As trial diversity becomes a must, so does a change in how to recruit
Codifying requirement is a start, but sponsors will need to go beyond standard approaches to deliver on trial diversity goals
It’s evident that most biopharma companies would like to address diversity and equity in clinical trials, and equally clear that almost none of them know how to do that. New tools, directives and the recently passed DEPICT Act could partly tackle the problem, but change won’t happen organically — sponsors will need to put some elbow grease into creating properly fit-for-purpose clinical trials that represent the make-up of the patient population.
Addressing the problem that minority racial and ethnic groups are underrepresented in clinical trials has shot to the top of the to-do list for FDA, and many in industry have recognized the need for change in particular in the wake of the pandemic.
It’s hard to know how much impact the recent enlightenment is having. The statistics, which are dire, are largely a lagging indicator, reflecting trial designs put in place years ago. They provide a benchmark for measuring improvement, however, even if it’s a low bar.
At a panel on disparities in the clinical trial environment at the Jan. 8 UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI) summit, FDA’s Patrizia Cavazzoni said that despite significant progress in certain areas, “we see from countless examples we’re clearly not there yet.”
“This will be the first time that there’s ever been a standard for diversity in clinical trials in law.”
The issue goes beyond questions of equal access and social justice, which are major motivators alone. The trials as conducted don’t give FDA, physicians, patients or payers full information to support use of therapies.
The lack of diversity in recruitment, said Cavazzoni, “translates to evidence that doesn’t necessarily tell us how the drug will perform in people who will take it up after it’s approved.”
Cavazzoni, who is director of FDA’s Center for Drug Evaluation and Research (CDER), co-moderated the panel with Laura Esserman, professor of surgery and radiology at the University of California San Francisco.
The goal is to have diversity in clinical trials reflect the prevalence of the disease in different demographic subgroups. “It really has to be bigger than the percent of the population. It has to be commensurate with the burden of disease,” said Ricki Fairley, co-founder and CEO of Touch, The Black Breast Cancer Alliance.
FDA has issued guidance on diversity in clinical trial enrollment, and its Oncology Center of Excellence Director Richard Pazdur has been vocal about requiring cancer trials to represent the U.S. population. Recently, FDA has rejected applications for cancer therapies based on China-only patient data.
Now, the agency has gained more muscle with the incorporation of the DEPICT Act into the omnibus spending bill that passed at the end of last year. DEPICT requires drugmakers to report to FDA how they will include representative patient groups in their clinical trials.
While FDA’s most recent draft guidance on the topic calls for sponsors to submit clinical trial diversity plans to the agency, the legislation makes this a formal requirement.
“This will be the first time that there’s ever been a standard for diversity in clinical trials in law,” Rep. Anna Eshoo (D-Calif.) told the CERSI meeting. “In the past, FDA has sought to improve clinical trial diversity through voluntary guidance,” she added. Embedding this in law is the first step to putting more weight behind the drive to diversity, said Eshoo. Next, she is picking up the baton from former Democratic California lawmaker Jackie Speier, who spearheaded legislation that would bring insurance coverage into the loop to help achieve diversity in trials.
The new law focuses on clinical trial diversity in late-stage and registrational trials, but FDA wants sponsors to be building diversity plans before they even enter the clinic.
“A clinical diversity recruitment plan is something that really has to span the entire breadth of the development of a drug,” said Cavazzoni on the panel. “Researchers and companies should come to us early, and ideally, they should start talking about these strategies at the very first touch point with FDA.”
The law will require sponsors to submit to FDA a “diversity action plan” for Phase III and most other pivotal trials, outlining the goals for enrollment, the rationale behind the goals, and an explanation of how the sponsor intends to meet the goals. Sponsors need to do this “as soon as practicable,” and at latest by the time they submit a protocol.
FDA can give waivers to the diversity requirements if the prevalence or incidence of the disease under investigation makes the requirements impracticable, or if a waiver is needed to protect public health during a public health emergency. There is also an exemption for submissions for compassionate use.
“Ideally they should start talking about these strategies at the very first touch point with FDA.”
The law tasks FDA with updating or issuing guidance on the diversity action plan, and on promoting decentralized clinical trials, use of digital health technology and telehealth to enable a clinically diverse population. It will come into effect 180 days after FDA finalizes the guidance.
The agency also needs to hold public workshops to gain input from stakeholders on enrollment of historically underrepresented populations in clinical studies.
The workshops must cover how and when to collect prevalence or incidence data by demographic subgroup along with data sources and methodologies for assessing the information. They’ll also address how to disseminate post-approval the clinical study enrollment demographics, how to establish the goals for enrollment, and how to go about gaining the participation of underrepresented groups to achieve those goals.
FDA must submit an annual report to Congress on progress against the goals.
Going further afield
Now that clinical trial diversity is on regulators’ and sponsors’ radar, the biggest stumbling block will be achieving participation of underrepresented groups, which requires a departure from the standard approach of operating via the major academic medical centers.
Michael Drake, president of the University of California, said on the panel that going out of the big medical centers is essential for ensuring that socioeconomic differences are balanced. Referring to an analysis of studies done previously at major academic centers and hospitals, he said, “the average level of education of a patient in a clinical trial was about one year of graduate school, and that really didn’t mirror the population as a whole.”
Fairley, who is a breast cancer survivor, said there’s a two-way gap — a lack of outreach to minority communities and a lack of awareness and understanding in those communities of the value of participating.
“First of all, doctors aren’t inviting us to clinical trials — that’s the biggest problem. But really, there’s a significant fear of the unknown, so you add to that earned medical mistrust,” and the result is an uphill struggle to recruit patients, she said. “We don’t understand how the science works, we don’t understand standard of care, we don’t understand really what the benefits of trials are, and so we shy away from them.”
Fairley’s organization engages Black women who have had breast cancer to educate others about participating in clinical trials. She said many women in Black communities don’t trust doctors, researchers or pharmaceutical companies. “They trust people who are in the same position as them.”
Fairley said the campaign signed up 5,000 Black women in six months into clinical trial portals.
“If you can’t go and get your standard of care at the place where the trials are, you basically can’t participate.”
Esserman underscored the need for active outreach rather than assuming that passively opening trials to everyone will work. She cited efforts to recruit women to the WISDOM trial, which is testing a personalized approach to screening for breast cancer against annual mammograms.
Esserman said that at the outset, the idea was that taking the trial beyond academia and opening it up to the whole population would provide a representative patient cohort. That did not work well. “After two and a half years, we had 1% enrollment of African-American women,” said Esserman. Working with Fairley and other groups embedded in diverse communities raised the enrollment to 16%.
Sohail Rao, president and CEO of DHR Health Institute for Research and Development, has been working in Texas’ Hidalgo County to increase the number of clinical trials performed there, and increase participation of the Hispanic community. Historically, patients in that region have not been interested or active in trials, he said on the panel. “Even if we do recruit patients, there is a very high incidence of loss to follow-up.”
Rao likewise engaged patients to talk to other patients, and said that educating the children of community members by going to high schools and colleges was an effective means of teaching the importance of research that could be transmitted up to the parents’ generation, and seeding trust for future trials.
Decentralizing the trials helped bridge to patients that would normally face difficulties participating. “We understood that these are uninsured patients — that their access to medical care is very poor,” said Rao. “We now have clinical coordinators and physician and mid-level providers who go to patients’ homes for follow-up visits, so the patient doesn’t have to come to our center,” said Rao. He added that they are also creating brick-and-mortar facilities that are distinct from the main center to provide infusion therapies or other advanced types of therapies.
The Clinical Trials Coverage Act introduced by Speier aimed to assist with costs by requiring insurance companies to cover health services provided to individuals participating in approved clinical trials. Eshoo said she is following through with the bill, which did not make it through the last Congress, and wants to add coverage for transportation and childcare costs.
Esserman, who worked with Speier on the bill, said that insurance coverage is essential for access. “If trials are only available in certain places, and if you can’t go and get your standard of care at the place where the trials are, you basically can’t participate, so this is a matter of equity.” A similar law was enacted in California in 2002.
Creating effective diversity plans will involve balancing needs that are in some cases opposing forces. The quest for increasing amounts of data to understand a molecule’s action needs to be offset against the burden of collecting the information. And the recruitment requirements will bring a cost, in terms of both dollars and time, that could be particularly onerous for small companies, and counter-effective to bringing new therapies to market.
Digital technologies and decentralized trials are going to be key to the solution. During the pandemic, these proved effective in some cases for accessing populations that were difficult to recruit. For example, on The BioCentury Show in October, NIH’s National Institute on Drug Abuse (NIDA) Director Nora Volkow said that virtual recruitment has started to prove its worth in trials on substance use disorders.
Cavazzoni said that progress is being made in digital solutions as a result of the ACT for ALS. Funds from the legislation have been used for grants, for example studying use of telemedicine to enable patients in wheelchairs to avoid needing to attend a clinical center, as well as for creating functional readouts that can be collected at home.
Development of such technologies can be leveraged to broaden the use of decentralized trials. Digital technologies open the door to collection of a wide range of different data points that can inform new endpoints and gauge patient response in new ways, sometimes on a continuous basis rather than the periodic readouts that centralized hospital visits entail.
“We need to strike a balance against making development programs impossible to execute.”
At the same time, making trials more accessible to community settings will mean they have to be simplified, a lesson that was key to the success of the U.K.’s RECOVERY trial during the pandemic.
Cavazzoni emphasized that will mean leaving some wish-list data on the table. It involves “getting to a point where clinical trial protocols and execution are fit-for-purpose for the questions that are being asked, and not complicated by a whole bunch of things that may be intellectually interesting, that do not necessarily add to what the trial is really supposed to answer.”
FDA can influence this by ensuring clinical trial designs and statistical analysis plans are centered on quality-by-design principles, meaning they only involve aspects of quality that are meaningful and have a direct impact on the outcomes of the trial.
But Cavazzoni wants to see other parts of the ecosystem involved as well, citing NIH as one agency that could have a role in “striving to simplify clinical trials.” She said the academic community and medical journals are also on the hook. And payers have a role — they should want trials to provide data for all the patients who could eventually take the drug.
A report by the National Academies of Sciences, Engineering, and Medicine on improving clinical trials diversity proposed that CMS could incentivize community providers to drive participation by creating new payment codes, and reimbursing for time and infrastructure.
Cavazzoni acknowledged that extensive requirements can be a burden on some companies, and noted some pushback from industry. “We need to strike a balance against making development programs impossible to execute.”
“First and foremost,” said Cavazzoni, “planning for a diverse and inclusive clinical trial needs to be a standard approach and not the exception.”