FDA’s Lola Fashoyin-Aje: Stop getting stuck on the “risks” of diversity in drug development, it’s time to fix disparities in access

There’s a cultural perception in drug development that enrolling a diverse, heterogeneous patient cohort can be “risky” for detecting drug effects—a perception that needs to go away, said Lola Fashoyin-Aje, associate director of the Science & Policy Program to Address Disparities at the FDA’s Oncology Center of Excellence and a deputy division director in the agency’s Office of Oncologic Diseases.

“I think that there’s sort of the view around risks that have been conveyed by industry across many different levels, with many different considerations,” Fashoyin-Aje said to The Cancer Letter. “To that, I think I would say, we must set a higher bar for what we consider to be effective drugs.”

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.”

“I think there really needs to be a fundamental view change, a paradigm shift in terms of how diversity is viewed in drug development,” Fashoyin-Aje said. “I think it would be interesting to kind of move away from that focus and into more of, what is the value that diversity brings? 

“What are the opportunities for learning about drug effects across the population, and the potential to achieve true improvements in outcomes from new therapies if we can really better characterize the effects of these therapies across a broader population?”

As FDA expands its commitment to improve health equity in drug development and sets its sights on defining “adequate representation” of minorities in clinical trials, Fashoyin-Aje and her colleagues at OCE are reexamining trial design and accrual strategies, streamlining eligibility criteria, and leveraging real-world evidence to generate evidence for historically underrepresented groups.

“I think that another area with a growing interest is in the implementation of measures that mitigate some of the burdens of participating in a clinical trial—encouraging aspects of clinical trial decentralization, as an example,” Fashoyin-Aje said. “Even though this is not a new concept, I think that there has been increased visibility and interest in some of those measures as a way to really decrease the burden to patients who are participating in the clinical trials.

“But we want to do that while maintaining patient safety, preserving study integrity, and we want to ensure that there’s quality data at the end of the day that really answers the important scientific and clinical questions.”

The OCE is focused on correcting years of stark disparities in access to novel therapies and clinical trials, as well as on collecting data on diverse populations to close the gap in evidence generation, Fashoyin-Aje said.

“We have to start putting into action strategies that move us forward and not remain stuck in lamenting the challenges, risks, uncertainties, etc., of changing how we have done things for a very long time,” Fashoyin-Aje said. “It is not easy work, nor should the expectation be that it will be.”

Fashoyin-Aje spoke with Matthew Ong, associate editor of The Cancer Letter.

A video of the conversation appears here.

Lola Fashoyin-Aje: Sure, and thank you so much for the invitation to participate in this. 

First, let me say that diversity is a broad concept that can mean a lot of things. Often, when the term diversity is used, the reference is usually to racial and ethnic diversity.

In the Oncology Center of Excellence (OCE), and broadly across the FDA, when we promote diverse representation in clinical trials, we are thinking about it across demographic factors like race, ethnicity, sex, age, as well as across clinical characteristics that may impact outcomes.

Then, all of this really needs to be considered in the context of the entire drug development program, not just the single pivotal trial. 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. 

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.

From the clinical perspective, the oncology drug development ecosystem has had too high a tolerance for high toxicity, and this has led to really stringent clinical criteria for enrolling in clinical trials, such that the clinical trial participant is really different than the patients in the real-world setting who receive the drugs once they are approved, with less comorbidities and less organ dysfunction as examples.

So, we need to embrace a more inclusive approach to trial entry criteria to better match the trial population to the population that will receive the drug, and it’s really challenging I think to optimally develop a drug that is intended to improve population outcomes when the trial population is narrowly defined. 

I think from a global perspective, we need to optimize the opportunities for achieving diversity by bringing other regions, countries into the clinical trial enterprise, so to speak, to have better representation of trial participants from regions like Africa and Central and South America in oncology trials. 

So, global diversity is very much in alignment with the goals of evaluating drugs in a population that provides the opportunity to not only understand differential drug effects, but also to potentially learn about the disease itself.

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.

LFA: Sure, I can’t say that there are considerations in that guidance that are especially unique to oncology.

Many of the factors that contribute to disparities in enrollment and retention rates across groups that are defined by demographic characteristics like race are really cross-cutting across therapeutic areas.

But the existing FDA guidances related to the topic of diversity really provide recommendations on tangible measures that can be implemented to address these barriers.

And they typically comprise measures that may address trial-specific barriers like eligibility criteria or excessively burdensome trial-related procedures and testing during the trial, measures that address more structural ecosystem-related barriers, such as site selection, investigator selection, etc., and also measures that can really cultivate trust with the affected communities. 

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.

Finally, I think the success of these measures requires a thoughtful strategy that is implemented in a prospective way.

LFA: Well, first let me clarify that the OCE’s Project Equity represents a longstanding interest in driving change with regards to the clinical trial diversity. 

We have just recently put a name to those efforts. But it is important to understand that we have had a longstanding commitment to this issue even before it garnered the visibility and interest that it has during this past almost two years.

But getting back to your question, I think some of what I described earlier about our broad view of what diversity means is important, so that we are as inclusive in our approach as possible. 

But, really, 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. 

We recently published a perspective in JAMA Oncology this past summer on why it is really important to address diversity in cancer drug development and why this is a priority for the OCE.

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.

Our approach to implementing our strategic priorities is multipronged, focusing on outreach, engagement, collaboration, policy development and implementation, and research and information sharing, and I would refer your readers to our prospective piece in JAMA Oncology.

LFA: I think we recognize that the factors that contribute to this problem are interrelated and can seem really daunting for any one entity to undertake. 

And I think the challenge sometimes is really convincing folks that we need not wait until we have an all-encompassing and perfect approach to really get working on this issue. 

We have to start putting into action strategies that move us forward and not remain stuck in lamenting the challenges, risks, uncertainties, etc., of changing how we have done things for a very long time. It is not easy work, nor should the expectation be that it will be. 

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. 

Dr. [Richard] Pazdur [OCE director] likes to remind us not to let perfection be the enemy of the good. So, we must really recognize the value and the learning that comes with moving from kind of a talking space—all the roundtables, all the assessments and the workshops—to sort of the “doing” phase of things. As I mentioned, we all have a part that we can work on.

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.

These measures should be implemented as early as possible, including for those studies that are conducted to characterize the pharmacokinetics and the pharmacodynamics of a drug.

We are also taking a look at well-known barriers like eligibility criteria, and encouraging sponsors to streamline them, and to implement them in a way that is informed by the science and not historical practice. We’ve been working on this for many years with other stakeholders and have several guidances addressing this issue.

But really, just being more proactive and also being more vigilant when we review protocols to ensure that sponsors are actually following those guidances.

And I think the challenge sometimes is really convincing folks that we need not wait until we have an all-encompassing and perfect approach to really get working on this issue.

I think that another area with a growing interest is in the implementation of measures that mitigate some of the burdens of participating in a clinical trial—encouraging aspects of clinical trial decentralization, as an example. 

Even though this is not a new concept, I think that there has been increased visibility and interest in some of those measures as a way to really decrease the burden to patients who are participating in the clinical trials.

But we want to do that while maintaining patient safety, preserving study integrity, and we want to ensure that there’s quality data at the end of the day that really answers the important scientific and clinical questions.

So, some of these things are not necessarily within the FDA purview, so there needs to be infrastructure and capacity at the community level to support these decentralization measures, but we certainly support the approach of implementing measures that increase access to trials, and that may increase the potential to retain participants in the trials.

Finally, I think that there’s also increased recognition that real-world data and real-world evidence can be really useful in addressing knowledge gaps when it is appropriately used. 

We have had ongoing efforts to help us understand how these types of data can be used again in the appropriate context, taking care not to relegate generating evidence for historically underrepresented groups to just the real-world data and real-world evidence as, really, these cannot and should not be used in lieu of the clinical trials, which still represents the gold standard to characterizing safety and effectiveness of new drugs. 

But these types of data can be really helpful in designing better trials. 

So, there are a few of the very tangible things that can be done and that we are doing in the Oncology Center of Excellence to move the needle on this issue, at least from our perspective and within our purview.

LFA: Yeah, I think 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. 

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.

And so, I think while the pediatric cases are a specific authority, in other settings, I think even without the explicit authority, we can all do a lot more to drive adequate representation and clinical trials.

LFA: Well I’m not sure there’s a particular disease that is really deserving of more attention than others. 

There are certainly some diseases that disproportionately affect, for example, racial and ethnic minorities and/or older adults, where there really should be a lot of focus to ensure that the data that are generated from the trials are generalizable to those populations.

There are some diseases like multiple myeloma, for example, where there are known biological differences in the disease presentation that track with or are associated with race or age, where really specific attention, I think, is required to ensure that we are really evaluating new therapies, taking into account those known associations.

And there may be other biological factors, drivers of cancer that are not exclusive to one group, but that may be more prevalent in one group compared to another, and we may not uncover those differences without a more inclusive approach to trial enrollment for this population.

So, I guess, to answer your question, I think that we are so far behind where we need to be in terms of conducting inclusive drug development programs that I don’t think focusing on one trial or a one disease area is the appropriate approach, because, as I mentioned, many of the barriers, once they are addressed, will really benefit all patients.

LFA: Well, I think this is really a question for pharmaceutical companies. But I would say that there’s no question that it is a gargantuan task to go from decades of not having a prospective and comprehensive approach to addressing this issue to doing so in 2021.

I think some companies have made great strides in that direction over a number of years now, but it is certainly not the majority.

And I think a big barrier for companies, really, has been a cultural view of the importance of diversity and the value of diversity. 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.

So, I think it is really important to be transparent about what is viewed as a risk. I think that what will really fundamentally lead to change is a shift from this view that diversity poses risks to drug development to a view that there’s uncertainty that has to be embraced if we’re really going to change, and that change will not come from a place of aversion to risks or challenges, but rather in the doing despite the perceived risks and challenges and learning from those experiences.

I think pharmaceutical sponsors are probably better equipped to respond to this question, but I think there really needs to be a fundamental view change, a paradigm shift in terms of how diversity is viewed in drug development.

LFA: I’m not sure I understand it either, but 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. 

I think there’s also a view that enrolling populations that have typically not been enrolled in clinical trials poses a great deal of uncertainty regarding what the outcomes may be, and that unknown is risky. 

I think a third concern and consideration that I’ve heard is that there is a lot of time and expense spent on enrolling these populations or members of these populations in the clinical trial, and that the risks of setting enrollment goals, is that you slow down enrollment or maybe you don’t completely accrue in the trial.

So, I think that there’s sort of the view around risks that have been conveyed by industry across many different levels, with many different considerations.

I think it would be interesting to kind of move away from that focus and into more of, what is the value that diversity brings? 

What are the opportunities for learning about drug effects across the population, and the potential to achieve true improvements in outcomes from new therapies if we can really better characterize the effects of these therapies across a broader population?

And what is the value of extending the clinical trial enterprise to regions that are typically not represented, where you may have such richness in genetic diversity that would really inform understanding of the diseases and drug effects in those diseases?

Thank you for expounding on that. So, what should we be expecting to hear from FDA and the OCE over the next few months or a year on these matters? What’s in the works?

LFA: Well, we’re working on the same issue. We’ve been working on the same issues since before 2020 and will continue to work on these issues, until we really get to a place where we feel that we are implementing some strategies that have been described that have been successful in certain settings that we are applying those more broadly.

But we’re also learning from the experiences about how to do this and how to do this well.

So, that is what we expect to continue to do and to continue to provide more transparency regarding our expectations as we learn more.

And what advice do you have for our readers, both at cancer centers and at life sciences companies who read us on a weekly basis, for what they can do to help achieve the goals of Project Equity and FDA’s larger approach to this?

LFA: That’s a tough question. I mean, it takes a village, and we all have a part to play.

We all have a part to do, and we all have a part to play to keep each other accountable, and so, I would say it takes a village and everyone should do their part.

I think the other is Dr. Pazdur’s famous words, “Let’s not let perfection be the enemy of the good.” There is a lot of value in learning from our successes, but also from our failures.

We have to get started somewhere, and as we learn will get better, hopefully. That’s the goal. 

Did we miss anything?

LFA: I think this conversation could go on and on and on, but I thank you for inviting us to participate in this interview.

Thank you so much for taking the time.