Clinical Researcher—December 2022 (Volume 36, Issue 6)

SPECIAL FEATURE

Arturo Loaiza-Bonilla, MD, MSEd

 

The fight for fairness and equity in medicine took a dramatic step forward last June, when the U.S. House of Representatives passed legislation intended to increase the racial and ethnic diversity of patients enrolled in clinical trials of new drugs. The proposed law would require sponsors of clinical trials to develop and submit diversity action plans describing their goals and strategies for achieving demographic equity in Phase III studies of novel therapies.

Lack of diversity in clinical research is not a new problem; the U.S. Food and Drug Administration (FDA) has periodically issued guidance calling for greater inclusiveness in clinical trials since 1988. However, while new regulations and incentives for sponsors may help, no negative actions have been taken in the FDA’s oncology review divisions in cases of sponsor failure to conduct more diverse trials, and vague diversity guidance continues to raise concerns.

Lola Fashoyin-Aje, associate director of the FDA Oncology Center of Excellence and deputy director of the Center for Drug Evaluation and Research’s Division of Oncology III, said that the agency recognizes clinical development does not stop at application approval, adding that in some cases more studies may be necessary if diversity targets are not met.

“There may be circumstances where it is appropriate to do post-approval studies,” Fashoyin-Aje said after a session on enhancing clinical trial diversity, equity, and inclusion at the National Organization for Rare Disorders Breakthrough Summit. “Part of that will include understanding why we fell short. We will learn about what works and doesn’t work.”

Indeed, the global life sciences industry has much to learn to bridge the diversity divide in cancer clinical trial participation. The good news is advanced technology can help—it’s time to leverage such modern innovations as artificial intelligence (AI), digital tools, and analytics software to move the needle.

The Extent of the Problem in Oncology Research

Black people are significantly more likely to die of many forms of cancer than white people. Yet, while about 15% of cancer patients in the U.S. identify as Black or African American, they make up just 4 to 6% of participants in trials of investigational cancer therapies. Similarly, 13% of cancer patients identify as Hispanic or Latino, but that’s true of just 3 to 6% of enrollees in oncology trials. These figures may be even lower, since fewer than one-third of cancer trials report race and ethnicity data.{1}

These disparities contribute to the larger problem of social injustice in medicine, which was highlighted by the COVID-19 pandemic’s disproportionately cruel impact on communities of color but has persisted in the delivery of healthcare in the United States for millennia. What’s more, underrepresentation in clinical research is bad for medical science, since it frequently means that the racial composition of a patient cohort in a trial doesn’t mirror the disease burden in the real world and, consequently, the resulting therapeutics are not always equally effective for all demographics.

Black Americans are underrepresented in 85% of clinical trials—by a lot.{2} In a study published in Health Affairs last March, researchers began by compiling data on the portion of Black patients included in each of 225 pivotal trials (cancer trials made up more than one-third). Next, they looked at the general population of people who have each of the diseases treated in these studies and identified what percentage of these patients is Black. Comparing the two sets of data showed that the representation of Blacks in clinical trials was about one-third of what it should have been to reflect the diversity of patients who have each disease studied.

That’s a serious flaw in a study’s design. Underrepresentation of a demographic group in a clinical trial can fail to reveal a benefit or risk that an investigational therapy may have for a given demographic group, since it’s well established that race and ethnicity can affect the pharmacokinetics and pharmacodynamics of a drug, and thus its safety and effectiveness. There are many examples of this phenomenon—for instance, doctors avoid prescribing ACE inhibitors to Black patients, who tend not to respond well to these blood pressure medications.

Nowhere is this more impactful than in cancer, where there are more diagnoses now but lower mortality rates (the death rate from cancer fell 32% between 1991 and 2019) presumably due, in part, to an increase in novel treatments and clinical trials. Fortunately, it appears that the industry is passionate about rectifying this pervasive problem, but it’s not going to be easy. Good intentions, and even regulatory changes, may not be enough. A true fix must address many multifaceted hurdles.

“We can improve population representation in cancer clinical trials by investing in the education and recruitment of more diverse trial investigators,” said Elena Rios, MD, MSPH, MACP, president and CEO of the National Hispanic Medical Association. “Hispanics and Latinos [make up] about 19% of the U.S. population, yet less than 7% are physicians and less than 1% work in academic facilities. Hispanic clinicians tend to attract patients from their own communities. If more Hispanic clinicians were involved in clinical research, naturally, more of their Hispanic patients would participate in their trials.”

Hurdles to Overcome

Why is it such a challenge to establish equitable participation of people of color in clinical trials? It’s a complex question that lacks easy answers, but some factors include:

• System Mistrust—This is an unfortunate legacy of past research abuses such as the infamous Tuskegee Syphilis Study, in which Black men who had the sexually transmitted disease were recruited to participate, but never offered treatment. In several studies, Black people told investigators they believed that patients in clinical trials were “guinea pigs.”{2}
• Clinician Bias—A recent joint statement{1} on the need to increase racial and ethnic diversity in clinical trials from the American Society of Clinical Oncology (ASCO) and Association of Community Cancer Centers cited clinician bias as one barrier. “Clinicians may believe people from racial and ethnic minority populations will be unwilling to enroll or unable to comply with trial protocols,” the authors speculated. Finding the right clinical trial for each cancer patient takes a lot of time, too, which many oncologists lack. Further, a new paper presented at ASCO’s annual meeting in June found that 40% of Black patients with metastatic breast cancer said that no one on their healthcare team mentioned the possibility of enrolling in a clinical trial versus 33% of White patients.
• Financial Barriers—People from underserved communities tend to have lower socioeconomic status, making it difficult to cope with costs associated with participating in a clinical trial, such as travel and lodging expenses. Most recently, decentralized trials are helping to offset these issues. Hybrid trials—combining a mixture of site-based and decentralized solutions—make it possible to conduct aspects of the trial remotely, supporting a better patient experience and increasing access to trials while still conducting the aspects that require in-person interactions.
• Lack of Clinical Trial Awareness—Low health literacy disproportionately affects Black Americans, and studies have found that levels of knowledge about clinical trials are lower in communities of color whereas education about trials has been shown to increase willingness to participate.{2}

“Our foundation is building a network of Hispanic and Latino clinicians running clinical trials as well as educating and promoting the profession of researcher to young residents,” explained Dr. Rios. “We do this through scholarship, mentoring, and annual meetings in conjunction with the [National Institutes of Health] to foster research skills and passion for research. In the end, it is these physicians who will be instrumental in promoting trial participation in their local communities.”

• Restrictive Inclusion/Exclusion Criteria—Oncology trials are notoriously stringent in their participation criteria. In fact, 40% of patients with cancer trials available to them are not eligible to enroll due to eligibility requirements, according to a report, and there can be an unintended bias.{3} For instance, Blacks are more likely to have comorbidities, such as cardiovascular disease, that prevent them from enrolling in clinical trials due to stringent exclusion criteria. While these criteria are intended to ensure patient safety and create a homogenous study cohort, they may be too rigid. The U.S. National Cancer Institute (NCI) concluded that eligibility criteria arbitrarily eliminate patients and should be simplified and relaxed.

The Biggest Hurdle of All—And How to Overcome It

Arguably, the biggest barrier to fair representation in cancer trials is the disconnect that exists between where most cancer trials are conducted and where most patients live.

Across the United States, 71 NCI-designated cancer centers perform novel oncology research. Most NCI-designated cancer centers are affiliated with academic medical centers, which tend to be in large urban centers. While the contributions of these hotbeds of oncology research can’t be overstated, they serve a minority of cancer patients. Of the 1,700,000 Americans diagnosed with cancer in 2021, only about 15%, or roughly 255,000, were treated at NCI-designated cancer centers. The other 85% received care at community-based practices.{4} This means that the NCI-designated sites with breadth of knowledge and experience in conducting clinical trials serve relatively few patients while community-based practices with huge volumes of patients handle very few trials.

As an industry, we can dramatically improve diversity in trials if we recruit from the entire community of cancer patients instead of a select group that happens to have the geographical advantage of living near an NCI-designated site. New technology, driven by AI and powerful algorithms, can help cancer patients and their clinicians rapidly identify trials that aren’t necessarily being studied at the clinic down the road, but that could add years to their lives. In fact, SYNERGY-AI is an innovative platform that uses AI to extract information automatically from patients’ electronic health records, including biomarker and other test results, and quickly identify cancer trial matches. The platform has onboarded more than 102,000 patients since 2020 with an additional 6,000 patients every month.{5}

“AI and machine learning technologies can play a major role in identifying both patients and clinicians of color,” according to Dr. Rios. “It would help more, though, if it were no longer optional to notate your ethnicity in healthcare records. We need to track ethnicity for everyone so it’s easier to find diverse patient pools and oncologists. We know where doctors work, but we don’t always know their ethnicity.”

This seemingly simple approach is now feasible with the advent of decentralized or hybrid trials which makes geography less of a non-starter for trial participation. Increasingly, investigators leveraging these trial models allow patients to participate largely from their own homes by supplementing site visits with digital alternatives such as telemedicine, wearable devices, smart apps, and direct delivery of study drugs and materials to patients. These trials are not only faster and more efficient than traditional trials where patients must report regularly to a clinical site, but also more democratic and inclusive.

The Bloomberg New Economy International Cancer Coalition brings together academia, industry, government, patient advocacy and policy think tanks to leverage technology and collaboration to improve patient access to clinical trials and to harmonize regulations aiming to accelerate cancer cures and prevention worldwide. The coalition members convene regularly to explore ways to achieve better access to clinical trials, and one conclusion is that “innovations in information technology should be part of the solutions to overcoming many of diversity barriers.”

When it comes to cancer patient matching, the coalition agrees:

Specifically, with clinical information entered appropriately into an electronic health record during routine care, the central registration and trial management software can systematically identify patients and match them to trials based on the molecular features of their tumors and other eligibility criteria. Efforts should also be put toward increasing awareness of biomarker testing through physician and patient education, as well as decreasing barriers to access through infrastructure improvement and the adoption of new technology.

The technology is here today that can help finally overcome many of the biggest barriers to population representation in cancer clinical trials, but it takes more than just technology. As we get excited about the potential promise of AI and analytics-based solutions, it’s just as critical to help patients through that last mile in trial enrollment. Companies that provide high-touch care for patients who are often overwhelmed by trials and, at the same time, exhausted by the side effects of their treatment and disease. In this “last mile,” one-on-one patient handholding can also serve to sensitively identify and eliminate any unanticipated participation barriers, such as travel logistics and costs, and maintain their active engagement until the very last dose of their investigational treatment.

References

1. Oyer RA, et al. Increasing Racial and Ethnic Diversity in Cancer Clinical Trials: An American Society of Clinical Oncology and Association of Community Cancer Centers Joint Research Statement. Journal of Clinical Oncology 40:2163–71.
2. Rivers D, et al. 2013. A Systematic Review of the Factors Influencing African Americans’ Participation in Cancer Clinical Trials. Contemporary Clinical Trials 35(2):13–32.
3. American Cancer Society. Cancer Action Network. 2018. Barriers to Patient Enrollment in Therapeutic Clinical Trials (by members of project steering committee including Jeff Allen, PhD, Kendall Bergman, Suanna Bruinooge, MPH, et al.) https://www.fightcancer.org/sites/default/files/National%20Documents/Clinical-Trials-Landscape-Report.pdf
4. National Cancer Institute. National Institutes of Health. 2019. NCI-Designated Cancer Centers. https://www.cancer.gov/research/infrastructure/cancer-centers
5. Massive Bio Onboards Over 100,000 Cancer Patients. 2022. Applied Clinical Trials. https://www.appliedclinicaltrialsonline.com/view/massive-bio-onboards-over-100-000-cancer-patients

 

Arturo Loaiza-Bonilla, MD, MSEd, is Co-Founder and Chief Medical Officer at Massive Bio in New York and Medical Director of Oncology for Capital Health (US) in New Jersey and Pennsylvania.