The Consolidated Appropriations Act, 2023, Pub. L. No. 117-328, which was signed into law at the end of 2022, includes a number of provisions seeking to improve clinical trial diversity, modernization and inspection.

The law clarifies the FDA’s authority to conduct inspections of clinical sites, sponsors, contractors hired by sponsors, and institutional review boards. The law notes that it "shall not be construed as a basis for inferring that, prior to the date of enactment [the FDA] lacked the authority to conduct such inspections.”

The law also directs the FDA to review the processes and practices in effect applicable to inspections of foreign and domestic sites and facilities and evaluate whether any updates are needed to aid the consistency of the processes and practices. The agency also is directed to issue guidance describing the processes and practices applicable to inspections of sites and facilities, including with respect to the types of records and information required to be provided, best practices for communication between the FDA and industry in advance of or during an inspection or request for records or other information, and other inspections-related conduct. Draft guidance is expected in 18 months with final guidance coming not later than one year after the close of public comment on the draft guidance.

The bill also requires sponsors of Phase 3 and “other pivotal” drug or device trials to submit a diversity action plan to the FDA. Last April, the FDA issued draft guidance recommending sponsors provide the agency with a race and ethnicity diversity plan early in clinical development.

The diversity action plan must include the sponsor’s:

• goals for enrollment in the clinical study;
• rationale for those goals; and
• explanation of how the sponsor intends to meet the goals.

The law said the plan must be submitted “as soon as practicable but not later than the date on which the sponsor submits the protocol” for a Phase 3 or other pivotal trial study of the drug. The law permits sponsors to submit plan modifications “in the form and manner specified by guidance.”

In addition, the FDA may waive any of the requirements if it “determines that a waiver is necessary 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 (including in terms of the patient population), if conducting a clinical investigation in accordance with a diversity action plan would otherwise be impracticable, or if such waiver is necessary to protect public health during a public health emergency.” The agency must issue a written response granting or denying a request for a waiver within 60 days of receiving the request.

Diversity Action Plan Guidance Mandated

The FDA also was directed to update or issue guidance relating to the format and content of the diversity action plans pertaining to the sponsor’s goals for clinical study enrollment, disaggregated by age group, sex, and racial and ethnic demographic characteristics of clinically relevant study populations, and may include characteristics such as geographic location and socioeconomic status, including with respect to the rationale for the sponsor’s enrollment goals, which may include:

• the estimated prevalence or incidence in the United States of the disease or condition for which the drug or device is being investigated in the relevant clinical trial, if such estimated prevalence or incidence is known or can be determined based on available data;
• what is known about the disease or condition for which the drug or device is being investigated;
• any relevant pharmacokinetic or pharmacogenomic data;
• what is known about the patient population for such disease or condition, including, to the extent data is available demographic information, which may include age group, sex, race, geographic location, socioeconomic status and ethnicity;
• non-demographic factors, including co-morbidities affecting the patient population;
• potential barriers to enrolling diverse participants, such as patient population size, geographic location and socioeconomic status;
• any other data or information relevant to selecting appropriate enrollment goals, disaggregated by demographic sub-group, such as the inclusion of pregnant and lactating women; and
• an explanation for how the sponsor intends to meet the goals, including demographic specific outreach and enrollment strategies, study-site selection, clinical study inclusion and exclusion practices and any diversity training for study personnel.

The guidance also would discuss submission of modifications to the plan; considerations for the public posting by a sponsor of key information from the diversity action plan that would be useful to patients and providers on the sponsor’s website, as appropriate; the criteria that the agency will consider in assessing whether to grant a sponsor’s request to waive the requirement; and how sponsors may include in regular reports as required the sponsor’s progress in meeting the goals, plan updates, and ‒ if the sponsor does not expect to meet the goals ‒ the sponsor’s reasons for not meeting the goals.

The new draft guidance is expected in a year and the final guidance is expected nine months after the draft guidance comment period ends.

The requirement to submit a diversity action plan will apply only to clinical investigations for which enrollment commences 180 days after the publication of the final guidance.

Workshop on Increasing Trial Participation Set

In addition, within a year the agency, in consultation with drug sponsors, medical device sponsors, clinical research organizations, academia, patients, and other stakeholders, will convene one or more public workshops to solicit comment 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, where appropriate, and other topics, including:

• how and when to collect and present the prevalence or incidence data on a disease or condition by demographic subgroup, including possible sources for such data and methodologies for assessing the data;
• considerations for the dissemination, as appropriate, after approval, of information to the public on clinical study enrollment demographic data;
• the establishment of goals for enrollment in clinical trials, including the relevance of the estimated prevalence or incidence, as applicable, in the United States of the disease or condition for which the drug or device is being developed;
• approaches to support inclusion of underrepresented populations and to encourage clinical study participation that reflects the population expected to use the drug or device under study, including with respect to the establishment of inclusion and exclusion criteria for certain subgroups, such as pregnant and lactating women and individuals with disabilities, including intellectual or developmental disabilities or mental illness;
• considerations regarding informed consent with respect to individuals with intellectual or developmental disabilities or mental illness, including ethical and scientific considerations;
• the appropriate use of decentralized trials or digital health tools;
• clinical endpoints;
• biomarker selection; and
• studying analysis.

The FDA will establish a public docket for each public workshop, with a 60-day comment period. Six months after the close of the comment period the agency will provide an online report with a summary of topics discussed and responses to any recommendations.

The law also requires the agency to provide an online annual summary report on increasing diversity in clinical studies starting in two years. The report will summarize, in aggregate, the diversity action plans received in the preceding year, whether the clinical studies met the demographic subgroup enrollment goals from the plans, and the reasons provided, if any, for why enrollment goals were not met.

Public Meeting To Discuss Adopting COVID Trial Flexibilities

The law also requires the Department of Health and Human Services to have a public meeting on clinical study flexibilities initiated in response to the COVID pandemic not later than six months after the COVID emergency period ends. The meeting will discuss the FDA’s recommendations to mitigate disruption of clinical studies, including recommendations in its guidance – Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency.

The meeting will include representatives from the pharmaceutical and medical device industries who sponsored clinical studies during the COVID–19 emergency and organizations representing patients and discuss:

• actions sponsors took to use the FDA’s recommendations and the frequency at which the recommendations were employed;
• the characteristics of the sponsors, studies, and patient populations impacted by the recommendations;
• consideration of how the recommendations intended to mitigate disruption of clinical studies during the COVID–19 emergency, including any recommendations to consider decentralized clinical studies when appropriate, may have affected access to clinical studies for certain patient populations, especially unrepresented or underrepresented racial and ethnic minorities; and
• recommendations for incorporating certain clinical study disruption mitigation recommendations into current or additional guidance to improve clinical study access and enrollment of diverse patient populations.

Within three months of the public meeting the FDA will issue an online report about the meeting.

Decentralized Trial Guidance Required

The law also mandates that within a year, FDA issue or revise draft guidance that includes recommendations to clarify and advance the use of decentralized clinical studies to support the development of drugs and devices, including recommendations for how to advance the use of flexible and novel clinical trial designs and to help improve trial participant engagement, recruitment, enrollment, and retention of a meaningfully diverse clinical population, including with respect to race, ethnicity, age, sex and geographic location, when appropriate.

The guidance must address:

• Recommendations related to digital health technology or other assessment options, such as telehealth, local laboratories, local health care providers or other options for remote data collection that could support decentralized clinical studies, including guidance on considerations for selecting technological platforms and mediums, data collection and use, data integrity and security, and communication to study participants through digital technology.
• Recommendations for subject recruitment, retention and engagement, including considerations for sponsors to minimize or reduce burdens for clinical study participants through the use of digital health technology, telehealth, local health care providers and laboratories, health care provider home visits, direct-to-participant engagement, electronic informed consent or other means, as appropriate.
• Recommendations with respect to the evaluation of data collected within a decentralized clinical study setting.
• Recommendations for methods of remote data collection, including clinical trial participant experience data, through the use of digital health technologies, telemedicine, local laboratories, local health care providers or other options for data collection.
• Considerations for sponsors to minimize or reduce burdens for clinical trial participants associated with participating in a clinical trial, such as the use of digital technologies, telemedicine, local laboratories, local health care providers, or other data collection or assessment options, health care provider home visits, direct-to-participant shipping of investigational drugs and devices, and electronic informed consent, as appropriate.
• Recommendations regarding conducting decentralized clinical trials to facilitate and encourage meaningful diversity among clinical trial participants, including with respect to race, ethnicity, age, sex and geographic location, as appropriate.
• Recommendations for strategies and methods for recruiting, retaining and engaging with clinical trial participants, including communication regarding the role of clinical trial participants and community partners to facilitate clinical trial recruitment and engagement, including with respect to diverse and underrepresented populations, as appropriate.
• Considerations for review and oversight by sponsors and institutional review boards, including remote trial oversight.
• Recommendations for decentralized clinical trial protocol designs and processes for evaluating proposed clinical trial designs.
• Recommendations related to digital health technology and other remote assessment tools that may support decentralized clinical trials, including guidance on appropriate technological platforms and tools, data collection and use, data integrity, and communication to clinical trial participants through such technology.
• A description of the manner in which the FDA will assess or evaluate data collected within a decentralized clinical trial to support the development of the drug or device, if the manner is different from that used for a non-decentralized trial.
• Considerations for sponsors to validate digital technologies and establish appropriate clinical endpoints for use in decentralized trials.
• Considerations for privacy and security of personally identifiable information of trial participants.
• Considerations for conducting clinical trials using centralized approaches in conjunction with decentralized approaches.

No later than one year after the comment period closes for the draft guidance, a final version must be issued.

Congress Wants FDA To Issue Guidance on Use of Digital Health Tech in Clinical Trials

The law also mandates that the FDA issue or revise draft guidance regarding the appropriate use of digital health technologies in clinical trials to help improve recruitment for, retention in, participation in, and data collection during, clinical trials, and provide for novel clinical trial designs using technology to support the development of, and review of applications for, drugs and devices.

The guidance must include:

• Recommendations for data collection methodologies by which sponsors may incorporate the use of digital health technologies in clinical trials to collect data remotely from trial participants;
• Considerations for privacy and security protections for data collected during a clinical trial, including recommendations for the protection of trial participant data that are collected or used in research using digital health technologies and compliance with the Health Insurance Portability and Accountability Act of 1996 (42 U.S.C. 1320d–2 note), 21 C.F.R. 50 Subpart B, 21 C.F.R. 56 Subpart C, 45 C.F.R. 46 Subpart A, 42 C.F.R. 2, and recommendations for the protection of clinical trial participant data against cybersecurity threats, as applicable;
• Considerations on data collection methods to help increase recruitment of clinical trial participants and the level of participation of such participants, reduce burden on clinical trial participants, and optimize data quality;
• Recommendations for the use of electronic methods to obtain informed consent from clinical trial participants, taking into consideration applicable federal law, including 21 C.F.R. 50 Subpart B, and, as appropriate, state law;
• Best practices for communication between sponsors and the FDA on the development of data collection methods;
• Appropriate format to submit the data;
• Manner in which the FDA may assess or evaluate data collected through digital health technologies to support the development of the drug or device;
• Recommendations regarding the data and information needed to demonstrate that a digital health technology is fit-for-purpose for a clinical trial, and a description of how the FDA will evaluate the data and information; and
• Recommendations for increasing access to, and the use of, digital health technologies in clinical trials to aid the inclusion of diverse and underrepresented populations, as appropriate, including considerations for access to, and the use of, digital health technologies in clinical trials by people with disabilities and pediatric populations.

The final guidance is expected not later than 18 months after the public comment period on the draft guidance ends.

Guidance on Innovated Trials Requested

The law also requires the FDA to issue or revise draft guidance in the next year on the use of seamless, concurrent, and other innovative clinical trial designs to support the expedited development and review of applications for drugs, as appropriate.

The guidance must include:

• Recommendations on the use of expansion cohorts and other seamless clinical trial designs to assess different aspects of product candidates in one continuous trial, including how such clinical trial designs can be used as part of meeting the substantial evidence standard under section 505(d) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(d)).
• Recommendations on the use of clinical trial designs that involve the concurrent conduct of different or multiple clinical trial phases, and the concurrent conduct of preclinical testing, to expedite the development of new drugs and facilitate the timely collection of data.
• Recommendations for how to streamline trial logistics and facilitate the efficient collection and analysis of clinical trial data, including any planned interim analyses and how such analyses could be used to streamline the product development and review processes.
• Considerations to assist sponsors in ensuring the rights, safety, and welfare of clinical trial participants, maintaining compliance with good clinical practice regulations, minimizing risks to clinical trial data integrity, and ensuring the reliability of clinical trial results.
• Recommendations for communication between sponsors and the FDA on the development of seamless, concurrent, or other adaptive clinical trial designs, including review of, and feedback on, clinical trial protocols.
• Manner in which the FDA will assess or evaluate data collected through seamless, concurrent, or other adaptive clinical trial designs to support the development of drugs.

The final guidance is expected not later than 18 months after the public comment period on the draft guidance ends.

The law also directs HHS to work with foreign regulators in developing a memoranda of understanding or other arrangement governing the exchange of information to facilitate international harmonization of the regulation and use of decentralized clinical trials, digital technology in clinical trials, and seamless, concurrent, and other adaptive or innovative clinical trial designs.

The law also requires the FDA to issue guidance regarding post-approval studies on: how sponsor questions related to the identification of novel surrogate or intermediate clinical endpoints may be addressed in early stage development meetings with the agency; the use of novel clinical trial designs to conduct post-approval studies; the expedited withdrawal procedures; and considerations related to the use of surrogate or intermediate endpoints that may support the accelerated approval of an application, including considerations in evaluating evidence related to the endpoints.