Note: This is Part 2 in a series of blog posts on developments from the U.S. Food and Drug Administration (“FDA”) regarding its commitments set forth under the Prescription Drug Under Fee Act Reauthorization Performance Goals and Clinical Trial Diversity and Modernization mandates established by Congress under the Food and Drug Omnibus Reform Act of 2022 (FDORA), including developments on the intersection and use of digital health technology in clinical trials and clinical trial diversity. Part 1, covering the Digital Health Technologies framework is available here.
The Food and Drug Administration (FDA) has released draft guidance intended to help modernize the design and conduct of clinical trials by making them more efficient and enabling them to incorporate the newest technological and methodological advancements into their design.
FDA continues to issue guidance in the wake of the Food and Drug Omnibus Reform Act of 2022 (FDORA), which in part requires FDA to provide further oversight and guidance on “Clinical Trial Diversity and Modernization.” Under Section 3607(c) of FDORA, consistent with its obligations modernize clinical trials, FDA is specifically required to “work with foreign regulators pursuant to memoranda of understanding or other arrangements governing the exchange of information to facilitate international harmonization of the regulation” as it pertains to innovative approaches to clinical trial design and implementation.
The new draft guidance, released on June 6, is adopted from the E6(R3) draft guideline for good clinical practice (GCP) recently issued International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). That ICH guideline was released for consultation in May 2023 and is intended to provide a unified standard for the conduct of trials such that the trial data would be acceptable for all ICH member countries.
Note that ICH is a consensus-driven process that involves technical experts from regulatory authorities throughout the globe and industry parties in detailed technical and science-based harmonization work that results in the development of ICH guidelines. As a founding member of ICH, FDA plays a major role in the development of each of the ICH guidelines, which FDA and other regulatory authorities in ICH member countries through the globe commit to adopt and issue as guidance to industry. In this case, the new FDA draft guidance, once finalized, would update the existing guidance adopted by FDA in 2018 titled, E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (March 2018).
The new FDA draft guidance, E6(R3), follows upon guidance issued last month that governed decentralized clinical trials and the DHT Framework FDA released to help guide the use of DHT-derived data from drug and biologics clinical development programs.
Notable Updates to Sponsors, Investigators and Institutional Review Board Obligations
The draft guidance notably emphasizes flexibility in trial methodology for use of innovative design elements and fit-for-purpose digital health technologies. Innovation can also encourage inclusion of diverse patient populations, while also engaging various stakeholders to ensure there is both quality in the data and trial outcomes.
“These draft recommendations were developed with the aim to streamline trials, making them more efficient and flexible as the trial enterprise continues to evolve,” said M. Khair ElZarrad, director of the FDA’s Center for Drug Evaluation and Research’s Office of Medical Policy, in a press release. “We hope these recommendations, once finalized, will encourage thoughtful approaches to conducting clinical trials with a focus on participant safety and data integrity.”
At baseline, the core of GCP is to establish a set of principles and standards whereby clinical trial participants are adequately protected, clinical trials are conducted ethically, the professionals conducting clinical trials are qualified and appropriately trained, and that quality is the focus throughout clinical design and operation. Sponsors, investigators and Institutional Review Boards (IRBs) all carry significant responsibility for compliance with GCP within their respective roles, each of which are carefully detailed in the draft guidance.
Sponsors are ultimately responsible for a clinical trial, nevertheless, the draft guidance focusses on directing trial investigators on the use of a risk-based and proportionate approach across the lifecycle of the trial relative to processes most important to data integrity and participant safety. Investigators’ responsibilities under GCP become increasingly imperative where, for example, local health care professionals are engaged to provide support in a decentralized clinical trial (DCT). In the recent DCT draft guidance, FDA finds investigator use of local health care professionals to conduct procedures that are considered routine clinical practice to be acceptable but cautions that there could be some variability in the data as a result. As such, maintenance of accurate and reliable records are paramount in the investigator’s role in a clinical trial.
IRBs continue to play an essential role in the ethical oversight of clinical trials and the treatment of clinical trial participants. There are significant updates in this draft guidance, however, that are worth noting as it pertains to the IRBs role and scope. The IRB is given leeway in determining the extent to which patient remuneration is coercive or presents an undue influence. Travel and lodging are not considered to be “typically coercive.” Parameters around IRB membership are consistent with prior guidance, although non-IRB members can be invited to provide subject matter expertise or specific information about at trial, if needed. More explicit references to minors are also present, particularly for IRB assurance that the necessary assent documentation is consistent with local regulatory requirements in addition to appropriateness for “the age, maturity and psychological state of the minor.”
Impacts on Data Integrity and Data Quality in GCP
A key takeaway from this draft guidance is an increased focus on data integrity and data quality related to GCP compliance in clinical trials. In the past several years, we have seen more FDA enforcement on data integrity issues in good manufacturing practice noncompliance. With the rapid introduction of clinical trial modernization strategies and technologies, however, GCP compliance in clinical trials will need to be carefully managed with proper oversight and operationalization.
The draft guidance encourages sponsors to be more proactive when it comes to building quality into the “scientific and operational design and conduct of clinical trials.” Sponsors are encouraged to identify factors critical to the trial and to take steps to account for these factors throughout the life-cycle of a trial. Critical factors are those trial attributes that are “fundamental to the protection of participants, the reliability and interpretability of the trial results and the decisions based on those trial results.” Once identified, a sponsor can then implement clinical trial processes and risk mitigation strategies to support the conduct of the trial in a way that is proportionate to the importance of the data being collected and the risks to trial participant safety and data reliability.
Sponsor and investigator oversight of GCP compliance will likely be scrutinized by FDA as it pertains to inspections (pre-approval and for cause) and the review of marketing applications. There must be appropriate planning of clinical trial design and other specific operational aspects of clinical trials, for example, data and statistical management, monitoring, third-party vendor management, risk and quality management, personnel qualification and training, and cybersecurity (especially to the extent digital health technologies are used for data collection or consent platforms). To ensure such planning is feasible and cohesive institutional operationalization, whether at the sponsor or investigator sites, will be important. Operationalization strategies and planning may include establishing compliance policies, programming, and template plans for different clinical trials to adequately incorporate GCP principles across clinical trials.
The FDA draft guidance will be available for public comment until August 4. Reed Smith will continue to follow these and other developments regarding any impacts on best practices for enhancing GCP in light of this draft guidance an FDA’s ongoing clinical trial modernization efforts. If you have questions on this topic, please reach out to the health care lawyers at Reed Smith LLP.