Abstract
This study examines the lack of race-adjusted measurements for renal function in eligibility criteria for participation of black men in prostate cancer trials.
Black patients are underrepresented in clinical trials despite widespread efforts to increase minority participation. Eligibility criteria may disproportionately prevent black patients from participating due to racial variations in laboratory values. We studied this potential barrier by examining clinical trials in prostate cancer, a disease in which black men face higher incidence and mortality.
Methods
A list of trials was collected on January 16, 2017, from clinicaltrials.gov using the following criteria: (1) study type, interventional studies; (2) conditions, prostate cancer; (3) interventions, drug; and (4) outcome measures, overall survival. These results were cross-checked against variations of prostate cancer, including prostatic neoplasm and prostate, to ensure that all applicable trials were captured. Institutional review board approval was obtained from the Dana-Farber Cancer Institute before undertaking this study.
Characteristics gathered from each trial included sponsor type, phase, accrual goal, start year, and toxicity. We determined the sponsor type by categorizing each trial as sponsored by industry, cooperative group, or academic investigator. Phase was categorized as phase 1 (0, I, or I/II), 2 (II or II/III), 3 (III or IV), or unknown. Trials were defined as having high toxicity if 1 of the possible treatment arms included chemotherapy, immunotherapy, surgery, brachytherapy, and/or cryoablation. All other treatments, including hormone therapy; nonimmunotherapeutic targeted agents, including biologics; external beam radiotherapy; vitamins/supplements; and nonchemotherapeutic medications, were considered low toxicity.
We investigated the use of serum creatinine (sCr) alone instead of race-adjusted measurements for renal function and the use of an absolute neutrophil count (ANC) threshold that could exclude men with benign ethnic neutropenia. Black patients have higher sCr for any given renal function, and using this measurement may falsely underestimate their renal function. Similarly, the 6.7% to 8.0% of black patients with benign ethnic neutropenia, a condition defined as neutropenia (ANC<1.5 × 109 cells/L) without attributable cause, may be excluded despite healthy immune systems.
Trial characteristics were compared using the Pearson χ2 test for categorical variables and the Wilcoxon rank sum test for continuous variables. Statistical testing was 2-sided and performed using Stata/SE, version 14.2 (StataCorp) on complete data, with a significance level set at P < .05.
Results
We identified 401 interventional prostate cancer clinical trials with an overall survival end point from clinicaltrials.gov (Table). Overall, 47.9% (192) of these trials used sCr alone and/or required participants to have an ANC of 1.5 × 109 cells/L or higher. Specifically, 25.2% (101) of the trials used sCr alone to determine eligibility and 41.4% (166) of the trials required patients to have an ANC of 1.5 × 109 cells/L or higher. The use of sCr alone and/or an ANC cutoff level of 1.5 × 109 cells/L or higher to determine eligibility was more common in trials that were sponsored by academic investigators or cooperative groups vs industry (P < .001), were phase 1 or 2 vs 3 (P < .02), had lower accrual (P < .001), or had at least 1 treatment arm that was considered high toxicity (P < .001) (Table).
Table. Baseline Trial Cohort Characteristics and Use of Potentially Exclusionary Criteriaa.
| Characteristic | sCr | ANC | sCr and/or ANC | Total No. | |||
|---|---|---|---|---|---|---|---|
| No. (%) | P Value | No. (%) | P Value | No. (%) | P Value | ||
| Sponsor type | |||||||
| Academic/investigator initiated | 55 (34.8) | <.001 | 85 (53.8) | <.001 | 101 (63.9) | <.001 | 158 |
| Cooperative group | 28 (33.3) | 51 (60.7) | 60 (71.4) | 84 | |||
| Industry | 18 (11.3) | 30 (18.9) | 31 (19.5) | 159 | |||
| Phase | |||||||
| 1 | 19 (31.7) | .47 | 25 (41.7) | .001 | 31 (51.7) | .02 | 60 |
| 2 | 48 (23.8) | 102 (50.5) | 109 (54.0) | 202 | |||
| 3 | 33 (25.2) | 38 (29.0) | 50 (38.2) | 131 | |||
| Unknown | 1 (12.5) | 1 (12.5) | 2 (25.0) | 8 | |||
| Year | |||||||
| 1990-2005 | 33 (35.5) | .03 | 41 (44.1) | .72 | 52 (55.9) | .18 | 93 |
| 2006-2011 | 34 (23.6) | 56 (38.9) | 63 (43.8) | 144 | |||
| 2012-2017 | 34 (20.9) | 68 (41.7) | 76 (46.6) | 163 | |||
| Unknown | 0 | 1 (100) | 1 (100) | 1 | |||
| Accrual | |||||||
| Median (IQR) | 60 (27-228) | .02 | 52.5 (28-150) | <.001 | 54.5 (28-164) | <.001 | 85.0 (39-362) |
| Unknown | 1 (100) | 1 (100) | 1 (100) | 1 | |||
| Toxicity | |||||||
| Less toxic | 38 (19.7) | .02 | 59 (30.6) | <.001 | 72 (37.3) | <.001 | 193 |
| More toxic | 63 (30.3) | 107 (51.4) | 120 (57.7) | 208 | |||
| Total | 101 (25.2) | 166 (41.4) | 192 (47.9) | 401 | |||
Abbreviations: ANC, absolute neutrophil count; IQR, interquartile range; sCr, serum creatinine.
P values derived from Pearson χ2 test for categorical variables and the Wilcoxon rank sum test for continuous variables.
Discussion
Of clinical trials in prostate cancer collected for this study, 47.9% used criteria that disproportionately excluded black patients. The reevaluation of these 2 eligibility criteria could improve minority trial enrollment. First, 41.4% of prostate cancer clinical trials excluded patients with benign ethnic neutropenia, even though evidence suggests that these patients do not have an increased risk of infection. Lowering the ANC cutoff level for patients with benign ethnic neutropenia would increase the number of eligible black participants, as 89% of these patients have an ANC of 1.0 × 109 cells/L or higher. Second, 25.2% of trials used sCr alone to determine eligibility, even though black patients have higher sCr levels for any given renal function. Use of race-adjusted equations would take into account these clinically insignificant racial differences. This study examined only prostate cancer clinical trials and 2 laboratory measures, which may limit the generalizability of the results. While adopting race-based differences in trial criteria may add slight logistical challenges when ensuring that patients meet trial eligibility, these adjustments would prevent healthy individuals from being excluded solely because of benign laboratory differences caused by their race.
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