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

by Arnall Golden Gregory LLP

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 In the guidance, which finalizes the agency’s July 2016 draft guidance on this topic, FDA discusses the potential uses of real world data and the factors it evaluates to determine whether that data can support a regulatory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.


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:


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.

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