Sex Representation in Clinical Trials Associated with FDA Cancer Drug Approvals Differs Between Solid and Hematologic Malignancies

Mendis, Shehara; Anand, Seerat; Karasinska, Joanna M.; Dasari, Arvind; Unger, Joseph M.; Gothwal, Anirudh; Ellis, Lee M.; Varadhachary, Gauri R.; Kopetz, Scott; Overman, Michael J.; Raghav, Kanwal; Loree, Jonathan M.

doi:10.1002/onco.13534

Cited by 18 publications

(14 citation statements)

References 40 publications

(44 reference statements)

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“…These included FDAAA801, 10 a federal act that required reporting of demographic enrollment data to ClinicalTrials.gov within 12 months of study completion, with monetary penalties of up to $10 000 per day and/or withholding of grant funds for noncompliance; the public release of these data on ClinicalTrials.gov 11 ; and updates to the Declaration of Helsinki that considered public registration of trials and disclosure of enrollee demographic characteristics obligatory research practices. 12 Little is known about disparities in enrollment and the effects of these policies on enrollment diversity for patients with acute myeloid leukemia (AML) 13 or acute lymphoblastic leukemia (ALL), rare but potentially curable blood cancers with numerous idiosyncratic care patterns that likely influence enrollment; these care patterns include the short time from diagnosis to therapy initiation, the inpatient setting of treatment, the high proportion of tertiary or quaternary care, and the historic paucity of effective treatments. 7,14 …”

Section: Introductionmentioning

confidence: 99%

Racial and ethnic enrollment disparities and demographic reporting requirements in acute leukemia clinical trials

et al. 2021

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Data regarding racial and ethnic enrollment diversity for acute myeloid (AML) and lymphoid leukemia (ALL) clinical trials in the United States (US) are limited, and little is known about the effect of federal reporting requirements instituted in the late 2000s. We examined demographic data reporting and enrollment diversity for US ALL and AML trials from 2002-2017 as well as changes in reporting and diversity after reporting requirements were instituted. Of 223 AML and 97 ALL trials with results, 68 (30.5%) and 51 (52.6%) reported enrollment by both race and ethnicity. Among trials that reported race and ethnicity (AML N=6,554; ALL N=4,149), non-Hispanic (NH)-Black, NH-Native American, NH-Asian, and Hispanic patients had significantly lower enrollment compared to NH-white patients after adjusting for race-ethnic disease incidence (AML odds: 0.68, 0.31, 0.75, and 0.83; ALL: 0.74, 0.27, 0.67, and 0.64; all p≤0.01). The proportion of trials reporting race increased significantly after the reporting requirements (44.2 to 60.2%; p=0.02), but race-ethnicity reporting did not (34.8 to 38.6%; p=0.57). Reporting proportions by number of patients enrolled increased significantly after the reporting requirements (race: 51.7 to 72.7%, race-ethnicity: 39.5 to 45.4%; both p<0.001), and relative enrollment of NH-Black and Hispanic patients decreased (AML odds: 0.79 and 0.77; ALL: 0.35 and 0.25; both p≤0.01). These data suggest that demographic enrollment reporting for acute leukemia trials is suboptimal, changes in diversity after the reporting requirements may be due to additional enrollment disparities that were previously unreported, and enrollment diversification strategies specific to acute leukemia care delivery are needed.

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Section: Introductionmentioning

confidence: 99%

Racial and ethnic enrollment disparities and demographic reporting requirements in acute leukemia clinical trials

et al. 2021

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“…In our study, the female gender was more evenly distributed in patients with SGC compared to patients with RCC (55% vs, 16%, respectively) and this may partly explain the higher geometric mean cabozantinib C min levels observed in the SGC group. This potential gender effect warrants further research in larger cohorts as indications for cabozantinib are extending and females are often underrepresented in clinical trials 28 . Another possible explanation for the observed difference in cabozantinib concentrations in SGC and RCC patients may be the difference in serum albumin concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…This potential gender effect warrants further research in larger cohorts as indications for cabozantinib are extending and females are often underrepresented in clinical trials. 28 Another possible explanation for the observed difference in cabozantinib concentrations in SGC and RCC patients may be the difference in serum albumin concentrations. Previously, lower albumin concentrations have been associated with lower maximal cabozantinib concentrations.…”

Section: Discussionmentioning

confidence: 99%

Exposure‐toxicity relationship of cabozantinib in patients with renal cell cancer and salivary gland cancer

Krens¹,

Boxtel²,

Uijen³

et al. 2021

Intl Journal of Cancer

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Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 μg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured Cmin at steady‐state. The geometric mean (GM) Cmin at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty‐seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM Cmin at the start dose was 1456 μg/L (95% CI: 1185‐1789) vs 682 μg/L (95% CI: 572‐812) (P < .001) for SGC and RCC patients, respectively. When dose‐normalised to 40 mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients (Cmin 971 μg/L [95% CI: 790‐1193] vs 669 μg/L [95% CI: 568‐788]) (P = .005). Dose reductions due to toxicity were needed in 91% and 60% of SGC and RCC patients, respectively. Median BTD was between 20 to 30 mg for SGC and 40 mg for RCC patients. GM Cmin at BTD were comparable between the SGC and the RCC group, 694 μg/L (95% CI: 584‐824) vs 583 μg/L (95% CI: 496‐671) (P = .1). The observed cabozantinib exposure at BTD of approximately 600 μg/L is below the previously proposed target. Surprisingly, a comparable exposure at BTD was reached at different dosages of cabozantinib for SGC patients compared to RCC patients Further research is warranted to identify the optimal exposure and starting dose to balance efficacy and toxicity.

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“…However, trial populations may not always represent the population that they are trying to emulate. It has been shown in several studies, in both oncology and nononcology clinical trial settings, that women may be underrepresented in clinical trials 10‐13 . Although some reports refute this claim and a plethora of barriers exist to clinical trial participation and enrollment, there are known differences in the clinical outcome of medications, such as adverse drug reactions, which may be missed in underrepresented trials 14‐16 .…”

Section: Introductionmentioning

confidence: 99%

“…Other studies have shown the existence of racial and age disparities in oncology clinical trials, but are less robust in assessing gender variation 17,18 . Mendis et al recently showed a slight female underrepresentation in hematological trials and a significant underrepresentation in solid organ malignancies using the International Agency for Research on Cancer and odds ratios for female trial enrollment 13 . The purpose of this study was to further clarify whether there is truly a gender disparity in clinical trials leading to cancer drug approvals using US Food and Drug Administration (FDA)‐approved clinical trials from January 2014 to April 2019 by calculating enrollment incidence disparity (EID) using the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program database.…”

Section: Introductionmentioning

confidence: 99%

Assessment of gender representation in clinical trials leading to FDA approval for oncology therapeutics between 2014 and 2019: A systematic review‐based cohort study

Dymanus

Butaney

Magee

et al. 2021

Cancer

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Background Ensuring representative data accrual in clinical trials is important to safeguard the generalizability of results and to minimize disparities in care. This study's goal was to evaluate differences in gender representation in trials leading to US Food and Drug Administration (FDA) cancer drug approvals. Methods An observational study was conducted from January 2014 to April 2019 using PubMed and the National Institutes of Health trials registry for primary trial reports. The National Cancer Institute's Surveillance, Epidemiology, and End Results program and US Census were consulted for national cancer incidence. The outcome was an enrollment incidence disparity (EID), which was calculated as the difference between male and female trial enrollment and national incidence, with positive values representing male overrepresentation. Results There were 149 clinical trials with 59,988 participants—60.3% and 39.7% were male and female, respectively—leading to 127 oncology drug approvals. The US incidence rates were 55.4% for men versus 44.6% for women. Gender representation varied by specific tumor type. Most notably, women were underrepresented in thyroid cancer (EID, +27.4%), whereas men were underrepresented in soft tissue cancer (EID, –26.1%). Overall, women were underrepresented when compared with expected incidence (EID, +4.9%; 42% of trials). Conclusions For many specific tumor types, women are underrepresented in clinical trials leading to FDA oncology drug approvals. It is critical to better align clinical trial cohort demographics and the populations to which these data will be extrapolated. Lay Summary This study assesses whether gender disparities exist in clinical trials leading to US Food and Drug Administration (FDA) cancer drug approvals. From January 2014 to April 2019, 149 clinical trials leading to FDA oncology drug approvals showed 60.3% and 39.7% of the enrollees were male and female, respectively. Gender representation varied by specific tumor when compared with the expected incidence rate of cancer in the United States, although women were more often underrepresented. Increased efforts are needed with regard to ensuring equitable representation in oncology clinical trials.

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Sex Representation in Clinical Trials Associated with FDA Cancer Drug Approvals Differs Between Solid and Hematologic Malignancies

Cited by 18 publications

References 40 publications

Racial and ethnic enrollment disparities and demographic reporting requirements in acute leukemia clinical trials

Racial and ethnic enrollment disparities and demographic reporting requirements in acute leukemia clinical trials

Exposure‐toxicity relationship of cabozantinib in patients with renal cell cancer and salivary gland cancer

Assessment of gender representation in clinical trials leading to FDA approval for oncology therapeutics between 2014 and 2019: A systematic review‐based cohort study

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