United States: FDA Releases Long-Awaited LDT Regulatory Framework And Finalizes Companion Diagnostics Guidance

On July 31, 2014, the Food and Drug Administration (FDA) took several significant actions to clarify its policies regarding regulation of certain in vitro diagnostic devices (IVDs). First, FDA released its long-awaited plan for the regulation of laboratory developed tests (LDTs). Second, FDA denied three citizen petitions related to regulation of LDTs. Third, FDA issued final guidance on in vitro companion diagnostic devices. Although the companion diagnostics guidance is likely to be relatively uncontroversial, the LDT framework's release represents the first step in a multi-year process that could spur legislative activity or legal challenges and may have significant effects on the future market for diagnostic tests.

Notification to Congress: Framework for Regulating LDTs

In section 1143 of the Food and Drug Administration Safety and Innovation Act (FDASIA), enacted in 2012, Congress required FDA to provide a 60-day notification before issuing any draft or final guidance on the regulation of LDTs. FDA has complied with that requirement by delivering two proposed guidance documents: Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) (Framework Guidance) and FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs). Section 1143, originally proposed by opponents of FDA regulation of LDTs, presumably was intended to allow Congress to react to any FDA proposal to regulate such tests. In the current political environment, however, any meaningful congressional activity is unlikely in the near term. As a result, FDA will likely formally publish these guidance documents this fall.

A. Framework Guidance

In the Framework Guidance, FDA announces its intention to regulate LDTs, marking a change from its long-standing policy of exercising enforcement discretion with respect to these diagnostic tests. The proposed framework would phase in FDA regulation over nine years (and possibly longer, depending on FDA resources), with the level of premarket and postmarket oversight varying according to risk. As described by the Director of FDA's Center for Devices and Radiological Health (CDRH), FDA's intent is to adopt a risk-based oversight framework with phased implementation "beginning with the highest-risk tests (which include companion diagnostics- crucial to personalized medicine by targeting treatments for cancer, heart disease and other conditions) to give laboratories time to comply.1

Scope. The proposed framework applies to LDTs. The guidance defines LDT as "an IVD that is intended for clinical use and designed, manufactured and used within a single laboratory." FDA states that it is aware that some laboratories may currently be offering devices as LDTs even though they do not meet FDA's definition (e.g., laboratories that have licensed the rights to a diagnostic test from another entity). Nevertheless, to avoid disrupting access to these tests, FDA states that it intends to apply the proposed guidance's risk-based framework to any IVD offered as an LDT by a CLIA-certified laboratory. By contrast, FDA states that the proposed guidance does not apply to direct-to-consumer (DTC) diagnostic tests, as FDA's policy is generally not to exercise enforcement discretion with respect to such tests even if they satisfy the definition of an LDT.

Need for FDA Oversight of LDTs. The proposed guidance asserts that FDA has long had statutory authority to regulate LDTs, but historically has chosen to exercise enforcement discretion, leaving their regulation to Centers for Medicare and Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments (CLIA). FDA justifies its proposed policy shift on the nature of modern LDTs, which are often offered beyond local populations and manufactured in high volume, used widely to screen for common diseases, used to direct critical treatment decisions (e.g., prediction of drug response), and involve non-transparent algorithms, automated interpretation, or other highly complex features. As a result, FDA says, such tests are not adequately addressed by CLIA requirements, which do not assess analytical or clinical validity of LDTs prior to their marketing, require adverse event reporting, require removal of unsafe devices from the market, impose manufacturing quality standards, or require informed consent for patients who participate in LDT clinical studies.

Risk-Based Regulatory Framework. Recognizing the wide range of risks associated with LDTs, FDA states that it intends to implement a risk-based regulatory approach.

  1. Devices Receiving Continued Enforcement Discretion for All Applicable Regulatory Requirements. FDA intends to continue to exercise enforcement discretion for all applicable regulatory requirements for two categories of LDTs:

    • (1) LDTs used solely for forensic (law enforcement) purposes, and
    • (2) Certain LDTs for transplantation when used in CLIA-certified, high-complexity histocompatibility laboratories.
  2. Devices Receiving Enforcement Discretion with Respect to Premarket Review and Quality System Requirements. FDA intends to exercise enforcement discretion for applicable premarket review requirements and Quality System Regulation (QSR) requirements, but enforce other applicable regulatory requirements, including registration and listing and adverse event reporting, for the following:

    • (1) Low-risk LDTs (Class I devices),
    • (2) LDTs for rare diseases and "Traditional LDTs" that reflect the types of LDTs that existed when the enforcement discretion policy was initially implemented, and
    • (3) "LDTs for Unmet Needs," when no FDA-approved or cleared equivalent device is available.
  3. Devices No Longer Receiving Enforcement Discretion. For other high and moderate risk LDTs, FDA intends to enforce applicable regulatory requirements, including registration and listing, adverse event reporting, premarket review, and QSR requirements.

Timeline. FDA intends to phase in regulation of LDTs over several years in order to balance the need to ensure safety and effectiveness of LDTs with the need to provide sufficient time for implementation. The guidance describes the following timeline:

  1. Registration and Listing/Notification and Adverse Reporting. Six months after final guidance is issued, manufacturers of LDTs should notify FDA if they are developing LDTs and must begin to report significant adverse events to FDA.
  2. Premarket Review. FDA will rely upon the existing medical device classification system to evaluate the risk of a category of LDTs, using expert advisory panels to help classify devices not previously classified by FDA, and intends to issue draft guidance to describe what it considers generally to be Class I, II, or III within 18 months of finalization of the framework guidance. FDA intends to phase in enforcement of premarket review requirements for LDTs over time based on relative risk. The phased enforcement, starting with the highest-risk devices, will begin 12 months after the guidance becomes final. FDA also states that clinical literature will often be available to support the clinical validity of an LDT, which should lessen the burden of obtaining premarket approval or clearance of such tests.

    • High-risk LDTs (Class III medical devices): Premarket review requirements begin 12 months after this guidance is finalized for the "highest risk devices" and phase-in over four years for the remaining high-risk devices. The "highest risk devices" are (1) LDTs with the same intended use as a cleared or approved companion diagnostic, (2) LDTs with the same intended use as an FDA-approved Class III medical device, and (3) certain LDTs for determining the safety or efficacy of blood or blood products. FDA believes that most high-risk LDTs will require a premarket approval (PMA) application.
    • Moderate-risk LDTs (Class II medical devices): Premarket review requirements begin after the review of high-risk (Class III) LDTs is completed, meaning five years after the guidance is finalized, and phase-in over four years. FDA expects that such devices will require 510(k) clearance rather than PMA approval and that accredited third parties will carry out most of these 510(k) reviews. Once a category of LDT is "called in" for premarket review, laboratories will have 12 months to submit a premarket application for their LDT if FDA clears a test in that category.

    Aside from the "highest risk devices," FDA will prioritize enforcement of premarket review requirements for other LDT categories based on risk using a public process, including expert advisory panels as appropriate. The number and type of LDTs "called in" for premarket review at a given time will be "commensurate with available agency resources." Priority lists will be published describing the order and timeframe in which the agency intends to enforce premarket review requirements for different categories of LDTs. FDA expects to announce the priority list for high-risk, Class III, devices within 24 months from finalization of the guidance, with enforcement to commence 12 months after such announcement. FDA expects to announce the prioritization of moderate-risk, Class II, LDTs within four years of issuing final guidance and expects to complete phased-in enforcement of premarket requirements for such devices within 9 years of finalizing the guidance.

  3. Quality System Regulation. Under the proposed framework, laboratories that manufacture LDTs would comply with the QSR when a premarket approval application (PMA) is submitted or FDA issues a 510(k) clearance order for the LDT.

B. Notification and Medical Device Reporting Guidance

In addition to the Framework Guidance, FDA's notification to Congress included a proposed companion guidance providing additional direction on the notification and medical device reporting requirements for LDTs.

Notification. As stated in the Framework Guidance, FDA will require most LDTs to comply with registration and listing requirements within six months of issuance of final guidance. However, as an alternative, FDA intends to continue to exercise enforcement discretion with respect to registration and listing requirements provided that clinical laboratories notify FDA that they are manufacturing LDTs and provide basic information regarding each of these LDTs within this six-month timeframe. Laboratories that provide such notifications will not need to pay annual establishment user fees to FDA. FDA intends to make such notifications public.

Notably, FDA states that establishments that manufacture other devices in addition to LDTs will not have the option of using the notification process and must comply with registration and listing requirements for their LDTs. In addition, once a laboratory has submitted a PMA or 510(k) to the FDA, FDA will require compliance with registration and listing requirements.

Medical Device Reporting. FDA intends to enforce the MDR regulations at 21 C.F.R. Part 803 with respect to laboratories manufacturing LDTs. Laboratories manufacturing LDTs would be required to comply with MDR requirements as both device user facilities and as device manufacturers. Laboratories would be responsible for reporting adverse events to FDA within the timeframes established in the regulations, as well as developing, maintaining, and implementing written MDR procedures and MDR event files.

Citizen Petition Responses

On the same day FDA issued the above notification to Congress of its intention to regulate LDTs, the agency denied three citizen petitions relating to the regulation of LDTs2 The three petitions highlight the highly contentious nature of the issue of FDA oversight of LDTs. There could well be a messy fight ahead, with the potential for protracted litigation.

Two of the petitions denied by FDA—the American Clinical Laboratory Association (ACLA) and Washington Legal Foundation (WLF) petitions—asserted, among other things, that the FDA lacks statutory authority to regulate LDTs. The ACLA petition further argued that FDA regulation of LDTs would be contrary to the public health, stifling innovation and limiting patient access to crucial diagnostic testing. FDA denied the ACLA and WLF petitions on all grounds. With respect to the ACLA's arguments that FDA regulation of LDTs would harm the public health, FDA stated that its oversight is crucial to protecting the public health, as CLIA alone does not adequately assure safety and effectiveness of modern LDTs.

The third petition FDA denied was submitted by Genentech. In contrast to the ACLA and WLF petitions, Genentech argued that FDA does possess authority to regulate LDTs and requested, among other things, that FDA establish regulations governing all LDTs and take enforcement action against laboratories selling LDTs that have not been approved or cleared. FDA agreed with Genentech that it has the authority to regulate LDTs and that there are strong public policy reasons for exercising regulatory oversight over LDTs, but rejected Genentech's specific requests for agency action.

Final Guidance on Companion Diagnostics

FDA finalized its guidance on companion diagnostic devices with very few changes from the draft guidance released in 2011.

Scope. The guidance addresses the development, approval, and labeling of both IVD companion diagnostic devices and the corresponding therapeutic products. The guidance applies to therapeutics for which the use of an IVD is "essential for safe and effective use" and to the corresponding IVDs. "Essential" means that "use of a diagnostic device is required in the labeling of a therapeutic product."

Contemporaneous Development and Approval. The guidance provides that IVD companion diagnostic devices and the corresponding therapeutic products should generally be developed contemporaneously. Sponsors are encouraged to meet with both the relevant therapeutic and device review divisions early in development. FDA review of the IVD companion diagnostic device and therapeutic product will be carried out collaboratively among relevant FDA offices.

The guidance further provides that, if an IVD is essential to the safe and effective use of a novel therapeutic product or indication, FDA generally will not approve the therapeutic product or new indication if an IVD companion diagnostic device is not approved (or cleared) for that indication. There are two scenarios where the guidance contemplates approval of a new therapeutic product or indication prior to approval or clearance of a companion diagnostic: (1) the therapeutic is intended to treat a "serious or life-threatening condition for which no satisfactory alternative treatment exists," and (2) the labeling of an approved therapeutic needs to be updated to address a "serious safety issue" by indicating use with an IVD companion diagnostic.

Approval Pathways. FDA will determine the regulatory pathway for IVD companion diagnostic devices using the same risk-based criteria it applies to all medical devices. However, in a footnote, FDA states that "most IVD companion diagnostic devices will be Class III devices[.]" The guidance further clarifies that FDA does not expect most therapeutic-companion diagnostic pairs to meet the definition of combination products, though the agency intends to require separate marketing applications for the therapeutic product and diagnostic regardless of whether the products could constitute a combination product.

Labeling. The guidance briefly addresses the labeling of in vitro companion diagnostic devices and their corresponding therapeutic products. Ordinarily, information about the use of an IVD companion diagnostic device must be included in the therapeutic product's labeling. Likewise, an IVD companion diagnostic device must be cross-labeled for use with the therapeutic product for which it has been approved or cleared for use.

Investigational Use. IVD companion diagnostic devices used in clinical trials to make critical treatment decisions, such as patient selection or treatment assignment, will be considered significant risk devices, and the device sponsor will be required to comply with investigational device exemption (IDE) requirements. If a diagnostic device and a therapeutic product are to be studied together to support their respective approvals, both products can be studied in the same investigational study, if the study is conducted in a manner that meets both the requirements of the IDE regulations and the investigational new drug (IND) regulations.

Connection with Proposed LDT Framework. Although the final guidance reflects few changes from the 2011 draft guidance, the release of the final guidance on the same day FDA released its proposed LDT framework provides important additional context. Under the proposed LDT regulatory framework, LDTs serving as companion diagnostics would eventually be required to go through the PMA approval or 510(k) clearance process in accordance with the policies outlined in FDA's companion diagnostic guidance.

Notably, the companion diagnostic guidance and LDT framework provide an opening for the use of unapproved LDTs as companion diagnostics in some contexts. Specifically, unapproved LDTs could still be used to support therapeutic product approval in cases that fall under the two exceptions to concurrent approval: (1) therapeutics intended to treat a "serious or life-threatening condition for which no satisfactory alternative treatment exists," and (2) approved therapeutics seeking a new indication for use with a companion diagnostic to address a "serious safety issue." This is because the proposed LDT regulatory framework provides for continued enforcement discretion with regard to premarket review requirements for LDTs for "rare diseases" and LDTs serving unmet medical needs.

Footnotes

1 Jeffrey Shuren, Curbing Risk, Not Medical Innovation, in Personalized Medicine, FDA Voice (July 31, 2014), available here.

2 Petition of the American Clinical Laboratory Association, Docket No. FDA-20130P-0667 (Jun. 4, 2013); Petition of Genentech, Inc., Docket No. FDA-2008-P-0638 (Dec. 5, 2008); Petition of the Washington Legal Foundation (WLF), Docket No. FDA-2006-P-0149 (Sept. 28, 2006).

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
 
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 (you must 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