By Kalah Auchincloss, JD, MPH, and Donald D. Ashley, JD, Greenleaf Health
The Food and Drug Omnibus Reform Act (FDORA),1 signed into law by President Biden on Dec. 29, 2022, which we initially wrote about in February with regard to inspections, also includes numerous provisions intended to modernize clinical trials. These provisions enact and expand upon FDA initiatives over the last decade and could go a long way toward advancing clinical research. The provisions are broadly divided into two categories: (1) encouraging the enrollment of more diverse patient populations in clinical studies; and (2) facilitating novel clinical trial designs and methods for conducting clinical trials, in part by continuing certain flexibilities initiated during the COVID-19 public health emergency.
Clinical Trial Diversity
The diversity (or lack thereof) of patients enrolled in clinical trials has long been a topic of consideration and concern for those in the public health field. There is evidence that minorities, women, the elderly, children, and other demographic subgroups are underrepresented in clinical research, leading to gaps in understanding the safety and efficacy of certain drugs used in those populations.
In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) recognized this gap and required the FDA to report on and create an Action Plan to improve the analysis of demographic subgroup data in clinical trials, expand the inclusion of such data in labeling, and make such data more available and transparent to the public.2 In the decade following FDASIA, the FDA took numerous steps to implement this FDASIA provision, including issuing the required report in August 2013, followed by the Action Plan in 2014, and convening a public meeting in between.3
The FDA’s efforts culminated in a draft guidance released in April 2022 (contemplated in the 2014 Action Plan), which encourages the inclusion of diverse patient populations in research conducted to support marketing applications for medical products.4 The draft guidance, titled Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, describes when diversity action plans are recommended, the timing for submission of such plans, and the suggested content.
FDORA sections 3601-3604 further promote clinical trial diversity by enacting into law a requirement for diversity action plans as well as requiring additional public communications and information gathering to facilitate diversity in clinical trials, as described below.5
§ 3601. Diversity action plans for clinical studies
- Amends the FD&C Act to require a “diversity action plan” for all Phase 3 or other pivotal studies (excluding bioequivalence and bioavailability studies) for drugs and biological products and for many medical devices
- The diversity action plan must include the sponsor’s goals for enrollment in the clinical study, the rationale for such goals, and an explanation of how it intends to meet the goals. The plan must be submitted with the clinical study protocol
- The FDA may waive the requirement for a diversity action plan in certain circumstances, including “based on what is known or what can be determined about the prevalence or incidence of the disease or condition for which the new drug is under investigation” or if conducting the study in accordance with a diversity action plan “would otherwise be impracticable” or is against the interests of public health during a public health emergency
- Applies to clinical trials for which enrollment begins 180 days after publication of the final guidance described in § 3602. See § 3602(c).
§ 3602. Guidance on diversity action plans for clinical studies
- Requires the FDA to issue or update guidance (e.g., the April 2022 draft guidance) on the requirement for clinical trial diversity action plans, including on their format and content, modifications to such plans, public posting by a sponsor of key information from a diversity action plan that would be useful to patients and providers, criteria the FDA will use when determining whether to grant a waiver for the requirement to follow a diversity action plan, and regular reporting to the FDA on the sponsor’s progress in achieving the goals described in the diversity action plan.
- Draft guidance is due 12 months after enactment of FDORA (by Dec. 29, 2023); final guidance must be published within nine months of the close of the comment period of the draft guidance.
§ 3603. Public workshops to enhance clinical study diversity
- Requires the FDA, in consultation with drug and medical device sponsors, clinical research organizations, academia, patients, and other stakeholders, to convene one or more public workshops to solicit input from stakeholders on “increasing the enrollment of historically underrepresented populations in clinical studies and encouraging clinical study participation that reflects the prevalence of the disease or condition among demographic subgroups[.]”
- The FDA must establish a public docket in association with the meeting and must publish a report on the topics discussed at the meeting(s) within 180 days after the public comment period closes.
§ 3604. Annual summary report on progress to increase diversity in clinical studies
- Requires the FDA to publish an annual report beginning two years after enactment of FDORA (Dec. 29, 2024) summarizing, in aggregate, diversity action plans received by the FDA, whether the clinical studies conducted under diversity action plans met the enrollment goals in the action plans, and if not, the reasons provided for why not.
Clinical Trial Flexibilities
Similar to efforts surrounding clinical trial diversity, the FDA and other stakeholders have been considering novel clinical trial designs for at least a decade, including whether the FDA’s regulatory framework must be modified to accommodate the oversight of such trials and allow evidence generated from those studies to satisfy the “substantial evidence” statutory standard.6
The FDA held a public hearing to solicit input on a broad effort to “encourag[e] the use of innovative models that may enhance the effectiveness and efficiency of the clinical trial enterprise”7 in 2012 and was subsequently granted new authorities related to novel clinical trial design and real-world evidence (RWE)/real-world data (RWD) in the 21st Century Cures Act of 2016.8 These efforts continued in PDUFA VI (FY18–FY22) and PDUFA VII (FY23–FY27), both of which include commitments related to RWE/RWD and to advancing the FDA’s capacity to review complex innovative trial designs, including Bayesian and adaptive protocols.9 As a result, the FDA has issued several guidance documents reflecting updated thinking on clinical trial design, trial conduct and compliance with good clinical practice (GCP), and the collection and analysis of data.10
A number of these initiatives were further advanced during the COVID-19 pandemic through flexibilities the FDA exercised to protect the safety of patients and investigators and to ensure adherence to GCP, while also minimizing disruptions to clinical research. The efforts are described in a guidance the FDA issued early in the pandemic that allowed for certain accommodations in the conduct of clinical trials.11 For example, the guidance described when it could be appropriate to conduct remote clinical visits for study participants, remotely monitor clinical sites, and ship investigational product to local providers for administration. The flexibilities outlined in the guidance were intended to address challenges associated with quarantines, travel restrictions, supply chain interruptions, and other disruptions associated with COVID-19.
With the termination of the public health emergency on May 11, 2023, many of the FDA’s guidances issued during the pandemic will sunset.12 Notably, the FDA has indicated that the guidance on the conduct of clinical trials will remain in effect for 180 days after the end of the PHE as a transitional period.13 This dovetails with a provision in FDORA that requires the FDA to hold a public meeting to better understand the effectiveness of the clinical trial flexibilities the FDA exercised during the pandemic. Two other sections of FDORA related to decentralized clinical trials, novel clinical trial designs and digital health technology in clinical trials, continue the progress on clinical trial modernization. Below, we describe these three provisions of FDORA in more detail.
§ 3605. Public meeting on clinical study flexibilities initiated in response to COVID-19 pandemic
- Within 180 days from the end of the public health emergency (by Nov. 7, 2023), the FDA must hold a public meeting to discuss FDA recommendations during COVID-19 to mitigate disruption of clinical studies, including as described in the guidance.
- The FDA must issue a report summarizing the discussion at the public meeting. Topics to be included for discussion at the meeting include, but are not limited to:
- the frequency with which sponsors availed themselves of the flexibilities in the guidance;
- characteristics of the sponsors, studies, and patient populations impacted by such recommendations;
- impact of those flexibilities on patient access to clinical studies, especially underrepresented patient populations; and
- recommendations for incorporating these flexibilities into new guidance to improve clinical study enrollment and diversity.
§ 3606. Decentralized clinical studies
- Within one year after enactment of FDORA (by Dec. 29, 2023), the FDA must issue or update draft guidance to advance the use of decentralized clinical trials. The guidance must address numerous aspects of decentralized trials, including recommendations related to:
- collecting data remotely, considering the security and privacy of such options (e.g., digital health technology, telehealth, local providers and labs, and patient experience data);
- minimizing or reducing burdens on subject enrollment and participation (e.g., digital health technology, telehealth, local providers/labs, home visits, direct engagement with study participants, direct shipping of investigational drug to the study participants, electronic informed consent, and partnerships with community organizations);
- evaluating the protocol design of decentralized trials and data collected in decentralized trials, including whether evaluations will be different than for non-decentralized trials;
- using decentralized clinical trials to maximize participant diversity;
- validating digital technologies and establishing appropriate clinical endpoints for use in decentralized trials;
- combining centralized and decentralized clinical trial approaches; and
- oversight of decentralized clinical trial sites, including remote oversight.
§ 3607. Modernizing clinical trials
- Within one year after enactment of FDORA (by Dec. 29, 2023), the FDA must issue or update draft guidance regarding appropriate use of digital health technologies in clinical trials to improve diversity in recruiting and retention of participants and to facilitate novel clinical trial designs; final guidance must be published within 18 months after the close of comment period on the draft guidance.
- Within one year after enactment of FDORA (by Dec. 29, 2023), the FDA must issue or update draft guidance on the use of “seamless, concurrent, and other innovative clinical trial designs” to support development and review of new drugs; final guidance must be published 18 months after the close of comment period on the draft guidance.
- Directs the FDA to work with foreign regulators to facilitate international harmonization of the regulation and use of decentralized trials, digital health technology, and seamless, concurrent, and other adaptive or innovative clinical trial designs.
The FDA has already begun to implement the FDORA clinical trials provisions with the issuance of the required guidance on decentralized clinical trials in early May, described in more detail in a separate article.14 Given the short timeframes, we expect the other guidances (diversity action plans, digital health technology, modernizing clinical trials) to be forthcoming shortly and for the FDA to implement the remaining provisions, such as public meetings and reports, in a timely manner. The FDORA guidances are likely to build on the agency’s efforts over the last 10 years, including the already existing guidances discussed in this article. You would be well served to familiarize yourself with the current draft guidances and FDA reports and activities to prepare for the future.
- Food and Drug Omnibus Reform Act, as included in the Consolidated Appropriations Act of 2023, Pub. Law 117-328, https://www.congress.gov/117/bills/hr2617/BILLS-117hr2617enr.pdf.
- Food and Drug Administration Safety and Innovation Act (FDASIA) § 907, https://www.congress.gov/112/plaws/publ144/PLAW-112publ144.pdf
- Reporting of Inclusion of Demographic Subgroups in Clinical Trials and Data Analysis in Applications for Drugs, Biologics, and Devices, FDA-2013-N-0745, https://www.federalregister.gov/documents/2013/08/22/2013-20352/request-for-comments-on-the-food-and-drug-administration-safety-and-innovation-act-section-907; Notice of Public Meeting, April 1, 2014, https://www.govinfo.gov/content/pkg/FR-2014-03-04/html/2014-04625.htm; FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, August 2014, www.fda.gov/media/89307/download
- Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, Draft Guidance, April 2022, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-plans-improve-enrollment-participants-underrepresented-racial-and-ethnic-populations. FDA also issued a guidance in November 2020 on diversity, titled Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs, https://www.fda.gov/media/127712/download.
- FDORA, supra note 1.
- The FD&C Act (section 505(d)) requires a sponsor to demonstrate with “substantial evidence” that a drug is safe and effective, and defines substantial evidence as “evidence consisting of adequate and well-controlled investigations, including clinical investigations[.]” FDA has traditionally required two randomized, controlled clinical trials as substantial evidence, but has recently expanded its view of what may meet the statutory standard. See e.g., Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products, Draft Guidance, Dec. 2019, https://www.fda.gov/media/133660/download.
- Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice; Public Hearing, March 7, 2012, https://www.govinfo.gov/content/pkg/FR-2012-03-07/pdf/2012-5476.pdf
- 21st Century Cures Act §§ 3021, 3022, Pub. Law 114-255, https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf.
- PDUFA VI Commitment Letter, https://www.fda.gov/media/99140/download (see e.g., sections I.6 and J.4); PDUFA VII Commitment Letter, https://www.fda.gov/media/151712/download (see e.g., sections K.6 and L.4).
- See, FDA webpage listing clinical trials guidance documents, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trials-guidance-documents.
- FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public Health Emergency, March 2020, updated Aug 2021, https://www.fda.gov/media/136238/download.
- Guidance Documents Related to COVID-19, 88 Fed. Reg. 15417 (Mar. 13, 2023), https://www.federalregister.gov/documents/2023/03/13/2023-05094/guidance-documents-related-to-coronavirus-disease-2019-covid-19
- Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, May 2023, https://www.fda.gov/media/167696/download.
About The Authors:
Donald D. Ashley, executive vice president of regulatory compliance at Greenleaf Health, is an expert in compliance and enforcement matters with 25 years’ experience with the FDA and the Department of Justice (DOJ), including six years as director of CDER’s Office of Compliance. Before joining the FDA, he spent nearly two decades at DOJ in both the Civil and Criminal Divisions prosecuting violations of the Food, Drug, and Cosmetic Act and other criminal statutes as well as managing investigations on the national and international level. Ashley earned his J.D. from Harvard Law School and an A.B. from John Carroll University.
Kalah Auchincloss, J.D., M.P.H., is executive vice president of regulatory compliance and deputy general counsel for Greenleaf Health. She has more than 15 years of food and drug legal, policy, and regulatory experience at the FDA, on Capitol Hill, and in the private sector. At Greenleaf, Auchincloss advises pharmaceutical and medical device companies on compliance, policy, and other regulatory issues. Before moving to Greenleaf, Auchincloss spent six years at the FDA in the Commissioner’s Office and in CDER’s Office of Compliance and Office of Regulatory Policy. She earned her J.D. from Georgetown University, her M.P.H. from Harvard University, and her B.A. from Williams College.