Supporting open access to clinical trial data for researchers: The Duke Clinical Research Institute-Bristol-Myers Squibb Supporting Open Access to Researchers Initiative.

There are growing calls for sponsors to increase transparency by providing access to clinical trial data. In response, Bristol-Myers Squibb and the Duke Clinical Research Institute have collaborated on a new initiative, Supporting Open Access to Researchers. The aim is to facilitate open sharing of Bristol-Myers Squibb trial data with interested researchers. Key features of the Supporting Open Access to Researchers data sharing model include an independent review committee that ensures expert consideration of each proposal, stringent data deidentification/anonymization and protection of patient privacy, requirement of prespecified statistical analysis plans, and independent review of manuscripts before submission for publication. We believe that these approaches will promote open science by allowing investigators to verify trial results as well as to pursue interesting secondary uses of trial data without compromising scientific integrity.

Reimagining the United States organ procurement and transplant network.

The United States system of solid organ transplantation is overseen by the Organ Procurement Transplantation Network (OPTN). Recent announcements from the Health Resources and Services Administration (HRSA) indicate their clear intention to reform the system. We suggest that the original intention of the National Organ Transplant Act (NOTA) to require one entity to oversee transplantation is critical to integrate policy with the complex realities of organ procurement and transplantation practice. We suggest that a contemporary business platform model best captures the appropriate structure for coordinating organ transplantation, as the seamless exchange of organs between related groups is the essential function to facilitate. A business platform framework that includes public and private, academic and industry partners can best accomplish the important goal of equitable and efficient organ transplantation.

Doing it right: Caring for and protecting patient information for US organ donors and transplant recipients.

In the current US organ transplantation system, there are no regulations defining how organ procurement organizations must manage personal data and protect the privacy of donors and recipients. In response to the recent announcement of a major overhaul of the US transplantation system, we describe a practical approach to improving transplant data quality and protecting the autonomy of patients interacting with the system.

Design of the Healthcare Worker Exposure Response and Outcomes (HERO) research platform.

BACKGROUND: The SARS CoV-2 virus has caused one of the deadliest pandemics in recent history, resulting in over 170 million deaths and global economic disruption. There remains an urgent need for clinical trials to test therapies for treatment and prevention. DESIGN: An online research platform was created to support a registry community of healthcare workers (HCWs) to understand their experiences and conduct clinical studies to address their concerns. The first study, HERO-HCQ, was a double-blind, multicenter, randomized, pragmatic trial to evaluate the superiority of hydroxychloroquine (HCQ) vs placebo for pre-exposure prophylaxis (PrEP) of COVID-19 clinical infection in HCWs. Secondary objectives were to assess the efficacy of HCQ in preventing viral shedding of COVID-19 among HCWs and to assess the safety and tolerability of HCQ. METHODS: HCWs joined the Registry and were pre-screened for trial interest and eligibility. Trial participants were randomized 1:1 to receive HCQ or placebo. On-site baseline assessment included a COVID-19 nasopharyngeal PCR and blood serology test. Weekly follow-up was done via an online portal and included screening for symptoms of COVID-19, self-reported testing, adverse events, and quality of life assessments. The on-site visit was repeated at Day 30. DISCUSSION: The HERO research platform offers an approach to rapidly engage, screen, invite and enroll into clinical studies using a novel participant-facing online portal interface and remote data collection, enabling limited onsite procedures for conduct of a pragmatic clinical trial. This platform may be an example for future clinical trials of common conditions to enable more rapid evidence generation.

Meaningful Use of Electronic Health Records: Experiences From the Field and Future Opportunities.

BACKGROUND: With the aim of improving health care processes through health information technology (HIT), the US government has promulgated requirements for "meaningful use" (MU) of electronic health records (EHRs) as a condition for providers receiving financial incentives for the adoption and use of these systems. Considerable uncertainty remains about the impact of these requirements on the effective application of EHR systems. OBJECTIVE: The Agency for Healthcare Research and Quality (AHRQ)-sponsored Centers for Education and Research in Therapeutics (CERTs) critically examined the impact of the MU policy relating to the use of medications and jointly developed recommendations to help inform future HIT policy. METHODS: We gathered perspectives from a wide range of stakeholders (N=35) who had experience with MU requirements, including academicians, practitioners, and policy makers from different health care organizations including and beyond the CERTs. Specific issues and recommendations were discussed and agreed on as a group. RESULTS: Stakeholders' knowledge and experiences from implementing MU requirements fell into 6 domains: (1) accuracy of medication lists and medication reconciliation, (2) problem list accuracy and the shift in HIT priorities, (3) accuracy of allergy lists and allergy-related standards development, (4) support of safer and effective prescribing for children, (5) considerations for rural communities, and (6) general issues with achieving MU. Standards are needed to better facilitate the exchange of data elements between health care settings. Several organizations felt that their preoccupation with fulfilling MU requirements stifled innovation. Greater emphasis should be placed on local HIT configurations that better address population health care needs. CONCLUSIONS: Although MU has stimulated adoption of EHRs, its effects on quality and safety remain uncertain. Stakeholders felt that MU requirements should be more flexible and recognize that integrated models may achieve information-sharing goals in alternate ways. Future certification rules and requirements should enhance EHR functionalities critical for safer prescribing of medications in children.

Site-Directed Mutagenesis of the Sterol Methyl Transferase Active Site from Saccharomyces cerevisiae Results in Formation of Novel 24-Ethyl Sterols.

Delta(24(28))-Sterols are end products of a mono C-methylation pathway catalyzed by the native Delta(24(25))- to Delta(24(28))-sterol methyl transferase (SMT) enzyme from Saccharomyces cerevisiae. Using a Tyr(81) to Phe mutant SMT enzyme of S. cerevisiae, generated by site-directed mutagenesis of a highly conserved residue in the sterol binding site, we found that several Delta(24(25))- and Delta(24(28))-sterols, which are not substrates for the native protein, were catalyzed to mono- and bis-C24-alkylated side chains. The mutant protein behaved similarly to the native protein in chromatography and in binding zymosterol, the preferred substrate. Zymosterol was converted to fecosterol by the Y81F mutant protein with similar turnover efficiency as the native protein (K(m) = 12 &mgr;M and k(cat) = 0.01 s(-)(1)); trace 24-ethyl sterols were detected from these incubations. 4alpha-Methyl zymosterol, which is not a normal substrate for the wild-type SMT enzyme, was converted to 4alpha-methyl fecosterol in high yield. When fecosterol and 4alpha-methyl fecosterol were assayed individually at saturating concentrations only fecosterol served as an effective substrate for the second C-transfer step (K(m) = 38 &mgr;M and k(cat) = 0.002 s(-)(1)), suggesting that successive C-methylation of Delta(24(28))-substrates is limited by product release and that molecular recognition of sterol features involves hydrogen bond formation. Isomeric 24-ethyl sterol olefins generated from 24(28)-methylene cholesterol were characterized by chromatographic (GC and HPLC) and spectral methods (MS and (1)H NMR), viz., fucosterol, isofucosterol, and clerosterol. Changes in rate of C-methylation and product distributions resulting from deuterium substitution at C28 were used to establish the kinetic isotope effects (KIEs) for the various deprotonations leading to C24-methylene, C24-ethylidene, and C24-ethyl sterols. An isotope effect on C28 methyl deprotonation generated during the first C(1)-transfer was detected with zymosterol and desmosterol paired with AdoMet and [(2)H(3)-methyl]AdoMet. A similar experiment to test for a KIE generated during the second C(1)-transfer reaction with AdoMet paired with 24(28)-methylenecholesterol and [28-(2)H(2)]24(28)-methylene cholesterol indicated an inverse isotope effect associated with C27 deprotonation. Alteration in the proportion of the C24 alkylated olefinic products generated by the pure Y81F mutant resulted from the suppression of the formation of Delta(24(28))-ethylidene sterols (C28 deprotonation) by a primary deuterium isotope effect with a compensating stimulation of the formation of 24-ethyl sterols (C27 deprotonation). Kinetic study on the rate of product formation indicated a normal KIE of k(H)/k(D) = 2.62 for the first C(1)-transfer. Alternatively, an inverse KIE was established with k(H)/k(D) = 0.9 for the second C(1)-transfer resulting from conversion of the 24(28)-double bond (sp(2) hybridization) to a 24beta-ethyl group (sp(3) hybridization). From the structures and stereochemical assignments of the C-ethyl olefin products, the stereochemistry of the attack of AdoMet in the second C(1)-transfer was found to operate a Si-face (backside) attack at C24, analogous to the first C(1)-transfer reaction.

A registry-based randomized trial comparing radial and femoral approaches in women undergoing percutaneous coronary intervention: the SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women) trial.

OBJECTIVES: This study sought to determine the effect of radial access on outcomes in women undergoing percutaneous coronary intervention (PCI) using a registry-based randomized trial. BACKGROUND: Women are at increased risk of bleeding and vascular complications after PCI. The role of radial access in women is unclear. METHODS: Women undergoing cardiac catheterization or PCI were randomized to radial or femoral arterial access. Data from the CathPCI Registry and trial-specific data were merged into a final study database. The primary efficacy endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding or vascular complications requiring intervention. The primary feasibility endpoint was access site crossover. The primary analysis cohort was the subgroup undergoing PCI; sensitivity analyses were conducted in the total randomized population. RESULTS: The trial was stopped early for a lower than expected event rate. A total of 1,787 women (691 undergoing PCI) were randomized at 60 sites. There was no significant difference in the primary efficacy endpoint between radial or femoral access among women undergoing PCI (radial 1.2% vs. 2.9% femoral, odds ratio [OR]: 0.39; 95% confidence interval [CI]: 0.12 to 1.27); among women undergoing cardiac catheterization or PCI, radial access significantly reduced bleeding and vascular complications (0.6% vs. 1.7%; OR: 0.32; 95% CI: 0.12 to 0.90). Access site crossover was significantly higher among women assigned to radial access (PCI cohort: 6.1% vs. 1.7%; OR: 3.65; 95% CI: 1.45 to 9.17); total randomized cohort: (6.7% vs. 1.9%; OR: 3.70; 95% CI: 2.14 to 6.40). More women preferred radial access. CONCLUSIONS: In this pragmatic trial, which was terminated early, the radial approach did not significantly reduce bleeding or vascular complications in women undergoing PCI. Access site crossover occurred more often in women assigned to radial access. (SAFE-PCI for Women; NCT01406236).

The database for aggregate analysis of ClinicalTrials.gov (AACT) and subsequent regrouping by clinical specialty.

BACKGROUND: The ClinicalTrials.gov registry provides information regarding characteristics of past, current, and planned clinical studies to patients, clinicians, and researchers; in addition, registry data are available for bulk download. However, issues related to data structure, nomenclature, and changes in data collection over time present challenges to the aggregate analysis and interpretation of these data in general and to the analysis of trials according to clinical specialty in particular. Improving usability of these data could enhance the utility of ClinicalTrials.gov as a research resource. METHODS/PRINCIPAL RESULTS: The purpose of our project was twofold. First, we sought to extend the usability of ClinicalTrials.gov for research purposes by developing a database for aggregate analysis of ClinicalTrials.gov (AACT) that contains data from the 96,346 clinical trials registered as of September 27, 2010. Second, we developed and validated a methodology for annotating studies by clinical specialty, using a custom taxonomy employing Medical Subject Heading (MeSH) terms applied by an NLM algorithm, as well as MeSH terms and other disease condition terms provided by study sponsors. Clinical specialists reviewed and annotated MeSH and non-MeSH disease condition terms, and an algorithm was created to classify studies into clinical specialties based on both MeSH and non-MeSH annotations. False positives and false negatives were evaluated by comparing algorithmic classification with manual classification for three specialties. CONCLUSIONS/SIGNIFICANCE: The resulting AACT database features study design attributes parsed into discrete fields, integrated metadata, and an integrated MeSH thesaurus, and is available for download as Oracle extracts (.dmp file and text format). This publicly-accessible dataset will facilitate analysis of studies and permit detailed characterization and analysis of the U.S. clinical trials enterprise as a whole. In addition, the methodology we present for creating specialty datasets may facilitate other efforts to analyze studies by specialty groups.