FDA wants help with real-world data drug submission standards

By LAURA DIANGELO, MPH | Jan. 11, 2022

According to a new funding notice, the FDA is seeking research into how to map real-world data (RWD) standards into clinical research formats. The grant opportunity comes after the FDA released guidance indicating it would look to advance process for drug submissions leveraging RWD.

FDA requires sponsors to submit data in formats recognized by the agency – which do not often align with RWD sources.

  • Quick background: Under section 745(A) of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, many types of regulatory applications are now required to be submitted electronically. The FDA requires study data to follow certain standards in electronic submission.Study data contained in “certain” Investigational New Drug Applications (IND), New Drug Applications (NDA), Abbreviated Drug Applications (ANDA) and certain Biologics License Applications (BLA) must be submitted electronically using a “format that FDA can process, review, and archive.” This requirement also applies to submission subsequent to the initial application (e.g., amendments, supplements, reports).
  • The agency maintains a Data Standards Catalogue (“Catalog”) that outlines the currently supported and/or required standards for particular uses of data, as well as their date of recognition and when they were required. In general, clinical and non-clinical data are submitted to the FDA in standards from the Clinical Data Interchange Standards Consortium (CDISC). These include the Study Data Tabulation Model (SDTM), used for clinical data submissions, and the Standard for Exchange of Nonclinical Data (SEND), which is used for nonclinical data submissions.
  • These standards were designed for traditional research methods, and do not necessarily align with the use of novel data sources. In particular, the FDA-recognized standards in the Catalog do not represent the kinds of data standard or formats in which real-world data (RWD) is captured, such as data from electronic health records (EHRs), claims data, data in registries or captured by digital health technologies (DHTs).
  • Even as the FDA has worked to increase its acceptance of RWD for regulatory use, it has acknowledged the need to update its standards Catalog. In October 2021, the agency issued draft guidance with preliminary recommendations on how to translate data from real-world sources into the standards it recognizes for submissions. In that draft, the agency acknowledged that mapping data from RWD sources into FDA-recognized standards is likely to be challenging, as these sources tend to use their own standards and capture practices that do not align with those used/recognized by FDA. In general, it recommended that sponsors would need to show their work and justify their mapping procedures and processes.
  • Going forward, the FDA indicated in the draft that it intends to update its Data Standards Catalogue “and/or” issue further guidance to better align with the information derived form RWD sources. For now, however, sponsors are still expected to translate RWD into the FDA’s already recognized standards for submission – a key and significant hurdle for sponsors seeking to leverage RWD, even as the FDA has begun issuing guidance on regulatory use of multiple RWD sources, such as claims/EHR data, data from registries, and leveraging observational studies as a source of RWD. In effect, while the FDA is beginning to craft policy on how RWD should be considered in a regulatory context for life sciences product research (and in advance of an impending agency pilot on its use in decision-making), best practices for translating the way that RWD is captured into a format that the FDA can accept and interpret remains a very operational hurdle to the regulatory use of RWD in submissions.

The FDA is now looking for help in assessing how data should be mapped from RWD sources into regulatory standards.

  • According to a recently posted grant announcement, the agency is seeking research on the way data is captured and formatted in real-world sources, and particularly EHRs, and how it can be mapped or translated into the regulatory/research data standards that FDA typically uses. Notably, this doesn’t mean that the agency is specifically looking to recognize an RWD-specific standard for its catalog, but rather better understand how to translate between RWD sources and research/regulatory standards.
  • The announcement cites the “current fragmented state of healthcare data interoperability” and the “independent evolution of data standardization for research and regulatory submissions.” These are effectively two distinct challenges: first, that RWD itself is difficult to link between different sources (e.g., linking EHR to claims data, laboratory data in general), and second that the standards that exist for research/regulatory submissions were developed without considering the context of RWD sources and therefore the semantics and definitions often do not align.
  • While the first issue is not technically within the scope of the FDA’s purview, the agency is looking to address the second problem. “Even if a future state of optimized interoperability in healthcare were researched, where every EHR and claims system globally conforms to the same agreed-upon way to record, store, represent, and exchange data – a major achievement – it would do little, by itself, to bridge the gap between healthcare RWD and research/regulatory data,” the notice states. Even fully validated and linked RWD from disparate sources would not translate directly to the research/regulatory data standards, given differences in definitions.
  • For example, representation of gender/sex in a clinical trial would be based on “visual observation of relevant physical characteristics at birth,” or could be defined by genomic data of the X/Y chromosome composition – while data captured from a patient at the point of care (POC) or in a clinical registry may not include information on the specific sex assigned at birth, but rather recorded based on patient’s indicated identity or a provider’s assumptions based on presentation at the time of their visit. Further, concepts such as timing of certain measures (e.g., blood pressure readings or laboratory tests, which would be standardized in a trial protocol, or when a measure like gender was observed) will simply not exist in data garnered from real-world sources.
  • The FDA’s Request for Applications (RFAs) is specifically seeking “research developing innovative approaches, or building upon existing ones, that can help define RWD elements and domains with more accuracy and granularity – across the healthcare and research/regulatory spectrum – to allow meaningful comparisons of healthcare data and research data.”
  • In effect, the FDA is looking for research projects that can break down RWD domains into the least common denominator that can then be applied and translated into other data sources and their standards; “at a minimum, represent[ing] EHR systems and standards and clinical research data systems and standards.” The end goal of the project would be to develop a “(non-exhaustive list) providing information to reliably expand the data elements/attributes of source and destination data standards to accommodate all granularity levels,” or inform what the semantics of different data points actually mean in context, and how they relate between standards. “[A]lternatively, providing maximum clarity of semantic differences between concepts to promote more accurate mapping between standards” could be another “benefi[t] from successful work” under the grant.
  • There are several activities that the FDA would require, including an “environmental scan” of the work already done in this area, a “proposed approach” that would prioritize certain RWD domains on which to focus, a methodological approach to “identifying the granular structure of similar concepts” between RWD standards (prioritizing those for EHRs) and current research/submission standards, and a “proposed approach” of how the work will apply “for both human understanding and, potentially, later use in computational settings.”
  • What’s next? Any letters of intent for research projects are due February 2, 2022, with applications due by March 31. The earliest start date is July 2022. Overall, the research being sought is extremely foundational, in effect pulling some example domains into a proving ground for mapping between RWD and regulatory/research standards – which will likely remain a manual (rather than digital or automated) process for the time being. However, the October draft guidance still tasks sponsors with conducting such data translations and mapping when seeking to use RWD in their regulatory submissions – best practices for which may be informed by this and similar research projects.

Getting ahead of the requested environmental scan, AgencyIQ has previously discussed some similar efforts and projects.

  • A recent collaboration on mapping between an organization that develops EHR standards and the organization that develops the regulatory/research standards: In 2021, the standards organization that develops and maintains data standards used in EHRs, known as HL7, and the standards organization that develops and maintains the regulatory submissions standards, known as the Clinical Data Interchange Standards Consortium (CDISC), partnered together to develop a preliminary mapping tool between the HL7’s FHIR standard for EHRs and CDISC standards for regulatory submissions. The goal of that project, which produced a Joint Mapping Implementation Guide, was to “facilitate the use of electronic health record (EHR) data in clinical research.” However, as the organizations noted at the time, the first iteration is “purely a ‘descriptive’ guide,” and a fully manual process. Realistically, a key outcome of the partnership so far has been to identify the areas where different approaches in the CDISC and FHIR standards create mapping challenges – likely a baseline for which the new research FDA is seeking will need to address.
  • The FDA is also working on defining EHR data. The agency’s longitudinal real-world data surveillance system, Sentinel, is working to build a rubric for “regulatory grade” EHR data to help both developers and regulators understand when these data are good enough to support regulatory submissions. Further, the FDA is currently contracting for an RWD-based research project that would look at how (and whether) data captured at the point of care by clinicians could identify adverse events associated with metal-containing implanted devices. That project will explore whether EHR data can reasonably used to capture, and research, events that are not well defined in clinical trials.
  • Notably, the general state of health data interoperability in the U.S. continues to change, as ONC and other standards-setting and recognizing agencies do not have a unified approach. For example, on January 10th 2022, ONC released a new Interoperability Standards Advisory (ISA) Reference Edition, which is “ONC’s curated catalog of curated standards and implementation specifications for health information interoperability,” or reference catalogue of standards that ONC considers to be “best practice” for use in HIT even beyond what is federally required. Stakeholders interested in RWD policy may notice some common themes in concerns about data breaks and a lack of standardization, including frameworks for translating laboratory data into HIT or EHRs (as AgencyIQ has discussed, laboratory data is uniquely challenging in the healthcare space), ePrescribing and public health reporting. Notably, public health reporting is overseen by CDC, not ONC, and the ISA now includes an emerging standard on electronic transmission of lab results to public health agencies in order to “rais[e] awareness of the potential use of FHIR standard for public health reporting,” – but not to require its implementation nationwide.
  • These projects come in advance of an FDA pilot on RWE use in submissions. Under the upcoming reauthorization of the Prescription Drug user fee program (PDUFA VII), the FDA will stand up a new pilot in the next two years, the Advancing RWE Program, that would allow sponsors to volunteer to have their RWD-based research programs assessed by the agency – and is intended to help the FDA define and develop its own approach to reviewing these research programs. In effect, the pilot will pressure-test the agency’s own readiness to receive RWE in regulatory submissions, and allow sponsors and researchers to see what types of issues or concerns the agency may have in regulatory contexts. For some context or in anticipation of potential issues, the drug industry may be able to glean preliminary lessons from the experience of recent submissions for medical devices that relied on RWE.
  • The lessons learned from the pilot will be used to inform updates to the FDA’s RWE guidance documents – expected by the end of 2026 under the PDUFA agreements. In addition, as noted above, the FDA has already begun issuing draft guidance on using RWD for life sciences research, even as best practices on how to actually submit that data remain under development.

To contact the author of this item, please email Laura DiAngelo.
To contact the editor of this item, please email Alexander Gaffney.

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