By Kelliann H. Payne, Blake Wilson, and Megana Sankaran, Hogan Lovells US LLP
Historically, the gold standard for high-quality clinical trials has been prospective, multicenter, randomized, controlled, double-blinded studies. These studies are the “traditional” path to regulatory approval but require immense resources from industry and healthcare providers and are challenging to conduct. They are also often impractical, as clinical studies frequently require treating and following patients long term, during which time the standard of care, as well as available treatment options, may evolve. Given these shortcomings, and spurred by the increasing availability of patient-generated data from both traditional repositories (e.g., electronic health records (EHRs) and patient registries) and new sources (e.g., mobile devices, wearables, and other biosensors), in 2015-2016 Congress and the FDA took steps to add flexibility to product development by allowing this type of data to be leveraged for medical device development and approval.1 Then FDA-commissioner Robert Califf stated that leveraging real-world evidence (RWE) to inform FDA decision-making is a “top programmatic priority.”2 In general, the larger scientific community has pushed for utilization of health-related data generated outside of traditional clinical studies because this type of data reflects the reality of clinical care, helps with the challenges of traditional clinical studies, and is already collected via many sources, with the overall goal of bringing medical devices to market faster.
Regulatory Guidance On Use Of RWE
The concept of RWE was also introduced in the 21st Century Cures Act (Act).3 Section 3022 of the Act defines RWE as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.” The Act called for the Secretary of Health and Human Services to establish a draft framework to evaluate the use of RWE. To this end, on Aug. 31, 2017, the FDA’s Center for Devices and Radiological Health (CDRH) finalized a guidance document titled, Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices. The guidance document is intended to clarify when RWE can be used in FDA decision-making and affirms that RWE can be used in medical device regulatory submissions to aid in supporting regulatory decision-making. As explained in the agency’s guidance, real-world data (RWD) are “data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources” such as EHRs, claims and billing data, data from product and disease registries, among other sources. Meanwhile, RWE is the “clinical evidence regarding the usage, and potential benefits or risks, of a medical product derived from analysis of RWD.”
While CDRH’s guidance and efforts with respect to medical devices are the subject of this article, it should be noted that the Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER),4 as well as the Center for Veterinary Medicine (CVM),5 have also issued center-specific guidance on RWE.
In determining whether RWD constitutes valid scientific evidence for a medical device regulatory submission, the FDA will evaluate its reliability and relevance. In brief, relevance refers to whether data adequately addresses the applicable regulatory question or requirement. This includes factors such as the representativeness of the patients and its generalizability to the population being evaluated; location(s) and breadth of the data source; and how well the data reflects patient experience. Data reliability refers principally to “data accrual,” or how the data was collected, and whether the collection/analysis processes sufficiently assure quality, integrity, and bias minimization. Thus, companies should determine how the RWD they would like to use can answer a specific regulatory question (e.g., regarding long-term treatment effects, serious adverse events, etc.). According to the final guidance, such protocols and analysis plans should address the same elements that would be addressed in a traditional clinical trial protocol and statistical analysis plan.
The final guidance notes that RWE may be used to support humanitarian device exemptions (HDEs), premarket approval applications (PMAs), and de novo requests, as well as to identify, demonstrate, or support the clinical validity of a biomarker, to support device reclassification petitions and submissions for expanded labeling claims, and to preclude the need for 522 post-market surveillance studies, among others. Specific methods for using RWD include generation of hypotheses to be tested in a prospective clinical study, as a historical control arm or as a complete data set in support of a marketing submission. That said, companies are encouraged to submit their study protocol and analysis plan to the FDA for review and comment via a presubmission meeting request prior to either analyzing retrospective RWD or collecting prospective RWD.
While CDRH’s guidance represents the agency’s formal willingness to evaluate RWE to meet regulatory requirements, success has been mixed in practice. Specifically, the FDA has requested sponsors of medical device marketing applications to demonstrate that RWD is as robust as clinical trial data, which is often impractical. Specifically, the FDA has expressed concerns with sub-optimal data quality and reliability, lack of follow-up data, and selection bias.6 In addition, the FDA has commented that a single source of RWD may not be sufficient, and that multiple data sources may be needed. This, too, represents the agency’s view that RWD should have the same “elements” as data generated from a multicenter, prospective clinical trial.7 To help bring RWD collection in line with the FDA’s standards, the National Evaluation System for Health Technology Coordinating Center (NESTcc), a consortium of device manufacturers, health systems, academic institutions, and the FDA, developed a RWE protocol template that includes guiding principles. The template focuses on prespecifying characteristics of the data collection (e.g., patient population, monitoring plan, statistical analyses) and providing more context around the process for conducting the investigation (e.g., patient selection method, assessments procedures, etc.).
Examples Of FDA Decisions Using RWE
An example of the successful use of RWE occurred at the July 21, 2016 Advisory Panel meeting of the Dexcom G5 Mobile continuous glucose monitoring system.8 At this meeting, there was general agreement that the sponsor's simulation model data (validated by limited clinical data) in support of the proposed dosing indication were inferior to results from actual patients in randomized clinical trials. However, the panel voted in support of approval, relying largely on RWD demonstrating that many patients were already using the device off-label for the proposed expanded indication with promising results. While panel decisions are not binding on the FDA, they do tend to influence final regulatory determinations. The results from this panel with regard to RWD sources is an encouraging sign that such data are gaining acceptance at the FDA and in the broader scientific community.9 More recent examples can be found among approved HDE applications, like ApiFix Ltd.’s MID-C System for treatment of adolescent idiopathic scoliosis, which was approved in part based on RWE collected outside of the U.S.10 In addition, some 510(k) holders have been able to support an expansion of their device indications for use with RWE, such as Pursuit Vascular’s Clearguard Hd Antimicrobial Barrier Cap for use in hemodialysis catheters, which used RWE to expand its intended use from reduction of bacteria inside the device to reduction of central line-associated bloodstream infections.11
Although the clinical use scenarios of drugs differ from those of devices, the RWD sources for both drugs and devices are essentially the same and the criteria the FDA can impose upon collection and analytical methodologies (e.g., establishing consistent definitions, controlling data capture, etc.) can be applied to all RWE studies. Thus, it is worth noting how RWE has played a role in supporting drug approvals. For example, the FDA’s Oncology Drugs Advisory Committee unanimously recommended approval of a drug (tazemetostat) for a rare form of cancer, where the approval was supported in part by a Natural History Study.12 Furthermore, the FDA approved a new indication of a drug (palbociclib) primarily based on RWD such as electronic health records and post-marketing reports.13 The approval is an example of where the FDA accepted RWE to support an effectiveness decision and not only a safety evaluation. The palbociclib label expansion is also noteworthy because the data was sourced by Flatiron Health, an oncology-focused EHR company that has begun offering a suite of normalized oncology data (structured and unstructured) derived from an array of source systems. Businesses like Flatiron Health are helping to both collect and present RWE in a way that addresses the FDA’s concerns with data validity. The entry of RWE businesses means that it will be easier for sponsors to assess the costs and likely benefits of seeking new or expanded indications using RWE, which should improve the tolerance for uncertainties that remain in this regulatory option.
Given the FDA’s willingness to explore and employ the use of RWE in supporting marketing submissions, it seems likely that RWE will continue to play a bigger role in the regulatory approval processes. RWE was often used to support emergency use authorization of COVID-19 diagnostic tests, especially those authorized at the beginning of the pandemic. Use of RWE during the pandemic has demonstrated its utility in accelerating clinical development and ameliorating risks associated with traditional clinical trials (e.g., in-person trial visits), while maintaining the integrity of the clinical investigation. By forcing the FDA to become comfortable with the use of RWD in order to authorize COVID-19 diagnostic tests, the pandemic may have unintentionally forced the agency to reflect in a more pragmatic way on what characteristics of RWE it believes are essential for data integrity and what level of uncertainty it can tolerate in connection with RWE. However, only time will tell if the FDA’s moderation during these exigent circumstances will open the door to more productive discussions on how RWE can develop into a mainstay for medical product development.
About The Authors:
Kelliann Payne is a partner in the Global Regulatory Practice group at Hogan Lovells, based in the firm’s Philadelphia office. Prior to pursuing law, she majored in biology, and this education — along with her background in the medical device industry — allow her to quickly understand emerging medical device technologies and inform her current focus on related legal and business issues. Payne’s experience includes the development, regulation, advertising, and litigation of medical devices. She helps companies in their preclinical and clinical programs, including required submissions to FDA, and leads due diligence reviews for investments and acquisitions.
Blake Wilson is a senior associate in the Global Regulatory Practice group at Hogan Lovells, based in the firm’s Philadelphia office. He has advised on 510(k) premarket notifications, de novo submissions, premarket approval applications, and investigational device exemption applications, among other regulatory filings. Wilson also has experience in drafting clinical trial agreements and contracts for device development, manufacturing, and associated quality system regulation responsibilities. When clients need help with premarket clearance and approval of new medical devices, he smooths regulatory hurdles.
Megana Sankaran is a senior regulatory affairs specialist in the Global Regulatory Practice group at Hogan Lovells, based in the firm’s Washington D.C. office. She advises clients on medical device matters, with a particular focus on the premarket clearance and approval of new devices and statistical considerations. She has experience in both the design and the statistical aspects of clinical trials and has also advised clients about the presentation of clinical data for FDA submissions.