United States: Checking In On FDA's Enforcement Discretion Policy For Laboratory Developed Tests

Key Points

  • In a recent warning letter, the Food and Drug Administration (FDA) advised a laboratory to seek marketing authorization for its genetic tests that qualified as laboratory developed tests (LDTs)—which have largely benefited from enforcement discretion by FDA up to now.
  • FDA’s action evinces particular concern with the clinical validation of high-risk tests that purport to predict a drug response that may be inconsistent with FDA-approved drug labeling.
  • Both the warning letter and recent attention to “cloud-based” labs demonstrate the limitations of the LDT designation for innovative test technologies.

Introduction

As Congress considers comprehensive reforms to the regulatory paradigm for all in vitro clinical tests (IVCTs), including LDTs, recent developments are highlighting the limitations of FDA’s current posture of enforcement discretion.

  • First, FDA is sufficiently concerned about certain types of LDTs that might lack clinical evidence supporting their claims that the agency issued a warning letter to the laboratory that developed and operated the test—indicating that the agency’s policy of enforcement discretion is not absolute.
  • Second, FDA’s LDT policy may have limited applicability to “cloud-based” laboratory tests that operate using a software algorithm rather than traditional test methods.

Warning Letter

On April 4, 2019, FDA issued a warning letter to a health system laboratory, instructing it to stop marketing its MediMap pharmacogenetic tests absent FDA marketing authorization.1 The laboratory marketed five MediMap tests as genetic tests for predicting medication response, reducing negative side effects from certain medications, discovering the right drug and right dose for a patient, and avoiding trial-and-error prescribing by health care providers by testing patient receptivity to drugs that treat specific conditions. FDA expressed concern about whether data existed to establish the relationship between genotypes assessed by the tests and assertions regarding drug response for multiple drugs.

In FDA’s view, these claims make the tests medical devices that are subject to FDA jurisdiction under the Food, Drug and Cosmetic Act (FDCA)—meaning that the laboratory would typically need to obtain FDA’s premarket authorization to market the tests, but it had not. However, these particular tests are considered LDTs, a category of tests that have largely gone unregulated by FDA. At the same time, FDA updated a safety communication jointly issued by FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Devices and Radiological Health (CDRH) in October 2018 that warned consumers about genetic tests that purport to predict patients’ responses to specific medications.2 The two Centers jointly issued a statement regarding the warning letter, 3 signaling broad agency support for the advisory action.

FDA’s History of Enforcement Discretion for LDTs

Clinical laboratories have historically developed “home brew” tests for use within their own laboratories. Although FDA has asserted jurisdiction over these tests, the agency has generally exercised enforcement discretion as long as they were developed and used within an individual certified laboratory. Over the last decade, however, the rapid proliferation and increasing complexity of LDTs have prompted FDA to attempt to assert active regulatory oversight of these tests. FDA issued draft guidance in 2014 in which the agency reiterated its statutory authority over LDTs and proposed a risk-based framework.4 Under the proposed framework, certain high-risk LDTs would have been subject to premarket review, Quality Systems requirements, Medical Device Reporting for adverse events and malfunctions, and registration and listing requirements.5 Other lower-risk tests would have continued to be subject to enforcement discretion for most device requirements—so long as they met the agency’s definition of an LDT: “in vitro diagnostic that is intended for clinical use and designed, manufactured, and used within a single laboratory.” 6

FDA has not finalized the draft guidance, and in the midst of policy discussions surrounding the appropriate regulatory framework for LDTs, issued a discussion paper in 2017, which echoed a similar message but suggested a somewhat different regulatory approach.7 Given the lack of a formalized policy, the draft guidance still stands as the most recent articulation of the agency’s interpretation of what constitutes an LDT that is generally eligible for enforcement discretion.

Of particular importance here, the warning letter did not question that MediMap tests qualified as LDTs. According to the letter, “Although FDA has generally exercised enforcement discretion for LDTs, the Agency always retains discretion to take action when appropriate. . . .” 8 Warning letters for LDTs have been quite rare, so this serves as a reminder that FDA’s limited enforcement does not mean zero enforcement or advisory action.

High-Risk Nature of Laboratory’s Conduct

The laboratory’s tests in this case presented particularly high risks in FDA’s view, and thus served as a vehicle through which the agency could highlight the safety and effectiveness concerns related to certain LDTs, particularly genetic tests for which the agency believes there is insufficient clinical evidence.

Three aspects of the laboratory’s activities likely contributed to FDA’s decision to issue a warning letter:9

  • Lack of clinical validity, including for treatment recommendations that contradicted approved drug labeling.
  • Provision of the test results directly to patients.
  • The laboratory’s refusal to implement changes in response to FDA’s initial communications.

Following the issuance of the warning letter, the laboratory stopped offering the tests.10

Lessons for Test Developers

Although the warning letter may signal a greater willingness to enforce in the LDT space generally, the facts in this particular case made these tests especially ripe for agency attention. The warning letter and associated safety warning do not necessarily mean that all developers of laboratory tests face heightened enforcement risk, but laboratories and test developers may consider ways to limit their exposure to risk.

The letter indicates that FDA is concerned about two types of tests: (1) tests that have not been validated, but that recommend medications in a manner consistent with the drug’s FDA-approved labeling; and (2) tests that have not been validated and recommend medications in a manner that is inconsistent with the drug’s FDA-approved labeling.

For both types of tests, conducting studies to establish the test’s clinical and analytical validity would limit risk exposure. The first situation, in which tests are consistent with approved drug labeling, is inherently less risky, and conducting validation studies would generally be less burdensome. For example, in the case of next-generation sequencing tests, the criteria set forth for establishing clinical validity for cleared or approved tests are instructive. For tests that share biomarkers with already authorized tests, a test developer could document comparisons to authorized tests with the same biomarkers. To demonstrate clinical validity, a test maker may rely on publicly available clinical evidence, such as professional guidelines and/or peer-reviewed publications, i.e., the test maker does not necessarily need independently to establish clinical validity.11 Documentation that the test works effectively to identify the genotype and that the laboratory relied on the scientific community’s clinical evidence would work to lower the risk level.

The second type of test, one that analyzes biomarkers for which clinical validity has not been well established or produces results that may be inconsistent with FDA-approved labeling, is viewed as particularly high risk by the agency. Indeed, the agency has informally raised concerns with other such LDTs that lack marketing authorization.  Developers of such tests would face a greater challenge: documenting that the test works as intended and that there is clinical evidence to support recommendations for off-label uses of medications. Nevertheless, developers are less likely to face enforcement action if they conduct and document internally the testing to support these claims.

In addition, sending test information directly to patients might invite increased agency attention. FDA is concerned that test results could lead patients to adjust dosing inappropriately or stop medication completely without physician involvement, which may cause significant risks to patient safety. Compounding this factor in the warning letter, one of the cited tests provided medication recommendations for newborns.

In the event a laboratory’s tests do draw agency attention, the laboratory will often have the opportunity to engage with the agency before a warning letter is issued. Absent immediate public health concerns, such as adverse events, FDA often makes a practice of contacting a firm informally before issuing a warning letter. In this case, FDA requested that the laboratory change the tests and labeling to address the agency’s concerns, including by removing labeling regarding drug responses for specific medications unless and until FDA reviewed information to support the claims and granted marketing authorization. The laboratory responded to FDA that the tests qualified as LDTs and were therefore not subject to premarket review. FDA then issued the warning letter.

Cloud-Based Laboratories

The lack of clear policy from FDA regarding LDTs has also presented a challenge for companies that purport to conduct LDTs from a laboratory based in the cloud. For example, some tests run algorithms in a cloud-based laboratory. Such tests could theoretically meet FDA’s last-articulated definition of an LDT: in vitro diagnostic intended for clinical use and designed, manufactured and used within a single laboratory. However, in FDA’s 2014 draft guidance, FDA defined a “single laboratory” to mean a facility with a single Clinical Laboratory Improvement Amendments of 1988 (CLIA) certificate for high-complexity testing from the Centers for Medicare and Medicaid Services (CMS). 12

At the moment, cloud-based facilities that do not analyze physical specimens are not currently required to register with CLIA. Even if they do register, however, it is not clear that cloud-based laboratories could meet the standards required to obtain a CLIA certificate due to their inherent limitations as virtual laboratories. It is also unclear whether FDA would adhere to the criterion in the 2014 draft guidance that limits its policy of enforcement discretion to laboratories with such high-complexity certification. Of course, FDA never finalized the 2014 Draft Guidance, and as a result, there is no official FDA position defining the scope of LDTs.

A recent Clinical Laboratory Improvement Advisory Committee (CLIAC) touched on whether and, if so, how, CMS should regulate cloud-based laboratories and CMS is expected to issue guidance on this topic. In addition, proposed legislation, the Verifying Accurate, Leading-edge, IVCT Development Act (VALID Act), would establish a new regulatory framework for LDTs and other in vitro clinical tests. A broad group of stakeholders, including the American Clinical Laboratory Association, AdvaMedDx, the Biotechnology Innovation Organization and Friends of Cancer Research, recently sent a letter to the Senate Health, Education, Labor and Pensions (HELP) Committee and House Energy & Commerce Committee to urge lawmakers to finalize changes to the proposed legislation by the end of the year. 13 Given that FDA’s enforcement efforts in this area are not completely dormant, test developers of cloud-based laboratories would greatly benefit from bright-line clarity from Congress, CMS and FDA.

Footnotes

1  FDA, Warning Letter to Inova Genomics Laboratory (Apr. 4, 2019), available at https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm634988.htm [hereinafter “Genetic Test Warning Letter”].

2  FDA, Safety Communication, The FDA Warns Against the use of Many Genetic Tests with Unapproved Claims to Predict Patient Response to Specific Medications: FDA Safety Communication (issued Oct. 31, 2018; updated Apr. 4, 2019), available at https://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm624725.htm?utm_campaign=2019-04-05%20CDRH%20New&utm_medium=email&utm_source=Eloqua.

3  FDA, FDA Issues Warning Letter to Genomics Lab for Illegally Marketing Genetic Test That Claims to Predict Patients’ Responses to Specific Medications (Apr. 4, 2019), available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm635283.htm.

4  FDA, Draft Guidance, Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) (Oct. 3, 2014), available at https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm416685.pdf.

5  Id.

6  Id. at 5.

7  FDA, Discussion Paper on Laboratory Developed Tests (LDTs) (Jan. 13, 2017), available at https://www.fda.gov/downloads/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/LaboratoryDevelopedTests/UCM536965.pdf.

8  Genetic Test Warning Letter.

9  Id.

10  GenomeWeb, Inova Decides to End PGx Test Offerings in Response to FDA Warning Letter (Apr. 15, 2019), available at https://www.genomeweb.com/regulatory-news/inova-decides-end-pgx-test-offerings-response-fda-warning-letter#.XNHzaI5KiUk.

11  See FDA, Fact Sheet: CDRH’s Approach to Tumor Profiling Next Generation Sequencing Tests, available at https://www.fda.gov/media/109050/download.

12  FDA, Draft Guidance, Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) 5 n.5 (Oct. 3, 2014), available at https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm416685.pdf. (providing that a single laboratory refers to a facility with a single CLIA certificate as described in 42 C.F.R. § 493.43(a)-(b) and 42 C.F.R. § 493.55 and that meets the requirements outlined in 42 C.F.R. §§ 493.17(c)(4) and 493.25).

13  Letter from American Cancer Society Cancer Action Network, Friends of Cancer Research, American Clinical Laboratory Association, AdvaMedDx, and other stakeholders to Sens. Alexander, Murray and Reps. Pallone and Waldern (May 3, 2019), available at https://www.acla.com/wp-content/uploads/2019/05/Diagnostics-Reg-Reform-Stakeholder-Ltr-to-Hill-5-3-19.pdf.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on Mondaq.com.

Click to Login as an existing user or Register so you can print this article.

Authors
Similar Articles
Relevancy Powered by MondaqAI
 
In association with
Related Topics
 
Similar Articles
Relevancy Powered by MondaqAI
Related Articles
 
Related Video
Up-coming Events Search
Tools
Print
Font Size:
Translation
Channels
Mondaq on Twitter
 
Mondaq Free Registration
Gain access to Mondaq global archive of over 375,000 articles covering 200 countries with a personalised News Alert and automatic login on this device.
Mondaq News Alert (some suggested topics and region)
Select Topics
Registration (please scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions

Mondaq.com (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of www.mondaq.com

To Use Mondaq.com you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.

Disclaimer

The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.

General

Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions