FDA Issues Guidance on Use of Real-World Evidence for Medical Devices

by Arnall Golden Gregory LLP
Contact

On August 31, 2017, the Food and Drug Aministration issued a final guidance titled “Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices.” In the guidance, which finalizes the agency’s July 2016 draft guidance on this topic, FDA discusses the potential uses of real world data and the factors it evaluates to determine whether that data can support a regulatory decision. Additionally, FDA addresses when an Investigational Device Exemption (IDE) may be needed to collect and use real-world data for determining the safety and effectiveness of a device.

Background

This final guidance follows the 2016 passage of the 21st Century Cures Act (“Cures Act,”) which requires FDA to develop a program around the use of real-world evidence in regulatory decision making on drug products. Though the Cures Act only defines the term “real-world evidence,” the definitions provided in FDA’s guidance are in line with the definition provided by Congress. The guidance defines these terms as follows: 

  • Real-World Data (RWD): data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.

    • Examples include data from electronic health records, claims and billing data, data from product and disease registries, patient-generated data, and data from mobile devices. 
    • These sources can be used to support varying types of trial designs. 
  • Real-World Evidence (RWE): clinical evidence regarding the usage and potential benefits or risks, of a medical product derived from analysis of RWD.

Though FDA generally relies on clinical and non-clinical studies conducted by the device manufacturer or sponsor, FDA recognizes that RWD is collected through patient treatment and management, and it may have a role in helping the agency understand the benefit-risk profile of devices. However, FDA expresses concern that data collected during clinical care or in the home setting may not have the same controls in place as the data collected during a clinical trial.

FDA relies only on “valid scientific evidence” (defined in 21 CFR 860.7(c)(2)) in determining whether there is a reasonable assurance that a device is safe and effective. Yet, FDA notes that it is possible for RWE to meet the “valid scientific evidence” threshold when the underlying RWD was “accurately and reliably captured at clinically relevant time intervals throughout the device lifecycle.” If these conditions are met, RWE may support the clearance or approval of a new device, as well as the expansion of indications for devices already on the market. Aggregated RWD can be used, under certain circumstances, as a postmarket control to provide ongoing safety information and effectiveness evidence. Throughout the guidance, FDA cites patient registries as an example of aggregated RWD that may be a useful source of evidence.

FDA recognizes that “traditional” clinical trials may sometimes be impractical or overly challenging, and appropriate RWD can sometimes provide comparable information. While clinical trials are controlled and require monitoring and data auditing, they may be narrow in scope. RWD may be able to generate information on a broader patient population, but studies must be carefully designed, regardless of whether the RWD has already been collected or will be collected in the future. Protocols and analysis plans for RWD “should address the same elements that a traditional clinical trial protocol and statistical analysis plan would cover.”

Where RWE May be Used

Importantly, the guidance does not change FDA’s evidentiary standards for decision making, so the agency will evaluate the RWE in context to determine if it meets the quality standards for the decision at issue. FDA provides numerous examples of situations where it may be appropriate to utilize RWE: 

  • for generating hypotheses to be tested in a prospective clinical study; 
  • as a historical control, a priori in a Bayesian trial, or as one source of data in a hierarchical model or a hybrid data synthesis; 
  • as a concurrent control group or as a mechanism for collecting data related to a clinical study to support device approval or clearance in a setting where a registry or some other systematic data collection mechanism exists; 
  • to identify, demonstrate, or support the clinical validity of a biomarker; 
  • to support approval of an Humanitarian Device Exemption, Premarket Approval Application (PMA), or De Novo request; 
  • to support a petition for reclassification; 
  • as evidence for expanding the labeling of a device to include additional indications or to update the labeling to include new information on safety and effectiveness for public health surveillance efforts; 
  • to conduct required post-approval studies l or to potentially preclude the need for postmarket surveillance studies; 
  • for use in generating summary reports of Medical Device Reports (MDRs); and 
  • to provide postmarket data as a substitute for some premarket data.

FDA’s Assessment of RWD

In determining whether RWD is suitable for use in regulatory decision making, FDA will evaluate the relevance and reliability of the source and its elements. To assess relevance, FDA will evaluate the following factors to determine whether the data address the applicable question or requirement: 

  • whether the RWD contain sufficient detail to capture the use of the device, exposures, and the outcomes of interest in the appropriate population (i.e. the data apply to the question at hand); 
  • whether the data elements available for analysis are capable of addressing the specified question when valid and appropriate analytical methods are applied (i.e. the data are amenable to sound clinical and statistical analysis); and 
  • whether the RWD and RWE they provide are interpretable using informed clinical/scientific judgment. Important considerations for the assessment of this factor include:

    • whether the use of the device in a real-world population is representative, and is generalizable to the relevant population being evaluated; 
    • whether the RWD source is used regionally, nationally and/or internationally; 
    • the overall percentage of patient exposure to the device that are captured in the RWD source; 
    • the validation protocols used to evaluate how well the RWD source reflects the patient population’s experience; 
    • whether the RWD study design, study protocol, and/or analysis plan is appropriate to address the regulatory question and capable of being accomplished in a sufficiently timely manner; whether the RWD contains elements to capture specific device identification information (e.g., unique device identifier); 
    • whether the RWD adequately captures patient medical history and preexisting conditions, as well as follow-up information needed evaluate the question being addressed (e.g., whether administrative claims data have adequate continuity of coverage); 
    • whether sufficient data elements are collected to adjust for confounding factors; 
    • whether any linkages performed are scientifically appropriate and account for differences in coding and reporting across sources; 
    • the RWD source reporting schedule, including time interval between database close and release, and length of reporting periods; 
    • the prior documented (e.g., peer reviewed publications or practice guidelines) use of the RWD source for determining outcomes-based quality assessments, validated predictive risk modeling, signal detection, performance improvement, benchmarking, and other clinically-meaningful uses.

To assess reliability, FDA is primarily concerned with how the data were collected (data accrual), and whether there were people and processes in place to provide “adequate assurance” that the data quality and integrity are sufficient. The RWD source should have an operational manual (or similar document) in place specifying the methods and extent of data collection and aggregation. FDA provides a list of factors that it will consider the when assessing data accrual, many of which are considerations for any clinical trial (e.g., whether patient selection and enrollment criteria minimize bias and ensure a representative real-world population, use of a common data capture form).

Similarly, to assess data assurance, FDA provides a list of factors it will consider which include factors relevant to clinical trials that generate any data for support of an application (e.g., completeness (i.e., minimized missing or out of range values) of data necessary for specified analyses, including adjustment for confounding factors, evaluation of site and data monitoring practices).

When is an IDE Required?

An IDE allows a device to be shipped for the purpose of conducting investigations of the device without complying with other requirements under the FD&C Act. If a device is being used in the normal course of medical practice, an IDE would likely not be required to collect RWD. Because FDA does not regulate the practice of medicine, RWD could be collected on a legally marketed device for uncleared or unapproved uses (as long as the device is being used under authority of a healthcare practitioner in a practitioner-patient relationship). However, if data is collected to determine safety and effectiveness of the device, and the process would influence treatment decisions, an IDE may be required. For example, if physicians were instructed to administer the device to certain patients in a particular way to generate data, the registry would likely be subject to IDE requirements.

AGG Observations: 

  • The guidance is heavily focused on registry data, and FDA did not provide examples that apply to Class II devices in the pre-market phase. We will track any developments in FDA’s assessment of RWE for Class II devices not subject to a registry. 
  • FDA has not changed its general position that it does not consider purely anecdotal evidence (from the real world or anywhere else) appropriate for supporting regulatory decisions. This may be disappointing to some patient advocates. 
  • FDA suggests throughout the guidance that sponsors intending to use RWE communicate with the agency through the pre-submission process. FDA often uses the pre-submission process to communicate the data it would like to see. For sponsors who have already collected RWD, it may be more efficient to simply include that data with the submission, so the agency provides feedback. If a sponsor will be designing a new way to collect or analyze RWD, the pre-submission process may be helpful as FDA establishes positions on the relevance and reliability of different types of RWD. 
  • Sponsors should keep in mind that the guidance does not change FDA’s evidentiary standards for regulatory decision making. FDA may be evaluating different sources of information, but the agency applies at least the same level of rigor to its review of RWE as it does “traditional” clinical data.

To review the entire document and formatting for this alert (e.g., footnotes), please access the original below:

Downloads:

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

© Arnall Golden Gregory LLP | Attorney Advertising

Written by:

Arnall Golden Gregory LLP
Contact
more
less

Arnall Golden Gregory LLP on:

Readers' Choice 2017
Reporters on Deadline

"My best business intelligence, in one easy email…"

Your first step to building a free, personalized, morning email brief covering pertinent authors and topics on JD Supra:
Sign up using*

Already signed up? Log in here

*By using the service, you signify your acceptance of JD Supra's Privacy Policy.
Custom Email Digest
Privacy Policy (Updated: October 8, 2015):
hide

JD Supra provides users with access to its legal industry publishing services (the "Service") through its website (the "Website") as well as through other sources. Our policies with regard to data collection and use of personal information of users of the Service, regardless of the manner in which users access the Service, and visitors to the Website are set forth in this statement ("Policy"). By using the Service, you signify your acceptance of this Policy.

Information Collection and Use by JD Supra

JD Supra collects users' names, companies, titles, e-mail address and industry. JD Supra also tracks the pages that users visit, logs IP addresses and aggregates non-personally identifiable user data and browser type. This data is gathered using cookies and other technologies.

The information and data collected is used to authenticate users and to send notifications relating to the Service, including email alerts to which users have subscribed; to manage the Service and Website, to improve the Service and to customize the user's experience. This information is also provided to the authors of the content to give them insight into their readership and help them to improve their content, so that it is most useful for our users.

JD Supra does not sell, rent or otherwise provide your details to third parties, other than to the authors of the content on JD Supra.

If you prefer not to enable cookies, you may change your browser settings to disable cookies; however, please note that rejecting cookies while visiting the Website may result in certain parts of the Website not operating correctly or as efficiently as if cookies were allowed.

Email Choice/Opt-out

Users who opt in to receive emails may choose to no longer receive e-mail updates and newsletters by selecting the "opt-out of future email" option in the email they receive from JD Supra or in their JD Supra account management screen.

Security

JD Supra takes reasonable precautions to insure that user information is kept private. We restrict access to user information to those individuals who reasonably need access to perform their job functions, such as our third party email service, customer service personnel and technical staff. However, please note that no method of transmitting or storing data is completely secure and we cannot guarantee the security of user information. Unauthorized entry or use, hardware or software failure, and other factors may compromise the security of user information at any time.

If you have reason to believe that your interaction with us is no longer secure, you must immediately notify us of the problem by contacting us at info@jdsupra.com. In the unlikely event that we believe that the security of your user information in our possession or control may have been compromised, we may seek to notify you of that development and, if so, will endeavor to do so as promptly as practicable under the circumstances.

Sharing and Disclosure of Information JD Supra Collects

Except as otherwise described in this privacy statement, JD Supra will not disclose personal information to any third party unless we believe that disclosure is necessary to: (1) comply with applicable laws; (2) respond to governmental inquiries or requests; (3) comply with valid legal process; (4) protect the rights, privacy, safety or property of JD Supra, users of the Service, Website visitors or the public; (5) permit us to pursue available remedies or limit the damages that we may sustain; and (6) enforce our Terms & Conditions of Use.

In the event there is a change in the corporate structure of JD Supra such as, but not limited to, merger, consolidation, sale, liquidation or transfer of substantial assets, JD Supra may, in its sole discretion, transfer, sell or assign information collected on and through the Service to one or more affiliated or unaffiliated third parties.

Links to Other Websites

This Website and the Service may contain links to other websites. The operator of such other websites may collect information about you, including through cookies or other technologies. If you are using the Service through the Website and link to another site, you will leave the Website and this Policy will not apply to your use of and activity on those other sites. We encourage you to read the legal notices posted on those sites, including their privacy policies. We shall have no responsibility or liability for your visitation to, and the data collection and use practices of, such other sites. This Policy applies solely to the information collected in connection with your use of this Website and does not apply to any practices conducted offline or in connection with any other websites.

Changes in Our Privacy Policy

We reserve the right to change this Policy at any time. Please refer to the date at the top of this page to determine when this Policy was last revised. Any changes to our privacy policy will become effective upon posting of the revised policy on the Website. By continuing to use the Service or Website following such changes, you will be deemed to have agreed to such changes. If you do not agree with the terms of this Policy, as it may be amended from time to time, in whole or part, please do not continue using the Service or the Website.

Contacting JD Supra

If you have any questions about this privacy statement, the practices of this site, your dealings with this Web site, or if you would like to change any of the information you have provided to us, please contact us at: info@jdsupra.com.

- hide
*With LinkedIn, you don't need to create a separate login to manage your free JD Supra account, and we can make suggestions based on your needs and interests. We will not post anything on LinkedIn in your name. Or, sign up using your email address.