Allocation of authorship and patient enrollment among global clinical trials in oncology

Background

Oncology randomized controlled trials (RCTs) are increasingly global in scope. Whether authorship is equitably shared between investigators from high-income countries (HIC) and low-middle/upper-middle incomes countries (LMIC/UMIC) is not well described. The authors conducted this study to understand the allocation of authorship and patient enrollment across all oncology RCTs conducted globally.

Methods

A cross-sectional retrospective cohort study of phase 3 RCTs (published 2014–2017) that were led by investigators in HIC and recruited patients in LMIC/UMIC.

Findings

During 2014–2017, 694 oncology RCTs were published; 636 (92%) were led by investigators from HIC. Among these HIC-led trials, 186 (29%) enrolled patients in LMIC/UMIC. One-third (33%, 62 of 186) of RCTs had no authors from LMIC/UMIC. Forty percent (74 of 186) of RCTs reported patient enrollment by country; in 50% (37 of 74) of these trials, LMIC/UMIC contributed <15% of patients. The relationship between enrollment and authorship proportion is very strong and is comparable between LMIC/UMIC and HIC (Spearman’s ρ LMIC/UMIC 0.824, p < .001; HIC 0.823, p < .001). Among the 74 trials that report country enrollment, 34% (25 of 74) have no authors from LMIC/UMIC.

Conclusions

Among trials that enroll patients in HIC and LMIC/UMIC, authorship appears to be proportional to patient enrollment. This finding is limited by the fact that more than half of RCTs do not report enrollment by country. Moreover, there are important outliers as a significant proportion of RCTs had no authors from LMIC/UMIC despite enrolling patients in these countries. The findings in this study reflect a complex global RCT ecosystem that still underserves cancer control outside high-income settings.     

Attitudinal barriers to participation in oncology clinical trials: factor analysis and correlates of barriers

Patient participation in cancer clinical trials is low. Little is known about attitudinal barriers to participation, particularly among patients who may be offered a trial during an imminent initial oncology consult. The aims of the present study were to confirm the presence of proposed subscales of a recently developed cancer clinical trial attitudinal barriers measure, describe the most common cancer clinical trials attitudinal barriers, and evaluate socio‐demographic, medical and financial factors associated with attitudinal barriers. A total of 1256 patients completed a survey assessing demographic factors, perceived financial burden, prior trial participation and attitudinal barriers to clinical trials participation. Results of a factor analysis did not confirm the presence of the proposed four attitudinal barriers subscale/factors. Rather, a single factor represented the best fit to the data. The most highly‐rated barriers were fear of side‐effects, worry about health insurance and efficacy concerns. Results suggested that less educated patients, patients with non‐metastatic disease, patients with no previous oncology clinical trial participation, and patients reporting greater perceived financial burden from cancer care were associated with higher barriers. These patients may need extra attention in terms of decisional support. Overall, patients with fewer personal resources (education, financial issues) report more attitudinal barriers and should be targeted for additional decisional support.     

Estimating adjuvant treatment effects in Stage II colon cancer: Comparing the synthesis of randomized clinical trial data to real-world data

There is an ongoing discussion regarding the impact of adjuvant chemotherapy in Stage II colon cancer. We therefore estimated adjuvant treatment effect in Stage II colon cancer using pooled disease-free survival (DFS) data from randomized clinical trials (RCT approach) and compared this to real-world data (RWD approach) estimates. First, we estimated the treatment effect in RCTs by (i) searching relevant trials reporting DFS data, (ii) generating patient-level data from reported DFS data and (iii) estimating treatment effect in the patient-level data. Second, the treatment effect was estimated in an observational cohort of 1,947 patients provided by the Netherlands Cancer Registry using three propensity score methods; matching, weighting and stratification. In the RCT approach, patient-level data of 4,489 patients (events: 853) were generated from seven trials which compared two of the following treatment arms: control, 5FU/LV or FOLFOX. A Cox model was used to estimate a hazard ratio (HR) of 0.77 (0.43;1.10) for 5FU/LV vs. control and 0.93 (0.72;1.15) for FOLFOX vs. 5FU/LV. In the RWD approach, HRs for any adjuvant treatment vs. control were 0.95 (0.50;1.80), 0.88 (0.24;3.21) and 1.05 (0.04;2.06) using matching, weighting and stratification, respectively. There was no significant difference with the estimates from the RCT approach (interaction test, p > 0.10). The RCT data suggest a clinically relevant benefit of adjuvant chemotherapy in terms of DFS, but the estimate did not reach statistical significance. Stratified analyses are required to evaluate whether treatment effect differs in specific subgroups.     

Standardized audiotape versus recorded consultation to enhance informed consent to a clinical trial in breast oncology

BACKGROUND: The purpose of this study was to systematically compare two audiotape formats for the delivery of information relevant to informed consent to participate in a clinical trial in breast oncology, and to establish the feasibility of adding a consultation recording protocol to a clinical treatment trial. METHOD: Participants were 69 women with newly diagnosed breast cancer and 21 oncologists from 5 Canadian cancer centers. Patients were block randomized to one of three groups: 1. standardized audiotape; 2. consultation audiotape; or 3. both audiotapes. Patients received their tapes immediately following the clinical trial consultation. Patient outcomes included perception of being informed about clinical trials, knowledge of information relevant to providing informed consent to a clinical trial, and satisfaction with communication during the consultation. RESULTS: The consultation audiotapes contained less trial-related information than the standardized audiotape but there were no differences in clinical trial knowledge or perception of being informed across the intervention groups. Patients expressed a marginally significant preference for consultation audiotapes over standardized audiotapes. CONCLUSIONS: Patients tended to prefer receiving an audiotape of their own consultation over a standardized audiotape. The majority of oncologists considered the audiotape intervention feasible but were less enthusiastic about being involved in a larger study given the accrual challenges that arose when trying to "piggy-back" one randomized controlled trial on an existing clinical trial.     

Attitudes towards and participation in randomised clinical trials in oncology: A review of the literature

Background:Clinical trials are the principal means by which newtreatment approaches are evaluated in medicine. It has been argued thatrandomised clinical trials provide the highest standard of care and at thesame time help to contribute to scientific knowledge. However, only arelatively small proportion of cancer patients receive treatment as part ofa formal clinical trial. This article provides a broad review of the issuespertinent to physician and patient participation in randomised clinicaltrials. Methods:Search of computerised electronic databases (Medline,Psychlit, Cinhail, Embase). Results:There are a variety of physician and patientcharacteristics which have previously been shown to influence participationin randomised clinical trials. Additionally, ethical concerns about randomisedtrials in general and the additional requirements of informed consent forclinical trials, may impact on recruitment. Whilst there is some researchexamining strategies to improve patient understanding about clinical trialsand promote patient involvement in clinical decision-making, there aredeficiencies in these areas. In particular there is a paucity of researchexamining the association between knowledge about clinical trials, anxietyassociated with a new cancer diagnosis and willingness to participate inrandomised clinical trials. Conclusions:Further research also is needed to evaluatestrategies to better inform patients about clinical trials.     

Registry-based randomized clinical trials in surgery: Working with ACS-NSQIP and the AHPBA to conduct pragmatic trials

Randomized controlled trials (RCTs) represent the gold standard for evidence in clinical medicine because of their ability to account for the effects of unmeasured confounders and selection bias by indication. However, their complexity and immense costs limit their application, and thus the availability of high-quality data to guide clinical care. Registry-based RCTs are a type of pragmatic trial that leverages existing registries as a platform for data collection, providing a low-cost alternative for randomized studies. Herein, we describe the tenets of registry RCTs and the development of the first AHPBA/ACS-NSQIP-based registry trial.     

Generalizability of toxicity data from oncology clinical trials to clinical practice: toxicity of irinotecan-based regimens in patients with metastatic colorectal cancer

Background

The relevance of oncology trial results to clinical practice depends on whether the trial participants are similar to the actual population of patients receiving treatment for the malignancy and whether the patients are treated similarly in both circumstances. Chemotherapy treatments may be more toxic in patients of advanced age and poor performance status—patients typically excluded from clinical trials.

Methods

In a retrospective chart review that included all non-trial patients with metastatic colorectal cancer treated with irinotecan-based chemotherapy from January 2004 to September 2006 at our institution, we quantified and subsequently compared the toxicity rates of the irinotecan regimens in clinical practice with published toxicity rates from corresponding phase iii clinical trials. The primary endpoint was the incidence of grades 3 and 4 diarrhea.

Results

The study included 203 patients, and the irinotecan regimens considered included

• folfiri [irinotecan, leucovorin, 5-fluorouracil (5fu)],
• ifl (bevacizumab, irinotecan, 5fu, leucovorin),
• xeliri (capecitabine, 3-weekly irinotecan), and
• irinotecan monotherapy.

The rates of grades 3 and 4 diarrhea for folfiri, ifl, xeliri, and irinotecan monotherapy in clinical practice were 10%, 15%, 17%, and 21% as compared with 10%, 23%, 20%, and 31% respectively in clinical trials. When only patients meeting trial performance status and age criteria were analyzed, the rates of grades 3 and 4 diarrhea by regimen were 11%, 20%, 19%, and 26% respectively.

Conclusions

Overall, the toxicity rates for folfiri and irinotecan monotherapy in non-trial patients were not statistically different from the rates quoted in published clinical trials.     

Use of health-related quality-of-life assessments in daily clinical oncology nursing practice: a community hospital-based intervention study

BACKGROUND: The current study evaluated the efficacy of incorporating standardized health-related quality of life (HRQL) assessments as a routine part of the outpatient chemotherapy treatment of cancer patients in a community hospital in terms of: 1) facilitating nurse-patient communication, 2) increasing nurses' awareness of patients' HRQL, 3) patient management, 4) patients' satisfaction, and 5) patients' HRQL. METHODS: The study employed a sequential cohort design with repeated measures. Ten nurses and 219 patients participated in this community hospital-based study. The intervention involved patients completing standardized HRQL questionnaires via a touch-screen computer, the results of which were provided to nurses and patients in a graphic summary. Questionnaire and medical record data were used to assess outcomes. RESULTS: HRQL-related topics were discussed significantly more frequently in the intervention group than in the control group (mean = 4.8 topics vs 3.8 topics, respectively; P = .02). Nurses' awareness of patients' levels of daily activity, pain, and overall quality of life was significantly better in the intervention than the control group. The mean number of HRQL-related notations in the medical records was significantly higher in the intervention group (24 vs 20; P< .05). Only modest effects were observed in patient management (counseling behavior), and no significant effects were found in patient satisfaction or changes in HRQL over time. CONCLUSIONS: Incorporating standardized HRQL assessments in daily clinical oncology nursing practice primarily facilitates the discussion of HRQL issues and increases nurses' awareness. Additional efforts are needed to enhance the effect of routine HRQL assessments on patient management and HRQL.     

Systematic review of barriers and facilitators to clinical trial enrollment among adolescents and young adults with cancer: Identifying opportunities for intervention

Adolescents and young adults (AYAs) are underrepresented in cancer clinical trials (CCTs). Limited trial enrollment slows progress in improving survival rates and prevents the collection of valuable biospecimens. A systematic literature review was conducted to assess barriers and facilitators to AYA enrollment in CCTs and to identify opportunities to improve enrollment. The PubMed MEDLINE, Web of Science, Scopus, and PsycINFO databases were searched to identify studies relevant to AYA CCT enrollment. Eligibility criteria included the qualitative and/or quantitative evaluation of barriers and facilitators to AYA enrollment. One hundred fifty-five unique publications were identified; 13 were included in the final analysis. Barriers to AYA enrollment in CCTs included a lack of existing trials applicable to the patient population, limited access to available CCTs, and a lack of physician awareness of relevant trials. Facilitators of enrollment included optimizing the research infrastructure, improving the awareness of available CCTs among providers, and enhancing communication about CCTs between providers and patients. In conclusion, the limited available research reports institution- and patient-level barriers and facilitators to AYA CCT enrollment. Because of persistent disparities in AYA enrollment, there is an urgent need to further identify the barriers and facilitators to AYA CCT enrollment to determine actionable areas for intervention.     

Delivered relative dose intensity in adolescent and young adult germ cell tumours in England: Assessment of data quality and consistency from clinical trials compared to national cancer registration data

Adolescent and young adults (AYA) with germ cell tumours (GCT) have poorer survival rates than children and many older adults with the same cancers. There are several likely contributing factors to this, including the treatment received. The prognostic benefit of intended dose intensity is well documented in GCT from trials comparing regimens. However, evidence specific to AYA is limited by poor recruitment of AYA to trials and dose delivery outside trials not being well examined. We examined the utility of cancer registration data and a clinical trials dataset to investigate the delivery of relative dose intensity (RDI) in routine National Health Service practice in England, compared to within international clinical trials. Linked data from the Cancer Outcomes and Services Dataset (COSD) and the Systemic Anti-Cancer Therapy (SACT) dataset, and data from four international clinical trials were analysed. Survival over time was described using Kaplan-Meier estimation; overall, by age category, International Germ-Cell Cancer Collaborative Group (IGCCCG) classification, stage, tumour subtype, primary site, ethnicity and deprivation. Cox regression models were used to determine the fully adjusted effect of RDI on mortality risk. The quality of both datasets was critically evaluated and clinically enhanced. RDI was found to be well maintained in all datasets with higher RDIs associated with improved survival outcomes. Real-world data demonstrated several strengths, including population coverage and inclusion of sociodemographic variables and comorbidity. It is limited in GCT however, by the poor completion of data items enabling risk classification of patients and a higher proportion of missing data.