FDA is asking sponsors of all investigational medical products to focus on including diverse patients throughout the clinical development process.
Racial and ethnic minorities in the United States are “frequently underrepresented in biomedical research despite having a disproportionate disease burden for certain diseases relative to their proportional representation in the general population,” the agency states in a draft guidance published April 13.
In the draft guidance that would be applied across its regulatory portfolio, FDA recommends that sponsors start thinking about increasing representation of minorities early in clinical development, said Lola Fashoyin Aje, associate director of Project Equity at FDA’s Oncology Center of Excellence, and a key player in the conception of the new proposed guidance.
“As a research ecosystem, we have committed to change course from trials that have very few participants who are members of racial and ethnic minority populations represented, to achieving more diversity in clinical trials,” Fashoyin-Aje, who is also a deputy director in the Office of Oncologic Diseases, said to The Cancer Letter. “This requires a plan that specifies goals and how to achieve them—the draft guidance on Diversity Plans provides a framework for doing this.
“During clinical development, we will encourage sponsors to monitor enrollment status by demographics and determine whether additional measures are needed to meet their stated enrollment goals before the trial completes accrual.”
While the draft guidance doesn’t contain binding recommendations to increase racial and ethnic representation in clinical trials, FDA officials are encouraging sponsors and investigators to develop a Diversity Plan when submitting applications to the agency.
FDA has decided not to mandate the submission of these Diversity Plans at this time because it is an inaugural initiative. The agency may consider auxiliary measures in the future, for instance, based on whether sponsors are adopting these recommendations as they go into effect.
“There is a lot of experience needed with these Diversity Plans on both sides, FDA reviewers and sponsors alike,” Fashoyin-Aje said. “Once we gain that experience and assess the impact of these efforts over time, then I think it will be appropriate to consider whether additional policy is needed.”
Experts in oncology say a common perception, that a lack of interest from minority populations, e.g. African American communities, is driving underrepresentation in clinical trials, is inaccurate. Rather, the dearth of engagement from healthcare systems and practices has made clinical trials inaccessible to these communities—arguably an ironic self-fulfilling prophecy.
In 2021, University of Pennsylvania researchers demonstrated that institutional commitments to increasing diversity can be effective: the Abramson Cancer Center doubled clinical trial enrollment of Black patients with cancer from 12% to 24% within five years, according to data presented at the 2021 annual meeting of the American Society for Clinical Oncology (The Cancer Letter, June 25, 2021).
More recent studies and surveys, including from The Cancer Letter, have documented stark racial and ethnic inequities in other aspects of the healthcare ecosystem, including among leadership of North American cancer centers, senior scientists at NCI, and in patient populations across a vast majority of hospitals in the U.S. (The Cancer Letter, Oct. 9, 2020; July 30, July 2, 2021)
FDA anticipates that once the April 13 draft guidance is finalized, it would be applied to a broad range of regulatory processes, including for new drugs, investigational exemptions, and device approvals and clearances.
“FDA recommends a Plan be submitted for medical products for which an IND submission is required and/or for which clinical studies are intended to support a marketing submission … for a standalone Biologics License Application (BLA), or … for an NDA,” the draft guidance states. “A Plan is also recommended for medical products for which an IDE is required and/or for which clinical studies are intended to support a device marketing submission, whether a premarket notification (510(k)), premarket approval (PMA) application, a De Novo classification request, or a humanitarian device exemption (HDE) application. FDA will evaluate the Race and Ethnicity Diversity Plan as an important part of the sponsor’s development program.”
The proposed guidance is one example of the agency’s ongoing participation in President Joe Biden’s reignited Cancer Moonshot, which has a primary mission of cutting overall cancer mortality rates in half before 2050 (The Cancer Letter, Feb. 4, 2022).
“The U.S. population has become increasingly diverse, and ensuring meaningful representation of racial and ethnic minorities in clinical trials for regulated medical products is fundamental to public health,” FDA Commissioner Robert Califf said in a statement. “Going forward, achieving greater diversity will be a key focus throughout the FDA to facilitate the development of better treatments and better ways to fight diseases that often disproportionately impact diverse communities.
“This guidance also further demonstrates how we support the Administration’s Cancer Moonshot goal of addressing inequities in cancer care, helping to ensure that every community in America has access to cutting-edge cancer diagnostics, therapeutics and clinical trials,” Califf said.
While FDA has been issuing guidances aimed at improving diversity in clinical development for several years, this latest iteration is designed to provide a clear roadmap that defines the essential components of an expected Diversity Plan.
In certain regulatory contexts, i.e. in pediatric oncology, FDA is empowered by federal law to withhold marketing exclusivity from a company if the agency deems a trial design and accrual plan to have resulted in inadequate representation (The Cancer Letter, Nov. 12, 2021).
Although not mandatory, the April 13 draft recommendations should, in the short term, help FDA gain experience in reviewing and discussing diversity plans with industry partners; vice versa.
“Sponsors will gain experience developing, implementing them, and there is an opportunity for greater transparency around what specifically is being done to address this issue during drug development,” Fashoyin-Aje said.
Academic institutions, including cancer centers, are expected to play a significant role in working with industry to develop these diversity plans.
“Academic centers have institutional-level data that can shed light on the adjustments that can be made to lead to more inclusivity in our enrollment practices while also maintaining patient safety,” Fashoyin-Aje said.
“Academic medical centers are uniquely positioned to help broaden the pool of clinical investigators to include individuals who predominantly practice in underserved communities,” she said. “It is my hope that a similar framework can be applied broadly to develop plans for other clinically relevant but historically underrepresented groups.”
Fashoyin-Aje spoke with Matthew Ong, associate editor of The Cancer Letter.
Matthew Ong: Why is this guidance needed? Could you share the genesis story for this effort?
Lola Fashoyin-Aje: The Oncology Center of Excellence has had a longstanding interest in addressing disparate participation rates in the clinical trials we review, across various groups in the population defined by demographics such as race, ethnicity, age, etc.
So, the recent increase in the national and even global visibility of the underrepresentation of members of certain racial and ethnic populations in clinical trials does not fully reflect the discourse on and activity related to this issue which has been ongoing for many, many years.
Through these efforts FDA has issued guidances addressing the issue of demographic diversity including a guidance in 2016 titled, “Collection of Race and Ethnicity Data in Clinical Trials” and in November 2020, the guidance titled “Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs.”
The 2016 guidance included one sentence recommending that sponsors discuss a plan to enroll a diverse population in their clinical trials “at the earliest phase of development and, for drugs and biologics, no later than the end of the phase II meeting.”
However, the guidance did not elaborate on this point. Based on this recommendation, I came up with a small pilot, whereby the oncology divisions asked sponsors at end-of-phase II meetings to provide their plans to enroll a racially and ethnically diverse population onto their trials.
Approximately 86% responded, and though about half of the responders expressed interest or a commitment to addressing disparities in clinical trial representation, none stated what their goals were with regards to accrual of historically underrepresented racial and ethnic populations in their trials. These companies represented the spectrum of pharma from small and medium sized companies to larger ones.
Through our engagement with external groups like patient advocacy groups, organizations that represent clinicians, researchers, and patients like ASCO and AACR, academia, numerous listening sessions, the pilot I just described, and direct pleas from external stakeholder groups, it became clear that clarification of FDA’s expectations on this issue was needed.
So, I drafted an outline of what I considered the essential components of a Diversity Plan. We wrote the guidance initially as an oncology guidance, reflecting the importance the OCE places on being a responsive organization. In agency-wide discussions it became clear that the times necessitated a broader agency approach.
Thus, we revised the guidance to include medical devices and to broaden to diseases beyond oncology. We also wrote an Oncology Perspective article highlighting the plans essential elements, which was published in JAMA Oncology.
Why is FDA choosing not to mandate submission of a Diversity Plan?
LFA: Although current regulations do not require submission of a Diversity Plan, our aim is to move forward with implementing this draft guidance, with the goal of learning from Diversity Plan submissions and from the process of engaging with sponsors, and then determine whether additional steps are needed.
But I think it is important to recognize that we have not done anything like this before. So, there is a lot of experience needed with these Diversity Plans on both sides, FDA reviewers and sponsors alike. Once we gain that experience and assess the impact of these efforts over time, then I think it will be appropriate to consider whether additional policy is needed.
How do you expect or hope sponsors will use this guidance?
LFA: The draft guidance provides a recommended approach for developing a race and ethnicity Diversity Plan, that starts with assessing the distribution of the population with the disease, by race and ethnicity, assessing whether there are known clinically/scientifically important differences across the population, and defining target enrollment rates.
We recommend that sponsors start thinking about this early in clinical development, that is as early as in the dose-finding stage. Once you have defined who has the disease and defined a goal enrollment, then it is important to consider what measures need to be implemented to achieve this goal in the development program overall, and for specific trials.
So, our hope is that sponsors will fully integrate or embed this approach in their processes for planning their clinical development strategies and, to the same degree of specificity as is done when for example they select which countries to open the trials in, how many patients to enroll, the regulatory submission strategy, etc.
I also hope that sponsors will engage academic investigators early to discuss and agree on the strategy to enroll a diverse population at the site level—this may include having a discussion about eligibility criteria, study design to address burden level to patients and any flexibilities in the use of remote assessments that can be implemented, partnerships with practice settings wherein a greater proportion of racial and ethnic minority patients receive their care, and additional resources that may be needed to support accrual and retention.
Finally, while this guidance is specifically focused on Diversity Plans for racial and ethnic minorities, it is my hope that a similar framework can be applied broadly to develop plans for other clinically relevant but historically underrepresented groups.
So much of drug development is global, including for oncology. How will this guidance apply to enrollment across international sites?
LFA: Thank you for asking this question, because we do recognize that most cancer drugs we approve for cancer indications, enroll patients across international sites. In some cases, it would be infeasible to develop a drug without enrolling study participants across international sites when the disease, or a particular subtype of the disease, is perhaps more common outside the U.S.
So, we look at diversity with this as a consideration.
When appropriate steps are taken, including by developing a Diversity Plan prospectively, global drug development can provide additional opportunities to enroll diverse populations in the trials.
By thinking about the disease epidemiology early in drug development, sponsors can develop a strategy, including through the conduct of truly multi-regional trials, that ensures appropriate representation of the U.S population in the study population and that accounts for the diversity of the U.S population.
Unfortunately, for too long, the drug development ecosystem has not been extended to regions of the world that provide the opportunities to enroll a diverse population.
A review of oncology approvals over a six-year period of time indicates that regions like Africa and Central America are not represented—with fewer than 3% of study participants enrolled from these regions combined.
So, prospectively planning of global trials can contribute to enrolling a diverse population.
What is the role of academic cancer centers in ensuring diversity in clinical trials?
LFA: Academic medical centers absolutely have an important role to play in that this is where most trials we review are currently conducted.
This experience can be leveraged to identify trial design and trial operational practices that can facilitate or dampen efforts to achieve diversity.
For example, I think we recognize that in most cases eligibility criteria are too restrictive leading to many patients being ineligible for trials. Academic centers have institutional-level data that can shed light on the adjustments that can be made to lead to more inclusivity in our enrollment practices while also maintaining patient safety.
In addition, academic centers have hospital networks that can be leveraged to provide greater access to clinical trials to patients who have historically faced many barriers to clinical trial participation. We are seeing some of this through activation of trials in affiliate community hospitals for example, but more can be done.
In addition to increasing the pool of patients who have access to clinical trials, academic medical centers are uniquely positioned to help broaden the pool of clinical investigators to include individuals who predominantly practice in underserved communities and/or who are themselves members of racial and ethnic minority groups, by providing the opportunities for collaboration on clinical research.
What do you expect the outcome from this guidance will be, and when do you expect to see results?
LFA: The primary outcomes of implementation will likely be long-term—as you know, the time between trial initiation, completion, and submission and review of a marketing application can be long.
Therefore, we expect that it will be several years before we can truly assess the impact of these Diversity Plans on moving closer to achieving diversity in clinical trials.
As a research ecosystem, we have committed to change course from trials that have very few participants who are members of racial and ethnic minority populations represented, to achieving more diversity in clinical trials.
As a research ecosystem, we have committed to change course from trials that have very few participants who are members of racial and ethnic minority populations represented, to achieving more diversity in clinical trials.
This requires a plan that specifies goals and how to achieve them—the draft guidance on Diversity Plans provides a framework for doing this.
During clinical development, we will encourage sponsors to monitor enrollment status by demographics and determine whether additional measures are needed to meet their stated enrollment goals before the trial completes accrual.
An important short-term outcome of implementing this guidance, is that FDA will gain experience reviewing and discussing these plans with sponsors, sponsors will gain experience developing, implementing them, and there is an opportunity for greater transparency around what specifically is being done to address this issue during drug development.
We believe that submission of these plans will at minimum trigger a more thoughtful and consistent approach to developing a strategy to enroll a racially and ethnically diverse population in clinical trials. We will hopefully be able to identify best practices and determine whether additional policy through guidance or through some other mechanism is needed.
