FDA watchers and clinical trialists in oncology may want to pay close attention to the agency’s latest plans to increase representation of traditionally marginalized populations in drug development.
The agency is in the process of crafting a guidance that would define what constitutes a “health disparity” and how FDA would interpret “adequate representation” of ethnic and racial minorities in clinical trials, sources said.
FDA’s authority on this matter stems from a congressional mandate—based on a little-known provision in a 20-year-old law—to require “adequate representation” of ethnic and racial minorities in clinical trial protocols.
The measure in question is located within the Best Pharmaceuticals for Children Act of 2002, a landmark legislation that encourages and, in certain circumstances, requires pharmaceutical companies to develop medicines for children.
Section 18 of the law contains statutory language that amounts to a mandate for diverse enrollment: “In reaching an agreement regarding written protocols, the Secretary [of HHS] shall take into account adequate representation of children of ethnic and racial minorities.’’
While the focus of the provision is narrow, applicable to specific trials that may lead to a six-month marketing exclusivity for pediatric drugs, potential enforcement of the law would have broader implications for drug sponsors (The Cancer Letter, April 26, 2002).
For example, FDA could decide to withhold exclusivity from a company if it deems a trial design and accrual plan to have resulted in inadequate representation.
Now, officials at the Oncology Center of Excellence—an entity within FDA that uses an integrated, interdisciplinary approach to accelerate development of oncology products—are assessing options for enforcement, as well as strategies for ensuring greater diversity in adult trials.
“It certainly does give FDA enforcement authority on this issue, and we at the OCE are taking a really close look at enforcement of this authority,” said Lola Fashoyin-Aje, associate director of the Science & Policy Program to Address Disparities at the OCE, a deputy division director in FDA’s Office of Oncologic Diseases.
“But I want to emphasize that we want to see clinical trials in all populations really serve those populations, not only in providing access to the drug, but also just in generating evidence to support the safe and effective use of these therapies across a diverse group of patients,” Fashoyin-Aje said to The Cancer Letter.
An interview with Fashoyin-Aje appears here.
In conversations with The Cancer Letter, FDA officials, industry representatives, and group chairs at NCI’s National Clinical Trials Network say there is momentum across the board to reduce the disparity in access to novel therapeutics and clinical trials:
- “I think the events in 2020—the ongoing COVID-19 pandemic and how that really highlighted disparities that have existed for a very long time, and the murder of Mr. [George] Floyd—we are hearing from sponsors that they are mobilizing their teams to address this problem more proactively than they have in the past,” Fashoyin-Aje said.
- “Enhancing diversity in clinical trial populations can result in clinical studies that better reflect the patients that will use the new therapy or medicine being studied and help to improve health outcomes. Our member companies have developed and voluntarily adopted clinical trial diversity principles that address this and other aspects of clinical trial diversity,” said Andrew Powaleny, senior director of public affairs at PhRMA, a trade group that represents biopharmaceutical research companies in the U.S.
- “I think the state of diversity in oncology trials is somewhere inbetween. We did VERY poorly in the past, but have begun to make some progress. This problem is now getting increasing recognition, and we’re putting plans in place that do stand to make a difference,” said Charles Blanke, group chair of SWOG Cancer Research Network and a professor at OHSU Knight Cancer Institute.
- “Diverse participation is not great across the board, some research teams are doing better than others. In general, it is pretty dismal and we have a long way to go. First and foremost, investigators need to bridge trust with diverse populations to increase diverse participation in trials,” said Melissa Simon, chair of the Health Equity Committee at ECOG-ACRIN Cancer Research Group and founder and director of the Center for Health Equity Transformation and the Chicago Cancer Health Equity Collaborative at Northwestern University.
- “Our studies should be intentionally designed to minimize barriers to enrollment and made as broadly available to all populations. Also, the pediatric oncology community needs to increase the diversity of its members to ensure that every group has a voice and a representative in the field,” said Douglas Hawkins, group chair of Children’s Oncology Group and a professor of pediatrics at the University of Washington School of Medicine.
The responses from Blanke, Simon, and Hawkins appears here.
NCTN runs clinical trials at more than 2,000 academic and community treatment sites across the U.S. and internationally, and conducts publicly-funded research into new cancer treatments.
American cancer patients have collectively gained up to 14 million years of life since 1980 as a result of NCI-funded cancer trials conducted by the NCTN’s cooperative groups, a recent study led by SWOG Cancer Research Network found (The Cancer Letter, Oct. 1, 2021).
First steps: Designing actionable plans
Fashoyin-Aje is the program lead for OCE’s new Project Equity, which works to “improve access to clinical trials of oncology medical products for populations that have historically been underrepresented in clinical research.”
“Let me clarify that the OCE’s Project Equity represents a longstanding interest in driving change with regards to the clinical trial diversity,” Fashoyin-Aje said. “We have just recently put a name to those efforts.
“What undergirds our strategic priorities in this space is a firm belief that diversity is necessary from a social justice standpoint, and equally important, that diversity is a critical component to generating evidence in clinical trials that informs the safe and effective use of cancer therapies.”
Diverse participation is not great across the board, some research teams are doing better than others. In general, it is pretty dismal and we have a long way to go. First and foremost, investigators need to bridge trust with diverse populations to increase diverse participation in trials.Melissa Simon
FDA’s OCE is drawing on NCTN’s expertise to look at cancers that are particularly prevalent among ethnic and racial minority groups. As it stands, efforts to prospectively develop plans to ensure diverse enrollment are underway at each cooperative group—per FDA and NCI guidance.
“SWOG has developed a detailed methodology for increasing representativeness of its trials and is now in the stages of training members in the use of it. I know all the other [NCTN] network groups are doing the same,” SWOG’s Blanke said. “Even if they weren’t requiring steps to ensure diverse enrollment, it’s morally incumbent on us to do it anyway.”
This begs the question: Which populations are considered by FDA to be underrepresented in cancer drug development? While racial and ethnic minorities, particularly Black and Hispanic populations, are a primary focus, the agency also considers sex, age, and other clinical characteristics that may affect patient outcomes, Fashoyin-Aje said.
“The groups in cancer trials that we see consistently underrepresented relative to their representation among cases of the disease are participants who are members of racial and ethnic groups known to be underrepresented in clinical research in general—so, Blacks, Hispanics, etc.—older adults, and others,” Fashoyin-Aje said.
“Some of these groups and communities have been neglected by the biomedical research ecosystem for years and years, and so, the reception may not be warm and friendly. I think we have seen that with the COVID-19 vaccine development. But, if the commitment is there to improve things, we must persist.”
In a perspective piece published July 15 in JAMA Oncology, Fashoyin-Aje proposes a series of measures in OCE’s comprehensive plan to diversify cancer drug trials. OCE Director Richard Pazdur and Julia Beaver, OCE chief of medical oncology and OOD deputy director, are co-authors. A summary of those elements follows:
- Provide an overview of the disease or condition: Collect and discuss available epidemiological data and evidence in the overall population and in minority subgroups.
- Assess the drug development strategy: Describe elements of study designs and enrollment strategies, and evaluate pharmacological data.
- Target enrollment of members of racial and ethnic minority groups: Define and provide justification for the planned accrual of diverse patients.
- Identify measures to enroll a diverse population: Describe strategies and metrics to characterize safety and efficacy and to retain patients and meet diverse accrual goals.
- Delineate justification for deferral to postapproval: Describe proposed postapproval trials that will provide data on racial and ethnic minority patients, and a timeline for studies.
“We need to focus on correcting what has been for many, many years, an unfortunate disparity in access to potentially novel therapies and clinical trial participation, and just as equally important, disparity in the amount of evidence that is generated across more diverse populations,” Fashoyin-Aje said to The Cancer Letter.
“From an OCE perspective, we believe that thinking about diversity really early in drug development is key to actually moving from this all being a concept to be discussed and considered, to an action-driven effort. So, we are asking sponsors to develop and submit their plans for enrolling diverse populations in their clinical trials.”
Over the past year, the entire enterprise of cancer research and drug development has focused on building a diverse workforce and on characterizing cancer disparities in the catchment areas of cancer centers (The Cancer Letter, Nov. 5, June 25, 2021; Oct. 9, 2020).
Barriers vs. higher standards
The diverse enrollment provision in the Best Pharmaceuticals for Children Act of 2002 represents a “real opportunity for culture change,” said Nancy Goodman, founder and executive director of Kids v Cancer, a pediatric cancer think tank that has developed legislation to incentivize and require companies to invest in pediatric drug development.
“FDA has published a series of guidances to encourage industry to include underserved populations in clinical trials,” Goodman said to The Cancer Letter. “What is exciting about the BPCA provision is that here, FDA has express authority to require inclusion of diverse populations in clinical trials.”
The BPCA and the Pediatric Research Equity Act (PREA) have transformed the way medicines are developed and labeled for pediatric populations, PhRMA’s Powaleny said.
“Before BPCA and PREA became law, only about 20% of drug labeling had pediatric information. By 2012, 50% had pediatric information included in labeling,” Powaleny said. “These provisions have resulted in great strides against pediatric diseases, including HIV/AIDS, asthma, rare diseases and many forms of pediatric cancer (particularly blood cancers). Together, these laws spur pediatric research and development, through a careful balance of incentives and requirements and have greatly advanced children’s medical care in the United States.”
If FDA chooses to enforce the diverse enrollment mandate, drug sponsors would be able to adopt these best practices in non-pediatric trials, Goodman said.
“As companies work to comply with this new requirement, I think there is a decent chance the companies will choose to employ the strategies they develop for other clinical trials, including adult clinical trials,” Goodman said.
Pediatric cancer may be the one bright spot in diversity within trials. Because the overwhelming majority of children with cancer are treated at academic institutions, children of all ethnic and racial groups receive quality care and opportunities to be in clinical trials.Nancy Goodman
“Pediatric cancer may be the one bright spot in diversity within trials. Because the overwhelming majority of children with cancer are treated at academic institutions, children of all ethnic and racial groups receive quality care and opportunities to be in clinical trials.”
That said, a clinical trial investigator might wonder: Would a requirement for diverse enrollment introduce additional barriers to accrual and completion of some clinical trials?
“If the FDA did use this authority, it may have some impact on studies with investigational agents,” COG’s Hawkins said. “However, there are more complexities than simply exercising the authority.”
These “barriers” can be real or perceived, experts say. For instance, while minority patients may not trust investigational studies, physicians might believe—often based on unfounded assumptions—that certain patients may not be able to commit to participate in clinical trials. Other barriers could be structural in nature, as they pertain to insurance coverage, time, physical access, and affordability.
“There is deep mistrust in research. Science has mistreated and abused persons of color, especially in this country,” said ECOG-ACRIN’s Simon. “Tuskegee, Henrietta Lacks, and the contraceptive trials in Puerto Rico are some of the many examples. Scientists have unfortunately earned the distrust of many from participating in trials, and scientists have to work hard to earn trust back.
“This requires a variety of approaches including humility, and community engagement with community partners, ensuring that the clinical trials team is diverse, ensuring there are no out-of-pocket costs or other large barriers to participation in a trial, etc.”
Beyond well-worn discussions about barriers, investigators should focus on the value of extending the clinical trial enterprise to regions that are typically not represented—and prioritize generalizability of trial results, Fashoyin-Aje said.
“I think a big barrier for companies, really, has been a cultural view of the importance of diversity and the value of diversity,” Fashoyin-Aje said. “And I think, the conversation and the tone of the conversation tends to be too focused on the risks and not enough on the value and the benefits of diversity.
“I think that there’s a general view that the more heterogeneous that the study population is, the more noise you introduce to the investigation and the more difficult and challenging it may be to detect drug effects. And to that, I think I would say, we must set a higher bar for what we consider to be effective drugs.”
Blanke, group chair at SWOG, agrees that the conversation about the risks and benefits of diverse enrollment needs to evolve.
“I don’t believe this risk is real anymore, although it used to be,” Blanke said. “We have to think about diverse enrollment, and the cooperative groups have been focused on the value and benefits of it for a long time now.”
What Big Pharma can do
Pharmaceutical companies are aligned with FDA’s mission to encourage greater overall diversity in clinical trials, PhRMA’s Powaleny said.
“PhRMA and its member companies are committed to enhancing diverse participation in clinical trials including, but not limited to, pediatric and oncology trials,” Powaleny said. “These efforts include identifying and addressing potential barriers to enrollment while ensuring medicines get to patients in the most efficient manner. We are committed to working with the FDA, patient advocacy organizations and other stakeholders across the clinical research ecosystem to further collaborate and employ strategies to encourage greater participation in clinical trials.
“Additionally, real-world evidence has the potential to speed up the availability of additional information about a medicine across a diverse population of patients beyond those included in clinical trials.”
A recent report from PhRMA’s Equity Institute and the Deloitte Health Equity Institute listed five strategies to support robust engagement in communities to improve clinical trial diversity, build trust and help ensure clinical trials better reflect patient populations:
- Create a network of clinical trial sites in underserved communities: Establishing research sites in locations where potential participants already receive care, including non-traditional locations such as community health centers and pharmacies can help improve clinical trial diversity.
- Develop a diverse pool of investigators and staff: Racially and ethnically diverse investigators and staff who reflect the communities they serve are key community ambassadors for clinical trials and can help ensure trials are culturally competent and mindful of unconscious/implicit bias.
- Establish long-term relationships and investing in the community: Stakeholders of a community-based clinical-trial infrastructure should prioritize long-term and sustainable community building efforts, like investing in health education or supporting the next generation of diverse health practitioners and investigators.
- Engage the community in conversations: Sponsors should communicate and work toward shared understanding with the community about the importance of volunteer participation in trials. They should also commit to transparent engagement throughout the process including design of the trial, desired endpoints, and the results of the trial. They should also seek input into the elements of design that might impact community members’ ability to participate.
- Provide sustainable support and standardized platforms: Building a data infrastructure that leverages real world data could facilitate investigators identifying and engaging with patients appropriate for clinical trials and should include baseline measurements to improve data on race and ethnicity.
“Different populations may be at higher risk for certain diseases, such as sickle cell disease, certain cancers, diabetes or heart disease,” Powaleny said. “Clinical trials for the development of new medicines for these and all diseases should aim to reflect the patient population intended to take a new medicine.
“This is one way the industry can improve the care for the patients we serve.”
A renewed commitment to diversity in clinical trials should also include international considerations, Fashoyin-Aje said. FDA’s drug regulation pathways represent a gold standard for ensuring safety and effectiveness, and health agencies worldwide watch U.S. drug approvals very closely.
“All of this really needs to be considered in the context of the entire drug development program, not just the single pivotal trial,” Fashoyin-Aje said. “And, especially in oncology, where a majority of trials we review have a larger proportion of trial participants enrolled outside the U.S., we need to be thinking about diversity in the context of global drug development.
“So, there’s really a lot to unpack there, but it is really important to think of diversity more broadly than just race and ethnicity, to think about it early and throughout drug development, and consider the global context of cancer trials.
“Obviously, the factors contributing to disparities are multi-layered and thus there is no singular ‘fix’ to this problem. Rather, several measures really must be implemented in parallel and by multiple stakeholders to effectively and sustainably address this issue.
“Everyone has a stake in this and everyone must be held accountable for this.”
This story is part of a reporting fellowship on health care performance sponsored by the Association of Health Care Journalists and supported by The Commonwealth Fund.