Clinical Trial Diversity, Flexibility Championed by the Food and Drug Omnibus Reform Act

This article was originally published as a guest column in Clinical Leader.

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The FDA’s efforts culminated in a draft guidance released in April 2022 (contemplated in the 2014 Action Plan), which encourages the inclusion of diverse patient populations in research conducted to support marketing applications for medical products.4 The draft guidance, titled Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, describes when diversity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.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.


  1. Food and Drug Omnibus Reform Act, as included in the Consolidated Appropriations Act of 2023, Pub. Law 117- 328,
  2. Food and Drug Administration Safety and Innovation Act (FDASIA) § 907,
  3. Reporting of Inclusion of Demographic Subgroups in Clinical Trials and Data Analysis in Applications for Drugs, Biologics, and Devices, FDA-2013-N-0745,; Notice of Public Meeting, April 1, 2014, Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, August 2014,
  4. Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, Draft Guidance, April 2022, 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
  5. FDORA, supra note 1.
  6. 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,
  7. Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice; Public Hearing, March 7, 2012,
  8. 21st Century Cures Act §§ 3021, 3022, Pub. Law 114-255,
  9. PDUFA VI Commitment Letter, (see e.g., sections I.6 and J.4); PDUFA VII Commitment Letter, (see e.g., sections K.6 and L.4).
  10. See, FDA webpage listing clinical trials guidance documents,
  11. FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public Health Emergency, March 2020, updated Aug 2021,
  12. Guidance Documents Related to COVID-19, 88 Fed. Reg. 15417 (Mar. 13, 2023),
  13. Id.
  14. Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, May 2023,

The 8 Key Takeaways for FDA Inspections in the Food And Drug Omnibus Reform Act

This article was originally published as a guest column in Outsourced Pharma.

With President Biden’s signature, the Food and Drug Omnibus Reform Act of 2022 (FDORA), part of the larger Consolidated Appropriations Act of 2023 (Public Law 117-328), became law on Dec. 29, 2022. FDORA expands and modifies the inspection authority of the FDA in several key areas, including alternative tools to inspection, mutual recognition agreements, bioresearch monitoring, and unannounced foreign inspections.

1. Expanding the Availability of Alternative Tools to Inspection

FDORA expands FDA’s authority to make mandatory requests to industry for “records and other information” in advance, or in lieu, of an inspection. Section 704(a)(4) of the Food Drug and Cosmetic Act (FDCA) had previously limited use of this authority to drug establishments.1 Section 3611 of FDORA expands this authority to include device establishments and Section 3612 expands this authority further to bioresearch monitoring (BIMO) sites and facilities.

In guidance issued during the pandemic, FDA began to refer to section 704(a)(4) requests directed to drug establishments as a mandatory “remote regulatory assessment” (or RRA).2 Similar requests directed to non-drug establishments were categorized as voluntary RRAs, given the lack of a statutory basis to make a mandatory request. Despite this absence of specific statutory authority, CDER has made very robust use of voluntary RRAs seeking records and other information as part of its BIMO program.3 That practice should not only continue but increase, as responding to these requests will no longer be voluntary on the part of regulated industry.

Balanced against these expansions of agency authority under Section 704(a)(4), Section 3611 includes a new requirement that, whenever making a Section 704(a)(4) request, FDA must include a “rationale for requesting” the records and other information sought. In addition, by December 2023, the agency is required to issue guidance on the use of Section 704(a)(4) requests, including electronic processes for responding to such requests and the factors the FDA will use to determine whether requested records are provided within a reasonable timeframe and within reasonable limits, considering resource and other limitations, including for small businesses.

Arguably, FDORA’s most significant inspection related change is that Section 3613(b) now permits the FDA to rely on records and other information collected pursuant to Section 704(a)(4) “to satisfy requirements that may pertain to a preapproval or risk-based surveillance inspection, or to resolve deficiencies identified during such inspections, if applicable and appropriate.” This new authority is welcome news to those in industry advocating that FDA increase the use of inspection alternatives. How the agency utilizes this new permissive authority remains to be seen.

We predict this new provision will prove most useful in the area of risk-based surveillance, as Section 3613(b) removes the barrier that previously prevented FDA from relying on records and other information collected pursuant to Section 704(a)(4) to satisfy surveillance inspection requirements. The agency is required to inspect (“shall inspect”) drug establishments in accordance with a risk-based surveillance schedule pursuant to FDCA Section 510(h)(3). The agency has also interpreted the definition of inspection under FDCA Section 704(a)(1) to require a physical entry into the inspected establishment. Consequently, the agency’s view was that it could not satisfy surveillance inspection requirements in any manner short of a physical inspection. Given the nature of risk-based surveillance inspections and the backlog of such inspections resulting from the pandemic, we predict the agency will make great use of this new authority in the surveillance arena. 

While Section 3613(b) also applies to pre-approval inspections and warning letter follow-up inspections, there was never a legal requirement to rely on an inspection in either of those two contexts. In fact, the agency frequently determines it is not necessary to conduct a pre-approval inspection when considering a drug application and has also used “remote interactive evaluations” in lieu of pre-approval inspections during the pandemic.4 Regarding warning letter follow-up inspections, FDA has never taken the position that verification of post-warning letter corrections requires an inspection in all cases.5 The big question is whether the agency will amend its practice of steadfast reliance on re-inspections of drug establishments that have received warning letters. There may be some slight movement here, but the Section 3613(b) change is permissive only and FDA is very likely to maintain its strong preference for post-warning letter inspections based on historical post-warning letter inspection results. Historically, more than 50% of drug facilities have failed their post-warning letter re-inspections, despite having provided records and other information to the agency in advance of the inspection purporting to show that the firm had adequately remedied past violations at the facility and was ready to be re-inspected. 

2. Clarifying the Statutory Basis for Bioresearch Monitoring Inspections

In addition to extending Section 704(a)(4) to BIMO sites and facilities, FDORA Section 3612 establishes a specific statutory basis clarifying FDA’s authority to conduct BIMO inspections.6 Section 3612 provides a comprehensive framework describing the sites and facilities subject to BIMO inspections, the permitted purposes of such inspections, as well as the records and other information subject to inspection, including electronic information systems holding such information. In case you were wondering, this new statutory language also notes that it should not be inferred that FDA previously lacked the authority to conduct BIMO inspections. FDA is required to issue draft guidance describing the processes and practices applicable to BIMO sites and facilities by June 2024.

3. Recognition of Foreign Government Inspections

FDORA Section 3613(c) promotes further FDA use of mutual recognition agreements with foreign counterparts in two ways. It amends FDCA Section 809 to expressly permit FDA to include pre-approval inspections within the scope of foreign mutual recognition agreements. Section 3613(c) also adds a new provision to Section 809 requiring the agency to periodically assess whether additional mutual recognition agreements are appropriate and to report to Congress the results of those assessments every four years. The existing mutual recognition agreements with the EU and the U.K. are considered a great success in the agency. A new mutual recognition agreement was also just signed between the FDA and Switzerland on January 12. FDA is already routinely considering additional such agreements, but this new legislation should encourage further action in this area. Interestingly, the EU, U.K., and Swiss agreements already permit FDA to ask a treaty partner to conduct a pre-approval inspection.7 In the case of the agreement with the EU, FDA reports that implementation of the pre-approval inspection provision in the treaty has been held up by delays in developing a U.S.-EU joint work plan for pre-approval inspection capability assessments.8

4. Regional Compliance History Added as a Surveillance Inspection Criterion

In 2012, the Food and Drug Administration Safety Innovation Act (FDASIA) eliminated the requirement to inspect domestic drug facilities every two years and directed the FDA to remove any distinction between foreign and domestic facilities when determining surveillance inspection frequency. FDORA Section 3613(a) can be seen as a bit of backtracking on this point, as it directs the agency to now consider the compliance history of establishments in a particular country or region when determining the schedule for risk-based inspections of facilities located there. Some are also criticizing the provision for fear that it will work to the detriment of a facility with a good compliance history that happens to be in a country with a relatively poorer rate of compliance. However, we think these concerns are overblown, as decisions on surveillance inspection frequency are based on several factors, one of the most important of which is the compliance history of the specific facility being considered for inspection, which will surely be weighed more heavily by FDA than the overall compliance history of the region or country where the facility is located. Interestingly, one result of Section 3613 is that, everything else being equal between two facilities, a U.S. based facility may now be flagged by FDA for a surveillance inspection more frequently than a comparable European facility, as the data indicates that facilities in Europe have a lower overall level of Official Action Indicated (OAI) classifications than do those in the U.S.9  

5. GAO Directed to Prepare Report on Alternative Tools Used by FDA and Foreign Counterparts

FDORA Section 3614 directs the U.S. Government Accountability Office (GAO) to prepare a wide-ranging report on how the FDA and foreign counterparts use alternative tools to inspection, no later than June 2024.  Among other factors, the report must cover:

  • what alternative tools, including remote inspections/evaluations, other countries are using to facilitate inspections;
  • how frequently trusted foreign regulators conduct inspections that FDA could review in lieu of conducting its own inspections;
  • how frequently FDA is using mutual recognition agreements (MRA) and whether use of such agreements could be expanded;
  • whether FDA has accepted reports of inspection of facilities in China and India conducted by FDA’s MRA partners; and
  • what other countries has FDA considered and rejected for a possible MRA treaty. 

6. Expect More Unannounced Foreign Inspections

Foreign drug establishments should expect more unannounced FDA inspections due to FDORA Section 3615. Prior to the pandemic, FDA inspections of domestic drug establishments were almost always unannounced, while foreign establishments generally received advanced notice of their inspections. This disparity in treatment raised concerns, including within Congress and the GAO, that foreign facilities were being given the opportunity to fix problems before FDA investigators arrived. So much so, in a report accompanying FDA’s fiscal year 2021 appropriation, the House Appropriations Committee directed FDA to begin piloting the use of unannounced and short notice inspections in India and China and provided FDA funding to implement those pilots.10 In April 2022, FDA reported that unannounced foreign inspections had begun in India but had not yet begun in China due to local pandemic-related restrictions.

Section 3615 doubles down on direction to FDA in this area, requiring for the first time in statutory language that FDA conduct a pilot program to “increase[] the conduct of unannounced surveillance inspections of foreign human drug establishments[.]” Section 3615 further directs FDA to evaluate the observed differences between announced and unannounced inspections under the pilot, including the violations identified, costs, benefits, and any other significant differences, among other factors. Finally, FDA must produce a report on its findings and recommendations within 180 days after completion of the pilot. 

​​7. Previously Sunset Provisions to Prevent Shortages in Enforcement Cases are Revitalized

In 2012, FDASIA established new statutory requirements in the FDCA to help prevent drug shortages, including FDCA Sections 506(D)(b),(c), and (e) requiring, before FDA takes an enforcement action or issues a warning letter that could reasonably be anticipated to lead to a drug shortage: 1) advance coordination with CDER’s Drug Shortage Staff; and 2) an evaluation of the relative risks associated with the violations at issue and the likely patient impact resulting from the anticipated shortage. Pursuant to FDASIA’s original sunset provision, however, these coordination requirements ceased to be effective in July 2017. FDORA Section 3616 reestablishes and makes permanent those coordination requirements. It is worth noting that coordination efforts on drug shortages have remained strong within FDA since July 2017, despite these provisions having sunset. Nevertheless, permanently building these coordination requirements into the statute is a welcome development. In addition, Section 3616 inserts a new provision, FDCA Section 506D(g), directing FDA to ensure timely and effective coordination between ORA, CDER Compliance, and CDER’s Drug Shortage Staff concerning the review of inspection reports and follow-up actions taken in response to those reports, concerning inspections of facilities that raise potential drug shortage implications. 

8. Annual Report on Inspections

FDORA Section 3617 amends the requirements, first established in 2017 by Section 902 of the FDA Reauthorization Act (FDARA) (Public Law 115-52), for the FDA’s annual report on human drug and device inspections. Previously, the required report focused exclusively on inspections of facilities necessary to approve a drug or device, including: 1) the time it took to begin a requested facility inspection, as well as the timing for compliance actions following completion of the inspection (e.g., warning letters); and 2) the number of application approvals delayed or withheld because of these inspections. The Section 3617 amendments include a requirement to track the same information for drugs on the FDA shortage list as well as to convert the report from an annual to a fiscal year basis.


  1. FDCA Section 704(a)4) was previously limited to requests directed to “a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug[.]”
  2. See Conducting Remote Regulatory Assessments, Questions and Answers, Draft Guidance for Industry, July 2022,
  3. In fiscal year 2021, CDER conducted 133 BIMO RRAs. See FDA Bioresearch Monitoring (BIMO) Fiscal Year 2021 Metrics,
  4. See Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency, Guidance for Industry, April 2021. During the pandemic, CDER conducted remote interactive evaluations using livestreamed video of operations as well as remote, live interactions with facility personnel to assess manufacturing facilities named in marketing applications,
  5. See Regulatory Procedures Manual, Section 4-1-8 (“Usually, the standard for verifying that corrections have been implemented will be a follow-up inspection.”) (emphasis added),
  6. FDORA Section 3612 adds new Section 704(a)(5) to the FDCA concerning the authority to conduct BIMO inspections.
  7. See e.g., United States – European Union Amended Sectoral Annex For Pharmaceutical Good Manufacturing Practices (GMPs), Article 11,
  8. See Frequently Asked Questions – [U.S./EU] Mutual Recognition Agreement, Question 13,
  9. As of May 2020, only two percent of EU based drug manufacturing facilities were classified as OAI as compared to seven percent of U.S. based facilities. See FDA Testimony before the U.S. Senate Committee on Finance (Judith McMeekin), June 1, 2020, Figure 6,
  10. See House Committee on Appropriations Report 116-446, Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Bill FY21, p. 86,
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