Diagnostic Kits/USA Regulation Review

This section will detail the current state of Federal and State regulations required by government agencies for genetic tests. At present, the U.S. Food and Drug Administration ("FDA") and the Centers for Medicare & Medicaid Services ("CMS") regulate certain aspects of genetic testing. Although the vast majority of regulatory efforts are overseen by Federal Agencies, there are certain State-imposed standards for genetic tests that vary in scope by State.

Regulatory Agencies

U.S. Government Regulatory Entities

Agency Name	Abbreviation	Agency Type	Scope of Regulatory Oversight	External Link to Websites
Food & Drug Administration	FDA	Federal		fda.gov
Centers for Medicare & Medicaid Services	CMS	Federal		cms.gov
Federal Trade Commission	FTC	Federal		ftc.gov
Various State Agencies	(varies per state)	State		insert website list

Federal Agencies

The scope of FDA requirements, such as pre-market regulatory approvals, that apply to companies offering genetic tests depend almost entirely on the nature of the genetic test offered. In some cases, manufacturers must meet stringent requirements before marketing a genetic test, whereas in others, there are little or no substantive requirements.

CMS requires certain laboratory standards for all laboratories that conduct testing for patients in the United States. The requirements imposed by this agency are still somewhat dependent on the nature of testing conducted on the premises. For certain complex tests, including some genetic testing, laboratories must be approved by CMS and may require certain levels of supervision by highly trained individuals conducting the testing. However, for simpler tests, laboratories may perform testing without stringent oversight

State Agencies

Certain states have become increasingly involved in administering genetic testing oversight. In some cases, where states have implemented their own regulatory schemes for laboratories, laboratories located within an applicable state have become exempt from the requirements imposed by CMS. In other cases, laboratories located in a state which have state-mandated regulations that apply to laboratories must also meet CMS regulations.

New York and the state of Washington are two primary examples of where laboratories are exempt from CMS regulation. New York requires any laboratory which conducts testing to be evaluated and approved by license by the New York Department of Health before any testing can be conducted. Interestingly, these requirements also apply to laboratories that obtain specimens from patients residing within the state. Some commentators believe many laboratories avoid offering genetic testing services to New York residents.

California is an example of a state where laboratories must be both state and CMS regulations for clinical laboratory testing. Laboratories must obtain an approval license issued by the state before conducting direct-to-consumer genetic testing.

For all states that impose additional licensing or approval requirements for laboratory testing, companies manufacturing and marketing genetic tests will still be subject to any applicable FDA regulations.

Federal Regulatory Classifications 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 necessarily mean it is functionally different from a "laboratory developed test." The primary difference between these regulatory classifications is dependent on whether the tests are being commercially sold and how stringently they are regulated by the FDA.

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 personnel) 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 satisfy 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 Federal Food, Drug, and Cosmetic Act, 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)

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, or more generally, a health risk assessment.

IVDMIAs are a subset of IVD and LDT genetic tests. Currently, it's unclear whether such tests fit for regulatory purposes. 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 percentage calculations indicating probability 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.

See Also:

• http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm079148.htm
• http://www.regulations.gov/search/Regs/home.html#docketDetail?R=FDA-2006-D-0233

Analyte Specific Reagents (ASRs) -- a component of LDTs and IVDs

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.

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.”

FDA Regulations

The FDA's primary source of authority over genetic tests comes from the Food, Drug, and Cosmetic Act. This act allows the FDA to regulate "medical devices" which are defined as "an instrument, apparatus, implement, machine, continuance, implant, in vitro agent, or similar or related articles, including any component, part or accessory" that is "intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, or treat or prevention of disease, in man or other animals." Under this statutory authority, the FDA created and implemented a series of regulatory definitions, which further clarify what items and services are considered "medical devices," as well as a classification system which subject "medical devices" to various requirements.The FDA regulations further defined medical devices as "in vitro diagnostic products" which consistent of "those reagents, instruments, and systems, intended for use in the diagnosis of disease or other conditions."

Classification System of "Medical Devices"

The FFDCA contains a classification system for all medical devices intended for human use. Under this system, manufacturers of medical devices must satisfy certain requirements in the course of developing and marketing a product. Primarily, whether a device falls into a lower classification (e.g., Class I) is dependent on the level of complexity and inherent risks present in the device. The more complex devices are classified as Class II and III devices and subject to much more stringent requirements under the FFDCA. The contrast between requirements in the classification system is quite sharp. Class I devices typically have to satisfy simple reporting requirements whereas Class III devices must meet extensive clinical trials and pre-market approval standards set by the FDA.

Federal Food, Drug, and Cosmetic Act Classifications

Classification	Description of Classification	FDA Requirements Prior to Market Clearance
Class I	The device can reasonably safe and effective for its intended use with minimal supervision. The device is also not considered life-threatening, or life-sustaining or a substantially important in preventing impairment of human health, nor does use present a potential unreasonable risk of illness or injury.	Device and manufacturer must be registered and listed with FDA. The device must be: manufactured under a quality assurance program, suitable for its intended use, adequately packaged and labeled. Most Class I devices do not have to satisfy 510(k) Pre-Market Notification (PMN) requirements.
Class II	Heightened oversight into the process of manufacture and use of the device is necessary to provide reasonable assurance of safety and effectiveness of the device.	Class II devices must meet all the requirements of Class I devices. Class II devices may require special labeling, mandatory performance standards, and post-market surveillance. Many Class II device will require 510(k) Pre-Market Notification (PMN); however a small number of Class II devices are exempt from this requirement.
Class III	Class III devices are under the most stringently regulated category of medical devices. These devices usually support or sustain human life, or are of substantial importance in preventing the impairment of human health, or are those which may present a potential unreasonable risk of injury.	Most class III devices require Pre-Market approval (PMA) prior to being marketed. is or will be required. The review process consists of a administrative and limited scientific review, an in-depth scientific, regulatory, and quality system review, and review and recommendation by an FDA advisory committee.

More information on the classification system available at fda.gov website.

510(k) Pre-Market Notification (PMN)

Developers, manufacturers, and product relabelers (collectively, the "marketers") of Class I and II medical devices may also be required to submit a pre-market notification (also referred as "PMN" or 510(k)) indicating their intent to market a product in the U.S. Although some Class I devices require a PMN, the vast majority do not. Unless an exemption applies, all Class II device manufacturers must submit a PMN at least 90-days prior to offering a device on the market.

The PMN essentially requires a the marketers to establish that a device is at least as safe and effective as another device (commonly called a "predicate device") that is already sold, in compliance with the FDA, on the market for the same intended use and technological characteristics. If a new device only share the same intended use, but the technological characteristics differ, the manufacturer may submit data to the FDA which shows that the new device does not raise any questions of safety and effectiveness, and is at least as safe and effective as the legally marketed device.

More information on the FDA website page covering PMNs

Pre-Market Approvals (PMAs)

Manufacturers or designers of Class III medical devices are generally required to obtain pre-market approval (PMA) prior to offering a product for sale on the market. Due to the level of risk associated with Class III devices, the PMA is the most stringent type of pre-market regulatory approval conducted by the FDA and can be likened to the regulatory approval process the FDA requires for manufacturers of therapeutic drugs.

In order to obtain a PMA consists, manufacturers must submit scientific documentation to the FDA which demonstrates that a Class III medical device is safe and effective. This includes the submission of technical data, non-clinical studies (e.g., information on any microbiology, toxicology, immunology, biocompatibility, stress, wear, shelf life, and other laboratory or animal tests), clinical investigations (e.g., information on safety, effectiveness, patient information, patient complaints, data, statistical analysis).

The FDA conducts an in-depth review on submissions over a 180-day period. Occasionally, applications are referred to a outside panel of experts for review and recommendation.

For more information, see the FDA website pages on PMAs

FDA Regulations That Cover IVDs, LDTs, and ASRs

The "ASR Rule"

The FDA's approach to stringent regulation of ASRs has been met with criticism by many groups. Currently, the lack of stringent regulations covering the use of ASRs in in-house develop LDTs provides a valuable incentive, in terms of benefits of lower development costs and regulatory compliance, for companies to create LDTs rather than IVDs which have been traditionally regulated as medical devices.

In 1997, the FDA issued a final ruling covering the sale of ASRs. In this ruling, the FDA determined that it believes the majority of ASRs sold to be Class I "medical devices" as covered under the FFDCA. Importantly, this regulation covers the sale of ASRs between entities, but does not seem to cover those ASRs that are developed in-house by laboratories and used in LDT tests. Furthermore, this ruling clarified that manufacturers of ASRs would not be able to make statements concerning the potential clinical or analytical application of the performance of ASRs in certain test or provide instructions on how to use ASRs in a test.

There is also some evidence that the FDA has applied the ASR rule in very narrow situations. One commentator points to a instance in 2003 where Roche Molecular Diagnostics successfully argued that it's microarray technology product ("AmpliChip"), which was developed for use in identifying genetic abnormalities related to drug metabolism, constituted a Class I ASR.

The FDA's approach to what many commentators describe as "ASR regulation gap" may be at the precipice of change. In short, the FDA may clarify or amend its current regulatory practices and subject ASRs to more stringent regulation. In 2007, the FDA issued a guidance document which, again, described ASRs as medical devices, but permitted the use of ASRs without heightened regulatory oversight (e.g., as Class I and II devices) as long as the ASRs were not sold "in a specific assay or on a designated instrument." This essentially permitted laboratories to continue using ASRs as along as they were not being purchased as a "kit" that would otherwise qualify as an IVD device subject to more stringent regulations.

In summary, the current ASRs rule permit the majority of genetic diagnostic tests, such as LDTs with in-house developed ASRs, to eschew the pre-market approvals requirements.

CMS Regulations

The Centers for Medicare and Medicaid Services (CMS) is an agency within the U.S. Department of Health and Human Services. In addition to administering the Clinical Laboratory Improvement Amendments Act (CLIA), CMS administers the U.S. Medicare and Medicaid programs and works with health care entities subject to the Health Insurance Portability and Accountability Act (HIPAA).

In the context of the genetic diagnostic testing field, the CLIA program is especially relevant to laboratories which conduct genetic tests on human specimens. It's important to note that CMS regulations are not mutually exclusive of the FDA regulations. There are some areas of actual and potential regulatory overlap between the FDA's medical devices regulations and the actual testing procedures and ingredients are covered by CLIA regulations in laboratories. This will be discussed at length below.

Clinical Laboratory Improvement Amendments (CLIA)

The Clinical Laboratory Improvement Amendments Act or ("CLIA") 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.

CLIA Regulations which cover IVDs, LDTs, and ASRs

Overlapping Areas of FDA and CMS Regulations

See Also:

• CMS's CLIA Overview
• FDA's page on CLIA
• Wikipedia Entry on CLIA

FTC

Regulatory role: oversee marketing aspects of test offerings.

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