A study published by researchers at the University of Arkansas for Medical Sciences has caused quite a stir, reminding regulators and the public that, even in clinical studies for such cutting-edge therapeutics, the industry continues to struggle with achieving the goal of making clinical trials representative for all prospective patient demographic groups.
Examining Black Representation in Pivotal CAR-T Trials
The recent approval of several chimeric antigen receptor T (CAR-T) immuno-oncology therapies — leveraging a patient’s own genetically modified T cells to find and kill cancer — has been heralded as the beginning of a new era of promise for patients with the most difficult-to-treat cancers. However, in order to ensure that these new therapies will have maximal efficacy and safety for all patients, it is critical that the clinical trials leading to their approvals undergo deliberate subject selection to establish representative patient populations, particularly for the demographic groups most affected by the relevant cancers.
A recent study, conducted by Al Hadidi et al. and published in JAMA Network Open in late April, investigated the pivotal clinical trials that underpinned the U.S. FDA’s approval of CAR-T therapies for hematological malignant neoplasms to explore the proportion of black participants, particularly with regard to the increased prevalence of the disease in those communities. The cross-sectional study used publicly available data on drug products and demographic subgroups within seven clinical trials that investigated CAR-T therapies and led to the approval of five products for seven indications — diffuse large B cell lymphoma (KYMRIAHTM (tisagenlecleucel), YESCARTATM (axicabtagene ciloleucel), and BREYANZI® (lisocabtagene maraleucel)); acute lymphoblastic leukemia (KYMRIAH and YESCARTA); follicular lymphoma (YESCARTA); mantle cell lymphoma (TECARTUSTM (brexucabtagene autoleucel)); and multiple myeloma (ABECMA® (idecabtagene vicleucel)) — for patients with relapsed or refractory disease who had received multiple lines of previous therapies.
Of 1,057 patients enrolled in these studies, 746 received CAR-T therapy (71%), and efficacy was reported in 729 (69%). The number of black participants among the study populations was low in all cases, varying in the range of 1–12 participants per study (2–5% of the study population).
These low numbers are even more stark when placed in the context of the elevated prevalence of these diseases among black individuals. To reflect that context, the investigators calculated the participation-to-prevalence ratio (PPR) as the percentage of black participants within study populations divided by the percentage of black individuals within the disease population. A study that fully represented each demographic according to disease burden would exhibit a PPR of 1.0.
Representation came close to being achieved in the studies exploring follicular lymphoma (PPR = 0.8), potentially driven by the fact that follicular lymphoma is less common among black individuals than the other hematological cancers examined.
The most striking disparity was found in the studies exploring XPOVIO for multiple myeloma. Multiple myeloma affects black persons at an incidence rate more than twice as high as that for non-Hispanic whites, an issue compounded by reduced access to treatments, including hematopoietic stem cell transplantation. In the studies that led to the approval of XPOVIO, the PRR was a low 0.2. “Black patients with [multiple myeloma] face multiple disparities, including lower use of hematopoietic stem cell transplantation, palliative care, and novel therapeutics, which may result in worse outcomes. Lack of access to novel therapies that disproportionately affect Black persons may result in further widening of the existing established disparities,” the authors wrote in the study.
Representation Issues are Nothing New
While significant progress has been made in recent decades to meet regulatory guidance for balanced diversity in subject selection, there continue to be issues of underrepresentation in clinical trials, both for minority groups in U.S. clinical trials and for various racial and ethnic groups internationally.
The groups that are the least fairly represented in clinical trials are African-Americans in U.S. trials and Africans overall in international trials. A 2018 ProPublica study found, in trials for 24 of the 31 oncology drugs approved over the previous three years, that less than 5% of trial subjects were African-American, despite black Americans making up 13% of the U.S. population.2 This underrepresentation is made more significant by the fact that African-Americans have the highest death rate and shortest survival rates of any group in the United States for many classes of cancer, including those investigated by Al Hadidi et al. and others.3 Globally, as few as 2% of cancer clinical trials are conducted in Africa, home to 17% of the world’s population.4
The issues regarding representation are even starker in individual cases, a reality that has been known for some time. In 2015, a new drug for multiple myeloma was approved by the FDA following promising trial results. However, in that trial, which had a cohort of 722 patients, only 13 (1.8%) were African-American, despite the fact that African-Americans comprise 20% of the American population suffering from the disease. Demographic underrepresentation in a clinical study of a group that is overrepresented in the patient population muddles the fair subject selection guideline for ethical conduct and may also distort the validity of results.
While people of African descent face the lowest representation in clinical trials globally, African-Americans are not the only group that remains underrepresented in U.S. clinical trials. While Asians are well represented in international trials, Asian Americans account for less than 2% of U.S. trial participants, despite accounting for 6% of the population. Similarly, Native Americans and Alaska Natives, who make up 2% of the U.S. population, were not represented at all in 70% of clinical trials. These findings suggest that certain ethnic groups may be underserved both by trials and even eventually approved drugs.
In recent years, the FDA has pushed for better diversity and representation in clinical trials. Most recently, in draft guidance issued in April 2022, the agency recommended that new investigational new drug (IND), biologics license application (BLA), or investigational device exemption (IDE) applications include a “Race and Ethnicity Diversity Plan” in which companies define enrollment goals for black individuals and other underrepresented populations as pre-specified protocol objectives.5
Moving Forward
“CAR-T therapy represents an important recent advancement in the oncology field. The findings of this study suggest that low enrollment of Black persons exists in trials for CAR T therapy and that the disparity is substantial and ongoing, especially for therapies to treat [multiple myeloma]. Efforts should be made to understand and overcome barriers that lead to decreased enrollment of Black participants in clinical trials that include novel, potentially beneficial, and/or curative CAR T therapies in difficult-to-treat hematological malignant neoplasms with otherwise limited treatment options,” remarked author Samer Al Hadidi, M.D., in a press release.6
The authors suggest a number of mitigating factors depressing black participation in these trials, including disproportionate effects of out-of-pocket costs for patients and caregivers, as well as distance to treatment centers. While many clinical trials experts have been optimistic about the benefits of decentralized clinical trials and direct-to-patient provision of clinical materials, advanced therapies like CAR-T are less amenable to those protocols than more conventional drugs. Suggestions for achieving better representation include “allowing more medical centers that serve a higher percentage of black participants to be part of the currently ongoing CAR-T therapy clinical trials.”
References
- Al Hadidi, Samer, Carolina Schinke, and Sharmilan Thanendrarajan. “Enrollment of Black Participants in Pivotal Clinical Trials Supporting US Food and Drug Administration Approval of Chimeric Antigen Receptor–T Cell Therapy for Hematological Malignant Neoplasms.” JAMA Network Open. 5: e228161 (2022).
- Chen, Caroline & Riley Wong. “Black Patients Miss Out On Promising Cancer Drugs.” ProPublica. 19 Sept. 2018
- “Cancer Facts & Figures for African Americans.” American Cancer Society. 2018.
- Dent, Jennifer. “Patients of African descent are being denied the benefits of cancer breakthroughs. We’re changing that.” STAT. 21 Nov. 2018.).
- Diversity Plans to Improve Enrollment of Participants From Underrepresented Racial and Ethnic Populations in Clinical Trials; Draft Guidance for Industry. S. Food and Drug Administration. Apr. 2022.
- Schneider, Mary Ellen. “Study: Black patients underrepresented in pivotal CAR-T cell trials. Regulatory Affairs Professionals Society. 20 Apr. 2022.
