Seven Opportunities for Stakeholder Engagement on FDA Draft Guidance Proposing Updates to Good Clinical Practice Guidelines

On June 6, 2023, the U.S. Food and Drug Administration (FDA) issued a draft guidance entitled E6(R3) Good Clinical Practice (GCP) (hereinafter, “Draft Guidance”), the International Council for Harmonization’s (ICH’s) updated E6(R3) draft guideline.[1] This Draft Guidance builds on and serves as an update to the current E6(R2) version of the guideline (hereinafter, “R2”).[2]

At a high level, the Draft Guidance adds various recommendations to support the modernization of clinical trials, including detailed guidance on the use of electronic systems and data collection, areas on which FDA has issued other draft guidances over recent months.[3]  Additionally, the Draft Guidance emphasizes the use of risk-based and proportionate approaches across the lifecycle of a clinical trial, and encourages sponsors to be proactive when it comes to a trial’s quality considerations. 

Comments on the Draft Guidance must be submitted to FDA by September 5, 2023. To assist those who may be developing comments, this client alert highlights seven noteworthy areas for stakeholder engagement. In developing this list, we have placed particular emphasis on important differences between R2 and the Draft Guidance. 

1. Expanded sponsor responsibilities, particularly as to data and records. The Draft Guidance specifically recommends that sponsors ensure not just the integrity, but also the confidentiality of the data generated and managed during a clinical trial. This standard arguably is part of R2, given that protecting confidentiality of records that could identify participants is a principle of R2, and informed consent under R2 includes providing an explanation that records identifying the participant will be kept confidential.[4]  But the Draft Guidance goes a step further to explicitly incorporate this recommendation as a sponsor responsibility.

   
   Engagement Opportunity: Stakeholders could provide feedback as to whether the sponsor responsibilities enumerated in the Draft Guidance are consistent with existing expectations. Stakeholders could also consider asking FDA to clarify whether the inclusion of a specific sponsor obligation to protect confidentiality reflects a new obligation under the Draft Guidance, or a mere restatement of principles already articulated in R2.
   

2. Recommendations as to sponsor use of agreements. The Draft Guidance includes a new sponsor-specific section titled “Agreements” which gathers in one place and builds on recommendations for documenting agreements between sponsors and relevant stakeholders in R2. The Draft Guidance notes that a clinical trial may have one or several sponsors, and recommends that an agreement (or agreements) setting out respective responsibilities among the sponsors be executed. Where such agreements do not attribute a given responsibility to a specific sponsor(s), the Draft Guidance states that the responsibility lies with all sponsors.

   
   Engagement Opportunity: Stakeholders could consider providing feedback as to the Draft Guidance’s recognition of the option to have multiple sponsors for a single clinical trial. Stakeholders might also comment on the statement that any obligation not clearly delegated remains the responsibility of all sponsors in this context.

3. Clarifications as to sponsor/investigator responsibilities. The Draft Guidance adds some noteworthy clarifications regarding investigator delegation of responsibilities, including changes intended to address increasingly “blurred lines” between investigator and sponsor roles.[5]  For example, the Draft Guidance provides that “[t]he investigator may be supported by the sponsor to identify a suitable service provider(s) [e.g., home nurses arranged by the sponsor],” but the investigator: (1) “retains the final decision on whether the service provider intended to support the investigator is appropriate,” and (2) “retains the ultimate responsibility and maintains appropriate supervision of the persons or parties undertaking [delegated activities].” It is unclear whether the Draft Guidance’s position is fully consistent with the approach described in FDA’s Decentralized Clinical Trials (“DCT”) Draft Guidance. The DCT Draft Guidance discusses the investigator’s responsibility for conduct of a clinical trial and oversight of individuals (such as local HCPs) delegated to perform trial-related activities but also explains that sponsors should ensure proper coordination of decentralized activities such as mobile nurses for at home visits, and use of local HCPs.

   Engagement Opportunity: Stakeholders could consider engaging as to whether the approach described in the Draft Guidance is fully consistent with the approach described in FDA’s DCT Draft Guidance. Further, stakeholders could consider commenting on the potential implications of allowing investigators to retain final decision-making authority as to service providers identified by the sponsor, particularly for decentralized activities.

4. Additional informed consent considerations. The Draft Guidance provides that the informed consent discussion and materials should include, among other things: (1) reasonably foreseeable risks or inconveniences to the participant’s partner, if applicable; and (2) that the trial results and information on the participant’s actual treatment, if appropriate, will be made available to them if desired. The first element is not currently one of FDA’s informed consent requirements under 21 CFR § 50.25, nor is it part of the Common Rule’s requirements in 45 CFR § 46.116. Additionally, the first element was not part of FDA’s proposed rule to amend its informed consent regulations, issued in September 2022 as part of FDA’s effort to harmonize its informed consent requirements with those in the Common Rule, nor in recently finalized guidance from FDA for IRBs, investigators, and sponsors on informed consent. As to the second element, it also is not currently in FDA’s informed consent regulations. And although there is a similar requirement in the Common Rule, which also was included in FDA’s September 2022 proposed rule, the Draft Guidance’s recommendation may go beyond what is required under 45 CFR § 46.116(c)(8): “A statement regarding whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions.” FDA’s recently finalized guidance on informed consent supports the return of aggregate research results to participants at the completion of a trial, including by posting summary results to www.ClinicalTrials.gov.

   Engagement Opportunity: Stakeholders could consider providing feedback on new elements of informed consent set forth in the Draft Guidance that differ from FDA’s regulations under 21 CFR § 50.25, the Common Rule requirements under 45 CFR § 46.116, FDA’s past proposals to harmonize its informed consent requirements with those in the Common Rule, or FDA’s recently finalized guidance on informed consent.

5. Investigator and sponsor responsibilities regarding data governance. The Draft Guidance introduces a new section on data governance that provides guidance to investigators and sponsors regarding their responsibilities for “appropriate management of data integrity, traceability and security, thereby allowing the accurate reporting, verification and interpretation of the clinical trial-related information.”[6]  The new section recommends that key processes address the full data life cycle, including processes to ensure data protection of trial participants’ confidential data; processes for managing computerized systems to ensure that they are fit for purpose and used appropriately; processes to safeguard essential elements of the clinical trial, such as randomization, dose escalation, and blinding; and processes to support key decision making (e.g., data finalization prior to analysis; unblinding; changes in clinical trial design).
   
   The Draft Guidance states that sponsors should have procedures in place to cover: (1) data capture; (2) relevant metadata, including audit trails;[7]  (3) review of data and metadata; (4) data corrections; (5) data transfer, exchange, and migration; and (6) finalization of data sets prior to analysis. Systems and processes “should be designed and implemented in a way that is proportionate to the risks to participants and the reliability of trial results.”

   Engagement Opportunity: Stakeholders could consider commenting on the range of data governance procedures that the Draft Guidance recommends be in place. Stakeholders could also consider whether there are any gaps in the guidance, particularly given that data governance may frequently involve collecting, using, and sharing data across jurisdictions.

6. New recommendations for end of participation in a clinical trial. The Draft Guidance provides new recommendations for when a participant ends participation in a clinical trial. For example, R2 provides that in cases of early subject withdrawal, the investigator should make a reasonable effort to ascertain why a participant ended their participation. The Draft Guidance appears to go beyond this, however, by additionally recommending that investigators take steps intended to minimize withdrawals. Specifically, the investigator should consider discussing the participant’s “reasons for withdrawal to determine if there are ways to address the concerns,” and “should make an effort to explain to the participant the value and importance of continuing their participation to minimize trial participants withdrawal.

   Engagement Opportunity: Stakeholders could consider whether FDA should provide additional guidance on steps to minimize withdrawals that investigators can take, and how investigators can take these steps without upsetting the voluntary nature of subject participation in clinical trials.

7. Facilitating DCTs. The Draft Guidance provides a number of opportunities to facilitate DCTs. For example, the Draft Guidance makes clear that, where appropriate, sponsors can supply trial participants—not just investigators/institutions—with the investigational product once the necessary IRB/IEC approvals have been obtained. This revised approach from R2 aligns with recent draft guidance from FDA on direct shipment of the investigational product to the participant as part of a DCT.[8] The Draft Guidance also provides greater flexibility in approaches and use of digital technology in obtaining informed consent.

   Engagement Opportunity: Stakeholders could consider whether there are common DCT issues that would warrant additional guidance.

If you have any questions concerning the material discussed in this client alert, please contact members of our Food, Drugs, and Devices practice.

[1] The Members of the ICH Assembly endorsed E6(R3) on May 19, 2023 and released it for public comment. Before finalizing the ICH guideline, the ICH Efficacy Expert Working Group will consider any feedback received by FDA on this Draft Guidance, as well as feedback from other ICH member countries.

[2] FDA, E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (2018). The ICH adopted E6(R2) in November 2016.

[3] E.g., FDA, Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance (May 2023) (“DCT Draft Guidance”) (Covington alert); FDA, Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers (2023) (Covington alert).

[4] This same informed consent element is in the Draft Guidance. Both R2 and the Draft Guidance, therefore, appear to go beyond what is required of investigators under FDA’s informed consent regulations in 21 CFR § 50.25(a)(5), which require “[a] statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained . . . .”

[5] ICH, Explanatory Video – ICH E6(R3) Guideline – Good Clinical Practice.

[6] In R2, the discussion of data governance is relatively limited and scattered across various sections. See, e.g., R2 Section 4.9 (addressing the investigator’s responsibility for records and reports); id. Section 5.5 (addressing the sponsor’s obligations for trial management, data handling, and recordkeeping).

[7] The Draft Guidance recommends that systems capture various types of metadata and that audit trials are not disabled or modified.

[8] FDA, DCT Draft Guidance, supra n.3.