NIH-funded Trials Research Articles

Using PROMIS Methodology to Create Self-Report Measures of Mindfulness and Related Concepts.

Mindfulness meditation is ubiquitous in health care, education, and communities at large. Mindfulness-Based Interventions (MBIs) are the focus of hundreds of NIH-funded trials given the myriad health benefits associated with this practice across multiple populations. Notwithstanding, significant gaps exist in how mindfulness concepts are measured using currently available self-report instruments. Due to the number of available mindfulness measurement tools, each measuring different aspects, it is difficult to determine the extent to which individuals develop comparable mindfulness skills and attitudes and which health benefits can be attributed to which gains in mindfulness. The Patient-Reported Outcomes Measurement Information System (Puerto RicoOMIS®) has established a rigorous instrument development methodology to create brief, precise, and clinically relevant outcomes tools. This is the first of 4 papers representing an NCCIH-funded initiative (R01AT009539), which has applied Puerto RicoOMIS® instrument development methodologies to mindfulness measurement to improve the rigor, relevance, and reproducibility of MBI research results. This introductory paper sets the stage for why improved mindfulness measurement tools are needed and briefly describes the Puerto RicoOMIS® development approach. The second 2 papers highlight results from a national survey, focus groups, and expert interviews to identify and organize relevant mindfulness concepts, domains, and items for eventual item bank creation. The fourth paper reviews the item writing and development process of these new instruments, including results from stakeholder cognitive interviews and a translatability review. Together these papers feature the rigorous development approach, rationale, logic, and significance that supports the development, calibration, and validation of new Puerto RicoOMIS® measures of mindfulness and related concepts.

Baseline Characteristics and Barriers to Recruitment in Cardiac and Pulmonary Rehabilitation NIH-Funded Trials.

Baseline Characteristics and Barriers to Recruitment in Cardiac and Pulmonary Rehabilitation NIH-Funded Trials.

Use of modernized eligibility criteria in pancreatic cancer clinical trials.

6545 Background: In 2017, ASCO + Friends recommended modernized eligibility criteria to improve generalizability of clinical trial results. Traditional criteria contribute to disparities in trial participation, yet modernized criteria can equalize eligibility rates. We aimed to assess use of modernized eligibility criteria in pancreatic ductal adenocarcinoma (PDAC) clinical trials since the updated guidelines. Methods: Modernized eligibility criteria were obtained from ASCO + Friends guidelines. Clinicaltrials.gov was queried for “pancreas adenocarcinoma” trials from Jan. 1, 2018 onward and eligibility criteria were assessed for compliance with modernized criteria. Kruskal-Wallis and Fisher’s exact tests were used to determine differences in compliance based on disease stage(s), starting year, phase, and funder. Results: In total, 108 clinical trials were identified - 31.5% for resectable, 56.5% for unresectable, 12.0% for both resectable/unresectable disease. Most trials were phase 1 (24.1%), phase 1|2 (15.7%) or phase 2 (45.4%). Funding sources included industry (38.0%), NIH (22.2%) and other sources (39.8%). No trial was compliant with all modernized criteria. Only 34.7% of trials allowed patients with ECOG performance status of 2. HIV+ patients were not allowed in 56.5% of trials. Only 7 trials (6.5%) were compliant with assessing renal function whereas 64.8% appropriately used upper limit of normal cutoffs for labs. Among trials that excluded patients for CHF, 59.6% used a classification system for exclusion. Specific cardiac abnormalities were excluded in 60.2% of trials. Prior malignancy was allowed in 71.3% of trials if treated > 2 years prior and concurrent malignancy, if stable, was allowed in 21.3% of trials. Prior PDAC treatment was allowed for 38.0% and required for 24.1% of trials. If prior treatment was allowed, 94% justified drug exclusions, 40.3% did not require a washout period, and 35.8% required recovery from prior adverse events. Stable/treated brain metastases were allowed in 33.8% of trials for unresectable cancer. Compliance with prior malignancy criteria improved from 2018-2019 to 2020-2022 (56.0% vs 84.5%, respectively; p = 0.001). Requirement of prior PDAC treatment was associated with disease stage (8.8% for resectable, 32.8% for unresectable, and 23.1% for both; p = 0.024), as was exclusion based on prior therapy (58.8% for resectable disease, 14.8% for unresectable, and 30.8% for both; p < 0.0001). Earlier trial phase was associated with prior treatment allowance (p = 0.002), whereas later phase trials were less likely to allow prior treatment (p = 0.021). NIH-funded trials required prior treatment (37.5%) more than industry (29.3%) or other (11.6%) funded trials (p = 0.034). Conclusions: Modernized eligibility criteria are inadequately implemented in PDAC clinical trials. Efforts to improve their use are warranted to produce more generalizable results and advance inclusivity.

Age-based exclusions in clinical trials: A review and new perspectives

BackgroundDespite elderly populations having a greater risk of being diagnosed with serious medical conditions, there has been limited clinical testing conducted on geriatric patients. By analyzing cancer, cardiovascular diseases, and type 2 diabetes data from ClinicalTrials.gov, we investigate two factors that may have significant impact on the exclusion of elderly patients from clinical trials. MethodsWe examine age exclusion across phases and funder types and demonstrate the extent of these exclusions over all interventional studies that commenced enrollment on or after January 2010 to Oct 2021. ResultsCancer trials have the lowest percentage of age capped enrollment, with 22.18%, 24.13%, and 32.77% of the studies listing an upper age limit in Phases 1, 2, and 3, respectively. In comparison, cardiovascular disease trials are age capped in 51.32%, 39.9%, and 34.94% of trials, and type 2 diabetes capped in 90.3%, 74.42%, and 36.75% of trials in Phases 1, 2, and 3 respectively. Our result shows no significant changes in the percentage of trials with upper age limits pre- and post- NIH Inclusion Across the Lifespan Policy. ConclusionOur analysis reveals cancer trials were the most age-inclusive. Further, NIH-funded trials have historically set fewer age caps compared to those whose funding has come from non-NIH sources, which provides optimism that inclusivity can be feasible for all trials.

Abstract 11350: DNP-PhD Collaboration in NIH-funded Physical Activity Trials for Women at Risk for Cardiovascular Disease: A Team Science Approach

Doctorally prepared nurse scholars with the doctor of nursing practice (DNP) and the doctor of philosophy (PhD) degrees are equally well suited to engage in scholarship to advance cardiovascular nursing and health outcomes. Collaboration between DNP and PhD scholars is crucial to develop interventions to improve cardiovascular outcomes and encourage efficient translation of research findings into practice. The purpose of this paper is to (1) provide a targeted review of the current state of literature on examples of DNP-PhD collaboration, and (2) describe ongoing DNP-PhD collaborations across three NIH-funded trials (1 completed, 2 ongoing) testing physical activity interventions for women at risk for cardiovascular disease. First, a targeted review was conducted to identify examples of DNP-PhD collaboration, and identified 12 published articles. Articles described the DNP-PhD collaborations in research/scholarship ( n = 8) and education ( n = 5). Of the research articles, there was evidence of collaboration in evidence-based practice projects for various health outcomes. However, none of the articles described DNP-PhD collaboration in NIH-funded clinical trials, including behavioral interventions for cardiovascular health. Three physical activity interventions for women at risk for cardiovascular disease were or are being tested in three trials (NCT01700894, NCT03558828, NCT04556305). Examples of DNP-PhD collaboration are categorized according to the four Team Science Phases. Research teams are led by PhD nurse scholars who oversee design and implementation (Development, Conceptualization, Implementation, Translation). DNP scholars provide clinical feedback in advisory panels and focus groups (Development, Conceptualization), provide training to intervention teams, lead personal call and group interventions (Implementation), facilitate patient referrals for participation (Implementation), oversee intervention safety (Implementation, Translation), and contribute to dissemination (Translation). DNP-PhD collaboration is important for all phases of NIH behavioral trials to optimize outcomes. There is a need for additional publications to detail applicable DNP-PhD collaborations in NIH-funded nursing research.

Update on RFA Increasing Use of Cardiac and Pulmonary Rehabilitation in Traditional and Community Settings NIH-Funded Trials: ADDRESSING CLINICAL TRIAL CHALLENGES PRESENTED BY THE COVID-19 PANDEMIC.

In Brief We previously described the design of six NIH-funded clinical trials designed to increase uptake and reduce disparities in the use of cardiac rehabilitation (CR) and pulmonary rehabilitation (PR) based on age, gender, race/ethnicity, and socioeconomic status. The onset of the COVID-19 global pandemic necessitated signifi cant revisions to the trials to ensure the safety of participants and research staff. This article described necessary modifi cations for assessments, interventions, and data collection to support a no-contact approach centered on the use of virtual/remote techniques that maintain both safety and the original intent and integrity of the trials. The general shift from site-based to home-based interventions and hybrid models of CR and PR will be increasingly important in a post-COVID world.

Evaluation of Data Sharing After Implementation of the International Committee of Medical Journal Editors Data Sharing Statement Requirement

The benefits of responsible sharing of individual-participant data (IPD) from clinical studies are well recognized, but stakeholders often disagree on how to align those benefits with privacy risks, costs, and incentives for clinical trialists and sponsors. The International Committee of Medical Journal Editors (ICMJE) required a data sharing statement (DSS) from submissions reporting clinical trials effective July 1, 2018. The required DSSs provide a window into current data sharing rates, practices, and norms among trialists and sponsors. To evaluate the implementation of the ICMJE DSS requirement in 3 leading medical journals: JAMA, Lancet, and New England Journal of Medicine (NEJM). This is a cross-sectional study of clinical trial reports published as articles in JAMA, Lancet, and NEJM between July 1, 2018, and April 4, 2020. Articles not eligible for DSS, including observational studies and letters or correspondence, were excluded. A MEDLINE/PubMed search identified 487 eligible clinical trials in JAMA (112 trials), Lancet (147 trials), and NEJM (228 trials). Two reviewers evaluated each of the 487 articles independently. Publication of clinical trial reports in an ICMJE medical journal requiring a DSS. The primary outcomes of the study were declared data availability and actual data availability in repositories. Other captured outcomes were data type, access, and conditions and reasons for data availability or unavailability. Associations with funding sources were examined. A total of 334 of 487 articles (68.6%; 95% CI, 64%-73%) declared data sharing, with nonindustry NIH-funded trials exhibiting the highest rates of declared data sharing (89%; 95% CI, 80%-98%) and industry-funded trials the lowest (61%; 95% CI, 54%-68%). However, only 2 IPD sets (0.6%; 95% CI, 0.0%-1.5%) were actually deidentified and publicly available as of April 10, 2020. The remaining were supposedly accessible via request to authors (143 of 334 articles [42.8%]), repository (89 of 334 articles [26.6%]), and company (78 of 334 articles [23.4%]). Among the 89 articles declaring that IPD would be stored in repositories, only 17 (19.1%) deposited data, mostly because of embargo and regulatory approval. Embargo was set in 47.3% of data-sharing articles (158 of 334), and in half of them the period exceeded 1 year or was unspecified. Most trials published in JAMA, Lancet, and NEJM after the implementation of the ICMJE policy declared their intent to make clinical data available. However, a wide gap between declared and actual data sharing exists. To improve transparency and data reuse, journals should promote the use of unique pointers to data set location and standardized choices for embargo periods and access requirements.

Dissemination of a telehealth cardiovascular risk service: The CVRS live protocol

BackgroundMedical clinics are increasingly hiring clinical pharmacists to improve management of cardiovascular disease (CVD). However, the limited number of clinical pharmacists employed in a clinic may not impact the large number of complex patients needing the services. We have developed a remote telehealth service provided by clinical pharmacists to complement CVD services provided by on-site clinical pharmacists and aid sites without a clinical pharmacist. This cardiovascular risk service (CVRS) has been studied in two NIH-funded trials, however, we identified barriers to optimal intervention implementation. The purpose of this study is to examine how to implement the CVRS into medical offices and see if the intervention will be sustained. MethodsThis is a 5-year, pragmatic, cluster-randomized clinical trial in 13 primary care clinics across the US. We randomized clinics to receive CVRS or usual care and will enroll 325 patient subjects and 288 key stakeholder subjects. We have obtained access to the electronic medical records (EMRs) of all study clinics to recruit subjects and provide the pharmacist intervention. The intervention is staggered so that after 12 months, the usual care sites will receive the intervention for 12 months. Follow-up will be accomplished though medical record abstraction at baseline, 12 months, 24 months, and 36 months. ConclusionsThis study will enroll subjects through 2021 and results will be available in 2024. This study will provide unique information on how the CVRS provided by remote clinical pharmacists can be effectively implemented in medical offices, many of which already employ on-site clinical pharmacists.Clinical Trial Registration Information: NCT03660631: http://clinicaltrials.gov/ct2/show/NCT03660631

The matrix: building more bioactive extracellular matrices via tuning of substrate stiffness

Background & Aim Mesenchymal stromal cells (MSCs) have long been at the forefront of cellular therapy and regenerative medicine, and they are being explored in more than 700 NIH-funded trials for their therapeutic potential. The low frequency of MSCs in the human body, poor yield of MSCs from tissue biopsies, and high number of MSCs required for clinical applications demand that tissue-isolated MSCs undergo a lengthy expansion ex vivo, during which they exhibit senescence and become unsuitable for therapeutic applications. Decellularized extracellular matrices (dECM) present a novel solution to this issue, as MSCs grown on dECM maintain greater viability as compared to those grown on conventional tissue culture substrates. The effect of environmental parameters on extracellular matrix bioactivity requires further elucidation. Particularly, we will investigate the influence of substrate stiffness on the composition of MSC-derived ECM, to produce customized dECM which enhances cellular growth and functionality. This is achieved by culturing MSCs on hydrogels of varying stiffnesses, and assessing the bioactivity of the ECM produced during culture. Methods, Results & Conclusion Mechanical properties of tunable stiffness polyacrylamide gels were verified using an Instron Microtester. Cells used were isolated from the decidua basalis, and ECM was sourced from decidua basalis hTERT-transfected MSCs. ECM deposition was induced by addition of ascorbic acid. Instron measurements confirm the elastic moduli of fully-hydrated polyacrylamide gels to be 4 kPa, 10 kPa, and 40 kPa, tailored to mimic the stiffness of adipose tissue, skeletal muscle tissue, and collagenous bone tissue, respectively. MSCs exhibit a spindle-shaped morphology when cultured on the hydrogels. Confocal microscopy reveals microarchitectural differences between ECM deposited on softer vs. stiffer hydrogels. We have shown that MSCs can be grown on hydrogels of varying stiffnesses, and can be induced to laydown extracellular matrix. The functionalization of the gels with collagen I to aid cell adhesion has been confirmed with immunofluorescence. The deposition of ECM has also been confirmed with confocal microscopy, and the alignment of ECM fibrils has been shown to depend on substrate stiffness. Further work will involve proteomic characterization of the dECMs, and culturing MSCs on the dECMs to assess bioactivity. We expect that the substrate stiffness will modulate the ECM bioactivity, allowing customization of tailored dECM for MSC expansion.

Sex Bias in Interventional Clinical Trials.

Prior studies have shown that sex bias exists with subject enrollment in clinical trials, with more men being enrolled than women. The objective of this study was to identify if sex bias continues to exist in present day clinical trials entered into ClinicalTrials.gov . We hypothesize that males and females are not equally represented in recent clinical trials. Data were abstracted from all interventional Phase I, II, and III clinical trials with adult subjects entered into ClinicalTrials.gov from January 1, 2011 to December 31, 2013 and completed by November 30, 2015. Number and sex of subjects, funding source, allocation, end point classification, interventional model, and purpose were recorded. Studies pertaining to diseases that were sex specific were excluded. Of 1,668 studies included in the initial search, 167 were excluded due to sex-specific study topic. Of the remaining 1,501 studies, 177,656 (51.1%) male and 170,331 (49.0%) female subjects were included. There was a significant difference in the sex of the subjects included in Phase I (64.1% male/35.9% female), Phase II (48.4% male/51.6% female), and Phase III (51.0% male/49.1% female) clinical trials (p < 0.05). Similarly, there was a significant difference in the sex of the subjects included in industry (50.7% male/49.3% female), National Institutes of Health (NIH) (56.6% male/43.4% female), "Other US Federal" (62.5% male/37.5% female), and "Other" funded (53.4% male/46.6% female) clinical trials (p < 0.0001), as well as between randomized (50.5% male/49.6% female) and nonrandomized (54.8% male/45.2% female) clinical trials (p < 0.0001). Upon evaluating if the sex of the subjects included in the individual clinical trials was equally matched, we found that only 4.1% of clinical trials had 100% sex matching, 22.2% had 80% sex matching, and 56.5% had 50% sex matching. Using a liberal 50% sex-matching criteria, Phase III and II clinical trials matched the sex of the subjects more frequently compared to Phase I trials (60.8%, 57.8%, and 45.5%, respectively, p = 0.003). These data reveal that sex bias is present in current day clinical trials. Despite legislation requiring NIH-funded clinical trials to include women, NIH-funded trials were not better than industry-funded trials at matching the inclusion of both sexes.

Funding Support and Principal Investigator Leadership of Oncology Clinical Trials Using Radiation Therapy

Sources of funding and principal investigator (PI) leadership for clinical trials using radiation therapy (RT) are not well characterized but are important mediators of innovation, particularly because funding for trials from the National Institutes of Health (NIH) has decreased and industry funding has increased. We sought to determine characteristics of trials using RT that are associated with industry funding, NIH funding, and radiation oncologist (RO) PI leadership. www.ClinicalTrials.gov was queried for all open, interventional trials that administered RT. Logistic regression was used to identify associations between trial characteristics, receipt of funding type (NIH, industry, or other), and PI leadership. The authors identified 1469 oncology trials, of which 41% were based in the United States, 56% were based internationally, and 3% were based in the United States and internationally. Of these, 22% were RT monotherapy, 53% were bimodality (40% RT + drug, 13% RT + surgery), and 24% were trimodality. Although ROs led 60% of all trials, industry-sponsored trials were significantly less likely to have RO PIs (35% RO vs 65% non-RO PI; adjusted odds ratio [aOR], 0.45; 95% confidence interval [CI], 0.28-0.73), to fund trials that did not incorporate drug therapy (aOR, 0.19; 95% CI, 0.10-0.35), or to fund phase III trials (aOR, 0.25; 95% CI, 0.11-0.60) because industry-sponsored trials favored smaller phase I trials. NIH-funded trials were not associated with PI type and, although not statistically significant, favored larger phase III trials (unadjusted OR, 2.06; 95% CI, 0.99-4.29). ROs were less likely to lead trials incorporating drug therapy (aOR, 0.30; 95% CI, 0.22-0.41). ROs are less likely than other specialties to lead trials that use RT in combination with drug therapy or surgery and more likely to lead trials supported by nonindustry, non-NIH funding. This suggests a need for ROs to lead multimodality trials and to consider opportunities to interact with industry. As NIH resources decrease, alternative funding is needed to support innovation, particularly in in RT-alone trials.

Factors predicting publication of spinal cord injury trials registered on www.ClinicalTrials. gov

Treatment options for spinal cord injuries are currently limited, but multiple clinical trials are underway for a variety of interventions, drugs, and devices. The Food and Drug Administration website www.ClinicalTrials.gov catalogues these trials and includes information on the status of the trial, date of initiation and completion, source of funding, and region. This investigation assesses the factors associated with publication and the publication rate of spinal cord injury trials. Retrospective analysis of publically available data on www.ClinicalTrials.gov. The www.ClinicalTrials.gov was queried for all trials on patients with spinal cord injury, and these trials were assessed for status, type of intervention, source of funding, and region. Multiple literature searches were performed on all completed trials to determine publication status. There were 626 studies identified concerning the treatment of patients with spinal cord injury, of which 250 (39.9%) were completed. Of these, only 119 (47.6%) were published. There was no significant difference in the rate of publication between regions (p> 0.16) or by study type (p> 0.29). However, trials that were funded by the NIH were more likely to be published than trials funded by industry (p= 0.01). The current publication rate of spinal cord injury trials is only 47.6%, though this rate is similar to the publication rate for trials in other fields. NIH-funded trials are significantly more likely to become published than industry-funded trials, which could indicate that some trials remain unpublished due to undesirable results. However, it is also likely that many trials on spinal cord injury yield negative results, as treatments are often ineffective.

A systematic review of the inclusion of mechanisms of action in NIH-funded intervention trials to improve medication adherence

Medication nonadherence contributes to morbidity/mortality, but adherence interventions yield small and inconsistent effects. Understanding the mechanisms underlying initiation and maintenance of adherence could improve interventions. The National Institutes of Health (NIH) support adherence research, but it is unclear whether existing NIH-funded research incorporates mechanisms. We conducted a systematic review to determine the proportion of NIH-funded adherence trials that have tested hypothesized mechanisms of intervention effects.We included randomized and quasi-randomized NIH-funded trials with medication adherence in adults as the primary outcome. Studies were identified by searching electronic databases from inception to 6/2016, references, and clinicaltrials.gov.Two of 18 (11%) NIH-funded trials tested a hypothesized mechanism of an intervention's effect on medication adherence. Another 44 studies with medication adherence as a secondary outcome were described in protocol form, and are either ongoing or never published results, but none mentioned mechanism tests. Overall, 3% of NIH-funded trials with adherence as an outcome conducted, or plan to conduct, tests of behavior change mechanisms.These results mirror previous findings that very few studies of behavior change interventions actually test the mechanism by which the intervention is hypothesized to improve health behaviors. We must understand mechanisms if we are to improve the effectiveness of interventions.

CHARTing a Path to Pragmatic Tobacco Treatment Research.

It is important to consider the degree to which studies are explanatory versus pragmatic to understand the implications of their findings for patients, healthcare professionals, and policymakers. Pragmatic trials test the effectiveness of interventions in real-world conditions; explanatory trials test for efficacy under ideal conditions. The Consortium of Hospitals Advancing Research on Tobacco (CHART) is a network of seven NIH-funded trials designed to identify effective programs that can be widely implemented in routine clinical practice. A cross-sectional analysis of CHART trial study designs was conducted to place each study on the pragmatic-explanatory continuum. After reliability training, six raters independently scored each CHART study according to ten PRagmatic Explanatory Continuum Indicator Summary (PRECIS) dimensions, which covered participant eligibility criteria, intervention flexibility, practitioner expertise, follow-up procedures, participant compliance, practitioner adherence, and outcome analyses. Means and SDs were calculated for each dimension of each study, with lower scores representing more pragmatic elements. Results were plotted on "spoke and wheel" diagrams. The rating process and analyses were performed in October 2014 to September 2015. All seven CHART trials tended toward the pragmatic end of the spectrum, although there was a range from 0.76 (SD=0.23) to 1.85 (SD=0.58). Most studies included some explanatory design elements. CHART findings should be relatively applicable to clinical practice. Funders and reviewers could integrate PRECIS criteria into their guidelines to better facilitate pragmatic research. CHART study protocols, coupled with scores reported here, may help readers improve the design of their own pragmatic trials.

Publication status of contemporary oncology randomised controlled trials worldwide

BackgroundLittle is known about the extent of selective publication in contemporary oncology randomised controlled trials (RCTs) worldwide. This study aimed to evaluate the rates of publication and timely publication (within 24 months) for contemporary oncology RCTs from all over the world. We also investigated the trial characteristics associated with publication and timely publication. Patients and methodsWe identified all phase III oncology RCTs registered on ClinicalTrials.gov with a primary completion date between January 2008 and December 2012. We searched PubMed and EMBASE to identify publications. The final search date was 31 December 2015. Our primary outcome measure was the time to publication from the primary completion date to the date of primary publication in a peer-reviewed journal. ResultsWe identified 598 completed oncology RCTs; overall, 398 (66.6%) had been published. For published trials, the median time to publication was 25 months (interquartile range, 16–37 months). Only 192 trials (32.1%) were published within 24 months. Timely publication was independently associated with trials completed late in 2012. Trials conducted in Asia and other regions were less likely to have timely publication, but trials conducted in different locations were all equally likely to be published. Industry- and NIH-funded trials were equally likely to be published timely or at any time after trial completion. Among 391 published trials with clear primary outcomes, there was a trend for timely publication of positive trials compared with negative trials. ConclusionsDespite the ethical obligations and societal expectations of disclosing findings promptly, oncology RCTs performed poorly.

Trends in National Institutes of Health Funding for Clinical Trials Registered in ClinicalTrials.gov

Clinical trials inform evidence-based prevention and treatment recommendations. The National Institutes of Health (NIH) and the pharmaceutical industry have been major funders of trials. In general, the pharmaceutical industry funds trials that test their own products, whereas the NIH’s funding strategies are not commercially motivated. In 2005, registration of trials became required for publication in major journals. Registration is also required for trials that meet the definition of an “applicable clinical trial” from the US Food and Drug Administration Amendments Act 801 and that were either initiated after September 27, 2007, or initiated on or before that date and were still ongoing as of December 26, 2007. There are legal repercussions if sponsors or principal investigators do not register accurately. We hypothesized that the number of NIH-funded trials has decreased. We investigated trends in funding of trials using the NIH-built database, ClinicalTrials.gov, with a focus on NIH and industry funding.

Implementation of HIV-Related Clinical Research in the International Setting

The last twenty years have witnessed a dramatic increase in human immunodeficiency virus (HIV)-related therapeutic research conducted in international settings. Moving from a model of leadership based in a US or European institution, international sites have developed increasing autonomy and many now have the capacity for the conduct of high quality clinical research. In tandem with the increased availability of antiretroviral therapy and laboratory monitoring, investigators from resource-limited settings (RLS) now set their own research agenda, one which is relevant for their local and regional priorities. The development of this research capacity and expertise has included many challenges ranging from overarching ethical issues, to the practicalities of maintaining continuous electrical power. Many RLS are in areas of very high disease burden and overwhelming need for clinical care and laboratory services, which compete with the resources needed for clinical trials. International aid agencies have appropriately focused on building clinical capacity for prevention and treatment services, rather than research capacity. Inadequate health care infrastructure, understaffing, and complex regulatory hurdles also contribute to the difficulties. The editors of this supplement have had the privilege of participating in the process of development of international sites for the NIH-funded therapeutic trials networks. For example, the AIDS Clinical Trials Group (ACTG) now has 27 international clinical research sites. Developed under the leadership of Dr Constance Benson, the network has developed and implemented multiple pivotal clinical trials performed almost exclusively at the international sites, that have changed both clinical practice and management guidelines1. These include A5175 which evaluated alternative first line antiretroviral treatment regimens;2 A5199 which described the neurocognitive and neurologic complications of HIV and its therapies in RLS.3 The International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), in collaboration with the ACTG, conducted A5207 and A5208 which evaluated alternative ART regimens for the prevention of mother-to-child transmission and the consequences of single dose nevirapine therapy.4,5 Also performed in RLS, the SAPIT and CAMELIA studies demonstrated the benefits of early antiretroviral therapy (ART) in patients with TB, a finding which was confirmed in A5221 and contributed to changes in treatment paradigms6,7,8. The most recent groundbreaking study was the HIV Prevention Trials Network (HPTN) 052/A5245 demonstrating dramatic reduction in HIV transmission by ART in discordant couples.9 The primary paper was voted the “Science Breakthrough of the Year”.10 This trial also informs on ongoing debate about when to start antiretroviral therapy, by showing that early ART delayed the time to development of HIV-related clinical events, a finding originally shown by the CIPRA Haiti trial. 11,12 An important component of the success of the development of the international research capacity and agenda has been community engagement and capacity development.13–15 Community participation has been a key component of National Institute of Allergy and Infectious Diseases (NIAID) research activities since early in the HIV/AIDS epidemic, and continues to be so with the expansion of the research into RLS.16 Community representatives are integrated at every level, from creation of the scientific agenda and priorities to approval of a concept proposal and subsequent development and implementation of a protocol. We have developed strong collaborative relationships with many of the talented and hardworking site investigators and staff working in extraordinary conditions, and we have also had the opportunity to observe many of the issues encountered with research in the international RLS. Agenda setting, collaborating with multiple funding partners, negotiating an appropriate and achievable standard of care, and regulatory challenges including supporting nascent Institutional Review Boards (IRB) and other topics associated with multinational research made for extremely interesting discussions that we felt might also be of interest to a wider audience. This supplement describes some of the key issues encountered in the conduct of clinical research in resource-limited settings, with authors from representative international sites. We are very grateful for funding support from the Therapeutics Research Program at the Division of AIDS.

A Randomized Study of How Physicians Interpret Research Funding Disclosures

BackgroundThe effects of clinical-trial funding on the interpretation of trial results are poorly understood. We examined how such support affects physicians' reactions to trials with a high, medium, or low level of methodologic rigor.MethodsWe presented 503 board-certified internists with abstracts that we designed describing clinical trials of three hypothetical drugs. The trials had high, medium, or low methodologic rigor, and each report included one of three support disclosures: funding from a pharmaceutical company, NIH funding, or none. For both factors studied (rigor and funding), one of the three possible variations was randomly selected for inclusion in the abstracts. Follow-up questions assessed the physicians' impressions of the trials' rigor, their confidence in the results, and their willingness to prescribe the drugs.ResultsThe 269 respondents (53.5% response rate) perceived the level of study rigor accurately. Physicians reported that they would be less willing to prescribe drugs tested in low-rigor trials than those tested in medium-rigor trials (odds ratio, 0.64; 95% confidence interval [CI], 0.46 to 0.89; P=0.008) and would be more willing to prescribe drugs tested in high-rigor trials than those tested in medium-rigor trials (odds ratio, 3.07; 95% CI, 2.18 to 4.32; P<0.001). Disclosure of industry funding, as compared with no disclosure of funding, led physicians to downgrade the rigor of a trial (odds ratio, 0.63; 95% CI, 0.46 to 0.87; P=0.006), their confidence in the results (odds ratio, 0.71; 95% CI, 0.51 to 0.98; P=0.04), and their willingness to prescribe the hypothetical drugs (odds ratio, 0.68; 95% CI, 0.49 to 0.94; P=0.02). Physicians were half as willing to prescribe drugs studied in industry-funded trials as they were to prescribe drugs studied in NIH-funded trials (odds ratio, 0.52; 95% CI, 0.37 to 0.71; P<0.001). These effects were consistent across all levels of methodologic rigor.ConclusionsPhysicians discriminate among trials of varying degrees of rigor, but industry sponsorship negatively influences their perception of methodologic quality and reduces their willingness to believe and act on trial findings, independently of the trial's quality. These effects may influence the translation of clinical research into practice.

Clinical Research Involving Children: Registration, Completeness, and Publication

Effective health care for children must be based on thorough analyses of the best research evidence. The objective of this study was to examine registration, completeness, and publication of studies involving children. We searched the ClinicalTrials.gov registry to identify all closed studies involving children and examined them for completeness and availability of results. We examined publication in peer-reviewed journals for 160 randomly selected National Institutes of Health (NIH)-funded studies from 2000 through 2010 and for 758 randomly selected completed studies. Of 3428 closed studies involving children identified in ClinicalTrials.gov, 2385 (70%) were completed, 28 (0.8%) suspended, 152 (4.4%) terminated, and 38 (1.1%) withdrawn. The proportion of non-completed studies (terminated and suspended) increased linearly by 186% between 2001 and 2009, from 1.9% to 8.4%. Of the 152 terminated studies, 48 did not report reasons for termination, 21 cited safety concerns, and 83 cited poor recruitment or other administrative reasons. Only 29% of completed studies were published. Publication that did occur was an average of 2 years after study completion. Completed interventional studies were published more often than observational studies. Completed industry-funded studies were published less often than studies funded by the NIH. Registered NIH-funded trials were published more often than unregistered. Results are unavailable for more than half of the studies involving children, revealing a substantial publication bias. Registration and posting of results on ClinicalTrials.gov should be mandatory for all studies involving children.

Multicenter consensus development of a checklist for lung injury prevention

Acute lung injury (ALI) is linked to almost 75,000 US deaths annually. The syndrome is defined clinically by criteria that identify only patients with established ALI, at which point treatment options are limited and largely supportive. After 40 years and more than 25 NIH-funded trials of ALI interventions, only supportive therapy with lung protective ventilation has been associated with a mortality benefit. The US Critical Illness and Injuries Trials Group lung injury prevention subgroup seeks to standardize best practices for patients at risk of ALI. The recently validated lung injury prediction score (LIPS) identifies patients at risk of ALI, and can prompt the early use of preventative interventions. This may attenuate the progression to ALI. This study seeks expert consensus about best practices in patients at risk of ALI, as determined by their LIPS. These practices will be incorporated into a checklist for lung injury prevention. Standardization of care may protect patients against ALI development and provide a uniform background for enrollment in other ALI trials.