United States: 21st Century Cures Act Requires FDA To Expand The Role Of Real World Evidence

As we noted in our December 9th post, the 21st Century Cures Act (the "Cures Act") requires FDA to develop a framework and guidance for evaluating real world evidence ("RWE") in the context of drug regulation to support approvals of new indications for previously approved drugs, and to support or fulfill post-approval study requirements. This directive to apply RWE in the drug sphere is particularly interesting because FDA has issued a draft policy on the use of RWE in the context of medical devices, but has generally remained silent about applying RWE to pharmaceutical and biologic regulatory considerations. In this post, we briefly review the Cures Act's RWE provision, as well as FDA's recent public remarks about the use of RWE, and we provide some predictions on how FDA will implement the RWE evaluation program.

The Cures Act's RWE Provision

All requirements related to RWE appear in section 3022 of the Cures Act, which creates Section 505f of the Federal Food, Drug, and Cosmetic Act (the "FD&C Act"), or 21 U.S.C. § 355f. For the purposes of the Cures Act, "real world evidence" is defined as "data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials." The new provisions require FDA to establish a program to evaluate RWE for the following purposes:

  1. To help to support the approval of a new indication for a drug approved under section 505(c); and
  2. To help to support or satisfy post-approval study requirements.

FDA must establish a framework for the RWE program, which must be developed in collaboration with relevant stakeholders in the drug industry, and implement that framework within two years after the enactment date of the Cures Act. In addition, within five years of the enactment date, FDA must issue draft guidance describing (1) "the circumstances under which sponsors of drugs may rely" on RWE, and (2) acceptable standards and methodologies for collecting and analyzing RWE.

This provision explicitly states that the new RWE requirements stated in the Cures Act do not limit FDA's use of RWE for other purposes and do not change the standards of evidence required under sections 505(c) and (d) of the FD&C Act or section 351(a) of the Public Health Service Act.

FDA's Proposals on RWE Evaluation for Medical Devices

FDA has included a proposal in the MDUFA IV negotiations to add fifteen full-time employees to a coordinating center who will work on implementing the use of RWE in premarket decision-making. As we have discussed before, the NEST program incorporates RWE into its data collection and analysis framework.

In July 2016, FDA released a draft guidance entitled Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices (the "Device RWE Draft Guidance"), which explains FDA's current thinking on possible, acceptable uses for RWE in the established medical device regulatory scheme. For comparison, the Device RWE Draft Guidance defines two terms that are essentially equivalent to the singular RWE definition in the Cures Act:

  1. Real-World Data (RWD) – "Data collected from sources outside of traditional clinical trials"
  2. Real-World Evidence (RWE) – "Evidence derived from aggregation and analysis of RWD elements"

FDA lists many potential sources of device RWD, including "large simple trials, or pragmatic clinical trials, prospective observational or registry studies, retrospective database studies, case reports, administrative and healthcare claims, electronic health records, data obtained as part of a public health investigation or routine public health surveillance, and registries," and states that data from these sources, if appropriately validated, can provide valuable insight into the performance of medical devices used in actual clinical settings and in routine medical practice.

To ensure that RWE is suitable for evaluation in a regulatory context, FDA explained that it would apply threshold criteria to determine whether the RWE collected is (1) sufficiently relevant to the applicable regulatory question or requirement and (2) reliable enough to satisfy that regulatory question or requirement. By necessity, these criteria can only be evaluated on a case-by-case basis and entail significant Agency discretion.

FDA's Article in The New England Journal of Medicine

On December 8th, FDA Commissioner Robert Califf, along with the Directors of relevant Centers and Offices, published a commentary on RWE in The New England Journal of Medicine titled Real-World Evidence—What Is It and What Can It Tell Us? The article sets forth a general theory of RWE and its potential uses that closely parallels the Device RWE Draft Guidance.

First, the article gives a definition of RWE that is equivalent to the Cures Act and the Device RWE Draft Guidance: "information on health care that is derived from multiple sources outside typical clinical research settings, including [EHR], claims and billing data, product and disease registries, and data gathered through personal devices and health applications." Second, FDA identifies that, unlike clinical trials which impose strict eligibility criteria and controlled procedures, RWE can provide useful data about actual use in a clinical setting. However, FDA emphasizes in the article that clinical trial methodologies, such as randomization and planned intervention, are not inconsistent with methods for collection and analysis of RWE. Third, FDA repeats the warning that many RWE sources are not organized or optimized for supporting research or regulatory assessments. Finally, FDA's stated priority in developing an RWE framework is to make the best use of relevant RWE that are generated through reliable methods that limit the effect of bias and confounding factors as much as possible.

FDA also uses the article to differentiate the use of RWE in drug and device contexts by stating that since medical devices are developed in an iterative fashion, RWE is generated throughout the life-cycle of a device and relevant confounding factors are typically recognized and compensated for in the data analysis. However, in the context of accelerated approval of precision molecular treatments, RWE to confirm clinical benefit will need to be generated quickly and reliably to support the regulatory approval process.

The Future of RWE at FDA

While FDA has historically clung to the controlled, randomized clinical trial as the gold standard for generating data to support all regulatory determinations, the Agency recently acknowledged that RWE meeting certain criteria could be used to support some regulatory decisions, at least in the medical device sphere. Now, the Cures Act requires that FDA meet an accelerated timeline for developing a regulatory framework for RWE that applies to drug applications, as well.

Comparing the Device RWE Draft Guidance and FDA's NEMJ commentary reveal remarkable (and yet not so remarkable) similarities in the Agency's thinking on the use of RWE in both the device and drug regulatory schemes, as described above. Given the parallels in FDA's comments on controlling device and drug RWE, we expect that the RWE evaluation program framework required by the Cures Act will be based largely on the Device RWE Draft Guidance, applying similar criteria of relevant and reliability to RWE collection and analysis methodologies for drug products. Although the clinical use contexts of drugs differ greatly from those of devices, the real-world data sources for both drug and device use are essentially equivalent and the criteria FDA can impose upon collection and analytical methodologies (e.g., accounting for confounding factors, establishing consistent definitions, and controlling data capture) can be applied to all sources and RWE study types. However, since the Device RWE Draft Guidance was only released five months ago, there is little feedback from stakeholders and Agency officials about the effectiveness of the criteria described in the guidance and FDA has little experience applying the use of RWE in regulatory processes.

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
Check to state you have read and
agree to our Terms and Conditions

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.

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 by clicking here .

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.

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.