Food and Drug Administration approvals in phase 3 Cancer clinical trials.

BACKGROUND: Phase 3 oncologic randomized clinical trials (RCTs) can lead to Food and Drug Administration (FDA) approvals. In this study, we aim to identify trial-related factors associated with trials leading to subsequent FDA drug approvals. METHODS: We performed a database query through the ClinicalTrials.gov registry to search for oncologic phase 3 RCTs on February 2020. We screened all trials for therapeutic, cancer-specific, phase 3, randomized, multi-arm trials. We then identified whether a trial was used for subsequent FDA drug approval through screening of FDA approval announcements. RESULTS: In total, 790 trials were included in our study, with 225 trials (28.4%) generating data that were subsequently used for FDA approvals. Of the 225 FDA approvals identified, 65 (28.9%) were based on trials assessing overall survival (OS) as a primary endpoint (PEP), two (0.9%) were based on trials with a quality of life (QoL) PEP, and 158 approvals (70.2%) were based on trials with other PEP (P = 0.01). FDA approvals were more common among industry funded-trials (219, 97.3%; P < 0.001), and less common among trials sponsored by national cooperative groups (21, 9.3%; P < 0.001). Finally, increased pre-hoc power and meeting patients' accrual target were associated with FDA approvals (P < 0.001). CONCLUSIONS: The majority of FDA approvals are based on data generated from trials analyzing surrogate primary endpoints and trials receiving industry funding. Additional studies are required to understand the complexity of FDA approvals.

Exclusion of Men from Randomized Phase III Breast Cancer Clinical Trials.

Male breast cancer treatment regimens are often extrapolated from female-based studies because of a paucity of literature analyzing male breast cancer. Using ClinicalTrials.gov, we analyzed breast cancer randomized clinical trials (RCTs) to determine which factors were associated with male-gender inclusion. Of 131 breast cancer RCTs identified, male patients represented 0.087% of the total study population, which is significantly less than the proportion of male patients with breast cancer in the U.S. (0.95%; p < .001). Twenty-seven trials included male patients (20.6%). Lower rates of male inclusion were seen in trials that randomized or mandated hormone therapy as part of the trial protocol compared with trials that did not randomize or mandate endocrine therapy (2.5% vs. 28.6% male inclusion; p < .001). It is imperative for breast cancer clinical trials to include men when allowable in order to improve generalizability and treatment decisions in male patients with breast cancer.

Professional Medical Writer Assistance in Oncology Clinical Trials.

BACKGROUND: The use of professional medical writers (PMWs) has been historically low, but contemporary data regarding PMW usage are scarce. In this study, we sought to quantify PMW use in oncologic phase III randomized controlled trials (RCTs). METHODS: We performed a database query through ClinicalTrials.gov to identify cancer-specific phase III RCTs; we then identified whether a PMW was involved in writing the associated trial manuscript reporting primary endpoint results. RESULTS: Two-hundred sixty trials of 600 (43.3%) used a PMW. Industry-funded trials used PMWs more often than nonindustry trials (54.9% vs. 3.0%, p < .001). Increased PMW usage was further noted among trials meeting their primary endpoint (53.4% vs. 32.9%, p < .001) and trials that led to subsequent Food and Drug Administration approval (63.1% vs. 36.3%, p < .001). By treatment interventions, PMW use was highest among systemic therapy trials (50.2%). Lastly, the use of PMWs increased significantly over time (odds ratio: 1.11/year, p = .001). CONCLUSION: PMW use rates are high among industry-funded trials. We urge continued and increased transparency in reporting the funding and use of PMWs.

Performance Status Restriction in Phase III Cancer Clinical Trials.

BACKGROUND: Patients with good performance status (PS) tend to be favored in randomized clinical trials (RCTs), possibly limiting the generalizability of trial findings. We aimed to characterize trial-related factors associated with the use of PS eligibility criteria and analyze patient accrual breakdown by PS. METHODS: Adult, therapeutic, multiarm phase III cancer-specific RCTs were identified through ClinicalTrials.gov. PS data were extracted from articles. Trials with a PS restriction ECOG score ≤1 were identified. Factors associated with PS restriction were determined, and the use of PS restrictions was analyzed over time. RESULTS: In total, 600 trials were included and 238,213 patients had PS data. Of those trials, 527 studies (87.8%) specified a PS restriction cutoff, with 237 (39.5%) having a strict inclusion criterion (ECOG PS ≤1). Enrollment criteria restrictions based on PS (ECOG PS ≤1) were more common among industry-supported trials (P<.001) and lung cancer trials (P<.001). Nearly half of trials that led to FDA approval included strict PS restrictions. Most patients enrolled across all trials had an ECOG PS of 0 to 1 (96.3%). Even among trials that allowed patients with ECOG PS ≥2, only 8.1% of those enrolled had a poor PS. Trials of lung, breast, gastrointestinal, and genitourinary cancers all included <5% of patients with poor PS. Finally, only 4.7% of patients enrolled in trials that led to subsequent FDA approval had poor PS. CONCLUSIONS: Use of PS restrictions in oncologic RCTs is pervasive, and exceedingly few patients with poor PS are enrolled. The selective accrual of healthier patients has the potential to severely limit and bias trial results. Future trials should consider a wider cancer population with close toxicity monitoring to ensure the generalizability of results while maintaining patient safety.

Non-English language validation of patient-reported outcome measures in cancer clinical trials.

Patient-reported outcome measures (PROMs) are increasingly incorporated as endpoints in oncology clinical trials but are often only validated in English. ClinicalTrials.gov was queried for cancer-specific randomized control trials (RCTs) addressing a therapeutic intervention and enrolling primarily in the USA. Peer-reviewed validation of Spanish and Chinese versions of each PROM was assessed. Of 103 eligible trials, a PROM was used as a primary endpoint in 25 RCTs (24.3%) and as a secondary endpoint in 78 RCTs (75.7%). A total of 61 of the 103 eligible trials (59.2%) and 17 of the 25 trials with a PROM primary endpoint (68.0%) used a PROM with either no Spanish or Chinese validation. The absence of validated PROM translations may diminish the voices of non-English language speaking trial participants. With an increasingly diverse US population, validation of non-English PROM translations may decrease disparities in trial participation and improve generalizability of study results.

Surgery for nonlocalizing hyperparathyroidism in high volume center.

BACKGROUND: Patients with nonlocalizing hyperparathyroidism pose a significant challenge to surgeons when undergoing neck exploration for parathyroidectomy. METHODS: We evaluated 536 patients that had parathyroidectomy for primary hyperparathyroidism (PHPT) from 2005 to 2018 at a single tertiary academic center, and 155 (29%) had standard nonlocalizing preoperative imaging (negative ultrasound and sestamibi scans). RESULTS: There were a total of 102 (66%) non-ectopic single adenomas in the nonlocalizing group and 325 (85%) single adenomas in the localizing group. There was no significant difference (p = 0.09) in adenoma quadrant between localizing and nonlocalizing single adenomas, but the most common location in both groups was right inferior. Patients with nonlocalizing scans were more likely to have double adenomas (21% vs. 9%, p < 0.001), ectopic glands (10% vs. 5%, p = 0.052), and multi-gland disease (13% vs. 8%, p = 0.002). CONCLUSION: Nonlocalizing PHPT patients experienced similar cure and complication rates as localizing PHPT, but required more bilateral explorations and increased operative time.

Detecting the Dark Matter of Unpublished Clinical Cancer Studies: An Analysis of Phase 3 Randomized Controlled Trials.

Unpublished randomized controlled trial (RCT) frequency, correlates, and financial impact are not well understood. We sought to characterize the nonpublication of peer-reviewed manuscripts among interventional, therapeutic, multi-arm, phase 3 oncology RCTs. Trials were identified by searching ClinicalTrials.gov, while publications and abstracts were identified through PubMed and Google Scholar. Trial data were extracted from ClinicalTrials.gov and individual publications. Publication was defined as a peer-reviewed manuscript addressing the primary endpoint. Patient accrual cost was extrapolated from experimental data; investigators/sponsors were contacted to determine nonpublication reasons. Six hundred eighty-four completed RCTs met inclusion criteria, which accrued 434,610 patients from 1994 to 2015; 638 were published (93.3%) and 46 were unpublished (6.7%). Among the unpublished trials, the time difference from primary endpoint maturity to data abstraction was a median of 6 years (interquartile range, 4 to 8 years). On multiple binary logistic regression analysis, factors associated with unpublished trials included lack of cooperative group sponsorship (odds ratio, 5.91, 95% CI, 1.35 to 25.97; P=.019) and supportive care investigation (odds ratio, 2.90; 95% CI, 1.13 to 7.41; P=.027). The estimated inflation-adjusted average cost of patient accrual for all unpublished trials was $113,937,849 (range, $41,136,883 to $320,201,063). Direct contact with sponsors/investigators led to a 50.0% response rate (n=23 of 46); manuscript in preparation and/or in submission (n=10 of 23) was the most commonly cited reason for nonpublication. In conclusion, approximately 1 in 15 clinical oncology RCTs are unpublished and this has a profound impact on the research enterprise. The cooperative group infrastructure may serve as a blueprint to reduce nonpublication.

Racial and Ethnic Disparities Among Participants in US-Based Phase 3 Randomized Cancer Clinical Trials.

Although improving representation of racial and ethnic groups in United States clinical trials has been a focus of federal initiatives for nearly 3 decades, the status of racial and ethnic minority enrollment on cancer trials is largely unknown. We used a broad collection of phase 3 cancer trials derived from ClinicalTrials.gov to evaluate racial and ethnic enrollment among US cancer trials. The difference in incidence by race and ethnicity was the median absolute difference between trial and corresponding Surveillance, Epidemiology, and End Results data. All statistical tests were 2-sided. Using a cohort of 168 eligible trials, median difference in incidence by race and ethnicity was +6.8% for Whites (interquartile range [IQR] = +1.8% to +10.1%; P < .001 by Wilcoxon signed-rank test comparing median difference in incidence by race and ethnicity to a value of 0), -2.6% for Blacks (IQR = -5.1% to +1.2%; P = .004), -4.7% for Hispanics (IQR = -7.5% to -0.3%; P < .001), and -4.7% for Asians (IQR = -5.7% to -3.3%; P < .001). These data demonstrate overrepresentation of Whites, with continued underrepresentation of racial and ethnic minority subgroups.