United States: FDA Considering New Regulatory Approaches For NGS – Part I

The Food and Drug Administration ("FDA") announced a workshop to be held February 20th, 2015, entitled " Optimizing FDA's Regulatory Oversight of Next Generation Sequencing Diagnostic Tests" to obtain public input regarding its regulation of next generation sequencing ("NGS"). Specifically, the agency seeks public comment and feedback on the issues and questions raised in its discussion paper "Optimizing FDA's Regulatory Oversight of Next Generation Sequencing Diagnostic Tests – Preliminary Discussion Paper" ("FDA Discussion Paper") (copy here). This post will highlight FDA's issues and concerns regarding the analytical performance of NGS. Part II will address the agency's issues and concerns as they pertain to the clinical performance of NGS.

The Promise of NGS in Personalized Medicine

Personalized medicine relies on reliable and accurate testing of clinically relevant information. Almost all current FDA-approved in vitro diagnostic tests ("IVDs") measure only a single or a limited number of substances (for example, DNA or proteins). Thus, several patient samples and several tests may be required to evaluate a patient's clinical status or to select the best therapy for the patient. In contrast, NGS can detect over 3 billion bases in the human genome and may identify almost 3 million genetic variants in a single test. Thus, NGS has the potential to diagnose a number of diseases or conditions in one test.

The Challenges of Regulating NGS

Historically for traditional IVDs, FDA examines the test for accuracy and reliability (analytic performance) and if the results from the test correctly identifies the relevant disease or condition (clinical or diagnostic performance). The test is approved when FDA determines that an IVD has acceptable analytical and clinical performance. For traditional IVDs, the sponsor seeking FDA-approval provides the data and/or information demonstrating analytical and clinical performance of the test. NGS, in contrast, can potentially evaluate over 3 billion base pairs and therefore evaluating the analytical performance of each data point would take years. In addition,"[b]ecause it is possible to sequence the whole genome, it is not necessary to know what variant one wishes to identify prior to running and successfully interpreting an NGS test – a concept which is very different from how traditional IVDs are used." See page 2 of FDA Discussion Paper. NGS may identify rare variants for which it may be impractical for test developers to provide conclusive evidence supporting clinical significance. Moreover, how to communicate the significance of some genetic variants to physicians and consumers presents challenges to the agency. See page 2 of FDA Discussion Paper.

Exploring New Regulatory Approaches for NGS

Analytical Performance

FDA acknowledged that any new approach to regulating NGS tests must assure that the public has timely access to tests that have adequate analytical and clinical performance. See page 3 of FDA Discussion Paper. Only one NGS instrument (Illumina MiSeqDx") and its universal sequencing reagents and two accompanying assays for the diagnosis of cystic fibrosis (Illumina MiSeqDx" Cystic Fibrosis 139 Variant and Clinical Sequencing Assays) have been FDA- approved. Because it was impractical to detect every possible variant that might exist in a genomic sequence, analytical test performance for the MiSeqDx" system was demonstrated for a representative number of subsets of types of variants in various sequencing contexts. See page 4 of FDA Discussion Paper. The agency announced that it is considering extending this subset-based approach for other NGS sequencing platforms, but also invites suggestions for other approaches. One such approach that FDA seeks public comment is the development of methodologic quality-based standards that laboratories could meet to establish analytical performance developed by the lab. FDA specifically requests public feedback with regard to: (1) value of a standards-based approach to regulatory review of NGS tests (2) content of standards to be developed that will assure that conformity to the standard will assure test accuracy and reliability, (3) who should develop such standards, and (4) appropriate mechanisms to ensure compliance. See page 5 of FDA Discussion Paper. On page 5 of the FDA Discussion Paper, the agency asks the public ten specific questions relating to analytical performance:

  1. How are labs currently developing NGS tests and assessing their analytical performance?
  2. What are the benefits and risks to public health of having FDA independently evaluate the analytical performance of NGS tests and/or platforms using data submitted by the developer on an agreed upon subset of data points for the test?
  3. What are the benefits and risks to public health of a standards-based approach to regulating NGS analytical performance?
  4. Would a standards-based approach limited to NGS tests that use FDA cleared or approved components encourage continued development and consumer access to NGS tests with appropriate analytically performance?
  5. To what extent could computational approaches be used to assess analytical performance? If possible, who should develop such approaches, how could FDA facilitate their development, and how could they be validated?
  6. Are the concepts for standards outlined above adequate to ensure that NGS tests have appropriate analytical performance? If not, what else should be included? Alternatively, are some of the concepts for standards listed above unnecessary, and if so, which ones and why?
  7. How should changes or advances in technology be managed utilizing a standards-based approach? What types of changes in technology pose the most concern and what are the best standards to address those concerns?
  8. Who should develop the standards: FDA, an ad hoc committee of experts, a Standards Development Organization, others, or a combination of these approaches?
  9. What measures should be put in place to monitor progress and impact, both positive and negative, if a standards-based approach were adopted?
  10. How should conformity with standards be assessed?

Attending the Public Workshop

The Workshop will be held from 8:30 am to 5 pm at the Natcher Center at the National Institutes of Health Campus, 9000 Rockville Pike, Bldg. 45 Auditorium, Bethesda, MD 20814. Registration is free and available on a first-come, first-served basis. Persons interested in attending must register on line by 4 pm, February 12th, 2015. Registration is through FDA's Medical Devices News & Events-Workshops & Conferences at http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/default.htm. The Workshop will be webcast and individuals attending on-line must register by February 12th, 2015.

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.

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
Font Size:
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
Confirm Password
Mondaq Topics -- Select your Interests
 Law Performance
 Law Practice
 Media & IT
 Real Estate
 Wealth Mgt
Asia Pacific
European Union
Latin America
Middle East
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.


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.


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