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December 20, 2021

Research Roundup: FDA Uses Fall and Winter 2021 to Release Significant New Guidance Governing Hot-Button Life Sciences Research Topics


This Advisory provides an update on several recently issued US Food and Drug Administration (FDA or the Agency) draft guidance documents and advice addressing areas of increased attention.

  • First, following legislative commitments from the 21st Century Cures Act and feedback from stakeholders, FDA released a number of guidance documents articulating the Agency’s expectations for sponsors of real-world evidence studies, including requirements for ensuring the quality and integrity of real-world data intended to support regulatory submissions and/or label changes.
  • Second, responding to the increased interest in biomarker-moderated therapies, FDA routinely is asking for evidence of validation studies to support diagnostic products; often the validation studies necessary to support clearance, approval, or companion investigational use of in vitro diagnostic (IVD) products require the use of human specimens. FDA recently reminded industry of its expectations with respect to the application of good clinical practices (GCP) requirements to such studies in a Letter to Industry.
  • Finally, FDA released draft guidance on safety reporting responsibilities for clinical investigators conducting drug and device studies that consolidates and updates information conveyed in two decade-old FDA guidance documents. FDA’s decision to issue this investigator-specific guidance follows publication of a draft sponsor-specific safety reporting guidance in June 2021, and is part of an effort to ultimately replace the older guidance documents with role-specific guidance. A summary of these documents follows below.

Real-World Data (RWD) & Real-World Evidence (RWE) Draft Guidances

The last 10 years have seen an explosion in the use of RWD–not only to support regulatory submissions–but also to support reimbursement value propositions and develop better-informed treatment protocols. FDA has historically focused its attention in guidance documents on the conventional drug approval and device approval/clearance standards relevant to interventional clinical trials or investigations. This has made use of RWE data to support regulatory submissions a less predictable process, often requiring bespoke, product-specific judgments from medical reviewers or other Agency personnel. Several new guidance documents released in the latter half of 2021 take steps to address this need, two of which are highlighted below.

FDA Draft Guidance for Industry, Considerations for the Use of Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (Dec. 2021) (RWE Draft Guidance)

Increasingly concerned by the variability in the quality and completeness of data collected by or on behalf of sponsors in the real-world treatment setting, FDA issued a draft guidance on December 8, 2021, which clearly articulates the Agency’s position that non-interventional research—including RWE data collection—must still be subject to certain minimum quality and integrity standards when used to support regulatory submissions or meet regulatory requirements. While not explicitly addressing the use of RWD to support promotional claims, the draft guidance also provides directionally relevant guidance to sponsors who are assessing whether, for example, results of a real-world study publication can be used to support a safety or efficacy claim under the framework established by FDA in its 2018 guidances on medical product communications that are consistent with FDA labeling1 and payor communications.2

The RWE Draft Guidance discusses the applicability of FDA’s investigational new drug (IND) regulations under 21 CFR Part 312 to clinical study designs that use RWD, clarifies FDA’s expectations concerning studies using RWD submitted to FDA in support of regulatory decisions when those studies are not subject to Part 312, and focuses on non-interventional study designs (as opposed to interventional studies). Note, an interventional study or clinical trial is “a study in which participants . . . are assigned to one or more interventions, according to a study protocol, to evaluate the effect of those interventions on subsequent health-related . . . outcomes,” while a non-interventional study or observational study is a study in which “patients received the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol.”3

FDA starts by addressing the applicability of Part 312, and clarifies its view that an interventional study generally meets the definition of a clinical investigation, and is subject to Part 312, whereas a non-interventional study is not a clinical investigation under Part 312 and does not require an IND. Next, FDA addresses regulatory considerations for non-interventional (observational) studies using RWD. FDA reminds industry that while non-interventional studies may not be considered clinical investigations under Part 312, FDA’s informed consent and IRB requirements in 21 CFR Parts 50 and 56 still apply. FDA also suggests consulting with data privacy experts in protocol development to identify and address data privacy and security concerns attendant in accessing healthcare data.

The guidance addresses issues related to transparency of data collection and analysis, FDA’s access to RWD used in a non-interventional study intended for inclusion in a marketing application, study monitoring focused on RWD reliability and data integrity, safety reporting, 21 CFR Part 11 compliance for electronic systems used to manage data and produce required records, and sponsor oversight of studies, study activities, and third parties.

In support of transparency, FDA recommends that sponsors:

  • Engage with FDA in the early stages of designing a non-interventional study intended to support a marketing application;
  • Provide draft versions of their proposed protocol and statistical analysis plan (SAP) prior to finalization for Agency review and comment prior to conducting the study analyses;
  • Finalize the protocol and SAP prior to conducting the prespecified analysis to ensure data sources were not collected to favor a certain conclusion;
  • Document all analyses performed on the data during the study design phase, such as feasibility evaluations and exploratory analyses, and provide a justification for selecting or excluding relevant data sources from the study;
  • Demonstrate that the choice of the final dataset and analyses align with the research question of interest;
  • Assess source population characteristics that may impact the final study findings; and
  • Post study protocols on a publicly available website, like, to ensure transparency regarding study design.

Sponsors should ensure that they are able to submit patient-level data for any RWD analyzed as part of a clinical study included in a marketing application when required by regulations for new drug applications or biologic license applications. They should have agreements in place to ensure that any RWD owned by a third-party may be provided to FDA for inspection.4 The RWD submitted to FDA should permit the Agency to replicate the study analysis using the same dataset and analytic approach.

In terms of study oversight, FDA encourages sponsors to use a risk-based quality management approach. Study monitoring should focus on maintaining data integrity and, when applicable, ensuring that human subject protections are met. FDA requires that relevant adverse events be submitted in accordance with postmarketing safety reporting regulations under 21 CFR 314.80, 314.81, and 600.80. If a sponsor is conducting a study using only a subset of a larger real-world dataset, FDA does not expect the sponsor to search the entire dataset regarding all uses of the product for adverse events that would meet FDA postmarketing reporting requirements.

FDA also addresses sponsor responsibilities more generally, including for Part 11 compliance and study oversight. For marketing applications containing non-interventional studies submitted to support regulatory decisionmaking for product safety or efficacy, the sponsor’s electronic systems used to manage data and produce required records for a marketing application supported by a non-interventional study must comply with Part 11. The Agency also expects that sponsors submitting non-interventional studies for regulatory review take responsibility for all activities related to the design, conduct, and oversight of the studies. Additionally, the sponsor should retain and make available to FDA upon request, a log of any researchers who have significant involvement in the design or conduct of the study. Last, if sponsors engage third parties to perform certain study-related tasks, sponsors should document the roles and responsibilities of the organization performing the tasks and make such documentation available to FDA upon request. This is significant given that sponsors in the medical products industry often “farm out” RWE/RWD studies to clinical research organizations or research collaborators who have expertise in these kinds of study designs and methods.

FDA is accepting comments on the RWE Draft Guidance until March 8, 2022.

FDA Draft Guidance for Industry, Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products (Nov. 2021) (Registry Draft Guidance)

Historically, postmarketing patient registry commitments have been used by FDA and sponsors to track the medium-term and long-term risk-benefit profile of chronic use products with known safety signals. However, such studies offer the ability to gather much deeper insights, and with the increased use of sophisticated data mining tools, allow product developers the potential to quickly identify new product indications or modifications to existing indications. Such studies also allow regulators an ability to work with sponsors to “refine” indications or labels based on safety signals in certain subgroups rather than requiring wholesale changes or more drastic steps, such as the imposition of risk evaluation and mitigation strategies (REMS).

Recognizing the role that registries can play and sponsor/stakeholder interest in using registries to support regulatory decisionmaking about drug efficacy or safety, and pursuant to the mandate to issue guidance on the use of RWE in regulatory decisionmaking, FDA issued the Registry Draft Guidance. It covers the following categories of overarching considerations for parties seeking to design or use an existing registry5 to support regulatory decisionmaking:

  • A registry’s fitness for use in regulatory decisionmaking with a focus on aspects of a registry supporting the collection of reliable and relevant data;
  • Linking a registry to another data source for supplemental information (e.g., electronic health records); and
  • Supporting FDA review of submissions that include registry data.

This draft guidance does not provide recommendations on choice of study design or statistical analysis when analyzing registry data. But sponsors can use the guidance to help plan and utilize registries in a more effective manner and to inform their development and regulatory strategies to obtain meaningful data outside of interventional clinical trials.

FDA acknowledges that registries “range in complexity regarding the extent and detail of the data captured,” and “the data collected in a given registry and the procedures for data collection are relevant when considering how registry data can be used.”6 Such registry data can be used, when appropriate, to support medical product development and inform the design and conduct of clinical studies, and may be advantageous over other RWD sources.7 Yet the suitability of registry data to the regulatory context depends on several factors, including how the data is intended to be used, the patient population enrolled, the data collected, and how the data are created, maintained, and analyzed. Generally, registries are better suited for regulatory purposes when sponsors aim to capture objective endpoints (e.g., death or hospitalization), rather than subjective endpoints, and when the registry is designed to collect data to answer a specific research question, rather than being repurposed.

Before using registry data to support regulatory decisionmaking, FDA advises that sponsors consider whether the data are fit-for-use by assessing the data’s relevance and reliability. To assess relevance, a sponsor should determine whether the registry is adequate for their purposes by examining the data elements the registry measures and the registry’s patient selection, enrollment, and disenrollment practices.

Reliability of registry data is particularly important, and the agency instructs sponsors to ensure that have procedures to “govern registry operation, education and training of registry staff, resource planning, and general practices that help ensure the quality of the registry data.”8 Among these relevant “governance attributes” is Part 11 compliance, as applicable, including maintaining “access controls and audit trails to demonstrate the provenance of the registry data and to support traceability of the data.”9 Relatedly, when evaluating the registry data reliability, FDA will consider how the data were collected, whether the personnel and processes in effect during data collection and analysis were sufficient to limit errors, the sufficiency of data integrity, and privacy and security controls to ensure data confidentiality and security. FDA continues the lengthy discussion on reliability by advising on the registry’s data dictionary, the use of common data elements, the implementation of policies and procedures to support registry data reliability, and the use of safeguards–including data management strategies – to support data assurance. Additionally, FDA recommends that indicia of data consistency, accuracy, and completeness be assessed periodically, with the intervals for such assessments guided by the purposes of the registry data. Also under the umbrella of “reliability,” FDA advises that sponsors adhere to applicable human subject protection requirements.

FDA recognizes that registries may not capture all the necessary information to answer the question of interest in a study, and thus, sponsors may consider obtaining supplemental information from another source. Sponsors should consider the potential impact of additional data on the overall integrity of the registry data and attempt to correct for redundant data and resolve any data inconsistencies. Documentation of the process used to validate the transfer of data should be available for FDA to review during sponsor inspections.

Sponsors interested in using a specific registry as a data source to support a regulatory decision are advised to meet with the relevant FDA review division before conducting a study that will include registry data, and to submit protocols and statistical analysis plans for FDA review and comment before conducting a study that includes data from registries. Last, FDA advises that if registry data are owned and controlled by third parties, sponsors should have agreements with these parties to ensure that all relevant patient-level data can be provided to FDA and that source records necessary to verify the RWD are available for inspection, as applicable.10

FDA is accepting comments on the Registry Draft Guidance until February 28, 2022.

FDA Letter to Industry—Studies Using Leftover, Deidentified Human Specimens Require IRB Review (Oct. 18, 2021)

The applicability of FDA’s regulations governing “clinical investigations” has been a source of confusion and sometimes controversy for diagnostic technology developers–particularly those collecting clinical validation data through a partnership with a healthcare provider or Clinical Laboratory Improvement Amendments (CLIA) certified clinical laboratory. This is particularly true in the booming field of biomarker research, where testing is often done on human tissue or other samples aliquoted from medical procedures, unrelated clinical studies, or collected as part of a companion drug-diagnostic development collaboration. A recent FDA Letter to Industry succinctly describes FDA’s expectations for compliance with GCP regulations in clinical investigations of devices that involve human subjects, including those that use leftover, deidentified human specimens. In short, the Letter reminds industry that the requirement for IRB review applies to all clinical investigations of devices involving human subjects, even if human specimens are deidentified.11 This requirement applies to data used to support an investigational device exemption, device marketing application, or submission to FDA, including IVD technical or analytical studies using human specimens.

FDA clarified its stance that prior guidance does not exempt any such investigations from IRB requirements, though it does provide for some enforcement discretion for informed consent requirements. Consistent with the Agency’s view that, in certain circumstances, investigations can be conducted using leftover human specimens without the informed consent of the human subject who was the source of the specimen while still protecting that source,12 FDA may exercise enforcement discretion for obtaining informed consent according to the terms outlined in FDA Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable (Apr. 25, 2006).

FDA Draft Guidance for Industry, Investigator Responsibilities—Safety Reporting for Investigational Drugs and Devices (Sept. 2021) (Investigator Responsibilities Draft Guidance)

In September 2021, FDA published the Investigator Responsibilities Draft Guidance to inform clinical trial investigators of their safety reporting responsibilities for IND studies under 21 CFR 312.64(b) and investigational device exemption (IDE) studies under 21 CFR 812.150.13This guidance largely does not announce new responsibilities or advice. Rather, it pulls investigator-specific content from two older FDA guidances for investigators, sponsors, and IRBs: Safety Reporting Requirements for INDs and BA/BE Studies (Dec. 2012) (2012 Guidance) and Adverse Event Reporting to IRBs—Improving Human Subject Protection (Jan. 2009) (2009 Guidance). This draft guidance integrates and updates the investigator-specific content that was split between the 2009 and 2012 Guidances, giving investigators a one-stop-shop resource for safety reporting responsibilities.14 Release of this guidance and FDA’s efforts in this respect appear to be part of a larger effort to update and replace the 2009 and 2012 Guidance with sponsor-specific and investigator-specific guidance documents: in June 2021, FDA published Draft Guidance for Industry, Sponsor Responsibilities—Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies, that similarly consolidated the relevant sponsor content from the 2009 and 2012 Guidances. Once finalized, the new sponsor and investigator draft guidances will supersede the 2009 and 2012 Guidances, which will be withdrawn.

Approximately half of the draft guidance is devoted to a background on sponsor safety reporting requirements as context for investigators and to reviewing key regulatory definitions relevant to safety reporting for drugs and devices (e.g., “adverse event,” “adverse reaction,” “serious,” “UADE”). The other half highlights investigator regulatory reporting responsibilities to sponsors and IRBs for IND studies and IDE studies. With respect to investigator reporting to sponsors for IND studies, FDA addresses the assessment of causality, how to handle reporting of trial endpoints that meet the criteria for serious adverse events, and reporting of nonserious adverse events. For IRB reporting for IND studies, FDA covers reporting of adverse events as unanticipated problems to the IRB and required reporting of other unanticipated problems to the IRB (e.g., reports of medication errors, breach of privacy/confidentiality, etc.). For investigator reporting to sponsors and IRBs for IDE studies, FDA very briefly touches on the required reporting timeframes for UADEs and notes that investigators must provide progress reports to sponsors, monitors, and IRBs at regular intervals (no less than yearly), and that such reports to sponsors should include information about anticipated and unanticipated adverse device effects.

In terms of updates to the investigator content from the 2009 and 2012 Guidances, there are a few notable additions and omissions. With respect to “immediately” reporting serious adverse events to sponsors (whether or not drug-related) as required by 21 CFR 312.64(b), the guidance expands on the Agency’s prior interpretation of “immediately” (as soon as feasible after the investigator recognizes an event is a serious adverse event and obtains relevant information for the sponsor) by providing examples of “relevant information” for the sponsor. Such information will “generally include a specified subject, a suspected drug (if any), the reporting source (if not the investigator themself), and a clinical description of the event, including an assessment of whether a reasonable possibility exists that the drug caused the event.” 15 As the guidance notes 21 CFR 312.64(b) also requires the investigator to include in its report to the sponsor an assessment of whether there is a reasonable possibility (evidence to suggest a causal relationship between the drug and adverse event) that the drug caused the serious adverse event. The draft guidance provides further assistance to investigators in making this causality determination by providing the following factors to consider: temporal relationship of the event to the drug administration; biological plausibility based on the mechanism of action of the drug or similar drugs; nonclinical evidence; and dechallenge-rechallenge information.16

With respect to devices, the guidance notes that what qualifies as a serious adverse effect, as that term is used in the definition of a UADE,17 would be specific to the device and the study in which it is being used or tested. Additionally, FDA further interprets the term “serious adverse effect” used in the UADE definition similar to how “serious adverse event” is defined in the IND regulations at 21 CFR 312.32(a):

Generally, a serious adverse effect is one that is determined by the investigator or sponsor to be life-threatening, require hospitalization, result in disability or permanent damage, result in a congenital anomaly or birth defect, or require an intervention to prevent permanent impairment or damage. In the protocol, the sponsor should include information on adverse effects that helps investigators determine what would qualify as a serious adverse effect. Examples of adverse effects that could be considered serious include organ perforation and thrombus formation inside an aortic endovascular graft.18

Additionally, for reporting of UADEs to sponsors and IRBs, the guidance notes that what qualifies as a UADE is expected to vary depending on the specific device and the way the device is used within the study. As a result, sponsors are required to include risk information in the investigational plan to help investigators identify and assess potential UADEs.

*          *          *          *          *

Relative to recent years, in 2021, FDA has provided a significant amount of guidance across a variety of research-related disciplines, set expectations on GCP compliance, and emphasized the importance of data reliability and integrity in RWD/RWE collection. The comment periods for the draft guidance documents summarized above present a valuable opportunity for industry to provide feedback on, and help shape, emerging FDA policy, particularly in the RWD/RWE arena which looks to be an area of increased focus if Dr. Califf is confirmed as the new FDA Commissioner. Our Life Sciences and Healthcare Regulatory practice has closely followed these developments and has significant experience counseling clients on the underlying regulatory requirements. We would be happy to assist readers to comment on the draft guidance documents and to understand the impact the various guidance documents could have on their business goals.

*Sam Williams contributed to this Advisory. Mr. Williams is a graduate of the University of Michigan Law School and is employed at Arnold & Porter's Washington, DC office. He is not admitted to the practice of law.

© Arnold & Porter Kaye Scholer LLP 2021 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.

  1. FDA Guidance for Industry, Medical Product Communications That Are Consistent With the FDA-Required Labeling Questions and Answers (June 2018). Note, this guidance addresses studies that are inherently poorly designed and thus cannot be used to support claims, stating, “firms should note that if a CFL promotional communication relies on a study that is inadequate to support the representations or suggestions it presents, disclosure of the material limitations of that study does not correct the misleading message conveyed by the communication.” Id. at. 13.

  2. FDA Guidance for Industry, Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities—Questions and Answers (June 2018). For more information on the CFL and Payor guidances, see Arnold & Porter AdvisoryFDA Finalizes Guidance Documents on Payor Communications and Communications Consistent with Labeling (June 2018).

  3. RWE Draft Guidance at 2.

  4. While FDA does not address the privacy regulations governing sponsor data collection in this area (particularly HIPAA considerations regarding the use of electronic health record system information), RWE study sponsors must carefully consider those regulations when developing a RWD collection program.

  5. A “registry” is “an organized system that collects clinical and other data in a standardized format for a population defined by” a particular disease or condition or by exposure to a particular drug or health service.” Registry Draft Guidance at 2.

  6. Id. at 3

  7. According to FDA, registries may have advantages over other RWD sources: registries collect structured and predetermined data, can offer longitudinal data about a defined patient population, and can systematically collect patient-reported data that medical claims datasets or electronic health record datasets may lack. It is important to note though, that registries also have limitations: existing registries may focus narrowly on one disease, enrolled populations may not be representative of the target population of interest, and there may be issues with data heterogeneity or variation in approaches used to address data quality. Id. at 4.

  8. Id. at 7.

  9. Id. at 8.

  10. Note that HHS-OIG has raised concerns with payments to healthcare providers or healthcare institutions associated with postmarketing registry studies, given evidence that such studies have, in the past, been used as sham arrangements to reward referral or use of the sponsor’s reimbursed products. These written agreements must, therefore, also account for compliance with the Anti-Kickback Statute.

  11. Note, FDA considers investigations that use human specimens, including leftover specimens that are de-identified, to be clinical investigations. See Final Rule, Human Subject Protection; Acceptance of Data From Clinical Investigations for Medical Devices, 82 Fed. Reg. 7366, 7372 (Feb. 21, 2018).

  12. FDA, Good Clinical Practice (GCP) Requirements for Data Submitted from Clinical Investigations for In Vitro Diagnostic (IVD) Device Premarket Submissions (current as of Sept. 27, 2021).

  13. The guidance also provides recommendations to help investigators identify safety information that is considered an unanticipated problem involving risk to human subjects or others (and that requires prompt reporting to IRBs per 21 CFR 312.66) (for drugs), and safety information that meets requirements for reporting unanticipated adverse device effects (UADEs) to sponsors and IRBs per 21 CFR 812.150(a)(1) (for devices).

  14. As conveyed during an FDA webinar in September 2021, “in an effort to highlight distinctiveness between sponsor and investigative responsibilities, the guidance for sponsors and investigators has been reorganized into two guidances that are now audience specific.”

  15. Investigator Responsibilities Draft Guidance at 7.

  16. Id. at 8.

  17. Unanticipated adverse device effect means “any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.” 21 CFR 812.3(s).

  18. Investigator Responsibilities Draft Guidance at 6.