In recent years, the Food and Drug Administration (FDA) has begun increasing its focus on “real-world data” and “real-world evidence.” This article discusses this recent regulatory trend and its potential impact on mass tort litigation involving pharmaceuticals, medical devices, and other FDA-regulated products.
What Are Real-World Data and Real-World Evidence?
The term “real-world data” (RWD) refers to data relating to the status of patient health and the delivery of healthcare to patients. The data are collected from various sources, such as electronic health records; claims and billing activities; product and disease registries; patient-generated data, including home-use settings; and miscellaneous data sources, such as mobile devices.
The term “real-world evidence” (RWE) refers to clinical evidence regarding the usage and potential benefits or risks of a medical product derived from the analysis of RWD. RWE can potentially be generated from different study designs, including randomized clinical trials and observational studies.
Why Is the FDA Focusing on Real-World Data and Real-World Evidence Now?
With the advent of mobile devices, wearable technology, and the proliferation of advanced computer technology in general, RWD and RWE have come to the forefront as the FDA and the healthcare community at large seek to bring healthcare rulemaking into the twenty-first century, as the aptly named 2016 act employing such data—the 21st Century Cures Act—implies. Passed in 2016, the intent of the Cures Act is to foster health-related innovation and accelerate medical product development. With the passing of the Cures Act, section 505F of the Federal Food, Drug, and Cosmetic Act was created, and it is through both this section and the Public Health Service Act that the FDA intends to implement RWE to support new-use approvals for drugs and satisfy post-approval study requirements.
The use of RWE by the FDA is not entirely new. The FDA has, to name a few examples, used RWE to monitor and evaluate post-market product safety and to evaluate the comparative effectiveness of various vaccines. Its use and implementation, however, have not been as broad as the current proposed FDA framework provides. As the biomedical community increasingly relies on RWD, the FDA, in response to a congressional mandate and in an effort to promote further progress, is issuing draft guidance on these data sources, standards, and their possible implementation.
What Steps Has the FDA Taken?
In recent years, the FDA released several guidance documents on real-world evidence covering topics related to data sources, data standards, and regulatory considerations. Here is an overview of some of the most recent guidance documents.
Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products. In September 2021, the FDA issued this guidance document to provide “sponsors, researchers, and other interested stakeholders with considerations when proposing to use electronic health records or medical claims data in clinical studies to support a regulatory decision on effectiveness or safety.” See Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products. In particular, the guidance addresses “issues that are essential to determining the reliability and relevance of the data and that should be addressed in a sponsor’s protocol,” which include the following:
- the appropriateness and potential limitations of the data source for the study question and to support key study elements;
- time periods for ascertainment of study design elements;
- conceptual definitions and operational definitions for study design elements (e.g., 120 inclusion/exclusion criteria for study population, exposure, outcomes, covariates) and the results of validation studies; and
- quality assurance and quality control (QA/QC) procedures for data accrual, curation, and transformation into the final study-specific data set.
The guidance document has three main subtopics related to data sources, study design elements, and data quality during data accrual, curation, and transformation into the final study-specific data set. As to data sources, the FDA instructs that protocols submitted to the agency should identify all data sources proposed for the study in addition to relevant descriptive information. This means sponsors should demonstrate in their protocols “that each data source contains the detail and completeness needed to capture the study populations, exposures, key covariates, outcomes of interest, and other important parameters (e.g., timing of exposure, timing of outcome) that are relevant to the study question and design.” Id. at 4. The guidance document also provides detailed recommendations and considerations regarding continuity of coverage and comprehensiveness of data sources in capturing aspects of care and outcomes relevant to the study, data linkage and synthesis, distributed data networks and common data models for medical product safety surveillance and research, standardized computable phenotypes for selection of populations, enhancing efficiency with the use of unstructured data within electronic health records, dealing with missing data, and validation considerations.
The guidance document’s discussion of study design elements focuses on the ascertainment and validation of key study design elements and provides recommendations regarding defining time periods, selecting study populations, exposure ascertainment and validation, outcome ascertainment and validation, and covariate ascertainment and validation. Further, as to data quality during data accrual, curation, and transformation into the final study-specific data set, the guidance document includes recommendations regarding characterizing data, documentation of the QA/QC plan, and documentation of the data management process.
Data Standards for Drug and Biological Product Submissions Containing Real-World Data. In October 2021, the FDA released this guidance document, which “addresses considerations for the use of data standards currently supported by the FDA in applicable drug submissions containing study data derived from RWD sources.” See Data Standards for Drug and Biological Product Submissions Containing Real-World Data. The document states that the FDA “recognizes the challenges involved in standardizing study data derived from RWD sources for inclusion in applicable drug submissions.” In light of these challenges, the FDA recommends ensuring that adequate processes are in place to increase data confidence during the data curation and transformation phase. The guidance document also indicates that those processes, as well as changes to data to conform to FDA-supported data standards and any impact of those changes, should be documented in applicable drug submissions.
Further, sponsors are encouraged to refer to the Study Data Technical Conformance Guide when submitting study data in an applicable drug submission, and should discuss with the FDA any planned submission of study data from RWD sources in an applicable drug submission and approaches for transforming data to FDA-supported data standards.
The data standards guidance document notes that “[d]ocumentation of the sponsor’s rationale for choosing particular [Clinical Data Interchange Standards Consortium (CDISC)] data elements for RWD and documentation of the differences between the two is critical.” Thus, the sponsor should provide an appendix to the Study Data Reviewer’s Guide describing the general approach and foreseen impact of data mapping and should include a data dictionary documenting the definition of data elements and relevant information about those data elements. Sponsors should also document “data challenges encountered during transformation to an FDA-supported data standard and a justification of their approach to enable the application of an FDA-supported standard.”
Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products Guidance for Industry. In November 2021, the FDA released this guidance document to provide “sponsors and other stakeholders with considerations when either proposing to design a registry or using an existing registry to support regulatory decision-making about a drug’s effectiveness or safety.” See Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products Guidance for Industry.
The guidance document encourages sponsors to “consider both the strength and limitations of using registries as a source of data to generate evidence for regulatory decision-making” and acknowledges that “registries are better suited as a data source for regulatory purposes when sponsors aim to capture specific and objective endpoints, such as death or hospitalization.” By contrast, additional challenges are involved in standardizing measurements of subjective endpoints.
The assessment of a registry data’s relevance is context-specific. For this reason, “sponsors should consider the methods involved in patient selection and the effect those methods have on the representativeness of the population in the registry.”
In assessing the reliability of registry data, the FDA considers how the data were collected and whether registry personnel and processes adequately minimize errors and ensure data integrity. Sponsors should ensure adequate processes and procedures are in place to “govern registry operation, education and training of registry staff, resource planning, and general practices that help ensure the quality of the registry data.” Sponsors also should ensure that a registry adheres to applicable human subject protection requirements, including protecting the privacy and confidentiality of patient health information and data security, and should include common data elements to promote standardization in data collection. The guidance intends that, when possible, standardized terminology and data standards used by the registry should be consistent with those used by the FDA, and policies and procedures should be in place to allow third parties to assess data quality and address data errors. Indicators of data consistency, accuracy, and completeness should also be assessed periodically.
Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products. In December 2021, the FDA released this guidance document, which “discusses the applicability of FDA’s investigational new drug application regulations to various clinical study designs that utilize RWD.” See Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products. The guidance is intended to clarify the FDA’s “expectations concerning clinical studies using RWD submitted to FDA in support of a regulatory decision regarding the effectiveness and safety of a drug . . . when such studies are not subject to part 312,” with a primary focus on non-interventional (observational) clinical study designs.
The guidance document recommends that sponsors engage with the FDA in the “early stages of designing a non-interventional study intended to support a marketing application.” Doing so includes providing “evidence” that protocols and statistical analysis plans were finalized prior to reviewing the outcome data of a study and before performing the prespecified analyses. Sponsors should also provide the FDA with date-stamped revisions to the protocol (if any) with the rationale for each change.
In addition, sponsors should “describe in the study protocol all the data sources accessed when designing the study, as well as results from feasibility evaluations or exploratory analyses of those data sources.” In particular, the FDA recommends that sponsors generate audit trails in their data sets to track data source access and analyses and provide a justification for “selecting or excluding relevant data sources” from a given study. The FDA also recommends that sponsors document any analysis performed during the study design phase, demonstrate alignment of the research with the choice of the final analytic data set and the conduct of final analyses, ensure that they do not favor particular study findings, and describe and note any differences between patient characteristics of the source population and study population. Further, to “ensure transparency regarding their study design,” the FDA also recommends sponsors publish their study protocols on a publicly available website.
The guidance document states that sponsors “must ensure that they are able to submit patient-level data for any RWD that have been analyzed as part of the clinical study including in a marketing application when required under 21 CFR 314.50 and 601.2.” For this reason, if RWD are not owned or controlled by the sponsor, the FDA recommends that the sponsor put in place agreements with third parties necessary to ensure that “all relevant patient-level data can be provided to FDA and that source data necessary to verify the RWD are made available for inspection as applicable.” In addition, sponsors are encouraged to ensure documentation, annotation, and completion of RWD and programming codes and algorithms submitted to the FDA as necessary to allow the agency to replicate the study analysis using the same data set and approach.
According to the guidance document, sponsors submitting non-interventional studies for FDA review should be responsible for the design, conduct, and oversight of the studies and are encouraged to document the roles and responsibilities of third parties, including researchers, involved in studies and make them available to the FDA. In addition, the guidance advises sponsors to comply with 21 C.F.R. part 11 in how they manage data and produce records for non-interventional studies submitted in support of regulatory decisions regarding safety or effectiveness for a marketing application.
What Are FDA’s Next Steps?
The FDA has already issued these draft industry guidance publications, with the reported intention of releasing additional guidance on designing externally controlled and randomized controlled trials in a clinical setting (observational as opposed to randomized studies) that use RWD. The intention would be to replicate the results of randomized studies through the use of observational studies that employ RWD, and to generate RWE, or if the observational studies employ RWD and generate RWE. Academic data and opinions as to whether this will work vary, and the FDA intends to test and identify any limitations to the use of RWD and RWE in this setting.
In addition, while the focus of RWD has primarily been concerned with determining product safety, the FDA wishes to use RWD to support decisions related to product effectiveness, such as drug labeling and changes in dosage, regimen, or route of administration. The FDA is developing data standards for RWD and the Real-World Evidence program, which will be used alongside input from stakeholders and senior leadership in order to best implement this approach.
What Are the Potential Impacts on Mass Tort Litigation?
As life sciences companies begin to expand their use of RWD and RWE in connection with the FDA’s guidance documents and related activity, there is an increasing likelihood that the data will also have impacts on mass tort litigation. This is likely to happen in a number of ways, but we would like to highlight three potential impacts here.
Impact on general causation evidence. In mass tort litigation involving pharmaceuticals, medical devices, and other FDA-regulated products, a dispositive issue in the case is general causation—that is, whether there is reliable scientific evidence that the product at issue is capable of causing the injury at issue. In most cases, causation turns on scientific data from the “hierarchy of evidence,” which generally consists of randomized clinical trials, prospective cohort studies, retrospective case control studies, and other, less reliable forms of evidence. The FDA’s focus on RWD and RWE potentially opens the door for new and different types of evidence that might support general causation, requiring the parties, their experts, and courts exercising the Rule 702 gatekeeping obligations to delve more deeply into more and different categories of scientific data. Proliferation of data could also lead to a potential weakening of Rule 702 standards, such as peer review, testing, and error rates, which may seem less applicable to RWD and RWE.
Impact on experts. In addition to general causation, the emergence of and increased focus on RWD and RWE will require expert witnesses to become more conversant with scientific information from different sources and more adept at applying these sources to the issues in dispute in the case. Experts who are practicing physicians may be more inclined to offer RWD and RWE from their own practices, such as describing the number of adverse events experienced by their own patients who used a particular medical product. There may also be opportunities for experts in new areas that specialize in RWD and RWE.
Impact on discovery. If RWD and RWE continue to emerge as a focus of the type of information produced by life sciences companies for FDA use, then they will inevitably become the focus of discovery requests and disputes in mass tort litigation. This generally means opening up new and different categories of databases and production obligations for defendants, while requiring that plaintiffs’ lawyers and their experts are capable of reviewing, analyzing, and building their cases as appropriate.
Here, the proliferation of data will likely expand the nature and amount of discovery plaintiffs are required to produce. E-discovery from plaintiffs will arise from the increased focus on RWD and RWE from sources such as wearable devices, smart phones, and other technologies that contain a plaintiff’s health-related information.
As the FDA’s focus on real-world data and real-world evidence continues to evolve and become a part of the development and monitoring of pharmaceuticals, medical devices, and other FDA-regulated products, the potential impact on mass tort litigation will continue to grow.
Kelsey Tavares is an associate with DLA Piper in Boston, Massachusetts. William Kiniry III is an attorney with DLA Piper in Baltimore, Maryland. Chris Campbell is a partner with DLA Piper in Atlanta, Georgia.
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