Bridging the gap: how do we enroll more racial-ethnic minority patients in hematological drug trials?

KEYWORDS:

• Clinical trials
• disparity
• race
• ethnicity
• hematological malignancies

1. Introduction

The NIH Revitalization Act of 1993 established a mandate to encourage adequate representation of racial-ethnic minorities and women in NIH-funded research [1]. Since then, there have been efforts to improve recruitment of these groups in cancer clinical trials, however, these efforts have so far been insufficient in achieving widespread meaningful equity [2], with most gains being realized in solid tumor oncology [3]. In this editorial, we review the current state of disparities in outcomes and clinical trial enrollment in patients with hematologic malignancies, and review current and prospective strategies to address them meaningfully.

2. Where do we currently stand?

2.1. Acute myeloid leukemia (AML), Myeloproliferative Neoplasm (MPN), and myelodysplastic syndrome (MDS)

AML is the most common acute leukemia in adults and frequently has a dire prognosis. Large studies have shown that Non-Hispanic Black (NHB) and Hispanic patients have worse outcomes regardless of disease biology [4,5], likely related to decreased access to intensive treatment including hematopoietic cell transplantation (HCT) [6,7] as well as socioeconomic factors including poverty, deprivation, and structural racism [8]. There are scarce data looking at disparities in MDS and MPN but existing evidence seems to point to delay in diagnosis and referral as the main drivers of worse outcomes in the former [9,10] and vascular and thrombotic complications in the latter [11]. It is important to note that MDS has not been historically well represented as a cancer diagnosis and as such, several research efforts have limited analyses in this diagnosis area. Despite this, previous reports have shown underrepresentation of NHB in MDS clinical trials leading to FDA approval of drugs [12]. Inclusion in clinical trials has shown to somewhat remediate these differences [13], and while this protective effect can be mixed in some groups [14], access to novel therapies and improved supportive care appear to be the main driving factors [15]. Recent work has shown that in both adult and pediatric AML trials, racial-ethnic minority patients were less likely to be enrolled [16,17].

2.2. Acute lymphoblastic leukemia (ALL)

ALL represents the most common leukemia in children and is an emerging malignancy in adults, with recent studies demonstrating poorer outcomes particularly in Hispanic patients in the case of B-ALL [18], and NHB patients in the case of T-ALL. This appears to be due as much to biological disease differences [19], as to socioeconomic [20,21] and treatment-related factors [22]. ALL is another case where clinical trial enrollment has been noted to improve prognosis of racial-ethnic minority patients. Specifically, Hispanic patients enrolled in the CALGB 10,403 trial had outcomes comparable to non-Hispanic whites (NHW) and higher rates of treatment completion [23]. However, relative enrollment of Hispanic patients in this trial was lower when compared to nationwide (15% vs. 35%), which can at least be partially explained by most patients enrolled on this trial in the Midwest, a geographical region with less Hispanic population [24]. This geographically driven difference in enrollment has also been noted among a large number of acute leukemia trials evaluating both therapeutics and biobanking [25].

2.3. Multiple myeloma (MM)

MM is the second most common hematologic malignancy in the US, which despite several therapeutic advancements and an overall decreasing mortality, is considered incurable. NHB have more than double the incidence of MM compared to NHW (17.43 vs 7.48 per 100,000) [26]. NHB also have less aggressive biological subtypes of MM but despite this, have been reported to have worse outcomes in some analyses [27]. In MM, socioeconomic disparities not only play a large role [28], they appear to be a major determinant of the unequal outcomes among racial-ethnic groups [29]. NHB patients appear to derive the greatest benefit from inclusion in MM clinical trials, with their inclusion remediating outcome differences [30]; however, both NHB and Hispanic patients remain underrepresented in clinical trials, particularly in those that evaluate novel therapeutics [31].

2.4. Non-Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL)

Both NHL and HL constitute a diverse group of lymphoid malignancies that possess a different pathobiology and natural history. Disparities in outcomes have been documented for both HL [32] and NHL [33,34], affecting NHB and Hispanic patients. For most subtypes of lymphoma there does not appear to be a significant biological difference, as most disparities seem to be driven by socioeconomic and environmental factors [35–38], which appear to be overcome when these are accounted for [39]. An exception to this is peripheral T-cell lymphomas (PTCL), where angioimmunoblastic T-cell lymphoma and extranodal NK/T cell lymphoma are much more prevalent in Hispanics, American Indian/Alaskan Native (AI/AN) and Asian/Pacific Islander (A/PI) patients, while PTCL-not otherwise specified (NOS) and adult T-Cell lymphoma/Leukemia are more common in NHB. Across these diagnoses, the racial-ethnic minority groups have worse survival as compared to NHW [40–42]. Clinical trial enrollment by itself does not seem to be sufficient to fully overcome these outcome disparities, at least for HL [43]. Clinical trial enrollment continues to be insufficient in NHL overall [44], and particularly in PTCL, where the need seems to be most dire [45,46].

2.5. Hematopoietic cell transplantation (HCT) and Chimeric Antigen Receptor (CAR) T cell therapy

The use of HCT continues to increase, with the largest gains seen in the haploidentical and mismatched donor transplants [47]; however, there are known barriers to access including a relative lack of donors for racial-ethnic minority populations [48] as well as decreased access to transplant centers, lack of insurance or underinsurance among other socioeconomic factors [7,22,49–53]. An interplay of these factors has been postulated as leading to worse outcomes in these populations [54–56]. Inclusion of minority populations in HCT trials has been done mostly in the context of graft-versus-host disease (GVHD) prevention in haploidentical [57] and mismatched unrelated donor [58,59] transplants. These trials have shown an improvement in rates of complications and survival, suggesting a large benefit to racial-ethnic minority patients when they are enrolled in such studies [60]. Unfortunately, equitable inclusion in other trials such as transplant vs. no transplant [61], treatment of GVHD [62,63] or infectious complications [64] remains significantly suboptimal.

Chimeric antigen receptor (CAR) T-cell therapy is a novel therapeutic strategy which has shown great results in relapsed/refractory hematologic malignancies, gaining FDA approvals in MM, NHL, and B-ALL, but despite very promising response rates and curative potential there are still significant obstacles for access that underpin preexisting socioeconomic, geographical, and racial disparities [65,66]. This has been reflected in decreased rates of clinical trial enrollment and real-world utilization of CAR T-cell therapy, particularly for Hispanic [67] and NHB [68] patients.

One unique and disparate aspect of clinical trials that transcends diagnosis-specific issues but is frequently omitted from discussion is the control arm in large, randomized trials. As the therapeutic landscape changes rapidly, it may be known well before the completion of a trial that its control arm is no longer the appropriate standard of care, and since only a fraction of the trials have cross-over designs, patients may not gain access to the superior, novel therapeutic strategy. This reality hits the racial-ethnic minorities even harder as they may lose their chance to gain access to the much needed potentially lifesaving innovative options despite clinical trial participation [69].

3. How can we change the status quo?

In the US, strategies to increase representation in clinical trials can be categorized as: a) policy-level efforts from regulatory agencies and sponsors; b) trial-level efforts from investigators and institutions, and c) patient-level efforts from cancer centers, patient advocacy organizations and the wider society. Some examples of potential or ongoing efforts in each of these categories are listed in Figure 1.

Figure 1. Examples of patient-, trial- and policy-level potential and ongoing efforts to increase accrual of underrepresented racial-ethnic populations in clinical trials.

3.1. Policy-level efforts

These can potentially have the biggest impact in the shortest time, given the ability for the NIH/FDA to set binding directives for the execution of clinical trials, while only reporting is mandated under current standards. Should adequate representation be mandated, this could have a huge impact on the way we recruit patients and help us reach consensus on what truly is ‘equal representation’ [70]. While some recent directives have been brought forth laying out this aspiration, these are nonbinding guidelines and there is no clear understanding of the penalty of not meeting these directives [71]. Legislative efforts can also have an important impact in this field, as the recently passed Clinical Treatment Act mandates Medicaid to cover clinical trial associated costs which is expected to have an outsized impact on those vulnerable populations including racial-ethnic minorities, that rely on it as their primary form of insurance [72]. National Clinical Trial Networks (NCTN) and Cooperative Groups have shown the most initiative among large clinical trial sponsors; however, their efforts remain insufficient mostly due to implementation challenges [2], lack of funding, and delayed surveillance/reporting [73]. While pharmaceutical industry sponsors have shown tremendous interest in this issue, coordinated efforts, especially across different pharmaceutical companies are lacking.

3.2. Trial-level efforts

These have focused on making inclusion criteria for protocols more reflective of the general population so that adequate inclusion can be achieved [74,75], evaluating and addressing biases [76,77] and barriers [78,79] among clinical trial personnel [80], improving institutional processes [81] and access [82], and alleviating cost/logistic burden on patients [83,84]. While several of these efforts have been tested, studied and reported on isolated institution level, and frequently represent expert opinions, revamping clinical trial inclusion criteria as a concerted effort can have the largest impact toward inclusive, ‘real-world’ studies, with a paradigm shift in focus from drug-centric to patient-centric clinical trials.

3.3. Patient-level efforts

These have encompassed increasing awareness about the disparities themselves, and also the availability and potential benefit of clinical trials among all patients, especially racial-ethnic minorities [85,86]. Other efforts have included incorporating underrepresented groups in the development of clinical trial protocols and outreach strategies [87–91]. Efforts should be made across all major diagnoses, with the greatest urgency on those malignancies that are excessively overrepresented among racial-ethnic minority groups such as B-ALL, MM, and PTCL as well in trials testing novel therapeutic strategies across various diagnoses. Clinical trials remain the backbone for improving outcomes in cancer. As the number of therapeutic agents increases rapidly, it is imperative that clinical trials and the evidence they generate represent the true demographic of the real-world where these drugs are eventually utilized. The FDA implemented regulations for reporting of race/ethnicity in 2017 [92]. While this has helped delineate the problem of underrepresentation in clinical trials and drug development, there is still much work that needs to be done to mitigate these disparities [93]. According to the U.S. Census Bureau, the percentage of population from a race/ethnicity other than NHW will continue to increase in the upcoming years [94]. Additionally, most of the population in the world is of non-European descent, such that truly realizing the benefit from cancer therapeutic advancements on a global scale will require increasing integration and improved access to healthcare among the traditionally underrepresented and underserved groups [95]. Thus, the demand for cancer therapy that has been adequately evaluated across different racial-ethnic groups will only grow, and achieving this goal is not only an ethical mandate, but ultimately a necessary condition for the scientific and evidence-based practice of medicine in the 21^st century. We suggest concrete strategies to address disparate enrolment in clinical trials such that this urgent issue can be brought closer to a definitive resolution, leading to the basis for equitable access to novel therapeutic advancements for all, and making clinical trials more ‘patient-centric’ rather than their current ‘drug-centric’ focus.

Declaration of interests

S Ailawadhi has had consultancy with GSK, Sanofi, BMS, Takeda, Beigene, Janssen, Regeneron, Cellectar, Pfizer and received institutional research funding from GSK, BMS, Pharmacyclics, Amgen, Janssen, Cellectar, AbbVie, Ascentage, and Sanofi.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.