The Diversity of Research Participants in Randomized Controlled Trials and Observational Studies Conducted by the Canadian Critical Care Trials Group.

Rationale: Women, older individuals, and racial and ethnic minority groups are often underrepresented in research studies. Objectives: We evaluated the demographics and diversity of participants enrolled in randomized controlled trials (RCTs) and observational studies published by investigators in association with the Canadian Critical Care Trials Group. Methods: We performed quantitative content analysis of peer-reviewed RCTs and observational studies from December 1994 to December 2022. For each publication, we extracted participant demographic variables, including sex, gender, age, race or ethnicity, sexual orientation, pregnancy status, language proficiency, income/financial status, housing, education, disability, and geography. Results: A total of 120 publications (28 RCTs, 92 observational studies) included 211,144 enrolled participants. Most (107 of 120; 89.2%) were multicenter studies, and 70% (84 of 120) were conducted exclusively in Canadian centers; 77.5% (93 of 120) studies enrolled adult participants, and 19.2% (23 of 120) enrolled pediatric participants. All studies reported participant mean or median age, 118 (98.3%) reported binary sex or gender, and 9 (7.5%) reported race or ethnicity. No justification was provided in 35 studies that listed pregnancy as an exclusion. There was infrequent reporting of housing (n = 4), employment (n = 2), income (n = 2), and education (n = 1). No studies reported the language proficiency, sexual orientation, disability, or geography of participants. Of the studies reporting gender, women and/or girls comprised 42.3% participants (range, 8.9-67.7%). Within nine studies reporting race or ethnicity of 2,950 participants, 59.7% were White, 8% South Asian, 7% Indigenous, 3% Asian, 1% Black, 14% unknown, and 6% "other." Conclusions: Research publications from the Canadian Critical Care Trials Group infrequently report important participant demographics, and diversity of research participants is disproportionate compared with Canadian societal demographics.

Metastatic gastroesophageal cancer in older patients - is this patient cohort represented in clinical trials?

BACKGROUND: Older patients are underrepresented in the clinical trials that determine the standards of care for oncological treatment. We conducted a review to identify whether there have been age-restrictive inclusion criteria in clinical trials over the last twenty five years, focusing on patients with metastatic gastroesophageal cancer. METHODS: A search strategy was developed encompassing Embase, PubMed and The Cochrane Library databases. Completed phase III randomised controlled trials evaluating systemic anti-cancer therapies in metastatic gastroesophageal malignancies from 1st January 1995 to 18th November 2020 were identified. These were screened for eligibility using reference management software (Covidence; Veritas Health Innovation Ltd). Data including age inclusion/exclusion criteria and median age of participants were recorded. The percentage of patients ≥ 65 enrolled was collected where available. The change over time in the proportion of studies using an upper age exclusion was estimated using a linear probability model. RESULTS: Three hundred sixty-three phase III studies were identified and screened, with 66 trials remaining for final analysis. The majority of trials were Asian (48%; n = 32) and predominantly evaluated gastric malignancies, (86%; n = 56). The median age of participants was 62 (range 18-94). Thirty-two percent (n = 21) of studies specified an upper age limit for inclusion and over half of these were Asian studies. The median age of exclusion was 75 (range 65-80). All studies prior to 2003 used an upper age exclusion (n = 12); whereas only 9 that started in 2003 or later did (17%). Among later studies, there was a very modest downward yearly-trend in the proportion of studies using an upper age exclusion (-0.02 per year; 95%CI -0.05 to 0.01; p = 0.31). Fifty-two percent (n = 34) of studies specified the proportion of their study population who were ≥ 65 years. Older patients represented only 36% of the trial populations in these studies (range 7-60%). CONCLUSIONS: Recent years have seen improvements in clinical trial protocols, with many no longer specifying restrictive age criteria. Reasons for poor representation of older patients are complex and ongoing efforts are needed to broaden eligibility criteria and prioritise the inclusion of older adults in clinical trials.

Urban RCT participants were healthier than non-participants or rural women.

OBJECTIVE: To investigate sociodemographic characteristics and physical and mental health indicators between participants and nonparticipants of a large-scale 2-year exercise RCT including noninvited women living in nearby rural area in Finland. STUDY DESIGN AND SETTING: From a previous OSTPRE study cohort, 914 women (aged 72-84) participated in Kuopio Fall Prevention Study in 2016-2019. The participants were compared to non-participants (n = 4,536) and noninvited OSTPRE women (n = 7,119) living outside the urban recruitment area. RESULTS: Participants were younger (P< 0.001) with higher education (P< 0.001) and had more often regular hobbies (P< 0.001) and physical exercising (P< 0.001) than nonparticipants or noninvited. They reported better functional capability (P< 0.001), mental (P< 0.001) and subjective health (P< 0.001), lower number of medications (P< 0.001), less fear of falls (P< 0.001), but more frequent falls (P= 0.002) and more often musculoskeletal diseases (P= 0.006).  Participants also showed better functional capacity in the clinical measurements. In register analysis, urban-rural differences in the prevalence of diseases were detected. CONCLUSION: In population-based exercise interventions, participants are more likely to be better off in respect to physical and mental wellbeing, functional capability and sociodemographic status. Recruiting participants only from cities increases unavoidable selection bias due to urban-rural differences which should be noticed when interpreting and generalizing RCT results. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02665169.

Participation in a Chronic Limb Threatening Ischemia Randomized Trial Is Inversely Correlated With Regional Amputation Rate in Limb Threatening Ischemia Patients.

OBJECTIVE: The National Health Service demonstrated that regions of the United Kingdom with the highest number of patients enrolled in research studies had the lowest risk-adjusted mortality when patients were admitted to the hospital. Our goal was to investigate if this correlation was evident for patients with chronic limb threatening ischemia (CLI) treated in the United States (US). Accordingly, we examined correlations among sites participating in the Best Endovascular versus best Surgical Therapy in patients with Critical (BEST-CLI) trial, a multicenter, National Institute of Health-sponsored, international randomized controlled trial (RCT) comparing revascularization strategies in patients with CLI, and regional rates of major amputation from CLI. METHODS: We measured regional participation in the BEST-CLI trial by evaluating trial participation and enrollment rosters. To determine regional rates of lower limb amputation, we queried the Medicare database (2007-2016) for patients with concurrent peripheral arterial disease (PAD) and diabetes, then assessed how many had lower extremity amputations. Correlation of regional amputation rates with distribution of BEST-CLI sites in four US geographical regions was calculated using Pearson's correlation coefficients. Simple regression equations were used to calculate the significance of these correlation coefficients. RESULTS: Of 9,231,909 CLI patients, 342,406 underwent amputation in the Medicare dataset. Amputation rates per 1000 CLI patients differed by region (South 40.42, Midwest 40.12, West 34.81, Northeast 31.14). There were 116 US vascular centers, selected by volume and expertise that participated in BEST-CLI with the following distribution: South (n = 30, 26%), Midwest (n = 26, 22%), West (n = 29, 25%), and Northeast (n = 31, 27%). There was a negative correlation between the number of amputations per 1000 for Medicare CLI patients with diabetes and PAD and the number of BEST-CLI sites in the region which trended toward significance (Pearson R= -0.61, P = 0.39). CONCLUSIONS: Amputation rate among Medicare CLI patients is inversely correlated with US BEST-CLI site distribution. Higher participation in clinical research, especially within large RCTs, may be a marker of optimal PAD management.

Large Pediatric Randomized Clinical Trials in ClinicalTrials.gov.

BACKGROUND: Large, randomized controlled trials (RCTs) are essential in answering pivotal questions in child health. METHODS: We created a bird's eye view of all large, noncluster, nonvaccine pediatric RCTs with ≥1000 participants registered in ClinicalTrials.gov (last search January 9, 2020). We analyzed the funding sources, countries, outcomes, publication status, and correlation with the pediatric global burden of disease (GBD) for eligible trials. RESULTS: We identified 247 large, nonvaccine, noncluster pediatric RCTs. Only 17 mega-trials with ≥5000 participants existed. Industry funding was involved in only 52 (21%) and exclusively funded 47 (19%) trials. Participants were from high-income countries (HICs) in 100 (40%) trials, from lower-middle-income countries (LMICs) in 122 (49%) trials, and from both HICs and LMICs in 19 (8%) trials; 6 trials did not report participants' country location. Of trials conducted in LMIC, 43% of investigators were from HICs. Of non-LMIC participants trials (HIC or HIC and LMIC), 39% were multicountry trials versus 11% of exclusively LMIC participants trials. Few trials (18%; 44 of 247) targeted mortality as an outcome. 35% (58 of 164) of the trials completed ≥12 months were unpublished at the time of our assessment. The number of trials per disease category correlated well with pediatric GBD overall (ρ = 0.76) and in LMICs (ρ = 0.69), but not in HICs (ρ = 0.29). CONCLUSIONS: Incentivization of investigator collaborations across diverse country settings, timely publication of results of large pediatric RCTs, and alignment with the pediatric GBD are of pivotal importance to ultimately improve child health globally.

Demographic and Health Behavior Factors Associated With Clinical Trial Invitation and Participation in the United States.

Importance: Representative enrollment in clinical trials is critical to ensure equitable and effective translation of research to practice, yet disparities in clinical trial enrollment persist. Objective: To examine person-level factors associated with invitation to and participation in clinical trials. Design, Setting, and Participants: This cross-sectional study analyzed responses from 3689 US adults who participated in the nationally representative Health Information National Trends Survey, collected February through June 2020 via mailed questionnaires. Exposures: Demographic, clinical, and health behavior-related characteristics. Main Outcomes and Measures: History of invitation to and participation in a clinical trial, primary information sources, trust in information sources, and motives for participation in clinical trials were described. Respondent characteristics are presented as absolute numbers and weighted percentages. Associations between respondent demographic, clinical, and health behavior-related characteristics and clinical trial invitation and participation were estimated using survey-weighted logistic regression models. Results: The median (IQR) age of the 3689 respondents was 48 (33-61) years, and most were non-Hispanic White individuals (2063 [59%]; non-Hispanic Black, 452 [10%]; Hispanic, 521 [14%]), had more than a high school degree (2656 [68%]), were employed (1809 [58%]), and had at least 1 medical condition (2535 [61%]). Overall, 439 respondents (9%) had been invited to participate in any clinical trial. Respondents with increased odds of invitation were non-Hispanic Black compared with non-Hispanic White (adjusted odds ratio [aOR], 1.85; 95% CI, 1.13-3.02), had greater than a high school education compared with less than high school education (eg, ≥college degree: aOR, 4.84; 95% CI, 1.89-12.39), were single compared with married or living as married (aOR, 1.68; 95% CI, 1.04-2.73), and had at least 1 medical condition compared to none (eg, 1 medical condition: aOR, 2.25; 95% CI, 1.32-3.82). Respondents residing in rural vs urban areas had 77% decreased odds of invitation to a clinical trial (aOR 0.33; 95% CI 0.17-0.65). Of invited respondents, 199 (47%) participated. Compared with non-Hispanic White respondents, non-Hispanic Black respondents had 72% decreased odds of clinical trial participation (aOR, 0.28; 95% CI, 0.09-0.87). Respondents most frequently reported "health care providers" as the first and most trusted source of clinical trial information (first source: 2297 [59%]; most trusted source: 2597 [70%]). The most frequently reported motives for clinical trials participation were "wanting to get better" (2294 [66%]) and the standard of care not being covered by insurance (1448 [41%]). Conclusions and Relevance: The findings of this study suggest that invitation to and participation in clinical trials may differ by person-level demographic and clinical characteristics. Strategies toward increasing trial invitation and participation rates across diverse patient populations warrant further research to ensure equitable translation of clinical benefits from research to practice.

Inadequate reporting of participants eligible for randomized controlled trials - A systematic review and meta-analysis.

OBJECTIVE: to characterize randomized controlled trials (RCTs) that did not report the overall number of participants assessed for eligibility and to identify factors associated with higher enrollment rates. STUDY DESIGN AND SETTING: Systematic review and meta-analysis of RCTs in several pre-defined fields in internal medicine. We randomly extracted 360 articles that were published in 2017. Trials that reported numbers of assessed for eligibility patients were compared with those who did not. Recruitment rates were calculated in order to investigate whether they were associated with trial characteristics. RESULTS: A total of 360 RCTs were included. Only 2-thirds of the trials (242/360) reported the number of patients assessed for eligibility. Trials reporting eligibility data had better methodology, reported on the tested hypothesis, included a placebo arm, evaluated soft outcomes, published their findings in higher impact journals and recruited a higher number of randomized patients than those who did not. Recruitment rates in 225 (62.5%) trials enabling their calculation, were significantly higher in trials sponsored by industry, conducted in multiple centers and countries, including inpatients, tested non-inferiority hypothesis, included a placebo arm, and evaluated surrogate outcomes. CONCLUSIONS: Reporting of participant eligibility continues to be scarce. Inadequate reporting was associated with poor methodological characteristics in trials.

U.S. racial and ethnic participation in global clinical trials by therapeutic areas.

WHAT IS KNOWN AND OBJECTIVE: The discussion about health equity in the United States frequently involves concerns over racial and ethnic minority under-representation in clinical trials and particularly in trials conducted in support of product approvals. The FDA has long worked to encourage diverse participation in clinical trials and through its Drug Trials Snapshots (DTS) program, the U.S. Food and Drug Administration (FDA) has moved to make trial demographic data more accessible and transparent. We conducted a demographic study of U.S. participants in clinical trials for FDA-approved new drugs (new molecular entities [NMEs], and original Biologics License Applications [BLAs]) from 2015 to 2019, as reported in DTS database with a purpose of understanding the extent to which U.S.-based trials used to support product approvals represent the racial and ethnic diversity of the U.S. population by therapeutic area. METHODS: Participant-level trial data were collected by accessing the FDA electronic common technical document (eCTD), for the applications used to publish each Snapshot. The therapeutic area (TA) for each drug was determined by review division assignment. The demographic data were analysed and compared to U.S. census data. RESULTS AND DISCUSSION: We examined 102,596 U.S. participants in trials of new drugs that were approved and presented in Drug Trials Snapshots between 2015 and 2019. White participation ranged from 51% in psychiatric trials to 90% in cardiovascular (CV) trials; Black or African American participation ranged from 5% in medical imaging to 45% in psychiatric trials; Asian participation ranged from 0.75% in CV to 4% in dermatologic trials; and Hispanic or Latino participation ranged from 1% in medical imaging to 22% in infectious diseases and gastroenterology trials. WHAT IS NEW AND CONCLUSION: Our data showed variable representation of racial and ethnic minorities across therapeutic areas at the U.S. sites. Blacks or African Americans were represented at or above U.S. census estimates across most therapeutic areas, while Asians and American Indian or Alaska Natives were consistently underrepresented. Hispanic or Latino participation across most therapeutic areas was below U.S. census estimates, however, more variable, and a sizable proportion of data was missing. The next step is a comparison of trial participation based on disease prevalence and epidemiology, which is a more accurate assessment of trial diversity.

Inadequacy and underreporting of study subjects' race and ethnicity in federally funded pelvic floor research.

BACKGROUND: The inclusion of participants who are Black, Indigenous people of color, and participants of various ethnicities is a priority of federally sponsored research. OBJECTIVE: This study aimed to describe the reporting of race and ethnicity in federally funded research published by the Eunice Kennedy Shriver National Institute of Child Health and Human Development-funded Pelvic Floor Disorders Network. STUDY DESIGN: Pelvic Floor Disorders Network publications were reviewed to determine whether race or ethnicity was reported. The number of participants included in each manuscript who were identified as White, Black, Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and "other," and the number of participants who identified as having Hispanic ethnicity were recorded. Data were analyzed by publication and by the pelvic floor disorder investigated, including urinary incontinence, pelvic organ prolapse, fecal incontinence, pregnancy-related pelvic floor disorders, and multiple pelvic floor disorders. Many publications reported on overlapping patient populations, which included primary trials and secondary analyses and studies. Data were analyzed both by counting participants every time they were reported in all papers and by counting the unique number of participants in only the original trials (primary paper published). RESULTS: A total of 132 Pelvic Floor Disorders Network publications were published between 2003 and 2020. Of these, 21 were excluded because they were methods papers or described research without participants. Of the 111 remaining articles, 90 (81%) included descriptions of race and 55 (50%) included descriptions of ethnicity. All 13 primary trials described race and 10 of 13 (76.9%) described ethnicity. Of those publications that described race, 50 of 90 (56%) included only the categories of "White," "Black," and "Other," and 14 of 90 (16%) only described the percentage of White patients. Of the 49,218 subjects, there were 43,058 (87%) with reported race and 27,468 (56%) with reported ethnicity. Among subjects with race and ethnicity reported, 79% were reported as White, 9.9% as Black, 0.4% as Asian, 0.1% as American Indian or Alaska Native, and 4% as "other," whereas 13% were reported to be of Hispanic ethnicity. The racial and ethnic diversity varied based on the pelvic floor disorder studied (P<.01), which was driven by pregnancy-related and fecal incontinence studies because these had lower proportions of White patients than studies of other pelvic floor disorders. CONCLUSION: Federally funded Pelvic Floor Disorders Network research does not consistently report the race and ethnicity of participants. Even in the publications that report these characteristics, Black, Indigenous people of color, and people of Hispanic ethnicity are underrepresented. Consistent reporting and recruitment of a diverse population of women is necessary to address this systemic inequity.

Cancer Clinical Trial Participation at the 1-Year Anniversary of the Outbreak of the COVID-19 Pandemic.

Importance: During the initial outbreak of the COVID-19 pandemic, cancer clinical trial participation decreased precipitously. Given the continued pandemic-especially the severe wave of new cases and deaths in winter 2020 to 2021-a vital question is whether trial enrollments have remained low or even worsened. Objective: To examine the experience of cancer clinical trial enrollment 1 year after the COVID-19 outbreak. Design, Setting, and Participants: This cohort study examines initial enrollments to treatment trials and cancer control and prevention (CCP) trials conducted by the SWOG Cancer Research Network between January 1, 2016, and February 28, 2021. Participants include patients enrolled in the trials. Exposures: Landmark time points reflecting the onset and the apex, respectively, of the initial COVID-19 wave (March 1 to April 25, 2020) and the winter 2020 to 2021 wave (October 4, 2020, to January 23, 2021). Main Outcomes and Measures: This study used interrupted time-series analysis to examine enrollments over time related to the COVID-19-derived exposure variables using negative-binomial regression. Relative risk (RR) estimates representing weekly enrollment changes compared with expected rates (had the pandemic not occurred) were derived. The numbers of enrollments lost during the pandemic were estimated. Results: Overall, 29 398 patients (mean [SD] age, 60.3 [13.2] years) were enrolled (24 034 before the pandemic and 5364 during the pandemic), with 9198 patients (31.3%) aged 65 years or older, 17 199 female patients (58.6%), 3039 Black patients (10.8%), and 2260 Hispanic patients (7.9%). Most enrollments (19 451 [66.2%]) were to treatment trials. During the initial COVID-19 wave, there was a 9.0% model-estimated weekly reduction in enrollments (RR, 0.91; 95% CI, 0.89-0.93; P < .001), with effects compounding each week. Enrollment recovered thereafter, but decreased again during the winter 2020 to 2021 wave, although by only 2.0% each week (RR, 0.98; 95% CI, 0.97-0.99; P < .001). Overall, during the pandemic, actual enrollments were 77.3% of expected enrollments (5364 of 6913 enrollments; 95% CI, 70.5%-85.0%; P < .001). Actual enrollments were 54.0% of expected enrollments for CCP trials (1421 of 2641 enrollments; 95% CI, 43.0%-67.0%; P < .001) and 91.0% of expected enrollments for treatment trials (3922 of 4304 enrollments; 95% CI, 81.0%-102.0%; P = .12). Conclusions and Relevance: In this cohort study, clinical trial enrollments decreased during the full year of the COVID-19 pandemic. Enrollment reductions were primarily to CCP trials, whereas, remarkably, there was not strong evidence of enrollment reductions to treatment trials. This finding suggests that clinical research rapidly adapted to the circumstances of enrolling and treating patients on protocols during the COVID-19 pandemic.

Association Between Participation in Clinical Trials and Overall Survival Among Children With Intermediate- or High-risk Neuroblastoma.

Importance: Participants in clinical trials may experience benefits associated with new therapeutic strategies as well as tight adherence to best supportive care practices. Objectives: To investigate whether participation in a clinical trial is associated with improved survival among children with neuroblastoma and investigate potential recruitment bias of patients in clinical trials. Design, Setting, and Participants: This cohort study included pediatric patients with intermediate- or high-risk neuroblastoma in North American studies who were included in the International Neuroblastoma Risk Group Data Commons and who received a diagnosis between January 1, 1991, and March 1, 2020. Exposure: Enrollment in a clinical trial. Main Outcomes and Measures: Event-free survival and overall survival (OS) of patients with intermediate- or high-risk neuroblastoma enrolled in an up-front Children's Oncology Group (COG) clinical trial vs a biology study alone were analyzed using log-rank tests and Cox proportional hazards regression models. The racial/ethnic composition and the demographic characteristics of the patients in both groups were compared. Results: The cohort included 3058 children with intermediate-risk neuroblastoma (1533 boys [50.1%]; mean [SD] age, 10.7 [14.7] months) and 6029 children with high-risk neuroblastoma (3493 boys [57.9%]; mean [SD] age, 45.8 [37.4] months) who were enrolled in a Children's Oncology Group or legacy group neuroblastoma biology study between 1991 and 2020. A total of 1513 patients with intermediate-risk neuroblastoma (49.5%) and 2473 patients with high-risk neuroblastoma (41.0%) were also enrolled in a clinical trial, for a cohort total of 3986 of 9087 children (43.9%) enrolled in a clinical trial. The prevalence of prognostic markers for the clinical trial and non-clinical trial cohorts differed, although representation of patients from racial/ethnic minority groups was similar in both cohorts. Among patients with intermediate-risk neuroblastoma, OS was higher among those who participated in a clinical trial compared with those enrolled only in a biology study (OS, 95% [95% CI, 94%-96%] vs 91% [95% CI, 89%-94%]; P = .01). Among patients with high-risk neuroblastoma, participation in a clinical trial was not associated with OS (OS, 38% [95% CI, 35%-41%] in the clinical trial group vs 41% [95% CI, 38%-44%] in the biology study group; P = .23). Conclusions and Relevance: Approximately 44% of patients in this large cohort of patients with neuroblastoma were enrolled in up-front clinical trials. Compared with children not enrolled in clinical trials, a higher prevalence of favorable prognostic markers was identified among patients with intermediate-risk neuroblastoma enrolled in clinical trials, and unfavorable features were more prevalent among patients with high-risk neuroblastoma enrolled in clinical trials. No evidence of recruitment bias according to race/ethnicity was observed. Participation in a clinical trial was not associated with OS in this cohort, likely reflecting the common practice of treating nontrial participants with therapeutic and supportive care regimens used in a previous therapeutic trial.

Analysis of Female Enrollment and Participant Sex by Burden of Disease in US Clinical Trials Between 2000 and 2020.

Importance: Although female representation has increased in clinical trials, little is known about how clinical trial representation compares with burden of disease or is associated with clinical trial features, including disease category. Objective: To describe the rate of sex reporting (ie, the presence of clinical trial data according to sex), compare the female burden of disease with the female proportion of clinical trial enrollees, and investigate the associations of disease category and clinical trial features with the female proportion of clinical trial enrollees. Design, Setting, and Participants: This cross-sectional study included descriptive analyses and logistic and generalized linear regression analyses with a logit link. Data were downloaded from the Aggregate Analysis of ClinicalTrials.gov database for all studies registered between March 1, 2000, and March 9, 2020. Enrollment was compared with data from the 2016 Global Burden of Disease database. Of 328 452 clinical trials, 70 095 were excluded because they had noninterventional designs, 167 936 because they had recruitment sites outside the US, 69 084 because they had no reported results, 1003 because they received primary funding from the US military, and 314 because they had unclear sex categories. A total of 20 020 interventional studies enrolling approximately 5.11 million participants met inclusion criteria and were divided into those with and without data on participant sex. Exposures: The primary exposure variable was clinical trial disease category. Secondary exposure variables included funding, study design, and study phase. Main Outcomes and Measures: Sex reporting and female proportion of participants in clinical trials. Results: Among 20 020 clinical trials from 2000 to 2020, 19 866 studies (99.2%) reported sex, and 154 studies (0.8%) did not. Clinical trials in the fields of oncology (46% of disability-adjusted life-years [DALYs]; 43% of participants), neurology (56% of DALYs; 53% of participants), immunology (49% of DALYs; 46% of participants), and nephrology (45% of DALYs; 42% of participants) had the lowest female representation relative to corresponding DALYs. Male participants were underrepresented in 8 disease categories, with the greatest disparity in clinical trials of musculoskeletal disease and trauma (11.3% difference between representation and proportion of DALYs). Clinical trials of preventive interventions were associated with greater female enrollment (adjusted relative difference, 8.48%; 95% CI, 3.77%-13.00%). Clinical trials in cardiology (adjusted relative difference, -18.68%; 95% CI, -22.87% to -14.47%) and pediatrics (adjusted relative difference, -20.47%; 95% CI, -25.77% to -15.16%) had the greatest negative association with female enrollment. Conclusions and Relevance: In this study, sex differences in clinical trials varied by clinical trial disease category, with male and female participants underrepresented in different medical fields. Although sex equity has progressed, these findings suggest that sex bias in clinical trials persists within medical fields, with negative consequences for the health of all individuals.

Need for Ethnic and Population Diversity in Psychosis Research.

This article aims to evaluate "racial", ethnic, and population diversity-or lack thereof-in psychosis research, with a particular focus on socio-environmental studies. Samples of psychosis research remain heavily biased toward Western, Educated, Industrialized, Rich, and Democratic (WEIRD) societies. Furthermore, we often fail to acknowledge the lack of diversity, thereby implying that our findings can be generalized to all populations regardless of their social, ethnic, and cultural background. This has major consequences. Clinical trials generate findings that are not generalizable across ethnicity. The genomic-based prediction models are far from being applicable to the "Majority World." Socio-environmental theories of psychosis are solely based on findings of the empirical studies conducted in WEIRD populations. If and how these socio-environmental factors affect individuals in entirely different geographic locations, gene pools, social structures and norms, cultures, and potentially protective counter-factors remain unclear. How socio-environmental factors are assessed and studied is another major shortcoming. By embracing the complexity of environment, the exposome paradigm may facilitate the evaluation of interdependent exposures, which could explain how variations in socio-environmental factors across different social and geographical settings could contribute to divergent paths to psychosis. Testing these divergent paths to psychosis will however require increasing the diversity of study populations that could be achieved by establishing true partnerships between WEIRD societies and the Majority World with the support of funding agencies aspired to foster replicable research across diverse populations. The time has come to make diversity in psychosis research more than a buzzword.

The readability of informed consent forms for research studies conducted in South Africa.

BACKGROUND: Informed consent forms (ICFs) are used to obtain consent from participants. However the complexity and comprehensiveness of these forms may not be appropriate. Readability can be quantified by formulas in Microsoft (MS) Word, such as the Flesch Reading Ease test. The South African (SA) ethics guidelines suggest that the MS Word Flesch-Kincaid Reading Grade score should be used to assess the complexity of ICFs and should be the equivalent of grade 8 level, or lower. OBJECTIVES: To use readability formulas to determine whether current SA ICFs are appropriate for the general population. METHODS: This was a descriptive study of a sample of English ICFs (solicited from our studies, as well as from local researchers) which received approval from local ethical review boards during the past 5 years, for prospective (≥6 months) drug studies that explored treatment and prevention of HIV, tuberculosis, diabetes or cardiovascular disease. ICFs were evaluated in MS Word for Flesch Reading Ease and Flesch-Kincaid Reading Grade, with the Simple Measure of Gobbledygook (SMOG) index calculated using www.readabilityformulas.com. Recommended targets for easy readability are above 60 for the Flesch Reading Ease score, and less than or equal to a grade 8 reading level for the Flesch-Kincaid Reading Grade and SMOG. RESULTS:   A total of 75 consent forms from 35 individual research studies conducted in SA over the last 5 years were included. The consent forms had been approved by six ethics committees across seven of the SA provinces. The median (interquartile range (IQR)) Flesch Reading Ease score was 55.8 (48.7 - 59.7) and 18 (25.0%) of the ICFs had easy or standard readability, while the median (IQR) Flesch-Kincaid Grade was 10.2 (8.8 - 11.4), with 23 (30.6%) at least a grade 8 level or lower. The median (IQR) SMOG index was 9.8 (9.0 - 11.1) and 4 (5.3%) scored below grade 8 level. CONCLUSIONS: Two-thirds of the ICFs from this study fail to meet the SA readability standard, a result matched by using alternative readability formulas. Readability can be improved with simple techniques and by actively monitoring readability metrics.

Reporting of Study Participant Demographic Characteristics and Demographic Representation in Premarketing and Postmarketing Studies of Novel Cancer Therapeutics.

Importance: Adequate representation of demographic subgroups in premarketing and postmarketing clinical studies is necessary for understanding the safety and efficacy associated with novel cancer therapeutics. Objective: To characterize and compare the reporting of demographic data and the representation of individuals by sex, age, and race in premarketing and postmarketing studies used by the Food and Drug Administration (FDA) to evaluate novel cancer therapeutics. Design, Setting, and Participants: In this cross-sectional study, premarketing and postmarketing studies for novel cancer therapeutics approved by the FDA from 2012 through 2016 were identified. Study demographic information was abstracted from publicly available sources, and US cancer population demographic data was abstracted from US Cancer Statistics. Analyses were conducted from February 25 through September 21, 2020. Main Outcomes and Measures: The percentages of trials reporting sex, age, and race/ethnicity were calculated, and participation to prevalence ratios (PPRs) were calculated by dividing the percentage of study participants in each demographic group by the percentage of the US cancer population in each group. PPRs were constructed for premarketing and postmarketing studies and by cancer type. Underrepresentation was defined as PPR less than 0.8. Results: From 2012 through 2016, the FDA approved 45 cancer therapeutics. The study sample included 77 premarketing studies and 56 postmarketing studies. Postmarketing studies, compared with premarketing studies, were less likely to report patient sex (42 studies reporting [75.0%] vs 77 studies reporting [100%]; P < .001) and race (27 studies reporting [48.2%] vs 62 studies reporting [80.5%]; P < .001). Women were adequately represented in premarketing studies (mean [SD] PPR, 0.91; 95% CI, 0.90-0.91) and postmarketing studies (mean PPR, 1.00; 95% CI, 1.00-1.01). Although older adults and Black patients were underrepresented in premarketing studies (older adults: mean PPR, 0.73; 95% CI, 0.72-0.74; Black patients: mean PPR, 0.32; 95% CI, 0.31-0.32), these groups continued to be underrepresented in postmarketing studies (older adults: mean PPR, 0.75; 95% CI, 0.75-0.76; Black patients: mean PPR, 0.21; 95% CI, 0.21-0.21). Conclusions and Relevance: This study found that older adults and Black patients were underrepresented in postmarketing studies of novel cancer therapeutics to a similar degree that they were underrepresented in premarketing studies. These findings suggest that postmarketing studies are not associated with improvements to gaps in demographic representation present at the time of FDA approval.

Why trials lose participants: A multitrial investigation of participants' perspectives using the theoretical domains framework.

OBJECTIVES: To use the Theoretical Domains Framework (TDF) to identify barriers and enablers to participant retention in trials requiring questionnaire return and/or attendance at follow-up clinics. STUDY DESIGN AND SETTING: We invited participants (n = 607) from five pragmatic effectiveness trials, who missed at least one follow-up time point (by not returning a questionnaire and/or not attending a clinic visit), to take part in semistructured telephone interviews. The TDF informed both data collection and analysis. To establish what barriers and enablers most likely influence the target behavior the domain relevance threshold was set at >75% of participants mentioning the domain. RESULTS: Sixteen participants (out of 25 showing interest) were interviewed. Overall, seven theoretical domains were identified as both barriers and enablers to the target behaviors of attending clinic appointments and returning postal questionnaires. Barriers frequently reported in relation to both target behaviours stemmed from participants' knowledge, beliefs about their capabilities and the consequences of performing (or not performing) the behavior. Two domains were identified as salient for questionnaire return only: goals; and memory, attention and decision-making. Emotion was identified as relevant for clinic attendance only. CONCLUSION: This is the first study informed by behavioural science to explore trial participants' accounts of trial retention. Findings will serve as a guiding framework when designing trials to limit barriers and enhance enablers of retention within clinical trials.