Commercial Laboratory Tests and FDA Approval
Commercial laboratory tests are those that are performed using commercially manufactured kits and equipment. The majority of lab tests in use today fall into this category. Unlike tests developed for use in a single laboratory or laboratory company (known as lab-developed tests), they are manufactured, marketed, and sold in volume as kits to multiple laboratories and other healthcare facilities.
In the United States, the development and marketing of commercial tests are regulated by the U.S. Food and Drug Administration (FDA). They are considered “medical devices” and, specifically, “in vitro diagnostic devices (IVD).” As such, they must be evaluated and approved by the FDA. Likewise, many countries around the world have agencies comparable to the FDA that are responsible for approving the use of clinical laboratory tests. Examples of commercial tests and tests systems that are often sold as kits to various laboratories include tests that detect and/or measure glucose, cholesterol, therapeutic drugs, tumor markers, and infectious diseases.
The process required for a new commercial test to gain approval for marketing by the FDA can be long and costly, sometimes taking many years, depending on how complicated the test is. A number of ideas for tests never make it to the clinical trial stage, where the safety and efficacy are evaluated on patient volunteers, and sometimes a promising test that healthcare practitioners read about in the scientific literature never becomes commercially available.
If commercial tests do become available, the laboratory tests must meet stringent standards both during the manufacturing process and when they are used in the clinical laboratory.
About Commercial Lab Tests
FDA Classification and Requirements for Approval
Under the 1976 Medical Device Amendments that established the FDA’s regulation of medical devices and tests, manufacturers are required to notify the agency of their intent to market a device. This allows the FDA to classify the device. This classification determines the process by which medical devices, including laboratory tests, are cleared or approved by the FDA.
The FDA classifies laboratory tests based on the level of control needed to assure that the device is safe and effective. Laboratory tests that pose substantial risk of harm fall into the most stringent category and are subject to the highest standards of proof of their safety and effectiveness. These typically require the most time and resources to gain approval. That is why you may read or hear about an experimental test, but it does not become available or used in clinical practice for several months or even years later. By comparison, devices that pose little risk to human life and are generally not as complicated are exempt from FDA review.
FDA approval is also based on the intended use or uses of a test as stated by the manufacturer. An intended use of a test can be for screening or for diagnosis, or for certain populations, such as children or women, as examples.
The other factor used to classify tests is the FDA’s familiarity with the test process itself and the medical devices and equipment used to produce the result. If a manufacturer can demonstrate that a device is “substantially equivalent” or as safe and effective as a similar device already on the market, the FDA permits the device to be marketed. Devices or tests that have a new use generally require more time and resources for approval.
Laboratory tests fall into one of three categories for FDA clearance and approval to market:
Class I Tests
These devices present minimal potential for harm to the user and are often simpler in design than either Class II or Class III devices. Most Class I tests are exempt from FDA review of submissions, although a manufacturer must still register with the agency, list the products in commercial distribution, and make those products according to Quality Systems Regulations (formerly, Good Manufacturing Practices).
Class I devices are those that can be monitored by general controls. Some of the general controls that the FDA uses are: 1) the device must be registered with the FDA; 2) devices must be manufactured using Quality Systems Regulations; 3) the labeling of the device must at least tell the user the product name, intended use, type of procedure it is, and – if it is an instrument – installation, operating, and maintenance procedures; and 4) the manufacturer must submit a 510(k) pre-market notification before marketing the device or test.
Examples of Class I tests are point-of-care tests (POCT), those that that are performed at or near a patient and at the site where care or treatment is provided. Point-of-care tests are typically designed to be simple to use. Examples include a rapid strep test performed at a healthcare practitioner’s office or glucose meters for diabetes.
Class II Tests
Class II devices and tests are ones for which the general controls have not been deemed sufficient to ensure safety and effectiveness; therefore, they are subject to special controls such as special labeling, mandatory performance standards, and post-market monitoring.
These tests often require pre-market notification under the 510(k) process in which the company submits data on analytical performance relative to a “predicate device” (a device already on the market for a similar intended use); clinical data are sometimes needed to support a manufacturer’s intended use.
This class includes tests that may test for the same compounds or substances as Class I tests, but typically use more sophisticated instrumentation to do so. Laboratory instruments, such as automated CBC devices, are in this class, for example, as well as automated instruments that perform an array of chemistry tests, such as glucose, electrolytes, BUN, and creatinine.
Class III Tests
This is the most stringent category. This class includes tests that have a new use or for which there is not enough information about their safety and effectiveness to protect the public with just general or even special controls and/or tests that are of substantial importance in preventing impairment of human health.
These tests generally require submission of a pre-market approval (PMA) application with valid findings from human clinical trials that demonstrate that the device is clinically effective for its intended use. In addition to reviewing and approving the clinical data from the company-sponsored trials, FDA also confirms that the device will be manufactured in conformance to good manufacturing practices.
Examples of Class III tests include hepatitis B and hepatitis C tests and cancer tests, such as the epidermal growth factor receptor (EGFR) gene mutation test that is used to help guide treatment of non-small cell lung cancer (NSCLC).
To learn more about the FDA’s clearance and approval process for laboratory tests, visit the FDA webpage on Medical Devices.
After FDA approval
In addition to FDA approval, all commercial tests must be evaluated by individual laboratories before they are put into use. A lab must demonstrate that it can perform the test with the same accuracy and precision as specified by the manufacturer of the test. And commercial tests, once they have been put into practice, must be evaluated on a regular basis with in-house quality assurance programs to ensure that performance of these tests continues to meet specifications. As is true for any laboratory test, ongoing assessments of commercial tests by the laboratory using the test are regulated by the Clinical Laboratory Improvement Amendments (CLIA). This topic is discussed further in the article Lab Oversight: A Building Block of Trust.
Complexities of commercial tests
Once approved, FDA assigns complexity to a test, grouping it into one of three categories as specified by CLIA regulations: waived, moderate and high complexity.
- Waived tests are simple, easy to use, and have low risk for incorrect results. Some of these tests are even available over the counter. Common examples of waived tests include pregnancy, fecal occult blood tests, and some types of urine tests.
- Moderate complexity tests are not as simple or easy to use as waived tests. They require some degree of personnel education, training, and experience. This category includes the Provider-Performed Microscopy Procedures (PPMP) subcategory in which healthcare providers may perform some of the tests. Complete blood count, automated immunoassays, urinalysis or urine drug screens, and electrolyte or chemistry profiles are common examples of moderate complexity tests.
- High complexity tests require specialized laboratory expertise and may include molecular diagnostic tests, cultures or molecular tests that identify causes of infections (e.g., bacteria, viruses), cytology, immunohistochemistry, flow cytometry, blood smears, or gel electrophoresis. All laboratory-developed tests (LDTs) are classified as high complexity tests.
For moderate and high complexity tests, FDA employs the use of a “scorecard” to determine the level of complexity. The scorecard includes seven categories:
- Training and experience
- Materials and reagents (chemicals) preparation
- Characteristics of operational steps
- Calibration, quality control, and proficiency testing materials
- Test system troubleshooting and equipment maintenance
- Interpretation and judgment
FDA applies the scores of 1, 2 and 3 to each of these criteria, and any score above 12 classifies a test as high complexity. A score of 12 or below classifies a test as moderate complexity.
The Clinical Laboratory Improvement Amendments (CLIA), which require the federal government to certify non-research laboratory testing, call for stricter quality standards for tests with higher degrees of complexity.
Laboratories that enroll in the CLIA program can apply for different types of certificates to conduct different types of commercial tests:
- Certificate of Registration: this is a certificate issued for any laboratory that intends to perform non-waived (moderate and high complexity) tests to allow them to do testing while applying for a certificate of either compliance or accreditation.
- Certificate of Waiver (CW): allows labs to conduct waived tests.
- Certificate of Provider-Performed Microscopy Procedures (PPMP): offered to laboratory personnel such as doctors or dentists who do either waived tests or microscopic evaluations of samples that may include skin scrapings, urine or other types of body fluids. These tests are moderate complexity.
- Certificate of Compliance (COC) and Certificate of Accreditation (COA): labs that meet all relevant CLIA mandates are eligible for a COC. Those who conduct moderate or higher complexity tests must undergo a survey process once every two years to ensure the lab is complying with regulations and with CLIA. Labs can receive a COA if they meet federally approved standards of a private non-profit accreditation organization.
In the event a lab has any of the above certifications, it can also perform waived tests.
Additionally, proficiency testing (PT) is specifically required by CLIA regulations for some tests that are moderate or high complexity. To ensure that labs are conducting these tests accurately and competently, a lab must enroll in a PT program with a CMS-approved PT provider. The PT provider will send them several unknown samples throughout the year. The labs will perform the testing and return their results to the PT provider. The PT provider then grades each lab on how accurately their results were. For moderate or high complexity tests that do not have commercial PT available, the laboratory must perform its own evaluation of accuracy and competency in performing the test at least twice a year.
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. To access online sources, copy and paste the URL into your browser.
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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.
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