Regulation of Clinical Tests: In Vitro
Diagnostic (IVD) Devices, Laboratory
Developed Tests (LDTs), and Genetic Tests
Amanda K. Sarata
Specialist in Health Policy
Judith A. Johnson
Specialist in Biomedical Policy
March 27, 2014
Congressional Research Service
7-5700
www.crs.gov
R43438
Regulation of Clinical Tests
Summary
In vitro diagnostic (IVD) devices are used in the analysis of human samples, such as blood or
tissue, to provide information in making health care decisions. Examples of IVDs include (1)
pregnancy test kits or blood glucose tests for home use; (2) laboratory tests for infectious disease,
such as HIV or hepatitis and routine office blood tests such as for cholesterol and anemia; and (3)
tests for various genetic diseases or conditions. More recently, a specific diagnostic test—called a
companion diagnostic—may be used to select the best therapy, at the right dose, at the correct
time for a particular patient; this is often referred to as personalized medicine.
Federal agencies involved in the regulation of IVDs include the Food and Drug Administration
(FDA) and the Centers for Medicare & Medicaid Services (CMS). FDA derives its authority to
regulate the sale and distribution of medical devices, such as IVDs, from the Federal Food, Drug,
and Cosmetics Act and the Public Health Service Act. CMS’s authority to regulate IVDs is
through the Clinical Laboratory Improvement Amendments of 1988. FDA regulates the safety
and effectiveness of the diagnostic test as well as the quality of the design and manufacture of the
diagnostic test, and CMS regulates the quality of clinical laboratories and the clinical testing
process.
Traditionally, most genetic tests have not been subject to premarket review by the FDA. This is
because in the past, genetic tests were developed by laboratories primarily for their in-house
use—referred to as laboratory-developed tests (LDTs)—to diagnose rare diseases and were highly
dependent on expert interpretation. However, more recently LDTs have been developed to assess
relatively common diseases and conditions, thus affecting more people, and direct-to-consumer
(DTC) genetic testing has become widely available over the Internet. In June 2010 FDA
announced its decision to exercise its authority over all LDTs. FDA has provided a number of
reasons for the decision to assert its enforcement authority over LDTs, including that the public
needs assurances that LDTs are sound and reliable. FDA has not yet finalized guidance with
respect to all LDTs. A provision in the Food and Drug Administration Safety and Innovation Act
stipulates that the agency “may not issue any draft or final guidance on the regulation” of LDTs
without “at least 60 days prior to such issuance,” first notifying Congress “of the anticipated
details of such action.”
Concerning DTC genetic tests, which are mostly LDTs, the Government Accountability Office
(GAO) testified in 2010 before the Subcommittee on Oversight and Investigations of the House
Committee on Energy and Commerce that the results of DTC genetic tests for disease risk were
“misleading and of little or no practical use to consumers.” The GAO investigation focused on
four genetic testing companies that were “frequently cited as being credible by the media and in
scientific publications.” The cost of these genetic tests ranged from $299 to $999. The tests
provided risk predictions for diseases such as diabetes, hypertension, multiple sclerosis, leukemia,
breast cancer, and prostate cancer.
The extent to which LDTs should be regulated by the FDA, in conjunction with CMS, has been a
subject of debate. Some clinical laboratories and manufacturers of LDTs have maintained that
LDTs should be outside of the FDA’s regulatory purview. Legislation was introduced in the 110th
and 112th Congresses with the aim to clarify regulatory oversight as well as support innovation.
Approaches have included, among others, streamlining regulation by concentrating it in a single
federal agency or requiring the FDA to assert its enforcement authority over LDTs.
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Contents
Introduction ...................................................................................................................................... 1
FDA Regulation of IVD Devices ..................................................................................................... 5
FDA’s Authority to Regulate In Vitro Diagnostic (IVD) Devices ............................................. 5
IVD Regulatory Requirements .................................................................................................. 6
Commercial Test Kits vs. Laboratory Developed Tests (LDTs) .......................................... 8
Analyte Specific Reagents (ASRs)...................................................................................... 9
General Purpose Reagents (GPRs) ...................................................................................... 9
IVD Products for Research Use Only (RUO) or Investigational Use Only (IUO) ............. 9
IVD Companion Diagnostic Devices (CoDx) ................................................................... 10
Clinical Laboratory Improvement Amendments of 1988 (CLIA) ................................................. 11
Issues for Consideration................................................................................................................. 13
Oversight of Laboratory Developed Tests (LDTs) .................................................................. 13
Oversight of Direct-to-Consumer (DTC) Genetic Testing ...................................................... 16
FDA Approval or Clearance and Medicare National Coverage Determinations
(NCDs) ................................................................................................................................. 18
Contacts
Author Contact Information........................................................................................................... 19
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Introduction
In vitro diagnostic (IVD) devices, including genetic tests, provide information that is used to
inform health care decision making.1 IVDs are devices that are used in laboratory analysis of
human samples and include commercial test products and instruments used in testing, among
other things. IVDs may be used in a variety of settings, including a clinical laboratory, a
physician’s office, or in the home.
IVDs have a number of uses, such as diagnosis, screening, staging, and disease management,
including, for example, the selection and dosing of therapeutics. One estimate found that the
results of clinical laboratory tests influence approximately 70% of health care decisions.2 Despite
this broad effect on the delivery of health care, spending on IVDs represents a small portion of
overall health care costs.3 The Centers for Disease Control and Prevention (CDC) estimated that,
based on 2007 data, approximately 6.8 billion clinical laboratory tests are performed in the United
States annually, but noted that “publicly available information about the economic status and
quality of the laboratory medicine sector remains limited.”4
IVDs may be used in the care of a patient in numerous ways (see text box) and at various points
in the delivery of care. IVDs differ from other medical devices in that they do not act directly on a
patient to produce a result as does, for example, an implantable stent that keeps an artery open to
allow blood flow. Instead, the potential for risk of harm to the patient would be from the
generation of inaccurate test results that could lead to the mismanagement of a patient’s disease or
condition (i.e., false negative test result) or to treatment for a disease or condition that is in fact
absent (i.e., false positive test result).5
Given this potential risk, as well as the impact on the overall delivery of health care, the federal
government has taken a role in the oversight of IVDs. Federal oversight of IVDs spans several
federal agencies, including the Food and Drug Administration (FDA) and the Centers for
Medicare & Medicaid Services (CMS). Oversight efforts focus on ensuring the safety and
effectiveness of IVDs; the accuracy and reliability of IVDs; the quality of clinical laboratories
1 The term “in vitro,” meaning in glass, refers to testing that is carried out outside of the body. In contrast, “in vivo”
testing is carried out in a living organism, such as electroencephalography (EEG), electrocardiography (EKG), or
diagnostic imaging (X-ray).
2 UnitedHealth Center for Health Reform and Modernization, “Personalized Medicine: Trends and prospects for the
new science of genetic testing and molecular diagnostics,” Working Paper 7, March 2012,
http://www.unitedhealthgroup.com/~/media/uhg/pdf/2012/unh-working-paper-7.ashx.
3 The Lewin Group, “Laboratory Medicine: A National State Report,” May 2008, p. 2,
https://www.futurelabmedicine.org/pdfs/2007%20status%20report%20laboratory_medicine_-
_a_national_status_report_from_the_lewin_group.pdf, on October 20, 2012.
4 Ibid., p. 3.
5 IVDs evaluate the level of various biomarkers in a patient’s tissue or blood sample. A biomarker is used as a surrogate
marker for an outcome that is important to patients. The Institute of Medicine defines surrogate as “biomarker intended
to substitute for a clinical endpoint [and] expected to predict clinical benefit (or harm ... ) based on epidemiologic,
therapeutic, pathophysiologic, or other scientific evidence.” Although beyond the scope of this report, recent studies
have questioned the wisdom of relying on surrogate markers to accurately predict treatment effects on important
clinical outcomes, such as death and quality of life; http://www.iom.edu/Reports/2010/Evaluation-of-Biomarkers-and-
Surrogate-Endpoints-in-Chronic-Disease.aspx.
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that carry out IVD testing; the utility of the information in clinician and patient decision making;
and the truthfulness of claims made about IVDs that are marketed directly to consumers.
IVDs include genetic tests, a type of
The Role of IVDs in Health Care
diagnostic test that analyzes various aspects of
IVDs may be used in many components of the care of an
an individual’s genetic material (DNA, RNA,
individual patient. These include, for example:
chromosomes, and genes).6 Through basic
Diagnosing disease or ruling out the presence of a
research, scientists have “discovered hundreds
disease;
of genes that harbor variations contributing to
Predicting the potential risk of eventually developing a
human illness.”7 They have also found
disease or disorder;
“genetic variability in patients’ responses to
dozens of treatments” and are using IVDs “to
Determining the likely course or outcomes of a
disease;
better predict patients’ responses to targeted
therapy.”8 The use of an IVD companion
Choosing the most effective and appropriate treatment;
diagnostic device to select the best therapy, at
Guiding disease management; and
the right dose, at the correct time for a
Monitoring response to treatment throughout care.
particular patient is often referred to as
personalized medicine.9 Another term,
Sources: Raman G., Avendano EE, Chen M. Update on
Emerging Genetic Tests Currently Available for Clinical
pharmacogenomics, is sometimes used
use in Common Cancers. Evidence Report/Technology
interchangeably with personalized medicine.
Assessment No. GEND0511, Rockville, MD: Agency for
Pharmacogenomics is the study of how
Healthcare Research and Quality. July 2013.
individual genetic variation affects a person’s
response to drugs.10 Currently, more than 100 FDA-approved drugs contain pharmacogenomic
information in their labeling.11
The regulation of genetic testing has raised several issues. Traditionally, most genetic tests have
not been subject to premarket review by the FDA. It has been noted that, in the past, genetic tests
were developed mostly by academic or research laboratories primarily for in-house use—tests
referred to as laboratory-developed tests (LDTs)—to diagnose rare diseases and were highly
dependent on expert interpretation.12 In recent years, LDTs have been developed to assess
relatively common diseases and conditions. The extent to which all LDTs should be regulated by
the FDA has been a subject of debate.13
6 For more information about genetic testing and public policy, see CRS Report RL33832, Genetic Testing: Scientific
Background for Policymakers, by Amanda K. Sarata.
7 Margaret A. Hamburg and Francis S. Collins, “The Path to Personalized Medicine,” The New England Journal of
Medicine, vol. 363, no. 4 (July 22, 2010), pp. 301-304.
8 Ibid., p. 301.
9 Food and Drug Administration, Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical
Product Development, October 2013, p. 6, http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/
PersonalizedMedicine/UCM372421.pdf. For more information about the FDA’ s role in personalized medicine, see
http://www.fda.gov/scienceresearch/specialtopics/personalizedmedicine/default.htm.
10 Ibid., p. 8.
11 Food and Drug Administration, “Table of Pharmacogenomic Biomarkers in Drug Labeling,” http://www.fda.gov/
Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm.
12 Testimony of Jeffrey Shuren, M.D., Director, Center for Devices and Radiological Health, FDA, in U.S. Congress,
Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, U.S. House of Representatives,
Direct-to-Consumer Genetic Testing and the Consequences to the Public, hearings, 111th Congress, 2nd sess., July 22,
2010, http://www.fda.gov/NewsEvents/Testimony/ucm219925.htm.
13 Both the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) in April 2008 and the
(continued...)
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The appropriate degree and extent of federal regulation of direct-to-consumer (DTC) genetic
testing has also been a subject of much debate among relevant federal agencies as well as the
affected entities (mostly for-profit companies, for example, 23andMe, Pathway Genomics, or Life
Technologies). Genetic testing has become increasingly available for direct purchase by
consumers, generally over the Internet. In this type of testing—direct-to-consumer genetic
testing—the consumer sends in a tissue sample, often cells from the inside of the cheek, and the
results are conveyed directly to the consumer by the company that developed the test. Such DTC
genetic tests are often LDTs and therefore have historically not been regulated by FDA.14 In 2010,
the Government Accountability Office (GAO) testified that in its investigation of DTC genetic
tests—priced from $299 to $999—from four companies, it found the DTC genetic test results to
be “misleading and of little or no practical use to consumers.”15
Congress and the regulatory agencies have historically been interested in balancing the goals of
allowing consumers to have access, as quickly as possible, to new and improved medical devices
with preventing devices that are not safe and effective from entering or remaining on the market.
In the case of IVDs, and specifically, LDTs, Congress has introduced bills that attempt to address
both of these goals, that is, to support innovation and to increase or expand regulatory oversight.16
Approaches have included, among others, streamlining regulation by concentrating it in a single
federal agency or requiring the FDA to assert its enforcement authority over LDTs.
In addition to its role as regulator, the federal government has a role as a payer for IVDs,
primarily through the Medicare program.17 Medicare covers outpatient clinical laboratory testing
and generally reimburses for these tests based on the Clinical Laboratory Fee Schedule (CLFS).18
(...continued)
Secretary’s Advisory Committee on Genetic Testing (SACGT) in July 2000 have recommended that FDA be involved
in the regulation of laboratory developed genetic tests. For further information on SACGHS, see http://oba.od.nih.gov/
SACGHS/sacghs_home.html. For further information on SACGT, see http://oba.od.nih.gov/SACGHS/sacgt_info.html.
14 Although according to the FDA, LDTs come under the definition of “device” in the FFDCA as in vitro diagnostics,
FDA has historically chosen to exercise enforcement discretion over LDTs, and has therefore not traditionally enforced
regulatory requirements for LDTs. For more information, see “Oversight of Laboratory Developed Tests (LDTs).”
15 U.S. Government Accountability Office, Direct-To-Consumer Genetic Tests: Misleading Test Results Are Further
Complicated by Deceptive Marketing and Other Questionable Practices, GAO-10-847T, July 22, 2010, p. 4,
http://www.gao.gov/new.items/d10847t.pdf.
16 For example, see (1) 110th Congress: Laboratory Test Improvement Act of 2007, S. 736 (Kennedy); Genomics and
Personalized Medicine Act of 2007, S. 976 (Obama); (2) 112th Congress: Modernizing Laboratory Test Standards for
Patients Act of 2011, H.R. 3207 (Burgess); and (3) 113th Congress: Medical Testing Availability Act of 2013, H.R.
3005 (Burgess).
17 Medicare has recently made modifications to its reimbursement mechanism for some IVDs, including molecular
pathology tests that are often LDTs. Specifically, “[m]any LDTs do not have their own HCPCS codes; instead, they are
billed using unlisted codes for which Medicare Administrative Contractors (MACs) establish a payment amount for
their local jurisdictions. Prior to 2012, other LDTs were billed to Medicare using “stacking codes,” where a laboratory
submits a code for each step of the testing process. These “stacking codes” were eliminated at the end of 2012 and
replaced with new test-specific codes.” See 78 Federal Register 74229, December 10, 2013. The Department of
Defense, on the other hand, based upon the new codes, discontinued paying for certain LDTs through the TRICARE
program. Under 32 C.F.R. §199.4(g)(15)(i)(A) the Defense Health Agency does not cost-share medical devices
including LDTs if the tests are non-FDA approved, which DOD defined as not having received FDA marketing 510(k)
clearance or premarket approval. Such non-FDA approved LDTs are not covered by TRICARE, except under a
recently promulgated LDT demonstration project. For more information on TRICARE coverage, please contact CRS
Analyst Don Jansen.
18 “Under SSA Sections 1833 and 1861, outpatient clinical laboratory services are paid on a Fee Schedule under
Medicare Part B when they are furnished in a Medicare participating laboratory and ordered by a physician or qualified
non-physician practitioner who is treating the patient.” See CMS, “Clinical Laboratory Fee Schedule: Payment System
(continued...)
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Medicare also covers clinical laboratory testing conducted during inpatient care either in a
hospital or a skilled nursing facility (SNF).19 Although an in-depth discussion of this issue is
outside the scope of this report, the federal role as payer intersects with its role as regulator. This
is due to the fact that, as a payer, Medicare generally will only cover IVDs that have passed FDA
premarket review—either approval or clearance—where such FDA review is required by
applicable statute and regulation.20 However, in these cases, FDA approval or clearance is not
sufficient in and of itself to result in a favorable coverage decision by CMS for any given IVD.21
Definitions22
In Vitro Diagnostic (IVD) Device: Device used in the analysis of human samples; includes commercial test
products and instruments used in testing, among other things.
Laboratory-Developed Test (LDT): A class of IVD that is manufactured, including being developed and validated,
and offered, within a single laboratory. LDTs may sometimes be referred to as “home-brew tests.” (Source: FDA.
[2010] Oversight of Laboratory Developed Tests; Public Meeting; Request for Comments; F.R. 2010-14654.
http://www.gpo.gov/fdsys/pkg/FR-2010-06-17/html/2010-14654.htm)
All LDTs are IVDs.
Genetic Test: A test that analyzes various aspects of an individual’s genetic material (DNA, RNA, chromosomes,
and genes).
Al genetic tests are IVDs. Most genetic tests are LDTs.
This report provides an overview of federal regulation of IVDs by FDA, through the Federal
Food, Drug, and Cosmetics Act (FFDCA) and the Public Health Service Act (PHSA), and by
CMS, through the Clinical Laboratory Improvement Amendments (CLIA) of 1988.23 Terms used
throughout this report are defined in the text box. It then provides a discussion of issues for
consideration, including (1) the oversight of LDTs, (2) the oversight of direct-to-consumer
genetic testing, and (3) parallel FDA approval or clearance of an IVD and Medicare coverage
decisions.
(...continued)
Fact Sheet Series,” January 2012, http://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/
MLNProducts/downloads/clinical_lab_fee_schedule_fact_sheet.pdf.
19 For more information about payment under Medicare for clinical diagnostic laboratory services, see CRS Report
RL30526, Medicare Payment Updates and Payment Rates, coordinated by Paulette C. Morgan.
20 For novel and high-risk devices, premarket review entails conducting clinical studies, submitting the results of the
clinical studies along with a premarket approval (PMA) application, and requires evidence providing reasonable
assurance that the device is safe and effective. The PMA process results in a type of FDA permission called approval.
For moderate-risk devices, premarket review involves submitting a 510(k) notification demonstrating that the device is
substantially equivalent to a device already on the market (a predicate device) that does not require a PMA. The 510(k)
process, named for its authorizing FFDCA section, is unique to medical devices and results in FDA clearance.
Substantial equivalence is determined by comparing the performance characteristics of a new device with those of a
predicate device; clinical data demonstrating safety and effectiveness are usually not required.
21 For further details, see the Secretary’s Advisory Committee on Genetics, Health, and Society, 2006, “Coverage and
Reimbursement of Genetic Tests and Services;” p. 29, http://oba.od.nih.gov/oba/sacghs/reports/CR_report.pdf.
22 For the purposes of this report, the definitions include only those tests that are health-related.
23 P.L. 100-578, PHSA §353. All clinical laboratories that perform testing on a human specimen for health related
purposes are regulated under the authority of CLIA, regardless of whether they participate in either or both the
Medicare and Medicaid programs.
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FDA Regulation of IVD Devices24
As with other medical devices, the application of FDA regulatory requirements to IVDs depends
on the IVD’s risk classification according to its intended use. Risk classification “is based on the
risk the device poses to the patient or the user and the information available to address that risk.”25
The risk classification process is described in more detail in the “IVD Regulatory Requirements”
section of this report. IVDs are defined in regulation as a specific subset of medical devices that
include “reagents, instruments, and systems intended for use in the diagnosis of disease or other
conditions ... in order to cure, mitigate, treat, or prevent disease.... [s]uch products are intended
for use in the collection, preparation, and examination of specimens taken from the human
body.”26
As indicated by this definition, an IVD may be either a complete test or a component of a test. In
either case, the IVD comes under FDA’s regulatory purview. Test components include both non-
diagnostic ingredients, called general purpose reagents (GPRs),27 and the active ingredient in a
diagnostic test, referred to as the analyte specific reagent (ASR).28
There are two routes to market for an IVD used in the clinical management of patients. In one
route, the product is developed, produced, and sold by a manufacturer for distribution to multiple
laboratories—referred to as a “commercial test kit.” In the second route, the product is developed
by and used in a single laboratory—referred to as a “laboratory developed test,” or LDT. LDTs
may use ASRs or GPRs that are either manufactured in-house by the laboratory or that are
commercially developed and distributed. Currently, the application of FDA’s regulatory
requirements to each route differs markedly.
FDA’s Authority to Regulate In Vitro Diagnostic (IVD) Devices
IVDs that are used in the clinical management of patients generally fall under the definition of
medical device and therefore are subject to regulation by the FDA. The FDA derives its authority
to regulate the sale and distribution of medical devices from the Medical Device Amendments of
1976 (MDA, P.L. 94-295), which amended the FFDCA. Congress via the MDA provided a
definition for medical device and outlined a basic process for premarket approval and clearance
of such devices, among other things.
24 For further information about FDA regulation of medical devices broadly, see CRS Report R42130, FDA Regulation
of Medical Devices, by Judith A. Johnson.
25 Elizabeth Mansfield, Timothy J. O'Leary, and Steven I. Gutman, “Food and Drug Administration Regulation of in
Vitro Diagnostic Devices,” Journal of Molecular Diagnostics, vol. 7, no. 1 (February 2005), pp. 2-7.
26 21 C.F.R. §809.3(a); Definitions.
27 A GPR is “a chemical reagent that has general laboratory application, is used to collect, prepare, and examine
specimens from the human body for diagnostic purposes, and is not labeled or otherwise intended for a specific
diagnostic application ... [GPRs] do not include laboratory machinery, automated or powered systems.” 21 C.F.R.
§864.4010(a).
28 An analyte is defined as a substance or chemical constituent undergoing analysis. ASRs are “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.”
21 C.F.R. §864.4020(a).
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The term medical device is statutorily defined as “an instrument, apparatus, implement, machine,
contrivance, implant, in vitro reagent, or other similar or related article, including any component,
part, or accessory” (emphasis added) that is “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,
or is intended to affect the structure or any function of the body of man or other animals.”29 Some
tests may be used for non-health related purposes; for example, certain genetic testing may be
used to determine ancestry or may be used for forensic purposes. It has been noted that this type
of test would not come under the FDA’s regulatory purview.30
In some limited cases, IVDs may fall under the statutory definition of a biological product, and
are therefore subject to the requirements of the PHSA for the licensure of biological products.31
Such IVDs include, for example, blood donor screening tests for infectious agents (HIV, hepatitis
B and C), blood grouping, and cross-matching prior to transfusion.32 Given that IVDs may fall
under either the definition of medical device or biological product, they are regulated by FDA
primarily through the Center for Devices and Radiological Health (CDRH) and additionally by
the Center for Biologics Evaluation and Research (CBER).33
IVD Regulatory Requirements
FDA uses a risk-based regulatory scheme for medical devices, including IVDs. IVDs receive their
risk classification based on their intended use and the risk relative to that use. The intended use
“is established according to the claims the manufacturer or sponsor intends to make for the
device, and includes the target population and the clinical setting for the use of an IVD.”34 In
addition, classification is based on the risk the device poses to the patient; for IVDs, this is the
risk to the patient of an incorrect test result. Congress provided definitions in the MDA for the
three device classes—class I, class II, class III—based on the level of risk: low-, moderate-, and
high-risk, respectively. About 50% of IVDs are class I, 42% are class II, and 8% are class III.35
Device classification determines the type of premarket regulatory requirements that a
manufacturer must follow.
29 FFDCA §201(h).
30 See, for example, JK Wagner et al., “Tilting at windmills no longer: A data-driven discussion of DTC DNA ancestry
testing,” Genetics in Medicine, vol. 14, no.6 (2012), pp. 586-593.
31 PHSA §351; Regulation of Biological Products.
32 FDA, CDRH/CBER, Guidance for Industry and FDA Staff: In Vitro Diagnostic (IVD) Device Studies—Frequently
Asked Questions, Rockville, MD, June 25, 2010, p. 5, http://www.fda.gov/downloads/MedicalDevices/
DeviceRegulationandGuidance/GuidanceDocuments/UCM071230.pdf.
33 Ibid., pp. 6-7. Within CDRH, IVD products are reviewed by the Office of In Vitro Diagnostics and Radiological
Health (OIR), formerly called the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD);
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHOffices/
ucm115904.htm.
34 Zivana Tezak, Marina V. Kondratovich, and Elizabeth Mansfield, “US FDA and personalized medicine: in vitro
diagnostic regulatory perspective,” Personalized Medicine, vol. 7, no. 5 (2010), pp. 517-530.
35 FDA/CDRH Public Meeting: Oversight of Laboratory Developed Tests (LDTs), July 19, 2010, transcript, p. 45;
http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM226203.pdf.
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Many low-risk devices (class I) are deemed
General Controls
exempt from premarket review and
manufacturers need not submit an application
General controls include both pre- and postmarket
requirements, and are the minimum regulations that
to FDA prior to marketing.36 Premarket review
apply to all FDA regulated medical devices. Among other
is required for moderate- and high-risk devices
things, general controls include the following:
(class II and class III).37 In general, there are
1. Establishment Registration
two main pathways that manufacturers can use
to bring such devices to market. One pathway
2. Device Listing
consists of conducting clinical studies and
3. Good Manufacturing Practices
submitting a premarket approval (PMA)
4. Labeling
application, which requires evidence
providing reasonable assurance that the device
5. Premarket Notification
is safe and effective. The PMA process is
Source: See FDA, General Controls for Medical Devices,
generally used for novel and high-risk devices
May 13, 2009, http://www.fda.gov/MedicalDevices/
and results in a type of FDA permission called
DeviceRegulationandGuidance/Overview/
GeneralandSpecialControls/ucm055910.htm. Accessed
approval. The other path involves submitting a
July 30, 2013.
510(k) notification demonstrating that the
device is substantially equivalent to a device already on the market—a predicate device—that
does not require a PMA.38 The 510(k) process is unique to medical devices and, if successful,
results in FDA clearance. Substantial equivalence is determined by comparing the performance
characteristics of a new device with those of a predicate device; clinical data demonstrating safety
and effectiveness are usually not required. The FDA has 180 days to review a PMA application
and 90 days to review a 510(k) notification. Once a PMA application is approved or a 510(k)
notification is cleared for marketing, manufacturers must comply with regulations on
manufacturing, labeling, surveillance, device tracking, and adverse event reporting.39 In addition,
any future modification of the device must be cleared or approved by the FDA.
Class I devices are those under current law for which general controls “are sufficient to provide
reasonable assurance of the safety and effectiveness of the device.”40 This is the lowest risk
category; most class I devices are exempt from premarket review, though they still have to
comply with the other general controls (see text box). “Class I IVDs include certain reagents and
instruments, as well as a number of highly adjunctive IVD tests, where one test is dependent on
the results of another; consequently an incorrect result would generally be detected easily.... An
example of a class I test is a luteinizing hormone test that, if it gives a false result, may lead to
delayed conception but is unlikely to directly harm the patient.”41
Class II devices are those under current law “which cannot be classified as class I because the
general controls by themselves are insufficient to provide reasonable assurance of safety and
effectiveness of the device.”42 Class II includes devices that pose a moderate risk to patients and
are typically subject to general controls and special controls. It includes “many standard
36 FFDCA §513(a)(1)(A).
37 FFDCA §513(a)(1)(B) and (C).
38 For novel devices without a predicate, there is an alternative called the de novo 510(k) process; FFDCA §513(f).
39 For example, specific requirements on IVD device labeling are found at http://www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance/Overview/DeviceLabeling/InVitroDiagnosticDeviceLabelingRequirements/default.htm.
40 FFDCA §513(a)(1)(A).
41 Shuren, Direct-to-Consumer Genetic Testing, testimony on July 22, 2010.
42 FFDCA §513(a)(1)(B).
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laboratory tests, such as chemistry and immunology tests. Most class II tests are subject to FDA
review through premarket notification under section 510(k) of the Act. For example, a false
sodium result (a class II test) may be life-threatening if the error is unrecognized and treatment
decisions to correct the sodium level are made based on the false result.”43 Special controls may
include special labeling requirements, mandatory performance standards, and postmarket
surveillance.
Class III is the highest risk category. Under current law, general and special controls are not
sufficient to ensure safe and effective use of a class III device, which therefore is subject to
premarket approval—PMA—requirements.44 Class III “includes devices and tests that present a
potentially unreasonable risk of illness or injury. For example, a false negative result for a
hepatitis C virus test (a class III test) may result in failure to provide appropriate treatment,
leading to risk of liver failure due to delayed treatment. In addition, without the knowledge that
he or she is infected, the patient may put others at risk by spreading the disease.”45 The PMA
application must provide “valid scientific evidence,” which usually requires clinical studies.46
In most cases, a clinical evaluation of an investigational device must have an investigational
device exemption (IDE) before a clinical study is initiated.47 An IDE allows an unapproved or
uncleared device to be used in a clinical study to collect the data required to support a PMA
submission.48 The IDE permits a device to be shipped lawfully for investigation of the device
without requiring that the manufacturer comply with other requirements of the FFDCA, such as
registration and listing. Many IVD devices would be exempt from IDE requirements if, for
example, testing is noninvasive, does not require invasive sampling, does not introduce energy
into a subject, and does not stand alone (i.e., is not used for diagnosis without confirmation by
other methods or medically established procedures).49 However, even if a particular IVD study is
exempt from most IDE requirements, it still would be subject to other requirements, such as
informed consent of study subjects.50
Commercial Test Kits vs. Laboratory Developed Tests (LDTs)
FDA has historically focused its oversight of IVDs on diagnostic test kits that have been broadly
marketed to laboratories or the public. Examples include tests for infectious disease, blood
glucose tests, and pregnancy tests. In contrast, laboratory developed tests (LDTs)—a subset of
IVDs—may be defined as “a class of in vitro diagnostics that are manufactured, including being
43 Shuren, Direct-to-Consumer Genetic Testing, testimony on July 22, 2010.
44 FFDCA §513(a)(1)(C).
45 Shuren, Direct-to-Consumer Genetic Testing, testimony on July 22, 2010.
46 FFDCA §513(a)(3)(B) and (a)(3)(D).
47 See 21 C.F.R. §812. An investigational device is defined as “a device, including a transitional device, that is the
object of an investigation.” 21 C.F.R. §812.3.
48 FDA, Device Advice: Investigational Device Exemption (IDE), July 9, 2009, http://www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/default.htm.
49 See 21 C.F.R. §812.2(c)(3). Further details are provided in FDA, CDRH/CBER, Guidance for Industry and FDA
Staff: In Vitro Diagnostic (IVD) Device Studies—Frequently Asked Questions, Rockville, MD, June 25, 2010,
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/
UCM071230.pdf.
50 21 C.F.R. §50 (Informed Consent), 21 C.F.R. §56 (Institutional Review Board), 21 C.F.R. §812.119
(Disqualification of a Clinical Investigator).
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developed and validated, and offered, within a single laboratory.”51 LDTs are often used to test for
conditions or diseases that are either rapidly changing (e.g., new infectious diseases or new
strains of known infectious diseases) or that are the subject of quickly advancing scientific
research (e.g., genomic testing for cancer). LDTs have not traditionally been regulated by FDA;
this issue is discussed further later in the report (see “Oversight of Laboratory Developed Tests
(LDTs)”).
Analyte Specific Reagents (ASRs)
As noted previously, components of IVDs may be regulated as medical devices by the FDA, even
if the complete test is not. Analyte specific reagents (ASRs), a component of tests, have a
particular diagnostic use and therefore are regulated as class I, II, or III depending on their
application’s level of risk. An ASR is defined as “antibodies, ... 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.”52 For
example, ASRs used for diagnosis of human immunodeficiency virus (HIV) or other contagious
and fatal diseases must meet class III requirements because of the high risk posed by a test
malfunction.
General Purpose Reagents (GPRs)
A general purpose reagent (GPR) is defined as “a chemical reagent that has general laboratory
application, that is used to collect, prepare, and examine specimens from the human body for
diagnostic purposes, and that is not labeled or otherwise intended for a specific diagnostic
application.”53 Examples of GPRs include buffer solutions and some enzymes. General purpose
reagents are usually regulated as class I devices and are exempt from the premarket 510(k)
notification procedures.
IVD Products for Research Use Only (RUO) or Investigational Use Only (IUO)
In November 2013, FDA issued guidance on the use of IVD products labeled for “Research Use
Only” (RUO) or for “Investigational Use Only” (IUO).54 Such IVD products include reagents,
instruments, and systems that have not been approved, cleared, or licensed by FDA. “The term
RUO refers to devices that are in the laboratory phase of development. The term IUO refers to
devices that are in the product testing phase of development.”55 IUO products may be used in
research testing on human samples and the research may eventually lead to the clearance,
approval, or licensure of a new IVD for clinical diagnostic use. The manufacturer of such an
51 FDA, “Oversight of Laboratory Developed Tests; Public Meeting; Request for Comments,” 75 Federal Register,
14654, June 17, 2010, http://www.gpo.gov/fdsys/pkg/FR-2010-06-17/html/2010-14654.htm.
52 21 C.F.R. §864.4020; Analyte Specific Reagents.
53 21 C.F.R. §864.4010; General purpose reagent.
54 FDA, CDRH/CBER, Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational
Use Only, Guidance, November 25, 2013, http://www.fda.gov/downloads/MedicalDevices/
DeviceRegulationandGuidance/GuidanceDocuments/UCM376118.pdf.
55 Ibid., p. 7.
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RUO or IUO IVD product may legally sell it—without FDA premarket review—as long as the
product is only for research or investigational use and not for clinical diagnostic use.
FDA has expressed its concern that the “distribution of unapproved and uncleared IVD products
labeled RUO or IUO, but intended for purposes other than research or investigation (for example,
for clinical diagnostic use), has led, in some cases, to the clinical diagnostic use of products with
unproven performance characteristics, and with manufacturing controls that are inadequate to
ensure consistent manufacturing of the finished product. Use of such tests for clinical diagnostic
purposes may mislead healthcare providers and cause serious adverse health consequences to
patients, who are not aware that they are being diagnosed with research or investigational
products.”56 The purpose of the FDA 2013 guidance is to “clarify the requirements applicable to
RUO and IUO IVD products, including that RUO and IUO labeling must be consistent with the
manufacturer’s intended use of the device.”57
IVD Companion Diagnostic Devices (CoDx)
FDA defines an IVD companion diagnostic (CoDx) device as “an in vitro diagnostic device that
provides information that is essential for the safe and effective use of a corresponding therapeutic
product.”58 According to FDA, this definition excludes tests that are not a determining factor in
the safe and effective use of the therapeutic product. CoDx tests “identify patients who are most
likely to benefit from a particular therapeutic product” or are “likely to be at increased risk for
serious adverse reactions as a result of treatment with a particular therapeutic product.”59 The
instructions for use labeling of the therapeutic product would stipulate the use of the IVD
companion diagnostic device.
One of the earliest examples of the co-development of a drug and diagnostic was the FDA
approval in 1998 of a CoDx along with Herceptin as a treatment for breast cancer. “[C]linicians
now commonly use diagnostics to determine which breast tumors overexpress the human
epidermal growth factor receptor type 2 (HER2), which is associated with a worse prognosis but
also predicts a better response to the medication trastuzumab [Herceptin]. A test for HER2 was
approved along with the drug (as a ‘companion diagnostic’) so that clinicians can better target
patients’ treatment.”60 Another reason for the combined approval is that use of the CoDx can
avoid the toxic side effects to the heart caused by Herceptin in those who would not benefit from
the drug.61
Other examples of FDA-approved drugs and companion diagnostics include Erbitux used to treat
metastatic colorectal cancer; Gleevec for gastrointestinal stromal tumors; Zelboraf for late-stage
melanoma; Xalkori for late-stage lung cancer; Tarceva for non-small cell lung cancers; and
56 Ibid., pp. 4-5.
57 Ibid., p. 5.
58 FDA, Draft Guidance for Industry and Food and Drug Administration Staff, “In Vitro Companion Diagnostic
Devices,” July 14, 2011, http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/
ucm262292.htm.
59 Ibid.
60 Hamburg, “Path to Personalized Medicine,” pp. 301-304.
61 Institute of Medicine, “Refining Processes for the Co-Development of Genome-Based Therapeutics and Companion
Diagnostic Tests: Workshop Summary,” 2014, p. 8. IOM held a workshop in February 2013 on the “co-development of
targeted therapeutics and companion molecular tests for prediction of drug response.”
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Tafinlar and Mekinist for advanced melanoma.62 FDA expects that many companion diagnostic
devices will be class III “owing to the likelihood of harm to the patient if the diagnostic result is
incorrect.”63
Clinical Laboratory Improvement Amendments of
1988 (CLIA)
The Clinical Laboratory Improvement
Oversight of IVDs: The Role of CMS and
Amendments (CLIA) of 1988 provides CMS
FDA
with authority to regulate clinical
CMS: CMS regulates clinical laboratories that carry out
laboratories.64 CLIA establishes quality
diagnostic testing through the authority of the Clinical
standards for clinical laboratory testing and a
Laboratory Improvement Amendments of 1988 (CLIA).
certification program for clinical laboratories
FDA: The FDA regulates the distribution in interstate
that perform testing using IVD devices. All
commerce of IVDs and their components under the
laboratories that perform diagnostic testing for
authority of the FFDCA.
health-related reasons (i.e., with results
Source: Mansfield, “FDA Regulation of in Vitro Diagnostic
returned to the patient or a health care
Devices.”
practitioner) are regulated by CMS under the
authority of CLIA. For CLIA to apply, testing must be carried out on a human specimen.
The FDA pursuant to the FFDCA, and CMS, through CLIA, have different regulatory goals. FDA
regulation “addresses the safety and effectiveness of the diagnostic tests themselves and the
quality of the design and manufacture of the diagnostic tests.”65 CLIA regulates the quality of the
clinical testing process itself, mostly by assessing the quality of the clinical laboratory. However,
this oversight also includes requirements that assess the performance of the tests themselves and,
therefore, there is some overlap in the two agencies’ approaches. Specifically, CLIA requirements
evaluate a test’s analytical validity, whereas the FDA’s premarket review requirements assess a
test’s clinical validity. Analytical validity is defined as the ability of a test to detect or measure the
analyte it is intended to detect or measure; the clinical validity of a test is defined as its ability to
accurately diagnose or predict the risk of a particular clinical outcome.66
In 1988, Congress passed CLIA in response to concern about the quality of clinical laboratory
testing, and specifically, concerns about Pap smears. This law expanded the Department of Health
and Human Services’ (HHS’s) existing authority to regulate clinical laboratories (and therefore
clinical laboratory testing) to include any clinical laboratory that examines “materials derived
from the human body for the purpose of providing information for the diagnosis, prevention, or
treatment of any disease or impairment of, or the assessment of the health of, human beings.”67
62 Hamburg, “Path to Personalized Medicine,” p. 303, and FDA Commissioner’s Address, Annual Meeting of the
American Society of Clinical Oncology, Chicago, IL, June 2, 2013, http://www.fda.gov/NewsEvents/Speeches/
ucm354888.htm.
63 Tezak, “US FDA and personalized medicine,” p. 519.
64 PHSA §353.
65 Shuren, Direct-to-Consumer Genetic Testing, testimony on July 22, 2010.
66 For more information about analytical and clinical validity specifically in the context of genetic testing, see CRS
Report RL33832, Genetic Testing: Scientific Background for Policymakers, by Amanda K. Sarata.
67 PHSA §353(a), “Definitions.”
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All such facilities are required to receive certification demonstrating that they meet certain
requirements,68 as well as specific quality standards “to assure consistent performance by
laboratories issued a certificate ... of valid and reliable laboratory examinations and other
procedures.”69 CLIA does not apply to laboratories conducting only tests for research purposes, or
to laboratories in those states where state law establishes requirements of equal or greater
stringency (currently, these states are New York and Washington).
CLIA certification is based on the level of complexity of testing that the laboratory performs,
specifically (1) low (therefore, waived) complexity, (2) moderate complexity, and (3) high
complexity. The FDA has responsibility for categorizing tests according to their level of
complexity.70 This FDA role is distinct from the device risk classification discussed in the “IVD
Regulatory Requirements” section of this report. Laboratories that perform moderate and high
complexity testing must meet specific standards and requirements as a condition of certification,
including proficiency testing (PT), patient test management, quality control, personnel
qualifications, and quality assurance. Laboratories that perform only waived tests receive a
certificate of waiver (COW) from CMS; under current law, waived tests are those “that have been
approved by the FDA for home use or that, as determined by the Secretary, are simple laboratory
examinations and procedures that have an insignificant risk of an erroneous result.”71
In order to monitor the quality, accuracy, and reliability of testing carried out by CLIA-certified
laboratories (those conducting moderate and high complexity testing, as noted above), CMS
requires the laboratory to carry out proficiency testing. Proficiency testing is defined as “the
testing of unknown samples sent to a laboratory by a CMS-approved proficiency testing
program”72 and is required and defined in regulation for certain specialties and subspecialties
(e.g., virology, chemistry, endocrinology). Laboratories carrying out moderate or high complexity
testing must be certified in each specialty or subspecialty in which they carry out such testing.
Proficiency test samples must be tested in the same way that the laboratory tests its patient
samples, and sent back to the approved proficiency testing program for analysis. In this way, the
quality of the laboratory’s services may be evaluated. Given the role of proficiency testing in the
certification process, CLIA prohibits laboratories from sending the samples they receive for
proficiency testing out to another laboratory for processing. Additionally, as a condition of
certification, a laboratory must agree “to treat proficiency testing samples in the same manner as
it treats materials derived from the human body referred to it for laboratory examinations or other
procedures in the ordinary course of business.”73
Genetic tests, and most LDTs, are high complexity tests and therefore labs conducting these tests
would otherwise have to carry out proficiency testing. However, in practice, there are no specified
proficiency testing requirements for genetic testing laboratories, because genetics is not a
designated specialty area and none of the specified regulated analytes include nucleic acids
68 PHSA §353(d), “Requirements for Certification.”
69 PHSA §353(f), “Standards.”
70 See FDA, “CLIA Categorization Criteria,” http://www.fda.gov/medicaldevices/deviceregulationandguidance/
ivdregulatoryassistance/ucm124208.htm.
71 PHSA §353(d)(3), “Requirements for Certificate of Waiver.”
72 CMS, “CLIA: Proficiency Testing,” p. 2, https://www.cms.gov/CLIA/downloads/CLIAbrochure8.pdf.
73 PHSA §353(d)(1)(E), “Requirements for Certificates.”
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(RNA, DNA).74 Some labs that conduct genetic testing are also conducting moderate or high
complexity testing in other specialty or subspecialty areas that do have specified proficiency
testing requirements. The Centers for Disease Control and Prevention’s (CDC’s) Clinical
Laboratory Improvement Advisory Committee (CLIAC) recommended adding a genetic specialty
under CLIA, and CMS considered but eventually decided against such an action.75 This decision
was made partially based on a potential lack of sufficient proficiency testing samples for many
genetic tests and the absence of a mechanism for assessing clinical validity due to lack of
adequate data.76
Issues for Consideration
Federal regulation of IVDs, in particular LDTs and genetic tests, raises a number of policy issues.
FDA has focused its regulatory authority on commercial IVDs, which are broadly marketed to
labs or to the public. The agency traditionally has not required clearance or approval for LDTs. In
recent years, however, FDA has indicated its intent to regulate all LDTs using a risk-based
approach. This has drawn support from those concerned about device safety, and criticism from
some manufacturers who are concerned about the impact of regulation on innovation. It has also
attracted the attention of Congress.
DTC genetic tests—the majority of which are LDTs, and, therefore, not regulated by FDA—have
been the subject of considerable scrutiny because of concerns about the usefulness of the test
results. In response to such concerns, FDA recently instructed a company to withdraw its DTC
genetic test from the market until the company obtains agency clearance for the test.
There is also interest in a joint FDA-CMS pilot program to link FDA approval or clearance of
medical devices with the process used by CMS to decide whether to cover a device under the
Medicare program. Medicare coverage determinations have an impact on the coverage decisions
made by private health insurance issuers.
Oversight of Laboratory Developed Tests (LDTs)
Generally, the FDA has maintained that it has clear regulatory authority over LDTs, as it does
with all IVDs that meet the definition of medical device in the FFDCA.77 However, despite this,
the FDA has traditionally exercised enforcement discretion over LDTs, choosing not to enforce
applicable regulations with respect to such tests.78 Beginning in 1997, several governmental
entities have “questioned the appropriateness of the FDA’s policy of enforcement discretion
toward LDTs, including the National Institutes of Health (NIH) and Department of Energy’s Joint
Task Force on Genetic Testing, the Secretary’s Advisory Committee on Genetic Testing
74 42 C.F.R. §493, Subpart I, “Proficiency Testing Programs for Nonwaived Testing.”
75 CLIAC provides advice and guidance to HHS on improving clinical laboratory quality and laboratory medicine
practice. http://wwwn.cdc.gov/CLIAC/About.aspx.
76 SACGHS, “U.S. System of Oversight of Genetic Testing: A Response to the Charge of the Secretary of Health and
Human Services,” April 2008, http://oba.od.nih.gov/oba/SACGHS/reports/SACGHS_oversight_report.pdf.
77 Shuren, Direct-to-Consumer Genetic Testing, testimony on July 22, 2010.
78 FDA, “Oversight of Laboratory Developed Tests; Public Meeting; Request for Comments;” 75 Federal Register,
14654, June 17, 2010, http://www.gpo.gov/fdsys/pkg/FR-2010-06-17/html/2010-14654.htm.
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(SACGT), and the Secretary’s Advisory Committee on Genetics, Health, and Society
(SACGHS).”79 More recently, “other groups have pointed out the lack of effective oversight and
made specific recommendations regarding the regulation of LDTs.”80 Examples include the
pharmaceutical manufacturer Genentech, the Advanced Medical Technology Association
(AdvaMed), and the College of American Pathologists (CAP).81 On the other hand, some
representatives of clinical laboratories and manufacturers of LDTs have asserted that LDTs
should be outside of the FDA’s regulatory purview, including the American Clinical Laboratory
Association (ACLA).
In 2006, FDA published draft guidance on a specific subset of LDTs called In Vitro Diagnostic
Multivariate Index Assays (IVDMIAs).82 IVDMIAs are defined by the FDA as tests that, among
other things, provide results that are not transparent, and that the end user (usually a physician)
could not independently derive.83 The draft guidance announced that “the enforcement discretion
for tests meeting the definition of an IVDMIA would be terminated”; it attracted “both intense
criticism and strong support.”84 In a second draft guidance, published in 2007, the FDA states:
IVDMIAs raise significant issues of safety and effectiveness. These types of tests are
developed based on observed correlations between multivariate data and clinical outcome,
such that the clinical validity of the claims is not transparent to patients, laboratorians, and
clinicians who order these tests. Additionally, IVDMIAs frequently have a high risk intended
use. FDA is concerned that patients are relying upon IVDMIAs with high risk intended uses
to make critical healthcare decisions when FDA has not ensured that the IVDMIA has been
clinically validated and the healthcare practitioners are unable to clinically validate the test
themselves. Therefore, there is a need for FDA to regulate these devices to ensure that the
IVDMIA is safe and effective for its intended use.85
79 Tezak, “US FDA and personalized medicine,” p. 525. A July 2000 report by SACGT recommended that “FDA
should be the federal agency responsible for the review, approval, and labeling of all new genetic tests that have moved
beyond the basic research phase.” SACGT was chartered in 1998 “to advise the Department of Health and Human
Services (DHHS) on the medical, scientific, ethical, legal, and social issues raised by the development and use of
genetic tests.” Following expiration in August 2002 of SACGT’s charter, SACGHS was chartered in 2002 as “a public
forum for deliberation on the broad range of policy issues raised by the development and use of genetic tests and, as
warranted, to provide advice on these issues.” In an April 2008 report on the oversight of genetic tests, SACGHS
recommended that FDA “should address all laboratory tests in a manner that takes advantage of its current experience
in evaluating laboratory tests.” See Department of Health and Human Services, Secretary’s Advisory Committee on
Genetics, Health, and Society, U.S. System of Oversight of Genetic Testing: A Response to the Charge of the Secretary
of Health and Human Services, Washington, DC, April 2008, http://oba.od.nih.gov/oba/SACGHS/reports/
SACGHS_oversight_report.pdf.
80 Tezak, “US FDA and personalized medicine,” p. 526.
81 Ibid.
82 Ibid., p. 527.
83 FDA’s 2007 draft guidance defined IVDMIA as “a device that 1) 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 2) provides a result whose derivation is non-transparent and cannot be independently derived or verified by
the end user.” FDA, Draft Guidance for Industry, Clinical Laboratories, and FDA Staff - In Vitro Diagnostic
Multivariate Index Assays, July 26, 2007, http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/ucm079148.htm.
84 Tezak, “US FDA and personalized medicine,” p. 527.
85 FDA, Draft Guidance for Industry, Clinical Laboratories, and FDA Staff - In Vitro Diagnostic Multivariate Index
Assays, July 26, 2007, http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/
ucm079148.htm.
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The FDA never finalized its guidance concerning IVDMIAs, and instead announced its intent to
regulate all LDTs.86 In June 2010, FDA announced it would hold a public meeting the following
month to allow stakeholders the opportunity to discuss the agency’s decision to exercise its
regulatory authority over all LDTs.87 FDA presentations during that July 2010 public meeting
provided a number of reasons for its decision to assert its enforcement authority over all LDTs,
including the following:
• The volume and types of LDTs have grown considerably, with a high proportion
of these tests developed in commercial laboratories or biotechnology companies.
• LDTs have evolved to be more like commercial in vitro devices. LDTs are no
longer tests developed in a laboratory for patients in a regional medical setting
with consultation occurring between the pathologist and the ordering physician.
• The LDT route to market is viewed as a favorable business model and driving
venture capital funding for clinical diagnostics. Companies see the laboratory
developed testing pathway as an easier route to market to avoid FDA regulation
of their tests. In addition, manufacturers who develop commercial test kits, which
are required to go through FDA premarket review, may be at a competitive
disadvantage with LDT manufacturers.
• Some LDTs are aggressively marketed directly to clinicians via Internet sales.
• The public needs assurances that LDTs are sound and reliable. FDA asserted that
at the present time, “diagnostics critical for patient care may not be developed in
a manner that provides a reasonable assurance of safety and effectiveness.”88
Some clinical laboratories and manufacturers of LDTs have asserted that LDTs should be outside
of the FDA’s regulatory purview. On June 4, 2013, the American Clinical Laboratory Association
(ACLA) filed a citizen petition under the FFDCA requesting that the agency “refrain from issuing
draft or final guidance or a proposed or final rule purporting to regulate LDTs as devices.”89
ACLA states that FDA lacks statutory authority to regulate LDTs because ACLA claims that
LDTs are not devices as defined under the FFDCA. ACLA maintains that LDTs are “proprietary
procedures” and therefore not subject to regulation under the FFDCA. In addition, ACLA asserts
that LDTs do not meet the FDA definition of “commercial distribution,” which requires “that a
product be delivered, distributed, or placed on the market.”90
86 75 Federal Register 34462, June 17, 2010.
87 75 Federal Register 34462 June 17, 2010.
88 75 Federal Register 34462, June 17, 2010. Gail H. Vance, “College of American Pathologists Proposal for the
Oversight of Laboratory-Developed Tests,” Archives of Pathology Laboratory Medicine, vol. 135, (November 2011),
pp.1432-1435, based on FDA presentations by Courtney Harper and Elizabeth Mansfield at the July 2010 meeting,
http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM226203.pdf.
89 Citizen Petition, American Clinical Laboratory Association, June 4, 2013, http://www.acla.com/sites/default/files/
ACLA%20Citizen%20Petition%20re%20LDTs.pdf. Other citizen petitions “advocating against FDA regulation of
LDTs” were filed in 1992 by Hyman, Phelps and McNamara, and in 2006 by the Washington Legal Foundation. FDA
Law Blog, June 5, 2013, http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2013/06/fda-commissioner-calls-for-
more-active-fda-regulation-of-laboratory-developed-tests-and-acla-promptl.html.
90 Citizen Petition, American Clinical Laboratory Association, June 4, 2013, pp. 2-3, http://www.acla.com/sites/default/
files/ACLA%20Citizen%20Petition%20re%20LDTs.pdf.
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FDA has not yet finalized guidance with respect to all LDTs. In a June 2013 speech, FDA
Commissioner Margaret A. Hamburg stated that the agency has under development a “risk-based
framework” for the regulation of LDTs.91 A provision in the Food and Drug Administration Safety
and Innovation Act (FDASIA, P.L. 112-144) stipulates that the agency “may not issue any draft
or final guidance on the regulation” of LDTs without “at least 60 days prior to such issuance,”
first notifying Congress “of the anticipated details of such action.”92 According to one media
source, an FDA spokesperson stated draft guidance on LDT regulation that “will apply the same
standards already in effect for other in vitro diagnostics” is in administrative review.93
Oversight of Direct-to-Consumer (DTC) Genetic Testing
DTC genetic testing has grown over the past several years, with numerous companies entering the
market and offering health-related testing directly to consumers (e.g., 23andMe). Proponents of
DTC genetic testing maintain that such testing provides consumers with information necessary to
make better health care decisions and also that it generally empowers consumers, enhancing their
autonomy.94 However, as the field has expanded and issues related to the accuracy and utility of
the tests have grown, questions have arisen about the applicability of FDA and CLIA regulatory
requirements to DTC genetic testing.
Because FDA decided not to actively enforce its regulatory authority over LDTs, and because the
majority of DTC genetic tests are LDTs, the agency has generally not subjected DTC genetic tests
to regulation. (FDA-regulated ASRs contained in such tests may be regulated, but not all LDTs
contain regulated ASRs.) In 2010 testimony, Jeffrey Shuren, Director of FDA’s Center for
Devices and Radiological Health, noted, “[A]lthough FDA has cleared a number of genetic tests
since 2003, none of the genetic tests now offered directly to consumers have undergone
premarket review by the FDA.”95 The FDA reportedly has “stated publicly that DTC genetic
testing should be regulated by the agency. Several companies have decided to come to the FDA
with premarket submissions, and these are in the process of working with the FDA to come into
compliance.”96 Clinical laboratories performing health-related genetic testing on human
specimens are subject to CLIA requirements, whether or not the tests are provided directly to
consumers; however, regulators have had some difficulty determining whether companies
offering DTC genetic testing are utilizing CLIA-certified laboratories or not.97
91 FDA, Commissioner’s Address, Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2,
2013, http://www.fda.gov/NewsEvents/Speeches/ucm354888.htm.
92 Food and Drug Administration Safety and Innovation Act (FDASIA, P.L. 112-144), §1143; this provision sunsets in
July 2017.
93 Elizabeth Orr, “FDA Sees Role in LDT Regulation, But Industry’s Not So Sure,” Devices & Diagnostic Letter, June
10, 2013.
94 See, for example, Pascal Su, “Direct-to-Consumer Genetic Testing: A Comprehensive View,” Yale Journal of
Biology and Medicine, vol. 86 (2013), pp. 359-365.
95 Shuren, Direct-to-Consumer Genetic Testing, testimony on July 22, 2010.
96 David H. Spencer and Christina Lockwood, “Direct-to-Consumer Genetic Testing: Reliable or Risky?” Clinical
Chemistry, vol. 57, no. 12, (December 2011) pp. 1641-1644.
97 Manufacturer claims are also regulated by the Federal Trade Commission (FTC) although a full discussion of this
regulation is outside the scope of this report. “Section 5 of the Federal Trade Commission Act [(FTCA, 15 U.S.C. §45)]
prohibits unfair or deceptive acts or practices in or affecting commerce. Section 12 of the FTCA [(15 U.S.C. §52)]
specifically prohibits the dissemination of false advertisements for foods, drugs, devices, services, or cosmetics. The
FTC analyzes the role of advertising in bringing health-related information to consumers and can bring law
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Regulation of Clinical Tests
GAO has carried out a number of investigations and other oversight activities related to DTC
genetic testing. A 2006 GAO investigation of four companies selling DTC genetic tests found that
these companies “misled consumers by providing test results that were both medically unproven
and so ambiguous as to be meaningless.”98 GAO conducted a second investigation, from June
2009 to June 2010, of four different genetic testing companies, this time selecting companies that
were “frequently cited as being credible by the media and in scientific publications.”99 In July
2010, GAO provided testimony on this second investigation before the Subcommittee on
Oversight and Investigations of the Committee on Energy and Commerce. GAO stated that the
DTC genetic test results were “misleading and of little or no practical use to consumers.”100
Specifically, GAO found that identical DNA samples yielded contradictory predictions depending
solely on the company the DNA was sent to for analysis. Furthermore, GAO also observed that
“follow-up consultations offered by three of the companies provided only general information
and not the expert advice the companies promised to provide.”101 The tests in the second GAO
investigation cost from $299 to $999 and provided risk predictions for diseases such as diabetes,
hypertension, multiple sclerosis, leukemia, breast cancer, and prostate cancer.
GAO consulted with several external experts in the field of genetics about the results of this
second investigation. One expert stated that “the science of risk prediction based on genetic
markers is not fully worked out, and that the limitations inherent in this sort of risk prediction
have not been adequately disclosed.”102 An expert further noted “the fact that different companies,
using the same samples, predict different ... directions of risk is telling and is important. It shows
that we are nowhere near really being able to interpret [such tests].”103 When asked if any of the
test results or disease predictions were more accurate than the others, the genetics experts stated
that “there are too many uncertainties and ambiguities in this type of testing to rely on any of the
results.”104 For certain situations, the external experts agreed the limitations of the tests should be
“clearly disclosed upfront” and suggested that GAO attempt to obtain a refund; two companies
complied, but a third refused and the fourth did not respond to the refund request.105 SACGHS
also addressed the issue of the regulation of DTC testing in its 2008 report on the oversight of
genetic testing.106
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enforcement actions against false or deceptive advertising.” See Shuren, Direct-to-Consumer Genetic Testing,
testimony on July 22, 2010. The truthfulness of such claims in DTC genetic testing is an issue, compounded by the fact
that consumers are often ordering the test in the absence of consultation with a health care provider. Additionally,
companies may modify the content of their webpages in real time, creating difficulty in enforcing regulatory
requirements.
98 GAO, Direct-To-Consumer Genetic Tests: Misleading Test Results Are Further Complicated by Deceptive
Marketing and Other Questionable Practices, GAO-10-847T, July 22, 2010, p. 1, http://www.gao.gov/new.items/
d10847t.pdf; and GAO, Nutrigenetic Testing: Tests Purchased from Four Web Sites Mislead Consumers, GAO-06-
977T, July 27, 2006, http://www.gao.gov/assets/120/114612.pdf.
99 GAO, Direct-To-Consumer Genetic Tests: Misleading Test Results Are Further Complicated by Deceptive
Marketing and Other Questionable Practices, GAO-10-847T, July 22, 2010, p. 2, http://www.gao.gov/new.items/
d10847t.pdf.
100 Ibid., p. 4.
101 Ibid., p. 5.
102 Ibid., p. 8.
103 Ibid.
104 Ibid.
105 Ibid., p. 10.
106 “There is insufficient oversight of laboratories offering such tests, and their potential impact on the public health is
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Regulation of Clinical Tests
In response to recommendations by both SACGT and SACGHS, NIH has created a voluntary
genetic testing registry in order to provide a central location for information on “the test’s
purpose, methodology, validity, evidence of the test’s usefulness, and laboratory contacts and
credentials.”107 Such information, including whether or not the test was cleared or approved by
FDA, will allow physicians and patients to make better informed decisions about using these
tests. However, debate continues over whether such tests should fall into FDA’s regulatory
scheme for medical devices. The FDA recently acted to regulate certain LDTs when it sent a
warning letter to 23andMe instructing the company to discontinue marketing of its Personal
Genome Service (PGS) test until it receives FDA clearance for this test, an LDT that FDA says
falls under the definition of medical device under the FFDCA.108 Many manufacturers view this
action as clarifying the agency’s intent to move forward with the regulation of LDTs.
FDA Approval or Clearance and Medicare National Coverage
Determinations (NCDs)
Although CMS requires as a condition of coverage, with certain exceptions, that devices
(including IVDs) be FDA-approved or cleared where such approval or clearance is required, this
approval does not guarantee coverage, as there are a number of other factors that CMS considers
in its coverage decisions. CMS has stated that manufacturers will often focus their efforts on
gaining FDA approval, without realizing that upon receiving such approval, Medicare coverage of
the test is not automatic.109 Most private payer coverage decisions require FDA approval where
such approval is required by law, as well; for example, BlueCross BlueShield’s Technology
Evaluation Center (TEC) requires that final approval be received where required by law.110
There are a few specific circumstances where a device may be covered under Medicare without
FDA approval or clearance. These include cases where the FDA has (1) granted an IDE; (2)
provided a classification of nonexperimental investigational device, for which underlying
questions of safety and effectiveness have been resolved for that device type; and (3) required that
clinical trials be conducted, with Medicare beneficiaries participating in the FDA-approved
clinical trial.111
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an increasing concern. Direct-to-consumer marketing of laboratory tests and consumer-initiated testing have the
potential for adverse patient outcomes, social stigmatization, privacy concerns, and cost implications for the health care
system.” See Department of Health and Human Services, Secretary’s Advisory Committee on Genetics, Health, and
Society, U.S. System of Oversight of Genetic Testing: A Response to the Charge of the Secretary of Health and Human
Services, Washington, DC, April 2008, p. 9, http://oba.od.nih.gov/oba/SACGHS/reports/
SACGHS_oversight_report.pdf.
107 For further information, see the Genetic Testing Registry website, http://www.ncbi.nlm.nih.gov/gtr/.
108 See FDA Warning Letter to 23andMe, November 22, 2013, Document Number GEN1300666, http://www.fda.gov/
iceci/enforcementactions/warningletters/2013/ucm376296.htm. On February 20, 2014, partially in response to the
FDA’s warning letter to 23andMe, Senator Alexander sent HHS Secretary Kathleen Sebelius a letter requesting
clarification of the Administration’s position on patient access to personal health information,
http://www.alexander.senate.gov/public/index.cfm?p=PressReleases&ContentRecord_id=1fa364a5-3a14-4cce-b2ed-
9940c033aac3.
109 76 Federal Register 62808, October 11, 2011.
110 BlueCross BlueShield Association, http://www.bcbs.com/blueresources/tec/, click on the link: “Technology
Evaluation Center Criteria,” and see item 1.
111 MedPAC, “Report to the Congress: Medicare Payment Policy,” March 2003, Appendix B, “An introduction to how
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Regulation of Clinical Tests
Importantly, Medicare coverage determinations are often closely monitored by private health
insurance plans, and many private plans will follow Medicare’s decisions. Therefore, a decision
by CMS to cover a test through a positive national coverage determination (NCD) will often
result in more rapid diffusion and adoption of that test in the health care system.112 For this
reason, from the perspective of the device manufacturer, CMS’s coverage decision carries
significant weight.
The statutory basis of and processes used for determining FDA approval or clearance of a device
are distinct from the statutory basis of and processes used by CMS to make its NCDs.113 In each
case, the purpose of the review differs, as do the contextual factors of the decision. Currently,
FDA review and Medicare NCDs are carried out in a serial manner (i.e., one after the other).
However, in order to try to address the issue of serial FDA pre-market review and CMS national
coverage determination review and thus shorten the timeframe for getting a test into clinical use,
CMS and FDA launched a two-year pilot program for the parallel review of medical products in
October 2011;114 this pilot program was extended for an additional two years, effective December
2013.115 The agencies plan to evaluate the pilot once a representative group of products has gone
through the process and to extend the program to both drugs and biologics.
Author Contact Information
Amanda K. Sarata
Judith A. Johnson
Specialist in Health Policy
Specialist in Biomedical Policy
asarata@crs.loc.gov, 7-7641
jajohnson@crs.loc.gov, 7-7077
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Medicare makes coverage decisions,” at http://www.medpac.gov/documents/mar03_entire_report.pdf.
112 75 Federal Register 57046, September 17, 2010.
113 SSA §1862(a)(1). Under this authority, “CMS makes determinations regarding the coverage of specific items and
services. In short, CMS must make multiple decisions: It must decide what items and services it can and should pay for;
how it should accomplish the payment; and how much to pay.” 75 Federal Register 57046, September 17, 2010.
114 76 Federal Register 62808, October 11, 2011.
115 78 Federal Register 76629, December 18, 2013.
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