United States: FDA Issues Draft Guidance For Laboratory Developed Tests

Last Updated: November 4 2014
Article by Sharon Roberg-Perez

Sharon Roberg-Perez1

For almost 40 years the FDA has regulated in vitro diagnostics (IVDs) as medical devices. An IVD is a reagent, instrument, or system that is intended for the diagnosis of a disease or other condition, including the determination of the state of a patient's health, "in order to cure, mitigate, treat, or prevent" a disease or a complication.2 These products are intended for use in collecting, preparing and examining samples from patients, such as nucleic acid. For example, one of the more well-known IVDs is the assay for HER2 expression levels. HER2 is a gene that is amplified in 20% of breast cancer patients, and it is those particular patients—and not others— who can benefit from treatment with Herceptin.3

Historically, the agency distinguished between commercially-available IVDs and Laboratory Developed Tests, or "LTDs," which were tests that were designed, manufactured, and used within a single laboratory for clinical purposes.4 In 1976, the volume of LTDs was small. The treating physicians who interpreted the results were in the same institutions as the laboratory personnel who performed the assays. And the LTDs were often similar to standard IVDs, including components that were otherwise approved for clinical use, and/or were intended to diagnose a rare disease.5 Because the potential impact on the public was small, the FDA exercised enforcement discretion when it came to LTDs. It appears that is about to change. The FDA issued draft guidance for LTDs on Sept. 30th.

Today the molecular diagnostics landscape looks entirely different than it did in the mid-1970s. Using a next generation sequencing platform, an individual's entire genome can be sequenced in a day or two, in theory for $1000.6 PCR technology has advanced to the point where the lower limit of detection of a target sequence is in the range of 0.25 pg/µl, which is 1/24th the amount of DNA in a single human cell.7 Finding a needle in a haystack is now possible. Moreover, genetic differences between individuals can be examined by simultaneously querying 23 different genetic markers; with appropriate resources, this can even be done on a global scale.8

In light of these technological advances, it is no surprise that LTDs are performed at a much higher volume than they used to be. Many are much more complex than any assay that existed in 1976, relying on automated interpretation, multiple signals and/or algorithms to generate a result. They may also be performed using reagents or equipment that has not been approved for clinical use. They are often performed by a completely different entity than the institution that is providing patient care9 And—increasingly—they are used to inform critical treatment decisions.10 Many therapies can only be prescribed for patients with certain genotypes,11 and additional assays are being sought to improve the safety and effectiveness of existing therapies, or to assist in monitoring patients' responses to treatment.12 There is also value in being able to determine who won't respond to treatment. Currently, roughly 40-50% of patients with arthritis, asthma, depression, or diabetes do not respond to the first line of treatment because of genetic variations.13

The FDA's draft guidance recognizes that there is a wide range of risks associated with existing LTDs, and proposes a risk-based approach to regulatory enforcement.14 It will continue to exercise discretion when the risk to the public is low. For example, it will exercise its discretion regarding LTDs used for forensic purposes, and for LTDs used in advance of transplantation procedures, so long as the tests are performed in certain, Clinical Laboratory Improvement Amendments (CLIA) certified laboratories.15

The agency will also exercise enforcement discretion for premarket review and quality systems requirements for: (1) low-risk LTDs (Class I) devices; (2) "traditional" LTDs;16 (3) LTDs for rare diseases (<4,000 incidences per year); or (4) LTDs for unmet needs, where no FDA-approved option is available. For LTDs in these categories, the FDA will enforce the requirements for registering and listing the assay, and for reporting adverse events.17

Likewise, in other instances, the regulations for registering, listing and reporting will also be enforced, but so will premarket review requirements. For high-risk LTDs, premarket requirements will be enforced beginning 12 months after the guidance is finalized, with a four-year phase-in period. The assays that fall into this category are those with the same intended use as a companion diagnostic, which is a test that provides information essential for the safe and effective use of a corresponding therapy.18 This category also includes LTDs with the same intended use as a Class III medical device, and LTDs for determining the safety or efficacy of blood or blood products.19 Premarket review requirements for moderate-risk LTDs will begin after the high-risk tests have been addressed.20

The American Clinical Laboratory Association (ACLA) opposes FDA regulation, arguing that LTDs are "know-how," not physical articles, and that the FDA has exceeded its statutory authority.21 In the ACLA's view, any FDA regulation is duplicative of regulations already in place by the Centers for Medicare and Medicaid Services (CMS) under CLIA.22

While the FDA acknowledges that CLIA regulations ensure high quality laboratory standards, there are significant concerns that are not addressed.23Specifically, CLIA regulations do not ensure safety and effectiveness of the LDT prior to commercial launch. They do not require that adverse events be reported, or that unsafe devices be removed from the market. They assess how well an assay is performed, but not how well it was designed or manufactured. And they do not require informed consent from patients who participate in clinical studies designed to investigate the diagnostic, apart from any corresponding therapy.24

The comment period on the draft guidance begins on Oct. 3rd. As personalized medicine is big business,25 significant input from all stakeholders should be expected. Stay tuned.

Footnotes

1 Sharon Roberg-Perez is a principal at Robins, Kaplan, Miller & Ciresi L.L.P. in Minneapolis. Her practice focuses on biotechnology and medical device patent litigation and enforcement. Prior to her legal career, Ms. Roberg-Perez earned her Ph.D. from the Massachusetts Institute of Technology, and did postdoctoral work at Caltech. Ms. Roberg-Perez is licensed to practice before the United States Patent & Trademark Office.

2 FDA, Medical Devices, Overview of IVD Regulation (last accessed Oct. 1, 2014) ( http://www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm123682.htm ) .

3 National Cancer Institute, Targeted Therapies for Breast Cancer Tutorial (last accessed Oct. 1, 2014) ( http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/breastcancer_htmlcourse/page3 ).

4 FDA, Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories: Framework for Regulatory Oversight of Laboratory Developed Tests (LTDs) (Sept. 30, 2014) ( http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM416685.pdf ) (hereinafter "Draft Guidance") at 6-7.

5 Id. at 7.

6 Nature, Hayden, EC, Is the $1,000 genome for real? (Jan. 15, 2014) ( http://www.nature.com/news/is-the-1-000-genome-for-real-1.14530 ); PMC, The Case for Personalized Medicine (4th ed. 2014) ( http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/pmc_case_for_personalized_medicine.pdf ) at 5.

7 See e.g. Su, MJ et al., Review Article: Application of PCR-ELISA in Molecular Diagnostics (May 27, 2014) Biomed Research International ( http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058250/pdf/BMRI2014-653014.pdf ) at 3; International Florida Research Institute, Florida International University, Mccord, B., DNA Quantitation by Real Time PCR Advanced Issues (Mar. 15, 2011) ( http://dna.fiu.edu/Advanced%20DNA%20Typing%20lectures/An%20introduction%20to%20principles%20of%20QPCR-D.pdf ) at 3.

8 Purps, J. et al., A global analysis of Y-chromosomal haplotype diversity for 23 STR loci (Sept. 2014) Forensic Sci Int Genet. Sep 2014; 12(100): 12–23.

9 Draft Guidance at 7-8.

10 Id. at 8.

11 Supra n. 3, The Case for Personalized Medicine at 9-10, 42-60.

12 See e.g. NIH, National Cancer Institute, SBIR & STTR, 315 Development of Companion Diagnostics: Enabling Precision Medicine in Cancer Therapy (http://sbir.cancer.gov/funding/contracts/fy2013_03.asp ).

13 Supra n. 4, The Case for Personalized Medicine at 9.

14 Draft Guidance at 8.

15 Id. at 11-12.

16 A "traditional" LTD is one that is designed, manufactured and used by a single laboratory that is in the same facility within which patients are both diagnosed and treated. The assay itself should be comprised of approved components, and be performed by qualified professionals, without the need for automated instrumentation or software for interpretation. Id. at 21.

17 Id. at 12, 20-21.

18 Id. at 13, 23-24.

19 Id. at 24.

20 Id. at 13.

21 Fierce Medical Devices, Saxena, V., ACLA head makes case against FDA LDT regulation to Congress (Sept. 10, 2014) ( http://www.fiercemedicaldevices.com/story/acla-head-makes-case-against-fda-ldt-regulation-congress/2014-09-10 ).

22 American Clinical Laboratory Association, ACLA President Testifies in Opposition to FDA Intent to Regulate LDTs – Questions Statutory Authority, Cautions Against Duplicative Regulation that Could Stifle Innovation and Compromise Patient Access to Critical Diagnostic Tests (Sept. 9, 2014) ( http://www.acla.com/acla-president-testifies-in-opposition-to-fda-intent-to-regulate-ldts-questions-statutory-authority-cautions-against-duplicative-regulation-that-could-stifle-innovation-and-compromise-pati/ ).

23 Draft Guidance at 8-9.

24 Id. at 9.

25 In the last four years, one in five original, new molecules approved by the FDA has been a targeted therapy, with "substantial benefits in [a] smaller, molecularly defined, pharmacologically relevant subset of patients." Pacanoski, MA et al., Next-Generation Medicines: Past Regulatory Experience and Considerations for the Future, Clinical Pharmacology & Therapeutics 95(3): 247-249 at 247 (March 2014). The molecular diagnostics market is a multi-billion dollar market because being able to identify that subset of patients is key. Wattpad, Market Growth – Worldwide Molecular Diagnostics Market 2014 to 20120 (last accessed Sept. 30, 2014) ( http://www.wattpad.com/54193039-market-growth-worldwide-molecular-diagnostics ); DeciBio, Clinical Diagnostics (last accessed Sept. 30, 2014) (http://decibio.com/clinical-diagnostics.php ).

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
 
In association with
Related Video
Up-coming Events Search
Tools
Print
Font Size:
Translation
Channels
Mondaq on Twitter
 
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
 
Email Address
Company Name
Password
Confirm Password
Position
Mondaq Topics -- Select your Interests
 Accounting
 Anti-trust
 Commercial
 Compliance
 Consumer
 Criminal
 Employment
 Energy
 Environment
 Family
 Finance
 Government
 Healthcare
 Immigration
 Insolvency
 Insurance
 International
 IP
 Law Performance
 Law Practice
 Litigation
 Media & IT
 Privacy
 Real Estate
 Strategy
 Tax
 Technology
 Transport
 Wealth Mgt
Regions
Africa
Asia
Asia Pacific
Australasia
Canada
Caribbean
Europe
European Union
Latin America
Middle East
U.K.
United States
Worldwide Updates
Registration
Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:
  • To allow you to personalize the Mondaq websites you are visiting.
  • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our information providers who provide information free for your use.
  • Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.
    If you do not want us to provide your name and email address you may opt out by clicking here
    If you do not wish to receive any future announcements of products and services offered by Mondaq you may opt out by clicking here

    Terms & Conditions and Privacy Statement

    Mondaq.com (the Website) is owned and managed by Mondaq Ltd and as a user you are granted a non-exclusive, revocable license to access the Website under its terms and conditions of use. Your use of the Website constitutes your agreement to the following terms and conditions of use. Mondaq Ltd may terminate your use of the Website if you are in breach of these terms and conditions or if Mondaq Ltd decides to terminate your license of use for whatever reason.

    Use of www.mondaq.com

    You may use the Website but are required to register as a user if you wish to read the full text of the content and articles available (the Content). 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 & conditions or with the prior written consent of Mondaq Ltd. You may not use electronic or other means to extract details or information about Mondaq.com’s content, users or contributors in order to offer them any services or products which compete directly or indirectly with Mondaq Ltd’s services and products.

    Disclaimer

    Mondaq Ltd and/or its respective suppliers make no representations about the suitability of the information contained in the documents and related graphics published on this server for any purpose. All such documents and related graphics are provided "as is" without warranty of any kind. Mondaq Ltd and/or its respective suppliers hereby disclaim all warranties and conditions with regard to this information, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. In no event shall Mondaq Ltd 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 or performance of information available from this server.

    The documents and related graphics published on this server could include technical inaccuracies or typographical errors. Changes are periodically added to the information herein. Mondaq Ltd and/or its respective suppliers may make improvements and/or changes in the product(s) and/or the program(s) described herein at any time.

    Registration

    Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:

    • To allow you to personalize the Mondaq websites you are visiting.
    • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
    • To produce demographic feedback for our information providers who provide information free for your use.

    Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.

    Information Collection and Use

    We require site users to register with Mondaq (and its affiliate sites) to view the free information on the site. We also collect information from our users at several different points on the websites: this is so that we can customise the sites according to individual usage, provide 'session-aware' functionality, and ensure that content is acquired and developed appropriately. This gives us an overall picture of our user profiles, which in turn shows to our Editorial Contributors the type of person they are reaching by posting articles on Mondaq (and its affiliate sites) – meaning more free content for registered users.

    We are only able to provide the material on the Mondaq (and its affiliate sites) site free to site visitors because we can pass on information about the pages that users are viewing and the personal information users provide to us (e.g. email addresses) to reputable contributing firms such as law firms who author those pages. We do not sell or rent information to anyone else other than the authors of those pages, who may change from time to time. Should you wish us not to disclose your details to any of these parties, please tick the box above or tick the box marked "Opt out of Registration Information Disclosure" on the Your Profile page. We and our author organisations may only contact you via email or other means if you allow us to do so. Users can opt out of contact when they register on the site, or send an email to unsubscribe@mondaq.com with “no disclosure” in the subject heading

    Mondaq News Alerts

    In order to receive Mondaq News Alerts, users have to complete a separate registration form. This is a personalised service where users choose regions and topics of interest and we send it only to those users who have requested it. Users can stop receiving these Alerts by going to the Mondaq News Alerts page and deselecting all interest areas. In the same way users can amend their personal preferences to add or remove subject areas.

    Cookies

    A cookie is a small text file written to a user’s hard drive that contains an identifying user number. The cookies do not contain any personal information about users. We use the cookie so users do not have to log in every time they use the service and the cookie will automatically expire if you do not visit the Mondaq website (or its affiliate sites) for 12 months. We also use the cookie to personalise a user's experience of the site (for example to show information specific to a user's region). As the Mondaq sites are fully personalised and cookies are essential to its core technology the site will function unpredictably with browsers that do not support cookies - or where cookies are disabled (in these circumstances we advise you to attempt to locate the information you require elsewhere on the web). However if you are concerned about the presence of a Mondaq cookie on your machine you can also choose to expire the cookie immediately (remove it) by selecting the 'Log Off' menu option as the last thing you do when you use the site.

    Some of our business partners may use cookies on our site (for example, advertisers). However, we have no access to or control over these cookies and we are not aware of any at present that do so.

    Log Files

    We use IP addresses to analyse trends, administer the site, track movement, and gather broad demographic information for aggregate use. IP addresses are not linked to personally identifiable information.

    Links

    This web site contains links to other sites. Please be aware that Mondaq (or its affiliate sites) are not responsible for the privacy practices of such other sites. We encourage our users to be aware when they leave our site and to read the privacy statements of these third party sites. This privacy statement applies solely to information collected by this Web site.

    Surveys & Contests

    From time-to-time our site requests information from users via surveys or contests. Participation in these surveys or contests is completely voluntary and the user therefore has a choice whether or not to disclose any information requested. Information requested may include contact information (such as name and delivery address), and demographic information (such as postcode, age level). Contact information will be used to notify the winners and award prizes. Survey information will be used for purposes of monitoring or improving the functionality of the site.

    Mail-A-Friend

    If a user elects to use our referral service for informing a friend about our site, we ask them for the friend’s name and email address. Mondaq stores this information and may contact the friend to invite them to register with Mondaq, but they will not be contacted more than once. The friend may contact Mondaq to request the removal of this information from our database.

    Emails

    From time to time Mondaq may send you emails promoting Mondaq services including new services. You may opt out of receiving such emails by clicking below.

    *** If you do not wish to receive any future announcements of services offered by Mondaq you may opt out by clicking here .

    Security

    This website takes every reasonable precaution to protect our users’ information. When users submit sensitive information via the website, your information is protected using firewalls and other security technology. If you have any questions about the security at our website, you can send an email to webmaster@mondaq.com.

    Correcting/Updating Personal Information

    If a user’s personally identifiable information changes (such as postcode), or if a user no longer desires our service, we will endeavour to provide a way to correct, update or remove that user’s personal data provided to us. This can usually be done at the “Your Profile” page or by sending an email to EditorialAdvisor@mondaq.com.

    Notification of Changes

    If we decide to change our Terms & Conditions or Privacy Policy, we will post those changes on our site so our users are always aware of what information we collect, how we use it, and under what circumstances, if any, we disclose it. If at any point we decide to use personally identifiable information in a manner different from that stated at the time it was collected, we will notify users by way of an email. Users will have a choice as to whether or not we use their information in this different manner. We will use information in accordance with the privacy policy under which the information was collected.

    How to contact Mondaq

    You can contact us with comments or queries at enquiries@mondaq.com.

    If for some reason you believe Mondaq Ltd. has not adhered to these principles, please notify us by e-mail at problems@mondaq.com and we will use commercially reasonable efforts to determine and correct the problem promptly.

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