Diagnostic Kits/Glossary

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Analyte Specific Reagent (ASR)

Generally, the term “analyte specific reagent” or “ASR” is used to describe a component of a genetic test that is commonly sold or used with a “testing kit.” Scientists use the term to describe certain types of biochemical, chemical, or other substances, and occasionally devices, that are used to conduct a test at a laboratory. However, because the FDA regulates the use and sale of ASRs to some extent, the definition used within the FDA regulations is also commonly used in practice.

Although ASRs are often defined in layman’s terms as the “building blocks” or “active ingredients” of a test, it's helpful to understand how genetic tests are brought to market. Genetic tests tend to be developed either as a "Testing Kit" which is commercially sold to laboratories who conduct the tests, or as a "Laboratory Developed Test" (or LDT), which is developed by a laboratory solely for "in-house use," and is not commercially sold to other entities.

Testing Kits: When a device manufacturer develops a genetic test and sells it to a laboratory who will collect the specimen and actually conduct the test, they sell the test as a "kit" that includes all the necessary ASRs, as well as instructions on how to conduct the test.
LDTs: when a testing laboratory develops its own genetic test, including the ASRs, and uses the test (also called a in-house, home brew, or LDT) only at their testing laboratory and does not commercially sell the test to anyone else.

The differences of how the test is developed and sold is important for regulatory reasons. Different federal regulations apply to the sale and use of ASRs. This depends on whether the ASR is being used soley for in-house use at a laboratory (i.e., LDTs), or if it is being sold commercially by testing manufacturers as part of a kit.

For regulatory purposes, the FDA defines ASRs as:

“antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reaction with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens.”[1]

For more information on the regulatory distinctions of ASRs see our wiki page on U.S. Regulation.

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Clinical Laboratory Improvement Amendments (CLIA)

The Clinical Laboratory Improvement Admendments Act or ("CLIA")[2] was passed by Congress in 1988. This act established: "quality standards for all laboratory testing to ensure the accuracy, reliability and timeliness of patient test results regardless of where the test was performed. A laboratory is defined as any facility which performs laboratory testing on specimens derived from humans for the purpose of providing information for the diagnosis, prevention, treatment of disease, or impairment of, or assessment of health." This statute is enforced by the Centers for Medicare and Medicaid Services (“CMS”). CLIA regulates laboratories who conduct any type of testing—including genetic/genomic and non-genetic testing. The statute requires most laboratories who conduct testing for medical purposes to hold a CLIA certificate, issued by CMS.

The requirements for CLIA-certification vary depending on the type of testing which is conducted by the labs. For highly complex testing, such as certain genetic tests, the laboratories may be required to have structured level of supervision over testing technicians and high levels of training over individuals who conduct the testing procedures.

Certain areas of genetic diagnostics have been subject to more regulation under CLIA, by CMS, rather than the FDA (e.g., LDTs). For more information on this topic, please see our page on U.S. Regulation of Diagnostic Kits.

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Analytical & Clinical Validity & Utility

One problem that is repeatedly encountered in literature is how to quantify the proficiency and usefulness of a particular genetic test. At present, there are no universally established standards for genetic tests to determine proficiency and usefulness by a regulatory body. However, Professional Associations, Laboratory Accreditation Organizations, Policy Groups and Patient Advocacy Organizations all seem to agree that the follow criteria are important when addressing these questions.

Analytical Validity: refers to the level of accuracy and consistency with which a particular genetic characteristic, such as a DNA sequence variant, chromosomal deletion or biochemical indicator, can be identified in a given laboratory test.
Clinical Utility: defines the risks and benefits associated with the introduction of a test into practice, including the impact of positive and negative test results on health outcomes, cost-effectiveness, and ethical, legal and social issues associated with test use.
Clinical Validity: refers to the accuracy of a test when used to identify the presence of disease or predict a patient's clinical status.

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Genetics vs Genomics

Occasionally, the terms "Genetics" and "Genomics" are used interchangeably within the context of genetic testing. More specifically, both terms are sometimes used to refer to the testing of specific genes or the indexing of multiple tests of single genes. Unfortunately, the scientific community has distinct uses for these terms in contrast to marketing efforts by companies and in public discussion forums. The definitions below represent the scientific application of these terms.

Genetics

Genetics is a term that refers to the study of genes and their role in inheritance - the way certain traits or conditions are passed down from one generation to another. Genetics involves scientific studies of single genes and their effects. Genes (units of heredity) carry the instructions for making proteins, which direct the activities of cells and functions of the body. Genes influence traits such as hair and eye color as well as health and disease development. Genetics determines much (but not all) of a person's appearance and health status, but environmental differences also play a part. Examples of single gene disorders that would be considered as "genetics" include cystic fibrosis and PKU (phenylketonuria).

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Genomics

Genomics is a relatively new term that describes the study of all of a person's genes including interactions of those genes with each other and the person's environment. Genomics involves the scientific study of complex diseases such as heart disease, asthma, diabetes and cancer because they are caused more by a combination of genetic and environmental factors. Genomics is offering new possibilities for therapies and treatment of some diseases, as well as new diagnostic methods. The major tools and methods related to genomics studies are bioinformatics, genetic analysis, measurement of gene expression, and determination of gene function.

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Typology of Genetic Tests

Most genetic tests are conducted as in vitro (latin for "in glass") tests. That is, a sample specimen is collected from a patient's body and tested in a laboratory -- as opposed to an in vivo (latin for "in body") test such as an x-ray or CT scan. However, professionals working in the genetic testing industry commonly use terminology to describe genetic tests by how they are classified under FDA regulations. While there can be distinctions between technology utilized during testing, it's important to remember that just because a test is termed a "in vitro diagnostic" test does not mean it is functionally different from a "laboratory developed test." The primary difference between these regulatory classifications is dependant on whether the tests are being commercially sold and how stingently they are regulated by the FDA.

Learn more about the FDA's classification system on our U.S. Regulations Page

In-Vitro Diagnostics (IVD) Kits

Genetic IVDs are genetic tests commercially marketed by medical device manufacturers. Ultimately, these tests are sold as "testing kits" to laboratories who perform the tests. These testing kits typically include a set of test reagents, also termed analyte specific reagents, an assay or specimen collection devices, measurement apparatuses, and detailed instructions (for laboratory personel) describing how to perform the test.

Genetic IVDs are used for variety of purposes, including, clinical purposes, such as for the diagnosis or prevention diseases, or for research or investigative purposes, such as studying genetic disorders or characteristics.

Most genetic IVDs are either Class II or Class III "medical devices" under the FDA's Federal Food, Drug, and Cosmetic Act. In the case of Class III IVDs, the manufacturers must meet stringent requirements set by the FDA, including approval before the IVD is commercially sold. Class II IVDs are still subject to regulation and must statisfy less stringent requirements than Class III IVDs, such as being manufactured under a quality assurance program

Laboratory Developed Tests (LDTs)

LDTs are genetic tests developed and performed within a laboratory. LDTs are not commercially marketed to other entities or sold as "devices" in the diagnostics market. LDTs represent the majority of genetic diagnostics tests currently available on the market.

When compared to most IVDs, genetic LDTs share many characteristics -- i.e., both are in vitro tests which use identical or similar technologies to produce testing results. The main difference between and LDT and an IVD is that the LDT is developed within a laboratory and is not commercially sold to other entities. Industry professionals will also refer to LDTs as "proprietary", "in-house", or "home-brew" genetics tests.

In practice, there are two ways to utilize an LDTs in a laboratory. First, the majority of LDTs available in the market use analyte specific reagents (ASRs) which are developed within the laboratory for use within a particular genetic tests. Secondly, there are other LDTs that use analyte specific reagents purchased from manufacturers. Although this second type of LDT sounds similar to a IVD kit purchase, the only purchase being made is for the ASRs, there are no instructions or other equipment included as would be with a kit.

Although the FDA has stated they believe LDTs to be "medical devices" under the FFDCA, the laboratories who develop LDTs believe the tests are more aptly described as "testing services" not devices, and for this reason, they argue the FDA does not have the authority to regulate LDTs. Despite the fact the FDA has issued rules stating that LDTs are "medical devices" they do not actively enforce most of their regulations on laboratories who offer LDTs.

On the other hand, the FDA and CMS do impose certain regulations over the sale of ASRs to laboratories for use in LDTs. Under these regulations, the ASR manufacturers who are selling the ASRs must meet the regulations, rather than the laboratories themselves. However, under FDA regulations these ASRs are usually classified as Class I or Class II medical devices, which do not require approval by the FDA prior to sale.


In-Vitro Diagnostic Multivariate Index Assay (IVDMIAs)

IVDMIAs are a subset of IVD and LDT genetic tests. As the name implies, an IVDMIA is a test that assays multiple variables, like gender, age, weight, in combination with the results of certain genetic tests. These variables are then anayzled through a computer algorithm which generates a consumer-friendly report, detailing things such as health risk assessments and percentage calculations that indicate a disposition towards developing a disease.

In recent years, as manufacturers and laboratories have watched the application potential of IVDMIAs continue to increase, IVDMIAs have come under scrutiny for regulatory issues. Many testing providers would prefer IVDMIAs be classified as a LDT rather than a IVD or other type of medical device under the FDA's regulations. If classified as an LDT, IVDMIAs would be subject to less regulatory scrutiny and would not have to be approved by the FDA prior to sale on the market.

Another problem perceived by some commentators is that the results generated by IVDMIAs do not allow for independent appraisal by an outside official or medical professional. For instance, rather than reporting the raw data which allowed the computer algorithm to generate a given set of results, many IVDMIA reports only provide an index or score report that consists of percetage calculations indicating probablity of disease development or diagnosis.

In 2007, the FDA has released draft guidelines that stated IVDMIAs will be considered Class II or Class III medical devices under the FFDCA depending on their intended use. Since then, over 192 different stakeholders have submitted comments To date, however, no final ruling has been issued from the FDA on the classification of IVDMIAs.

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Direct Access Testing (DAT)

"As with home testing, direct access testing (DAT) has been growing in popularity over the past few years. Currently, 34 states permit consumers to order their own lab tests - without a medical order from their health care provider. Also known as patient authorized testing, DAT is a reflection of Americans' focus on health and preventive medicine, offering the opportunity for patients to take a more active role in their own health care.

In some respects, direct access testing has been around for some time. Over-the-counter home tests are a type of DAT since they do not require a prescription and can be bought and used at the consumer’s discretion. Now, the trend has expanded to include laboratories offering clinical tests at the patient’s request. In retail centers in Colorado, Montana, Missouri, Kansas, and Utah, patients can walk into a lab and request certain tests; wellness centers offer health screens and other lab tests; and free-standing and mobile testing facilities offer screening tests to the public, such as in grocery stores and pharmacies.

Most DAT labs limit the availability of tests to simple, general health tests such as complete blood counts (CBC), cholesterol levels, throat and urine cultures, diabetes screening (blood glucose tests), chemistry panels, PSA for prostate cancer, thyroid tests, HIV antibody tests, blood typing, pregnancy tests, and urine drug screens.

Direct access testing may reduce costs for the patient by eliminating the expense of doctor’s office visits, providing vital information to patients who are concerned with a particular health problem or who may otherwise avoid testing due to inconvenience or concerns over anonymity. However, most insurance companies do not cover tests that are not ordered by a physician; therefore, you should expect to pay out-of-pocket for these services. In addition, labs providing DAT services must provide consumers with reference ranges and some assistance in interpreting the results. However, you are not operating under the guidance of your physician, who may be better able to determine what tests you really need but also what the results of those tests mean in light of your specific clinical signs, symptoms, and medical history." [1]


Direct to Consumer (DTC)

IVDs sold directly to consumers who operate the tests themselves. Also known as Over the counter (OTC) or home-based kits. Some DTC products may also be considered DAT products. In these cases, the consumer collects the sample themselves with a sampling kit and mails it away for analysis in a commercial lab (DNAdirect's products work this way). In most DTC IVDs, such as home pregnancy tests or blood glucose tests, the sample collection and analysis happens together in the home.

"While the majority of diagnostic tests are conducted by clinicians and laboratory personnel, individual consumers also purchase diagnostics for private use in their homes. The market for home testing devices expanded from $1.19 billion in 1994 to $4.8 billion in 2002. Among home testing devices approved by the FDA are those that measure cholesterol levels, glucose levels, vaginal pH levels, blood clotting time (for patients on blood thinning drugs such as warfarin) and the presence of fecal occult blood (for detecting colon cancer). The FDA also has approved home testing devices that test for hepatitis C virus (HCV) and HIV, as well as for detecting menopause, pregnancy and drug abuse. The most frequently used home testing devices include blood glucose monitors for diabetics, pregnancy tests and cholesterol tests." [1]

  • [1]Goodman et al. The Value of Diagnostics: Innovation, Adoption and Diffusion Into Health Care. (2005) pp. 58-59

Reference Lab

"When diagnostic capabilities are needed beyond those provided in hospitals and physician practices, analysis is conducted in reference labs. While reference labs comprise only 2.8% of all clinical labs within the US, these facilities are responsible for 32% of the diagnostic industry’s revenue, due to their focus on processing large volumes of diagnostic tests for a broad client base. Reference labs generally perform both routine testing and esoteric testing. The largest reference labs may conduct more than 4,400 different types of tests, ranging from high-throughput routine tests (e.g., routine culture, cholesterol tests, Pap smears) to complex or specialized diagnostic tests for Lyme’s disease, cancer, cardiovascular disease and HIV." [1]

"Reference labs are usually private, commercial facilities that do high volume routine and specialty testing. Most of the tests performed are referred from physician’s offices, hospitals and other health care facilities (e.g., nursing homes and other facilities). While most hospitals try to do as many tests as possible in-house, reference labs are used for specialized tests that are ordered only occasionally or that require specialized equipment." [2]

"The major national reference labs including Quest, LabCorp, Specialty/Ameripath, Mayo and others account for at least 60% of the market for esoteric test services. The remaining 40% is shared by a group of some 3000 small, local market laboratories. The major reference labs have built a comprehensive menu of specialized test services and continue to expand their offerings via collaborations with leading medical research centers. They offer a huge presence in the market and manage distribution networks that touch just about every medical specialty. Thus many CLIA-registered company sponsored test services avail themselves of the marketing resources offered by the national reference labs." [3]

  • [1] Goodman et al. The Value of Diagnostics: Innovation, Adoption and Diffusion Into Health Care. (2005) pp. 28
  • [2] http://www.labtestsonline.org/lab/labtypes-3.html
  • [3] Rosen. Diagnostic Test Service Commercialization: A Roadmap to Diagnostics in the 21st Century. (2008) pg. 22

Pharmacogenetics & Pharmacogenomics (PGx)

Pharmacogenetics and/or pharmacogenomics (PGx) is the study of differential drug response due to genetic variation. The two terms tend to be used interchangeably, although the -genetics suffix suggests studies and assertions involving tens of genes while -genomics suggests hundreds or thousands. Many clinical applications to date have focused on drug-metabolizing enzymes such as CYP450s. Other tests examine tens of genes to predict the most efficacious anti-cancer drug. In general, PGx studies attempt to rationally optimize drug choice and dosage while minimizing side-effects.

Drug developers are increasingly including PGx studies in clinical trials and subsequently marketing both PGx diagnostics and the drug or drugs indicated by the test. Note that the included diagnostic does not necessarily help diagnose the condition, but instead determine the appropriate therapeutic response.

See the recent paper by Flockhart et al for a review of 11 pharmacogenomic diagnostics currently on the market.

PreMarket Approval (PMA)

"Premarket approval (PMA) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Class III devices are those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury. Due to the level of risk associated with Class III devices, FDA has determined that general and special controls alone are insufficient to assure the safety and effectiveness of class III devices. Therefore, these devices require a premarket approval (PMA) application under section 515 of the FD&C Act in order to obtain marketing clearance. Please note that some Class III preamendment devices may require a Class III 510(k). See "Historical Background" for additional information.

PMA is the most stringent type of device marketing application required by FDA. The applicant must receive FDA approval of its PMA application prior to marketing the device. PMA approval is based on a determination by FDA that the PMA contains sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s). An approved PMA is, in effect, a private license granting the applicant (or owner) permission to market the device. The PMA owner, however, can authorize use of its data by another." [1]

[1] http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/premarketapprovalpma/default.htm


PreMarket Notification 510(K)

The 510(k) process requires manufacturers of medical devices to notify the FDA, at least 90 days in advance, of their intent to market a product in the US. The Agency then determines if the product is exempt (subject only to the general controls of the statute), is as safe and as effective as a legally marketed device of the same generic type or that the device requires premarket approval. A new device found to be not substantially equivalent (“NSE”) is classified as class III and a substantially equivalent new device is classified in the same regulatory class, either class II or class I, as the device to which it is found equivalent. Therefore, the 510(k) process serves as a means to classify new devices. [1]

So all medical devices must pass through the 510(k) process on their path to the market, and the riskiest devices - those classified as Class III through the 510(k) - must also receive premarket approval, which is a much more elaborate process involving clinical trials.

  • [1] AdvaMed (2008), The 510(k) Process: The Key to Effective Device Regulation. pp. 8-9
  1. ↑ FDA Regs., Definition of Analyte-Specific Reagents, 21 C.F.R. § 864.4020.
  2. ↑ Clinical Laboratory Improvement Amendments Act ("CLIA") Reuglations can be found at 42 U.S.C. § 263a et seq ; 42 C.F.R. § 493.1 et seq
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