many of the newer genetic tests and should be discussed with your healthcare provider.
All laboratory tests 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(s) provided for a patient. The AMA publishes a list of such codes, which are annually updated in the CPT Manual. Each laboratory test performed must have a CPT code submitted to the insurance company to identify the test performed and to determine what reimbursement will be made.
The next step is a coverage determination policy, developed independently by private and government insurers. Most employers offer health insurance plans for their employees through private insurers. In addition, private insurers offer policies that individuals can purchase for themselves or their families.
Coverage determinations can vary greatly between different insurance companies. They can also vary within the same insurance company based on negotiated agreements between the private insurer and the employer. Some tests, like many of the newly developed genetic tests, may be covered under one employer’s plan but not be covered under another employer’s health plan, even though both plans are sponsored by the same insurance provider. Payment then becomes the responsibility of the patient.
Government insurers include Medicare, which is the federal health insurance program for over 55 million elderly and disabled Americans, and Medicaid, which covers another 72 million people, including the Children’s Health Insurance Program (CHIP). Both 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.
Some tests may be covered by private payers that are not recognized by Medicare. For those individuals who qualify for Medicare, Medicare becomes their primary insurer. Many individuals have a secondary, private insurer; thus for those tests not covered by Medicare, charges for that test would be resubmitted to a secondary private insurer for potential payment. Because many private insurers follow Medicare rules, there is no guarantee that reimbursement will be made and payment becomes the responsibility of the patient.
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 medical device (lab tests are considered medical devices). 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 healthcare practitioner, 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
The development of new laboratory tests give patients and healthcare practitioners 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. 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 healthcare providers. The process helps to ensure that new laboratory tests successfully balance the need for medical advancements with patient safety.
Exceptions to Regulations: Humanitarian Use and Clinical Trials
In certain cases, new or experimental laboratory tests may be made available to patients without FDA approval or regulation by CLIA. The use of such tests is considered exceptional; nevertheless, they are closely regulated by governmental, scientific, and professional entities.
The FDA’s Humanitarian Device Exemption
In the United States, an exemption to Food and Drug Administration (FDA) regulations waives certain approval requirements for devices (including laboratory tests) for conditions diagnosed in less than 4,000 patients annually. Known as the humanitarian device exemption (HDE), it’s intended to make the devices available to patients whose diseases are so rare that it would not be cost effective for manufacturers to conduct the required studies to get FDA approval.
Commercial laboratory tests — those produced and sold in volume to multiple laboratories — are categorized as devices and they receive FDA approval only after the developer or manufacturer submits research data showing the test is effective and useful. Manufacturers of tests falling under the HDE can sell the test kits without proving they are effective and useful. However, a manufacturer must still show that its exempted device does not pose a threat of illness or injury to patients and that the device’s probable benefits outweigh risks.
FDA exemption as a Humanitarian Device means that the device is not fully proven to work. As such, it is treated as experimental. Any healthcare provider who wants to use a humanitarian use device must get institutional review board (IRB) approval before using that device to treat, diagnose, or monitor patients. The IRB is a committee that is formally designated to approve, monitor, and review medical research involving humans with the goal of protecting research subjects’ rights and welfare. The IRB is responsible for initial and ongoing review of the humanitarian use device.
An example of a laboratory test exempted under the HDE is Mesomark, manufactured by Fujirebio Diagnostics. The FDA in January 2007 gave an exemption to Mesomark to measure the blood level of soluble mesothelin-related peptides (SMRP), protein fragments released into the blood by mesothelioma cells. Mesothelioma is a rare cancer of the membrane that covers and protects several organs as well as the chest and abdominal cavities. The approximately 2,000 to 3,000 U.S. patients diagnosed with mesothelioma annually usually have histories of working with asbestos.
The test is used to monitor patients diagnosed with malignant mesothelioma and is intended to add to the information from X-rays and imaging studies. Healthcare practitioners may order Mesomark to monitor mesothelioma’s progression, recurrence, or response to therapy. Approved under the humanitarian device exemption, this test may give healthcare practitioners an additional tool for monitoring this rare but serious cancer.
Participation in Clinical Trials
New and experimental tests may sometimes be made available to patients through participation in clinical trials. Clinical trials are research studies performed on consenting human subjects that follow a carefully controlled scientific procedure in order to gather information and data on the safety and effectiveness of a particular test. Researchers who are interested in developing new tests are required to evaluate them by conducting clinical trials with patients who consent to participate.
Patients who choose to participate in clinical trials often have the benefits of gaining access to tests that otherwise would not be available and often receive access to care at leading medical institutions. In addition, they can take an active role in decisions about their healthcare and with regard to their condition. They also contribute to medical research for the benefit of others. However, a clinical trial may also have inconveniences, such as increased demands on the patient’s time and risks such as side effects with varying degrees of severity. Sometimes the test being evaluated may not have the intended result or be effective for certain patients.
Benefits and risks to patients that are part of a clinical trial must be addressed prior to the start of any study and are closely monitored as the clinical trial proceeds. As with tests that are exempted as Humanitarian Use Devices, tests used during clinical trials are carefully regulated. It is required by federal law that every clinical trial conducted in the U.S. be approved by an Institutional Review Board (IRB). An IRB is a committee comprised of doctors, scientists, healthcare advocates, and others that initially approves the research protocol and periodically reviews the study. It is the responsibility of an IRB to ensure that possible benefits from the trial have true value and outweigh any possible risks to patients. The IRB also must ensure that the risks to patients remain at a minimum as much as possible. IRBs continually oversee clinical studies to ensure that ethical standards are adhered to and that the rights of patients are protected.
For more information about clinical trials or to find out about prospective or on-going studies for a particular condition, visit the federal government-sponsored site: ClincalTrials.gov.
Sources Used in Current Review
Medicare.gov. Your Medicare Coverage. Available online at https://www.medicare.gov/coverage/clinical-lab-services.html. Accessed October 2016.
(May 24, 2016) Centers for Medicare and Medicaid Services. Regulation and Guidance, Clinical Laboratory Improvement Amendments (CLIA). Available online at https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html. Accessed October 2016.
©2016 ABIM Foundation. Choosing Wisely. Available online at http://www.choosingwisely.org/. Accessed October 2016.
©2016 AvaMedDx. Our Industry and Technology, Uses of Diagnostic Tests. Available online at http://dx.advamed.org/diagnostics-policy/our-industry-technology-0. Accessed October 2016.
(June 4, 2016) U.S. Food and Drug Administration. Humanitarian Device Exemption. Available online at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/HumanitarianDeviceExemption/default.htm. Accessed October 2016.
(August 6, 2014) U.S. Food and Drug Administration. HDE Approvals. Available online at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/HDEApprovals/default.htm. Accessed October 2016.
(June 4, 2016) U.S. Food and Drug Administration. Listing of CDRH Humanitarian Device Exemptions. Available online at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/HDEApprovals/ucm161827.htm. Accessed October 2016.
(March 17, 2014) Gaffney A. Regulatory Explainer: Making Sense of Humanitarian Use Devices. Available online at http://www.raps.org/focus-online/news/news-article-view/article/4775/. Accessed October 2016.
The Free Dictionary. Class III device. Available online at http://medical-dictionary.thefreedictionary.com/class+III+device. Accessed October 2016.
(January-February 2006) Food and Drug Administration. Medical Device and Radiological Health Regulations Come of Age. Available online at http://www.fda.gov/aboutfda/whatwedo/history/productregulation/medicaldeviceandradiologicalhealthregulationscomeofage/default.htm. Accessed October 2016.
Congress.gov. H.R.3095 – Safe Medical Devices Act of 1990. Available online at https://www.congress.gov/bill/101st-congress/house-bill/3095. Accessed October 2016.
Food and Drug Administration. December 2014 PMA Approvals. Available online at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/PMAApprovals/ucm439050.htm. Accessed October 2016.
University of California San Francisco. Information sheet for clinical laboratory testing. Available online at https://accelerate.ucsf.edu/research/clinical-laboratory-testing. Accessed October 2016.
Centers for Disease Control and Prevention. Clinical Laboratory Improvement Amendments. Available online at https://wwwn.cdc.gov/clia/Resources/TestComplexities.aspx. Accessed October 2016.
Food and Drug Administration. CLIA categorizations. Available online at http://www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm393229.htm. Accessed October 2016.
HHS, Medicare Learning Network. The Clinical Laboratory Improvement Amendments (CLIA). Available online at https://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNProducts/Downloads/CLIABrochure.pdf. Accessed October 2016.
Food and Drug Administration, PMA Monthly approvals from 6/1/2016 to 6/30/2016 http://www.fda.gov/downloads/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/PMAApprovals/UCM510219.pdf Accessed October 2016.
(November 17, 2015) Jeffrey E. Shuren M.D., J.D. Director, Center for Devices and Radiological Health, U.S. Department of Health and Human Services. Food and Drug Administration, Statement on Examining the Regulation of Diagnostic Tests and Laboratory Operations before Committee on Energy and Commerce Subcommittee on Health. Available online at http://www.hhs.gov/asl/testify/2015/11/t20151117a.html. Accessed October 2016.
(June 4, 2014) U.S. Food and Drug Administration. Learn if a Medical Device Has Been Cleared by FDA for Marketing. Available online at http://www.fda.gov/MedicalDevices/ResourcesforYou/Consumers/ucm142523.htm. Accessed October 2016.
(October 3, 2016) U.S. Food and Drug Administration. Medical Device Exemptions 510(k) and GMP Requirements. Available online at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/315.cfm. Accessed October 2016.
Encyclopedia.com. Genetic testing. Available online at http://www.encyclopedia.com/topic/Genetic_Testing.aspx. Accessed October 2016.
(April 21, 2016) CLN Stat. Who should regulate LDTs? Available online at https://www.aacc.org/publications/cln/cln-stat/2016/april/21/who-should-regulate-ldts. Accessed October 2016.
Food and Drug Administration. The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies Available online at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm472773.htm. Accessed October 2016.
Food and Drug Administration. Laboratory Developed Tests. Available online at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm407296.htm. Accessed October 2016.
National Independent Laboratory Association. Press release: Members of Congress Approve Language to Delay FDA Oversight of LDTs. Available online at http://www.nila-usa.org/nila/Members_of_Congress_Approve_Language__To_Delay_FDA.asp. Accessed October 2016.
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.
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. 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. 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. 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. 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. 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. 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. Accessed August 2009.
National Cancer Institute. Mesothelioma: Questions and Answers. Available online at http://www.cancer.gov/cancertopics/factsheet/sites-types/mesothelioma. 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. Accessed August 2009.
Fujirebio Diagnostics. Managing Mesothelioma. Available online at http://www.fdi.com/mesomark/world/patients/managing_mesothelioma.html. 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/. Accessed August 2009.
(September 9, 2007) Clinical Trials.gov. Understanding Clinical Trials. Available online at http://www.clinicaltrials.gov/ct2/info/understand. 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. 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. 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. Accessed August 2009.
The Joint Commission. Accreditation, Laboratory Services. Available online at http://www.jointcommission.org/AccreditationPrograms/LaboratoryServices/HTBA/. 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. 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. Accessed August 2009.