A New Era of Inclusivity

On December 29, 2022, the landscape of clinical research dramatically transformed with the signing of the US Consolidated Appropriations Act, 2023, which included the groundbreaking Food and Drug Omnibus Reform Act of 2022, known as FDORA.

The FDORA act mandates the need for clinical trial sponsors to submit a Diversity Action Plan for pivotal studies before applying for a market authorisation, to ensure new treatments and devices are trialled on the diverse populations likely to be prescribed them.

This is not just another piece of legislation—it's a powerful statement about the urgent need for inclusivity in clinical trials. 

This particular journey began a few years before with the FDA Reauthorisation Act of 2017 also known as FDARA. FDARA laid the groundwork for a commitment to change and the initial framework for the DAP.

Two class acts: FDORA and FDARA

Both pieces of legislation include a  wide range of provisions that span across public health and research and development. 

Combined, one of the key objectives is to modernise and enhance the clinical trial process by promoting efficiency, flexibility, and patient access while ensuring that clinical data is reliable and transparent.  In addition, they support the FDA in making more timely and informed decisions about investigational products.

Efficiency 

Both FDORA and FDARA aim to accelerate clinical trial development for treatments addressing unmet medical needs. They promote the use of modern data and technology, such as real-world evidence from electronic health records, to enhance trial designs and regulatory decisions. This approach facilitates data collection beyond traditional randomised controlled trials and encourages the decentralisation of trials to reach diverse participants. 

Flexibility

They also encourage the use of adaptive trial designs and master protocols, enabling adjustments to trial parameters (e.g., dosage, sample size) based on interim results. And the use of platform trials that evaluate multiple interventions simultaneously.

Patient Access

Both acts enhance patient centricity and access to clinical trials, particularly for underserved communities. They stress the need to eliminate barriers to participation and urge trial sponsors to increase outreach to diverse groups .

They also focus on designing trials that truly resonate with patients’ needs. Instead of only measuring survival rates, there's a push to prioritise endpoints that reflect quality of life. By doing so, trials become more relevant and beneficial to the individuals they aim to serve.

COVID-19

A powerful illustration of the impact of FDARA and FDORA  can be seen in the response to the COVID-19 pandemic. The swift implementation of the provisions within both regulations was vital in guiding the FDA's approach during this crisis, especially in addressing disparities faced by underrepresented populations. They provided the essential framework and tools needed to confront and lessen health disparities in the development, approval, and accessibility of COVID-19 treatments, vaccines, and diagnostic tools.

In this article, we will delve into the evolution of the Diversity Action Plan (DAP). A key aspect of FDORA and FDARA’s transformative legislation and a significant milestone in an evolutionary journey aimed at addressing historical inequities in medical research.

The main objective of the DAP is to ensure that clinical research reflects the true demographics of the real-world patients who will ultimately benefit from the tested drugs and devices. This means making clinical trials more inclusive. 

By prioritising inclusive representation in clinical trials, we are not just checking boxes, we enhance the relevance of trial findings to ensure that treatments are safe and effective for all demographics—spanning a multitude of ages, genders, races, ethnicities, and socioeconomic backgrounds. 

In addition, the DAP serves as a vital tool for the FDA, helping to monitor and assess inclusivity goals, ensuring that as we push the boundaries of medical innovation, no one is left behind. 

Why champion inclusive clinical trials?

Diversity in clinical trials is crucial for developing safe, effective, and equitable treatments. It ensures that all populations benefit from medical advances, reduces health disparities, and builds trust in the healthcare system. 

When it comes to medications, our bodies aren’t all the same—genetic and biological differences among populations can have a significant impact on how we respond to treatments. For example:

• Many East Asians carry a variant in the ALDH2 gene that hampers their ability to break down acetaldehyde, resulting in ‘flushing’ and an increased risk of adverse effects when taking alcohol-based medications.

• In hypertensive patients of African descent, research shows that calcium blockers and diuretics tend to work better than ACE inhibitors and beta-blockers.

• Some Caucasian individuals have poor metabolism for codeine, making the medication ineffective for them.

Biological differences between men and women (e.g., hormone levels, metabolism, and immune system responses) can lead to different outcomes for the same treatment. For example:

• Women are more prone to certain side effects from medications like statins.

• Conditions like cardiovascular disease manifest differently in men and women, requiring distinct diagnostic and treatment strategies.

The examples above  highlight an important point: without including diverse participants in clinical trials, we risk leaving some populations without effective treatments or exposing them to unexpected side effects. A drug might appear to work well in a homogenous group, only to reveal its limitations when tested in a broader, more varied population.

In addition, many people and communities are underserved by research. Despite often facing a higher disease burden for certain conditions compared to the general population, they are frequently underrepresented or excluded from studies. It is crucial to do more to include these individuals and support their participation in research.

Diverse trials yield better data on how treatments perform across populations, reducing the likelihood of costly post-market safety issues or drug recalls. Addressing population-specific needs early can save resources and improve patient outcomes. 

Improving patient outcomes quickly, while reducing costs and resource utilisation is becoming increasingly important as the world shifts towards precision medicine. Precision medicine focuses on utilising an individual's genetic makeup, lifestyle, environment, and clinical data to develop more precise and effective treatments.

The goal is to move away from the “one-size-fits-all” approach to medicine and instead develop therapies that are targeted to the specific needs of each patient. It is essential for all groups to be involved in research aimed at developing precision medicine to prevent further disparities in quality of life and overall mortality rates. 

The Diversity Action Plan: A Bold Commitment to Diversity

The FDARA act of 2017 in the US included the recommendation for all clinical trial sponsors to develop a  DAP for certain pivotal studies. The FDA committed to drafting guidance to assist trial sponsors develop the plans required. The FDA published their first draft guidance five years later in April 2022, entitled ‘Diversity Plans to Improve Enrolment of Participants From Underrepresented Racial and Ethnic Populations in Clinical Trials’. 

It outlined a framework for sponsors to establish goals, strategise effectively, and tackle barriers to enrolment by considering disease epidemiology and the prevalence of conditions among specific demographic groups. 

While the guidance offered flexible recommendations it was non-binding, therefore it strongly encouraged sponsors to embrace the challenge of enhancing trial diversity. Sponsors were encouraged to draft and submit a DAP to the FDA early in the clinical development process. Ideally during the Investigational New Drug (IND) application or at a pre-IND meeting. The recommendations primarily applied to:

• Phase 3 clinical trials for drugs and biological products.

• Pivotal studies for medical devices.

Components of a Diversity Action Plan

The Diversity Plan is recommended to include the following elements:

1. Overview of the Disease/Condition

• Sponsors are encouraged to describe the demographics of the population most affected by the disease or condition (e.g., race, ethnicity, age, and gender).

• Use of publicly available epidemiologic data or disease burden information is recommended.

2. Clinical Study Enrolment Goals

• Sponsors are asked to specify goals for enrolment that reflect the demographics of the patient population affected by the disease or condition.

3. Strategies to Achieve Enrolment Goals

• Sponsors are expected to outline concrete strategies and operational measures to increase enrolment of underrepresented populations.

• Recommended strategies include:

• Partnering with community-based organisations.

• Engaging investigators and sites located in areas with diverse patient populations.

• Reducing participation barriers (e.g., transportation, language assistance, flexible visit hours).

• Conducting outreach through culturally tailored materials.

4. Status Updates on Enrolment Progress

• The guidance states sponsors should provide ongoing updates to the FDA regarding progress toward achieving diversity goals during clinical development.

Addressing Barriers to Participation

The guidance explicitly identified challenges faced by underrepresented populations, such as:

• Lack of access to trial sites.

• Language barriers.

• Socioeconomic factors and distrust of the healthcare system.

Sponsors are encouraged to address these barriers through tailored and practical solutions.

2024: New Guidance, New Rules 

In December 2023, the FDORA Act takes things further by making the submission of DAPs  mandatory for certain clinical trials. It also requires that the FDA specify the "form and manner" in which these plans should be submitted. This adds layers of accountability for the FDA, expands the scope of underrepresented populations for trial sponsors, and ultimately demands measurable outcomes. 

As a result, an updated draft guidance was published in June 2024, titled “DAPs to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies.”

Broadly speaking, it is fair to say the initial draft guidance of April 2022 outlines the responsibilities of the trial sponsor, while the most recent draft of June 2024 specifies the responsibilities of the FDA.

The June 2024 guidance supersedes the April 2022 version, introducing several key updates:

Legally Binding Requirements

Unlike the 2022 guidance, which offered non-binding recommendations, the guidance of June 2024 establishes legally binding obligations for sponsors. The updated guidance requires sponsors to submit plans which must specify: 

• The sponsor’s goals for enrolment in a clinical study

• The sponsor’s rationale for such goals

• An explanation of how the sponsor intends to meet those goals.

The legislation still applies to Phase 3 studies of new drugs and pivotal clinical studies of devices, as before, but now with specific timelines for submission relative to study phases and regulatory submissions.

Broadened Scope of Diversity Factors

The 2022 guidance focused primarily on underrepresented racial and ethnic populations. The 2024 guidance expands this focus to include additional demographic characteristics such as age, sex, and other factors, encouraging sponsors to consider a more comprehensive range of sub-groups in their clinical studies.

A DAP must now include the sponsor’s enrolment goals disaggregated by the race, ethnicity, sex, and age group of the clinically relevant study population. The sub-populations should align with the FDA’s guidance in each category (e.g., for race: Asian, Black/African American, etc.).

Waiver Process

The 2024 guidance outlines criteria and processes for sponsors to request waivers from the requirement to submit a DAP, providing a structured approach for exceptions. 

FDA reporting 

Each year, the FDA must present a comprehensive report to Congress and make it available on their website. This report will highlight the DAPs received and assess how well the clinical studies aligned with the demographic enrolment goals outlined in those plans. A crucial step towards demonstrating assessment and accountability.

What happens next? 

The next important date to keep in mind is June 26, 2025. The FDORA legislation requires the FDA to finalise its guidance no later than nine months after the comment period for the draft guidance closes. Since the comment period ended on September 26, 2024, the FDA has until June 26, 2025, to review the more than 150 comments submitted. Once the guidance is finalized, sponsors will have 180 days to comply with its requirements.

Navigating Requirements for International Clinical Trials

When it comes to conducting clinical trials outside the United States, understanding the implications of the upcoming June 2024 FDA guidance on DAPs is crucial. Whether you’ll need to follow these guidelines hinges on a key factor: will the data be submitted to the FDA for a marketing application?

No Submission to the FDA

If you’re not planning to submit your trial data to the FDA, you can breathe a sigh of relief—the guidance doesn’t apply to you. The FDA's reach doesn't extend to studies not aimed at supporting marketing applications in the U.S.

Planning to Submit International Trial Data to the FDA?

For those who do intend to submit their data to the FDA, compliance becomes essential. Sponsors will need to draft a DAP as specified in the guidance. The data gathered must align with the FDA's standards for inclusion and representation.

Key Considerations for Global Studies

Sponsors must ensure that global studies align with U.S.-specific diversity expectations, even if the study includes populations from outside the U.S. This reinforces the FDA’s goal of ensuring clinical trial data are relevant to the diverse U.S. population.

If global studies lack sufficient representation of U.S.-specific underrepresented populations, sponsors may need to provide a scientific justification for why the data are still generalisable to U.S. patients.

It’s important to note that while the FDA’s guidance is specific to its regulatory framework, other countries may have their own requirements regarding diversity in clinical trials.

Inclusivity: A global mission? 

The quest to enhance diversity within clinical trials extends far beyond the borders of the United States, creating a ripple effect in global health research.

The FDA (U.S.) has the most specific and direct regulatory requirements related to clinical trial diversity. How does it compare with other regulators around the world?

The Medicines and Healthcare products Regulatory Agency (MHRA) and the Health Research Authority (HRA) have introduced Inclusion and Diversity Plans (IDPs) to address underrepresentation in clinical trials and make research more inclusive and applicable to all segments of the population. The IDPs are strategic documents that outline how researchers and sponsors will actively address diversity and inclusivity in the design, recruitment, and conduct of clinical trials. The aim is to ensure inclusive participation across gender, age, ethnicity, and socioeconomic status. Additionally, to encourage the inclusion of people with disabilities as well as other  underrepresented groups.

The MHRA and HRA provide detailed guidance to help sponsors create IDPs as part of their clinical trial applications.

The draft guidance for IDPs has been developed through consultations with stakeholders, including sponsors, researchers, and patient advocacy groups. Feedback was incorporated to ensure the plans are practical and impactful. The IDP initiative will undergo a pilot phase in 2025, involving select sponsors and researchers. Insights from the pilot will help refine the guidance and prepare for broader implementation. IDPs will eventually be integrated into the approval process for clinical trials, making them a critical component of regulatory submissions. The IDPs currently take the form of guidance. There is no legal obligation to submit an IDP, however, the MHRA/HRA, encourage sponsors to submit their plans. 

The IDP framework was designed to align with the efforts of the FDA and other international organisations, to improve diversity in clinical trials while tailoring to the unique demographic and healthcare landscape of the UK.

Various international organisations, such as the World Health Organisation (WHO) and the European Medicines Agency (EMA), as well as regulatory agencies in countries like Australia, Canada, and Japan, promote and support diversity in clinical trials. However, they vary in the level of action required and the specific underrepresented ethnic (URE) sub-groups of interest.

In summary, while the FDA has taken the lead in mandating diversity in clinical trials through specific regulations—such as FDORA and FDARA—other global regulatory bodies have also made significant strides toward promoting inclusive clinical research. However, their approaches tend to be less formal and often not mandatory. It is possible that these agencies may adopt more stringent measures similar to the FDA's in the future.

The Road Ahead: A Collective Responsibility

Research has shown that the underrepresentation of subpopulations in clinical trials may stem from one or a combination of three primary issues: 

1. Mistrust

 This is often rooted in previous injustices, such as the Tuskegee Study, or a general mistrust of the healthcare system due to past experiences or evident disparities in health outcomes. 

2. Lack of Awareness/Information

Patients or healthcare providers may not be aware of research opportunities that could benefit them or their patients. Sometimes, healthcare professionals assume that specific groups may not be interested in participating in trials. At times, institutional bias is present, with research teams not effectively reaching out to potential participants in URE populations. 

3. Lack of Access/Resources

Participants may find it difficult to take part in research due to several barriers, such as not having enough availability or facing challenges like full-time jobs and childcare commitments that hinder attendance at regular visits. Additionally, patients living in rural areas may be excluded from research participation due to the frequency of required visits to research sites, often located in central or urban areas.

The introduction of DAPs (DAPs) compels trial sponsors to consider these barriers and strategically plan to mitigate as many of them as possible during the early stages of a clinical trial. This encourages sponsors to   incorporate inclusive trial planning and strategic feasibility into the development of their protocols at an early stage. 

While the DAP is a positive, significant, and absolutely necessary step it also presents challenges.

There is no universal DAP template; each plan requires input from those working within underrepresented populations to understand how diseases manifest in these groups and how to design trials that allow their participation. This might involve decentralising a trial, for example. 

The diversity plan will help inform the recruitment plan for the study but it may also inform or influence the protocol schedule of events, objectives and even endpoints.

It is evident that more time and resources will be needed to develop a comprehensive plan.

Many companies may not have the in-house resources needed to develop a DAP. As a result, it may be necessary to outsource this task to one or more vendors. Doing so ensures that several key factors are effectively addressed:

• A comprehensive identification and engagement of a diverse range of trial participants

• The collection and thorough evaluation of scientific data

• Effective project management that aligns the development of the DAP along with the study protocol and the overall study objectives. 

• From a regulatory standpoint, The FDORA Act does not define penalties for non-compliance with the DAP requirements, which may result in superficial adherence rather than a genuine commitment to diversity goals.

Sponsors are asked to keep in mind the FDA's ultimate objective. This is for each sponsor to develop a workable plan to ensure the inclusion and retention of all relevant groups - particularly underrepresented populations - in research that may benefit them. This effort should not create additional work that does not ultimately serve the interest of patients.

Sponsors should take advantage of the fact the FDA welcomes the early submission of DAPs, allowing sponsors to refine their plans with FDA guidance before finalising them for consideration. 

In addition to DAPs, each stakeholder in the drug development process has a role to play. Sponsors should design trials that are accessible to all patient types likely to receive their drugs. They should invest in the technology and the external resource required to identify an engage with the underrepresented populations relevant to their product use. 

Research facilities should create a workforce that reflects the diversity of the populations they serve to build trust between institutions and patients. Clinicians need to engage all suitable participants who could benefit from new treatments or trials. Meanwhile, industry and healthcare sectors should communicate the benefits and necessity of research and work to raise awareness across different populations. 

It is also important for patients to remain open to receiving information about research opportunities and to discuss these with friends, family, and clinicians.

Like many advancements in clinical trials—such as the fully integrated Clinical Trial Management Systems (CTMS), decentralised trials, and the globalisation of clinical trials—the adoption of the DAP will involve several challenges and may not be an easy process . The development of a strong diversity plan will become easier as trial sponsors gain a better understanding of the information the FDA requires and how to collect it. Additionally, once sponsors establish effective ways to engage with communities that they may not currently reach. 

Embracing the objective of the DAP will help ensure clinical trials are a safe and effective way of bringing new treatments to market for for all patients. Ultimately reducing disparities in health outcomes around the globe, helping to prevent the needless loss of health and life.