Diagnostic Kits/Glossary

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Analyte Specific Reagent (ASR)

Code of Federal Regulations Title 21 (21CFR809.30) states that ASRs may only be sold to: IVD manufacturers, CLIA labs capable of high-complexity testing, and organizations that use the reagents for non-clinical uses.

There are 3 classes of ASRs, I, II, and III. The analytical and performance characteristics of Class I ASRs are not established by the FDA, and for Class II and III ASRs are only established as a component of a cleared test. Because ASRs do not generally require full FDA pre-market review, they can be developed more quickly for less money. But they are not sold as complete diagnostics - instead, CLIA labs purchase ASRs to use in diagnostic tests they develop internally.

"ASRs were initially introduced to improve the availability of immunohistochemical stains for which manufacturers had not sought FDA market clearance because the cost was too high for the revenues that would come from such products. The ASR regulatory path has become the chosen commercialization route for many molecular tests for similar cost-versus-revenue reasons. The minimal regulatory burden involved in releasing tests as ASRs allowed for a lucrative market, even in the earliest stages of this market sector." [3]

Examples of ASRs:

  • Microarrays
  • Antibodies
  • Algorithms for interpreting IVDMIAs?


Can non-CLIA customers purchase ASRs for non-clinical use?

What is the distinction between the three classes of ASRs?


Clinical Laboratory Improvement Amendments (CLIA)

Passed by Congress in 1988, CLIA 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."[1]

The stringency of CLIA regulations increase with the complexity of the test being performed. Three categories have been established: waived complexity, moderate complexity, and high complexity.

The CMS implements CLIA (and receives certification and inspection fees from labs), the CDC is responsible for CLIA studies, and the FDA is responsible for test categorization.

"To enroll in the CLIA program, laboratories must first register by completing an application, pay fees, be surveyed, if applicable, and become certified."[1]

[1] http://www.cms.hhs.gov/CLIA/07_Program_Descriptions_Projects.asp
[2] http://www.fda.gov/cdrh/CLIA/


Analytical & Clinical Validity & Utility

"Analytical Validity is the accuracy 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." [1]

"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." [2]

"Clinical Validity is the accuracy with which a test identifies or predicts a patient's clinical status. [1]

Genomic

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. More at Genome.gov and at and at CDC.gov Genomics and Health Resources and CDC.gov Genomics Translation Resources

Genomic test

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). More at Genome.gov and at CDC.gov Genetics

Genetic test

Typology of Genetic tests

In Vitro Diagnostics can be categorized based on the location of testing.

ASRs

The vast majority of routine tests are performed in-house hospital labs or in reference labs. These tests may be supplied as a complete kit to the testing laboratory or may be developed in-house with Analyte Specific Reagents (ASRs). ASR-based diagnostics are interesting because the ASRs are sold alone, without specific testing procedures, instructions, or supporting materials. Instead of purchasing a complete kit, labs (which must be CLIA high-complexity certified) purchase just the ASR and develop their own tests around it.

OTC

Lastly, some kits are available directly to consumers over-the-counter. Of these, some can be operated in the home, such as pregnancy tests and blood glucose tests, while others require the user to ship a sample to a remote reference lab. DNA Direct is a company that operates in this space, providing gene-based OTC diagnostic kits that are evaluated in a remote lab.

In-Vitro Diagnostic (IVD)

Diagnostics may be sold in a complete kit to a testing provider, comprising specific testing instructions, tools, reagents, and measurement systems.

In-Vitro diagnostics can be categorized into 5 types: General (Clinical) chemistry, Immunochemistry, Hematology/Cytology, Microbiology/Infectious Disease, & Molecular, Genomic, Proteomic, & Metabolomic (Omics).

What they are not: Imaging (CAT/MRIs, ultrasounds) or In-Vivo: (assess health status inside of body or measure body functions as they occur, like a heart rate monitor, blood pressure, temperature)

Examples:

  • cholesterol test, urinalysis strips (Clinical Chemistry)
  • blood count, pap smear (Hematology/Cytology)
  • Strep test, SARS blood screening (Microbiology)
  • PSA test for prostate cancer, HIV antibody testing (Immunochemistry)
  • SARS PCR assay, HIV viral load, CYP450 diagnostics, BRCA cancer screening (Omics)

FDA Definition: "In vitro diagnostic products are those reagents, instruments, and systems intended for use in diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. [21 CFR 809.3]" [1]

"Principal uses include primary risk assessment (including predictive and early disease identification applications), diagnosis, secondary risk assessment (prognosis), drug selection and treatment targeting applications and disease/condition monitoring and management." [4]

Regulation

In 1976, Congress passed the Medical Device Amendments of 1976, giving direct and comprehensive regulatory control to the FDA for medical devices, distinct from regulatory powers the FDA already had over drugs.

Through the 510(k) process, the amount of regulation a new device requires before reaching market is determined.

Unlike Class III devices, Class I & II devices do not need premarket review and hence reach market much more quickly and cheaply.

"There are essentially two kinds of tests: those that are manufactured and sold in volume as kits to laboratories and those that are developed within a particular laboratory (called laboratory-developed assays or "home-brew" tests). In each case, their development and entry into the market - that is, their use on patient specimens - is governed by sets of rules that ensure their accuracy and reliability." [2]

Laboratory-developed assays often depend on Analyte-Specific Reagents (ASRs), which may be classified as Class I or II devices more often than complete diagnostic kits (but I have not found any sources directly suggesting this). However, ASRs must be used in CLIA-certified labs.

Note: see pp 58-65 of AdvaMed report; lots of great, deep info on regulation

Related: 510(k), Pre-Market Approval, CLIA.

The Diagnostic Process

The primary components of the diagnostic process: samples, controls, instruments, and accessories. [3]

In-Vitro Diagnostic Multivariate Index Assay (IVDMIA)

The FDA defines IVDMIAs as medical devices.

"The definition of a device is set forth at section 201(h) of the Food, Drug and Cosmetic Act ("the Act"). It provides in relevant part: "The term 'device' . . . means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is . . . (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals . . . ." (21 USC 321(h)). As described further in this guidance document, an IVDMIA is a device that: Combines the values of multiple variables using an interpretation function to yield a single, patient-specific result (e.g., a “classification,” “score,” “index,” etc.), that is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease, and Provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user. An IVDMIA is a device within the meaning of the Act. " [1]

IVDMIAs involve the use of an algorithm to correlate measurements of multiple (n=10 - 1000) biomarkers to specific clinical outcomes and disease conditions. So although IVDMIAs may be run and regulated like ASRs, because of the algorithm, they can actually be regulated as devices by the FDA, requiring premarket notification and / or review.

The FDA formally indicated it would begin considering IVDMIAs devices in a draft report published in 2006: "Guidance for Industry, Clinical Laboratories, and FDA Staff on In Vitro Diagnostic Multivariate Index Assays." [1] Since then, over 192 different stakeholders have submitted comments [2]. We currently have front-row seats to the development of policy for cutting-edge diagnostic technologies.


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
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