Quantifying the role of communication in recruitment status outcomes for a clinical trial on genetic testing uptake.

Mitigating Administrative Risks in Industry-sponsored Clinical Trials

Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children

Definition of Clinical Outcomes in Pediatric Anesthesia Research: It Is Like the Tower of Babel!

A Meta-Analysis of the Placebo Rates of Remission and Response in Clinical Trials of Active Ulcerative Colitis

Clinical trials improve care and save lives but need more clinician and consumer engagement Clinical trials provide essential evidence for more effective and lifesaving therapies and identify ineffective and unnecessary interventions.1 Patients taking part in clinical trials learn more about their health, play a more active role in decision making, and have better health outcomes.2 Hospitals that conduct clinical trials tend to provide better care, have more rapid uptake of newer treatment strategies and technologies, and have lower mortality rates.2 Australia is a leading destination for clinical trials, with over 1000 new trials commencing each year, representing over $1 billion in direct expenditure.3 Contributing to our success are a world-class health system, high quality research infrastructure, skilled health and research workforces, and tax incentives for research investment.1, 3 For each dollar invested in clinical trials, estimated benefits worth $5.80 are realised, mostly from improved patient outcomes and higher quality health care.1, 4 The Australian Government, in partnership with state and territory governments and other stakeholders, has introduced several reforms to increase competitiveness for clinical trial activity, including seeking to embed research as essential health system business, developing simplified and more standardised research ethics and governance systems, and making it easier to find, conduct, participate and invest in clinical research (including the National One Stop Shop and the National Clinical Trials Front Door initiatives led by the Australian Commission on Safety and Quality in Health Care).3, 5 Substantial funding has also been committed through the Medical Research Future Fund to stimulate more clinical trial activity.6 Improving the infrastructure for clinical trials is important but may fail to adequately address the most consistent impediment to clinical trial success: the failure to recruit patients, with only about half of all trials achieving the target sample size.7 The Australian governments' collective attention to systems and infrastructure is necessary but not sufficient; it needs to be matched by a focus on the people who make clinical trials work. Too often trial recruitment planning occurs without significant input from the clinicians and the population of patients on which it depends.8, 9 Awareness of and participation in clinical trials among the public is low in Australia. An estimated 95 000 Australians participated in trials in 2019, representing 0.4% of the population.3 By comparison, the per capita rate is 1.5% in the United Kingdom3 and around 2% in the United States.10 Women and vulnerable and minority groups are even less likely to be recruited,7, 8, 11 limiting generalisability of results across patient groups.11 Even in oncology, which has actively attempted to address participation rates,8, 12 only 3–5% of eligible adult patients with cancer are enrolled in trials.13 In Australia, successful growth in trial activity has yet to be matched by meaningful engagement of patients and clinicians. General practitioners, specialists and other health professionals have a fundamental role in guiding patient participation in clinical research. The advice of a trusted clinician is a significant factor in a patient's decision to participate.11 The Australian Clinical Trials Networks include hundreds of clinician researchers who collaborate to design and conduct trials that address important clinical questions and who play an active role in promoting trials to patients.14 However, most clinicians are not affiliated with these networks and face several barriers to engaging in clinical research and clinical trials. These include insufficient time to discuss trial participation with patients and inadequate information to support those discussions, and a work culture that does not promote and support research as part of health care delivery.3, 15 These and related issues are described in the recent Australian Academy of Health and Medical Sciences' report on integrating research into health care.1 It has been argued that clinicians should be taught the fundamentals of clinical trials through university courses and clinical specialty and certification programs delivered by professional bodies,13 and the topic of clinical trials should be routinely embedded in conversations between clinicians and patients.7, 16 Finding trials relevant to individual patients needs to be easier, along with access to succinct information about them. The Australian Clinical Trials website (www.australianclinicaltrials.gov.au), managed by the Australian Government, is intended to provide information and resources for consumers, health care providers, researchers and industry, but much of the information is not written in a way that is sympathetic to the needs of either patients or clinicians.7, 16 Multiple Australian websites and online resources provide general information about clinical trials including short videos in English and other languages.17-19 Some have been supported by time-limited advertising campaigns, such as the "Helping our Health" campaign in Australia in 2017–18.20 These communications can inform consumers but rarely integrate patients' perspectives on clinical trials or address known concerns.7 Different strategies will be needed for different target groups. National initiatives that deliver sustained and consistent messages could be funded by governments. More targeted messaging would best be developed through clinical trial researchers and networks that are better connected and more able to involve specific patient groups. Patients who have never heard of clinical trials, are not interested in participating, or fear being an experimental "guinea pig" may need rudimentary information and core messages that provide reassurance about health care quality and safety during a trial.11 Among minority groups, feelings of mistrust towards research and unproven interventions and a lack of accessible information can be major barriers to conversations about trial participation.21 Educating community leaders about research and clinical trials so that they can champion awareness and interest in culturally appropriate ways has been shown to build trust in the research process.7, 11 Translating information in multiple languages and involving bilingual health professionals can also support more effective communication about trials with non-English speaking patients.7 People who are already interested in participating in clinical trials may do so for different reasons and require differentiated communication strategies that reinforce existing perceptions. Healthy volunteers may be motivated by altruism, helping others, and contributing to fighting disease. Patients with health conditions may want to help others like them but may also be hoping for access to new treatments that have the potential to improve their health.11 The current Australian governments' investments in improving systems and processes for clinical trial activity need to be matched by investment in coordinated and sustained engagement with the people who are essential to successful clinical trials: clinicians and patients. There are working examples. The British governments have further strengthened their collective commitment to patient-focused clinical research across the UK. This includes active engagement at multiple levels with health care providers and members of the public as well as other stakeholders.22 Australian governments need a similar focus on clinician and consumer engagement. We provide examples of possible actions in the Box. Greater consumer involvement in all aspects of clinical trial design and conduct has the potential to deliver improved trial participation and ensures that clinical trials are dealing with issues and interventions that matter to patients. Consumers can help to make sure that potential participants are provided with relevant, understandable information to aid decisions about participation in a trial. Reducing the length and complexity of clinical trial information sheets and consent forms represents an important step in this process.23 A national, consumer-facing one stop shop could meet the needs of patients and consumers who are looking for trustworthy, reliable, and understandable information about clinical trials. The National Clinical Trials Front Door is intended to be "a public facing website that acts as a central access point to facilitate connectivity for health researchers, sponsors, industry, primary carers, allied health and the community".5 This leaves out many clinicians, including hospital-based doctors and nurses, and specialists in private practice.5 Such a resource needs to be designed with clinicians and consumers, and needs more than "one door" to allow consumers with different languages, information needs, and interests to enter. Even with these improvements, more is needed. Sustained marketing and education campaigns are necessary — funded by federal, state and territory governments and delivered nationally as well as locally — to raise awareness of the benefits of clinical trials and how people can get more information. Clinicians also need accessible, easy to understand information about clinical trials, and need to be incentivised to talk with their patients about them, for example, by changing job descriptions to include opportunities and time for clinical trial engagement and annual reporting of such activity, such as using existing continued professional development mechanisms. Once patients join a clinical trial, researchers need to ensure that participants have positive experiences, and that both participants and their clinicians are well informed about the outcomes so that they become advocates for participation in the next trial. If we really want more successful clinical trials in Australia, we need more focus on the people who need to be engaged. If trials remain dominated by researcher and industry cultures and address only systems and infrastructure, we are unlikely to break the cycle of poor recruitment and less definitive outcomes. Open access publishing facilitated by The University of Sydney, as part of the Wiley - The University of Sydney agreement via the Council of Australian University Librarians. No relevant disclosures. Not commissioned; externally peer reviewed.

Same-Day Consent for Regional Anesthesia Clinical Research Trials: It's About Time.

Current guideline statements for primary and secondary prevention of cardiovascular disease (CVD) rely on estimates of absolute risk of coronary events. For example, the American Heart Association guidelines on primary prevention state that persons with ≥10% risk over 10 years of myocardial infarction (MI) or coronary death should be considered for antiplatelet therapy with aspirin.1 Similarly, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines2 state that target low-density lipoprotein level should be based on projected absolute risk of future coronary events rather than on presence or absence of specific risk factors. These guidelines state that patients at high risk of MI and coronary death, defined as an absolute 10-year risk of ≥20%, should have a target low-density lipoprotein level <100 mg/dL and should receive statin therapy if needed to achieve this goal. Stroke, however, is not included as one of the outcomes contributing to these absolute risk levels. Included in the group of patients with elevated risk, moreover, are those who already have ischemic heart disease, as well as patients deemed to be “coronary heart disease (CHD) risk equivalents,” indicating those at the same elevated risk as patients with ischemic heart disease. CHD risk equivalents include patients with diabetes mellitus, those with multiple risk factors that put them at elevated risk based on calculation of their Framingham Score, and patients with “other forms of symptomatic atherosclerotic disease.” The latter group is further defined to include those with peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), and carotid artery disease. The category of “risk equivalents” in the ATP III guidelines, however, does not include the vast majority (≈80%3) of ischemic stroke patients without carotid artery disease as cause of their stroke. Ischemic stroke is therefore notably excluded from the list of outcomes contributing to …

Introduction: The enrollment of children into clinical trials is challenging. India is increasingly recognized as a site for clinical research due to its large population and growing research capabilities, though data regarding barriers for recruitment into pediatric vaccine clinical trials are scarce. Objective: The objective of this study was to assess the barriers in recruitment and to find out parental factors for non-participation of their babies in the vaccine clinical trial. Materials and Methods: This was a prospective cross-sectional non-interventional study which was carried out in the pediatric clinical research unit of a tertiary care multispecialty teaching hospital in Pune. The study social worker visited postnatal ward to prime mothers regarding the pneumococcal vaccine clinical trial. Parents of babies aged 6–8 weeks, who were eligible for participation in the ongoing pneumococcal vaccine trial were explained the informed consent form of this clinical trial and their willingness for participation was sought. The reason for refusal of the parents, who declined the study participation of their baby, was documented. Results: Even though eligible inborn baby pool was large (n=384), only 148 (38.54%) inborn babies were brought to our clinical research unit showing a major barrier in the recruitment. Of 204 babies who presented to clinical research unit, 94 babies (46.08%) were enrolled in the ongoing clinical trial and the majority of them were inborn (89.36%), whereas only 10 of 56 (17.86%) outborn babies were enrolled. There was no gender difference noted in enrolled versus non-enrolled babies. There was no significant association between baby’s gender and place of delivery. The major reasons for non-enrollment were “unwillingness” for participation in clinical trial (68.18%) followed by mothers going outstation, staying far away from our hospital, lack of time, and concerns due to research vaccine. Conclusion: Our study has shown that even though eligible inborn baby pool was large, only 38.54% of inborn babies were brought to our clinical research unit, thus a major barrier in recruitment. More effective counseling and recruitment strategies are needed to scale up the enrollment more so for the outborn babies.

CLINICAL TRIALS AND THE CONSEQUENT BENEFITS TO society are in jeopardy in the United States because of a decline in the ability to recruit patients in a timely manner to trials addressing key clinical issues. Current initiatives (eg, the Clinical Trials Transformation Initiative and the proposed National Center for Advancing Translational Sciences) and the recent Institute of Medicine report each recognize that successful recruitment and retention of participants in clinical trials is critical for improving the efficiency and effectiveness of phase 3 and 4 clinical trials and that action to ensure adequate enrollment is urgently needed. Too often trial enrollment fails or is significantly delayed, leading to substantial additional costs to the sponsor. Of particular concern is the failure of US trials to meet desired participant enrollment and the trend toward increasing emphasis on recruitment abroad. The National Heart, Lung, and Blood Institute (NHLBI) and cosponsors convened a workshop on December 7 and 8, 2010, in Bethesda, Maryland, to review, compile, and recommend successful recruitment and retention strategies in phase 3 and 4 clinical trials. Barriers to successful recruitment and key recommendations were discussed, including policies, guidelines, and reimbursement for studies involving human research participants and clinical trial enrollment experience and practice. Seventy-five participants included clinical researchers, private advocacy groups, federal sponsors, regulatory agencies, and industry. Several critical barriers to successful recruitment were identified. First, the importance of health care professionals as gatekeepers for clinical trial participation cannot be overstated. However, many clinicians are either not aware of active trials or do not refer their patients for participation in trials. Some have questioned the ethics of physicians involving their own patients in clinical trials, whereas others note the challenge of achieving equipoise when physicians have firm opinions about treatment choices. This is compounded by patients’ lack of knowledge about clinical trials for which they may be eligible, availability of experimental intervention in the community, and entrenched cultural and historical views and suspicions of clinical research. Second, the financial realities of funding clinical trials must be estimated accurately and met. Understated infrastructure needs or reimbursement costs associated with recruitment and retention can lead to failure. Substantial costs are necessary to enroll and retain diverse populations, and these additional costs compete for available funds in a fiscal climate in which cost containment is expected. Women and minority populations are more difficult and more costly to recruit and retain in trials because, for women, the costs of child care, transportation, and even usual health care are often out-of-pocket additional expenses for their participation. For minorities, extra time is needed to gain individual and community acceptance. Balancing the need to enroll these understudied populations and developing outreach strategies to support their participation is an ongoing challenge. Third, administrative burdens and regulatory requirements present unprecedented challenges, even for experienced trialists. Institutional policies that govern clinical investigation often create barriers for clinician investigators rather than encouraging their participation. Moreover, the entire concept of indirect costs related to clinical trials needs review, critical analysis, and optimization. Clinical trials are essential to evaluate new therapies and improve health care. Successful enrollment is pivotal for the success of every trial. The following are recommendations to help promote enrollment success.

Cardiovascular disease (CVD) is the most common cause of death in American women and accounts for a full one-third of all deaths.1 Although the common perception may be that CVD affects mainly men, there is equal prevalence of this disease between the genders by the age of 40, and by the age of 60 more women than men are affected. More women than men have died from CVD causes on a yearly basis since the mid 1980s, and whereas the CVD mortality has steadily declined in men over the past 30 years, it has remained steady in women until very recently when CVD mortality was noted to decrease for both genders.2 See accompanying article on page 277 The impact of cardiovascular disease (CVD) on the health status of American women is gaining more recognition and has become the focus of public education efforts such as the “Go Red for Women” campaign sponsored by the American Heart Association and the “Red Dress” project sponsored by the Department of Health and Human Services, the National Institutes of Health (NIH), and the National Heart Lung and Blood Institute (NHLBI). These programs are, in part, a response to the increasing awareness of cardiovascular disease as a major source of morbidity and mortality in U.S. women. The importance of CVD as a major source of mortality in women was recognized early on by federally funded institutes including the Public Health Service Task Force, which brought attention to concerns about the health information available to women and the historical lack of research focus on women’s health in its 1985 Report of the Public Health Service Task Force on Women’s Health Issues .3 In response to this report, the National Institutes of Health adopted a policy for the inclusion of women in clinical research …

Health Care Equity and Justice Scorecard To Increase Diversity in Clinical Trial Recruitment and Retention.

Introduction: This observational study was conducted to assess the knowledge, attitudes, and perceptions (KAP) of Malaysians toward participating in clinical trials. It also aimed to look for factors that will influence people’s willingness to participate in trials. We planned and developed future outreach, education tools, and recruitment strategies to increase clinical trial enrolment. Methods: A cross-sectional study was carried out on a randomly selected sample of 398 Malaysian literate adults. An online questionnaire was created and distributed to the respondents. Descriptive statistics were presented in the form of frequency and percentages. The chi-square test was employed to find the association between independent variables. Results: The majority had good knowledge (61.3%) and high awareness (88.7%) of clinical trials. However, most of them were not willing to take part in a clinical trial if they were assigned to a group of unlicensed drugs (90.2%) or randomly assigned (66.1%). The main reasons for participating in trials were recommendations from doctors (46.5%) and the potential for their own benefit (45.7%). Younger age was positively associated with the necessity and confidentiality of clinical trials. Most respondents indicated negative perceptions towards the safety of clinical trials regardless of demographic variables. Conclusion: We gained a better understanding of Malaysian people who are potential participants in a future clinical trial. These findings could help clinical researchers improve their understanding of the participants and develop effective outreach strategies for clinical trial recruitment and retention.

Compared with the seemingly orderly approach to science associated with controlled laboratory environments, the assessment of broad changes in clinical practices and their impact on society is maddeningly complex and difficult to ascertain with confidence. Yet, in the end, the favorable regard of most societies toward public funding of biomedical science hinges on the belief that the end product of such research will benefit human health. This critical societal trust has been eroded by a growing skepticism directed toward the biomedical research enterprise and its associated industries, particularly the pharmaceutical industry. In this issue of Hypertension , Campbell et al1 report on their analysis of the impact of a program to improve the treatment of hypertension across Canada, one that has corresponded with increased use of antihypertensive medications and reduced incidence of death, stroke, myocardial infarction, and heart failure. The authors took advantage of the confluence of a major change in guideline recommendations, concerted national efforts linking professional societies and public health to control hypertension, and excellent sources of public data. These data allowed them to track prescriptions written by Canadian physicians and to correlate them with rates of key events (death and major cardiovascular and neurologic events) in the overall population. Using the powerful statistical technique of time series analysis, they demonstrated that rates of these critical events declined in direct proportion to the increase in prescription of antihypertensive medications, beginning in 1999. Taken at face value, this study provides compelling evidence that broad changes in medical care, when supported by convincing evidence from clinical trials, can result in improvements in death and disability for populations at the national level. Skeptics will …

Limited data exist regarding the optimal clinical trial design for studies involving persons with disorders of consciousness (DoC), and only a few therapies have been tested in high-quality clinical trials. To address this, the Curing Coma Campaign Clinical Trial Working Group performed a gap analysis on the current state of clinical trials in DoC to identify the optimal clinical design for studies involving persons with DoC. The Curing Coma Campaign Clinical Trial Working Group was divided into three subgroups to (1) review clinical trials involving persons with DoC, (2) identify unique challenges in the design of clinical trials involving persons with DoC, and (3) recommend optimal clinical trial designs for DoC. There were 3055 studies screened, and 66 were included in this review. Several knowledge gaps and unique challenges were identified. There is a lack of high-quality clinical trials, and most data regarding patients with DoC are based on observational studies focusing on patients with traumatic brain injury and cardiac arrest. There is a lack of a structured long-term outcome assessment with significant heterogeneity in the methodology, definitions of outcomes, and conduct of studies, especially for long-term follow-up. Another major barrier to conducting clinical trials is the lack of resources, especially in low-income countries. Based on the available data, we recommend incorporating trial designs that use master protocols, sequential multiple assessment randomized trials, and comparative effectiveness research. Adaptive platform trials using a multiarm, multistage approach offer substantial advantages and should make use of biomarkers to assess treatment responses to increase trial efficiency. Finally, sound infrastructure and international collaboration are essential to facilitate the conduct of trials in patients with DoC. Conduct of trials in patients with DoC should make use of master protocols and adaptive design and establish international registries incorporating standardized assessment tools. This will allow the establishment of evidence-based practice recommendations and decrease variations in care.

A lack of consensus on the optimal outcome measures to assess opioid use disorder (OUD) treatment efficacy and their precise definition and computation has hampered the pooling of research data for evidence synthesis and meta-analyses. This study aimed to empirically contrast multiple clinical trial definitions of treatment success by applying them to the same dataset. Data analysis used a suite of functions, developed as a software package for the R language, to operationalize 61 treatment outcome definitions based on urine drug screening (UDS) results. Outcome definitions were derived from clinical trials that are among the most influential in the OUD treatment field. Outcome functions were applied to a harmonized dataset from three large-scale National Drug Abuse Treatment Clinical Trials Network (CTN) studies, which tested various medication for OUD (MOUD) options (n = 2492). Hierarchical clustering was employed to empirically contrast outcome definitions. The optimal number of clusters identified was three. Cluster 1, comprising eight definitions focused on detecting opioid-positive UDS, did not include missing UDS in outcome calculations, potentially resulting in inflated rates of treatment success. Cluster 2, with the highest variability, included 10 definitions characterized by strict criteria for treatment success, relying heavily on UDS results from either a brief period or a single study visit. The 43 definitions in Cluster 3 represented a diverse range of outcomes, conceptualized as measuring abstinence, use reduction and relapse. These definitions potentially offer more balanced measures of treatment success or failure, as they avoid the extreme methodologies characteristic of Clusters 1 and 2. Clinical trials using urine drug screening (UDS) for objective substance use assessment in outcome definitions should consider (1) incorporating missing UDS data in outcome computation and (2) avoiding over-reliance on UDS data confined to a short time frame or the occurrence of a single positive urine test following a period of abstinence.