Clinical Research Enterprise Research Articles

Baseline Assessment of a Global Clinical Investigator Landscape Poised for Structural Change.

Mergers and acquisitions, the convergence of clinical research into clinical practice, more effective site selection and management practices, and efforts to improve investigator competence and credentials are all expected to contribute to consolidation in the global investigative site landscape during the coming 3 to 5 years. Tufts CSDD conducted an analysis of the FDA's Bioresearch Monitoring Information System (BMIS) to gather baseline data with which to monitor this anticipated structural change. More than half-a-million records were analyzed on clinical investigators who have filed at least 1 form 1572 with the FDA annually between 2008 and 2015. The results show that the global landscape of unique FDA-regulated principal investigators remains highly fragmented, nascent, and unstable. Principal investigators who file the lowest volume of 1572 forms each year make up the highest proportion of the global landscape, and one-third of all principal investigators each year are first-time filers. Each year, 40% of principal investigators drop out of the clinical research enterprise. However, there are signs that the landscape is beginning to scale and mature, particularly among investigators in North America. In addition, the rate of globalization is slowing and shifting, where recent growth in the number of active principal investigators in Europe has outpaced that in North America and in the rest of world. The implications of this study and future areas of research are discussed.

The Importance of Patient Satisfaction: A Blessing, a Curse, or Simply Irrelevant?

Sir: We read with great interest the article by Cohen et al. published in Plastic and Reconstructive Surgery entitled “The Importance of Patient Satisfaction: A Blessing, a Curse, or Simply Irrelevant?”1 We agree with the authors that the introduction of patient-reported quality measures has become a mainstay of the health care system and an essential part of physician rankings and reimbursement. As the implementation of evidence-based medicine grows in everyday practice, there is increasing pressure to adopt validated survey instruments to demonstrate patient-reported outcomes.2 In plastic surgery, measuring the patient’s perspective is highly relevant, as many key outcomes, such as appearance and facial function, are best evaluated through self-report.3 Using qualitative methods to elicit patient stories and using these stories to develop patient-reported outcomes instruments represent a best practice approach to ensure content validity. Although a patient-reported outcomes instrument may be shown to have excellent psychometric properties, if it fails to measure the issues that matter the most to patients, it will not be useful in clinical practice, research, or quality improvement initiatives. Patient-reported outcomes in clinical trials, effectiveness studies, and public health research have been defined as “any report coming directly from subjects without interpretation of the physician or others about how they function overall or feel in relation to a condition and its therapy.”4 A well-developed and validated tool would allow the comparison of techniques, the quantification of positive effects, and the identification of patients most likely to benefit from the procedure, and could also provide a follow-up standard and a benchmark for clinical studies, regulatory studies, and efficacy studies. For all these reasons, it surely could be of fundamental help for every plastic surgeon in daily clinical practice. Using the latest psychometric methods, the patient’s self-assessment can provide information in time on satisfaction, and can help patients themselves in the search for relevant data to help them better understand the expected results. As Pusic et al. affirmed, comprehensive measurement of surgical outcomes requires the combination of both objective and subjective measures, and to appropriately measure the effect of surgically relevant outcomes, well-developed and validated patient questionnaires are needed. Patient questionnaires that are not formally developed or tested (ad hoc questionnaires) may pose reasonable questions, but unless they are psychometrically tested, we cannot be confident about their reliability or validity. The use of reliable, valid, and responsive patient questionnaires is essential to provide information about the impact and effectiveness of plastic surgery. Ad hoc outcome tools may be inadequate, as they lack proven reliability and validity. Generic measures may be insufficient because they may not be responsive to surgical change.5 Thus, we must use only specific surgical measures in our clinical practice, which are specific, valid, and sensible. In the literature, some recent systematic, meaningful, and validated instruments exist that we use currently in our clinical practice. DISCLOSURE The authors have no commercial associations that might pose or create a conflict of interest with information presented in this communication. No intramural or extramural funding supported any aspect of this work. Mauro Barone, M.D.Annalisa Cogliandro, M.D., Ph.D.Marco Morelli Coppola, M.D.Paolo Persichetti, M.D., Ph.D.Plastic and Reconstructive Surgery UnitCampus Bio-Medico UniversityRome, Italy

Engagement, Research, and Evidence: Leveraging the National Patient-Centered Clinical Research Network for Better Cardiovascular Health.

A deluge of information and new approaches spanning the continuum from discovery to implementation and policy promises to fundamentally alter our understanding of cardiovascular health and healthcare. Although the existing system for cardiovascular research has yielded impressive results, it remains fractured, slow, costly, and hindered by systematic gaps. Further, even when it delivers answers, they are often accompanied by uncertainty about how to interpret or apply that knowledge across different populations. If cardiovascular medicine is to maintain its traditional excellence in innovation and evidence generation, then our current research paradigms must evolve. At the same time, external forces are affecting healthcare, including the imperatives to improve the value of care by increasing quality and reducing costs, grapple with disparities in care and outcomes, and achieve meaningful integration with other technologies using electronic health data and sophisticated analytics. Also medical practice needs to be reoriented toward considering the needs, preferences, and values of individual patients and consumers instead of focusing narrowly on providing products and services. This approach is especially poignant for US healthcare, whose decades-old reimbursement model is transforming into a more patient-centered system. These challenges present a daunting prospect. But what if the move toward integrated, patient-centered, accountable healthcare could be harnessed to simultaneously drive improvements in our clinical research enterprise? What if building systems for electronic health data can also provide robust scaffolding for efficient evidence generation while breaking down silos that impede the flow of information and knowledge among all stakeholders, including patients? Throughout the …

Abstract TP419: A Common Data Language for Clinical Research Studies: The National Institute of Neurological Disorders and Stroke and National Library of Medicine Cerebral Aneurysms and Subarachnoid Hemorrhage Common Data Elements Version 1.0 Recommendations

Introduction: The National Institute of Neurological Disorders and Stroke (NINDS) and the National Library of Medicine (NLM) initiated development of cerebral aneurysms and subarachnoid hemorrhage (SAH)-specific Common Data Elements (CDEs) in 2015 as part of a joint project to develop data standards for funded clinical research in neuroscience. Objective: Through the development of these data standards for clinical research, the NINDS and NLM SAH joint CDE initiative strives to improve SAH data collection by increasing efficiency, improving data quality, reducing study start-up time, facilitating data sharing/meta-analyses and helping educate new clinical investigators. Methods: The working group consisted of international members with varied fields of expertise related to SAH and was divided into domains such as subject characteristics and assessments and exams. They developed a set of SAH-specific CDE recommendations by selecting among, refining and adding to existing field-tested data elements. Recommendations, based on reviewing the established Stroke CDEs as well as other disease-specific CDEs, were uploaded to the NIH CDE Repository. Following an internal working group review of recommendations, the SAH CDEs will be vetted during a public review on the NINDS website. Results: Version 1.0 of the SAH CDEs will be available in early 2017. New SAH CDEs and recommendations will include those developed for unruptured intracranial aneurysms and long-term therapies. The NINDS CDE website provides uniform names and structures for each data element, as well as guidance documents and template case report forms using the CDEs. Conclusion: The NINDS encourages the use of CDEs by the clinical research community in order to standardize the collection of research data across studies. The NINDS CDEs are a continually evolving resource, requiring updates as research advancements indicate. These newly developed SAH CDEs will serve to be a valuable starting point for researchers and facilitate streamlining and sharing data. Information provided at this meeting will include examples of how the SAH CDEs may be used by a research study, demonstrations of navigating the NINDS CDE and NIH CDE Repository websites and how users can submit feedback.

THE ROLE OF LOCAL CONTRACT RESEARCH ORGANISATIONS IN BUILDING GCP-COMPLIANT CLINICAL RESEARCH IN POVERTY-RELATED DISEASES IN AFRICA: A CASE OF CLINWIN RESEARCH SERVICES

BackgroundAfrica carries the largest burden of the poverty-related diseases in the world. Most of her populations live in resource-limited settings. These act as catalysts for poverty-related diseases in those populations....

Update on Trial Registration 11 Years after the ICMJE Policy Was Established

Laws and policies to establish a global trial reporting system have greatly increased the transparency and accountability of the clinical research enterprise. The three components of the trial reporting system are trial registration, reporting of aggregate results, and sharing of individual participant data.1 Trial registration is foundational to our understanding and interpretation of trial results, because it requires that information be provided about all relevant clinical trials (to put results in a broad context) and their prespecified protocol details (to ensure adherence to the scientific plan). In this article, we describe the current trial registration landscape and summarize evidence of . . .

Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors.

Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints. Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.

Gender Differences in Knee Joint Congruity Quantified from MRI: A Validation Study with Data from Center for Clinical and Basic Research and Osteoarthritis Initiative.

Objective Gender is a risk factor in the onset of osteoarthritis (OA). The aim of the study was to investigate gender differences in contact area (CA) and congruity index (CI) in the medial tibiofemoral (MTF) joint in 2 different cohorts, quantified automatically from magnetic resonance imaging (MRI). Design The CA and CI markers were validated on 2 different data sets from Center for Clinical and Basic Research (CCBR) and Osteoarthritis Initiative (OAI). The CCBR cohort consisted of 159 subjects and the OAI subcohort consisted of 1,436 subjects. From the MTF joint, the contact area was located and quantified using Euclidean distance transform. Furthermore, the CI was quantified over the contact area by assessing agreement of the first- and second-order general surface features. Then, the gender differences between CA and CI values were evaluated at different stages of radiographic OA. Results Female CAs were significantly higher than male CAs after normalization, male CIs were significantly higher than female CIs after correcting with age and body mass index ( P < 0.05), consistent across the 2 data sets. For the OAI data set, the gender differences were present at all stages of radiographic OA. Conclusion This study demonstrated the gender differences in CA and CI in MTF joints. The higher normalized CA and lower CI values in female knees may be linked with the increased risk of incidence of radiographic OA in females. These differences may help further understand the gender differences and/or to establish gender specific treatment strategies.

Defining Significant Events for Neonatal and Pediatric Transport: Results of a Combined Delphi and Consensus Meeting Process.

Objective To develop standardized definitions for a list of indicators that represent significant events during pediatric transport, which were previously identified by a national Delphi study. Methods We designed a three-phase consensus process that applied Delphi methodology to a combination of electronic questionnaires and a live consensus meeting. Results Thirty-one pediatric transport experts evaluated a total of 59 indicators. Twenty-four indicators represented events or interventions that did not require definition. One indicator was removed from the list. Definitions for the remaining 34 indicators were developed. Conclusion This standardized indicator list is intended for application to quality improvement and clinical research initiatives.

Higher Prevalence of Hydroxyurea Use Is Associated with Lower Hospitalization Rate in a Population of Children with Sickle Cell Disease

Higher Prevalence of Hydroxyurea Use Is Associated with Lower Hospitalization Rate in a Population of Children with Sickle Cell DiseaseCecelia L. Calhoun, MD; Ryan Colvin, MPH; Sherry Lassa-Claxton, MS; Arti Verlekar MS; F. Sessions Cole, MD; Monica L. Hulbert, MDBackgroundIndividuals with sickle cell disease (SCD) treated with hydroxyurea (HU) in clinical trials have had fewer hospitalizations and vaso-occlusive pain episodes than those on placebo. Since 2014, HU has been recommended for all children with Hemoglobin SS/S-β0 thalassemia, and many SCD centers have increased HU utilization. The effect of expanded HU treatment on hospitalization rate has not been reported in a population of children clinically treated with HU. In a pediatric SCD center cohort, we tested the hypothesis that increasing prevalence of HU treatment was associated with reduced hospitalization rate per patient-year and in total hospitalizations.MethodsPedsNet, a PCORI-funded clinical research initiative, was queried for all patients with inpatient or outpatient encounters for SCD at St. Louis Children's Hospital (SLCH) from 2010 through 2015. Data from patients with ICD-9 codes indicating any genotype of SCD were included. Patients were considered to be receiving HU when it was prescribed on 2 or more outpatient encounters. Exclusion criteria were lack of SCD diagnosis confirmation, lack of outpatient visits at SLCH, and presence of a significant unrelated medical condition. Patients were censored at their 21st birthday or date of hematopoietic stem cell transplant. Data generated at the adult hospital were excluded. All hospitalizations in the final cohort were included for analysis, regardless of diagnosis code. For comparisons, patients were grouped as having a severe genotype (SS, S-β0 thalassemia, SD) or less-severe genotype (SC, S-β+ thalassemia). Statistical analysis was performed using SAS 9.4. Logistic and Poisson regression were used to compare proportions and rates between groups, respectively. Generalized Estimating Equations were used to account for within patient correlation.ResultsThe PedsNet query identified 646 patients. Sixty patients were excluded due to lack of SCD diagnosis, 78 due to lack of outpatient care, and 4 due to severe unrelated disease (3 with congenital disease/malformation, 1 with cancer), leaving 504 who met all inclusion criteria (51.6% male). Hematopoietic stem cell transplant was performed in 23 patients during the study period. Of patients with a severe genotype, 28 (20.1%) received HU in 2010 compared with 111 (65.6%) in 2015 (p<0.0001). Fewer patients in the less-severe genotype group received HU: 5 patients (4.3%) in 2010 and 13 (14.3%) in 2015 (p=0.006). In the severe genotype group, the rate of hospitalizations per patient-year decreased from 1.71 to 1.01 (p<0.0001) and the total number of hospitalizations decreased from 345 to 197. Throughout the study period, HU-treated patients in the severe genotype group had a higher hospitalization rate than HU-untreated patients; both treated and untreated patients had a significantly lower rate in 2015 than 2010 (Table), suggesting that hospitalizations were prevented as children who were more prone to hospitalizations began HU therapy. There was no significant change in hospitalization rate over time in the less-severe genotype group, at 1.13 hospitalizations per patient-year in 2010 and 1.16 in 2015 (p=0.94), with no impact of HU in this group.ConclusionsIn this clinical cohort of children with SCD, increasing prevalence of HU treatment was associated with significantly fewer total hospitalizations and a lower hospitalization rate per patient-year. The constant hospitalization rate in the less-severe genotype group suggests that the reduction is attributable to HU, rather than to other changes in clinical practice affecting patients with all genotypes. Hospitalization rates were higher among HU-treated patients, suggesting that more symptomatic children remain more likely to receive HU despite published recommendations to treat all children with severe genotypes. Families and clinicians may be reluctant to initiate HU for primary prevention of pain and hospitalizations in asymptomatic children. Future work should examine HU effects on specific SCD complications and on costs of care. Family and clinician interventions are needed to promote HU utilization in targeted patient groups. [Display omitted] DisclosuresHulbert:Pfizer, Inc.: Other: spouse employment.

Paving the Way for Workforce Innovation

ACRP’s Editor-in-Chief presents some of the insights gained from a recent discussion with the Association’s new Workforce Innovation Officer, Terri Hinkley, RN, BScN, MBA, CCRC, FACRP, about how rapid change across the clinical research enterprise requires a new set of skills and competencies from its professionals.

Workforce Development for Clinical Research Associates

One of the greatest challenges in the clinical research enterprise today is ensuring that a competent workforce is available to carry out its activities. The purpose of this article is to discuss how professionals can break into the clinical research associates (CRA) role, and to present models that can help transition the novice into an expert. CRAs and employers need to ensure that an appropriate career path exists with ongoing development opportunities. The Joint Task Force for Clinical Trial Competency has outlined competencies for the clinical research professional that can be translated into the CRA role and serve as the ultimate goal for professional development. By creating a workforce development program that addresses the challenges of CRAs with varying levels of experience, the end result is a qualified and skilled role that is vital to the clinical research industry.

The AUA Quality Registry: Engaging Stakeholders to Improve the Quality of Care for Patients with Prostate Cancer

IntroductionDetermining the most effective treatments for complex medical conditions requires robust clinical data. Clinical registries comprise real-world observational data, which allow rapid assessment of the effectiveness of treatments and care processes. In 2014 the AUA (American Urological Association) launched the AQUA (AUA Quality) Registry, a national urological disease registry intended to measure and report health care quality and patient outcomes, and support health services and comparative effectiveness research. The initial focus of the registry is newly diagnosed prostate cancer. In July 2014 the AUA convened a Stakeholder Forum with more than 20 organizations interested in improving the quality of care provided to patients with prostate cancer. MethodsWe discuss the rationale and need for the AQUA Registry, define quality of care for prostate cancer, prioritize data and information needs, and identify potential future uses for AQUA data beyond quality improvement. ResultsAQUA data will provide high quality data on effective treatments. Good quality of care for prostate cancer focuses on patient centered outcomes based on current evidence. The highest priority data collection needs are patient characteristics, evaluation and intervention utilization data, clinical and patient reported outcomes, and cost and resource use. In the future the registry data may be used to fulfill urologist quality reporting requirements. The AQUA Registry will also allow for a range of local and national quality improvement, and health services research efforts driven by urologists. ConclusionThe AQUA Registry will provide an essential platform to improve health care quality and support the next generation of clinical urology research and policy initiatives.

TransCelerate's Clinical Quality Management System: Issue Management.

Issue management is one of the elements of the TransCelerate clinical quality management (QMS) conceptual framework. Effective issue management benefits clinical development organizations by allowing them to focus efforts on those issues that materially impact patient safety, rights, and well-being; data integrity and/or scientific rigor; compliance with regulatory requirements; or trust in the clinical research enterprise, which have been defined as "Issues that Matter." Issue management begins with a triage of issues to identify those issues that materially impact as defined above, which are then handled by an end-to-end corrective and preventive action (CAPA) process. An added benefit of a well-defined issue management framework is the capability for trending and analytics designed to provide data and insights into risk management and knowledge management efforts.

Influence of Studies Published by the Journal of the American Geriatrics Society: Top 20 Articles from 2000-2015.

Influence of Studies Published by the Journal of the American Geriatrics Society: Top 20 Articles from 2000-2015.

Advances in Clinical Research Toward the Data-Driven Economy

This article highlights how new ubiquitous, participatory, and fast-paced technology trends impact the clinical research enterprise. Social networks, mobile devices, new computing paradigms, and interoperability standards help to democratize clinical research, offer benefits for participant recruitment efforts, and enable high-quality data collection. Such developments have also pushed the demand for multidimensional data analytics, and for secure computing infrastructures capable of scaling up to address the ever-changing requirements and availability of unprecedented amounts and diversity of clinical research data.

Clinical Research Informatics for Big Data and Precision Medicine.

To reflect on the notable events and significant developments in Clinical Research Informatics (CRI) in the year of 2015 and discuss near-term trends impacting CRI. We selected key publications that highlight not only important recent advances in CRI but also notable events likely to have significant impact on CRI activities over the next few years or longer, and consulted the discussions in relevant scientific communities and an online living textbook for modern clinical trials. We also related the new concepts with old problems to improve the continuity of CRI research. The highlights in CRI in 2015 include the growing adoption of electronic health records (EHR), the rapid development of regional, national, and global clinical data research networks for using EHR data to integrate scalable clinical research with clinical care and generate robust medical evidence. Data quality, integration, and fusion, data access by researchers, study transparency, results reproducibility, and infrastructure sustainability are persistent challenges. The advances in Big Data Analytics and Internet technologies together with the engagement of citizens in sciences are shaping the global clinical research enterprise, which is getting more open and increasingly stakeholder-centered, where stakeholders include patients, clinicians, researchers, and sponsors.

Pragmatic clinical trials: Emerging challenges and new roles for statisticians.

Patients, clinicians, and policymakers alike need access to high-quality scientific evidence in order to make informed choices about health and healthcare, but the current national clinical trials enterprise is not yet optimally configured for the efficient creation and dissemination of such evidence. However, new technologies and methods hold significant potential for accelerating the rate at which we are able to translate raw findings gathered from both patient care and clinical research into actionable knowledge. We are now entering a period in which the quantitative sciences are emerging as the critical disciplines for advancing knowledge about health and healthcare, and statisticians will increasingly serve as critical mediators in transforming data into evidence. In this new, data-centric era, biostatisticians not only need to be expert at analyzing data but should also be involved directly in diverse efforts, including the review and analysis of research portfolios in order to optimize the relevance of research questions, the use of "quality by design" principles to improve reliability and validity of each individual trial, and the mining of aggregate knowledge derived from the clinical research enterprise as a whole. In order to meet these challenges, it is imperative that we (1) nurture and build the biostatistical workforce, (2) develop a deeper understanding of the biological and clinical context among statisticians, (3) facilitate collaboration among biostatisticians and other members of the clinical trials enterprise, (4) focus on communication skills in training and education programs, and (5) enhance the quantitative capacity of the research and clinical practice worlds.

Are Randomized Controlled Trials the (G)old Standard? From Clinical Intelligence to Prescriptive Analytics.

Despite the accelerating pace of scientific discovery, the current clinical research enterprise does not sufficiently address pressing clinical questions. Given the constraints on clinical trials, for a majority of clinical questions, the only relevant data available to aid in decision making are based on observation and experience. Our purpose here is 3-fold. First, we describe the classic context of medical research guided by Poppers’ scientific epistemology of “falsificationism.” Second, we discuss challenges and shortcomings of randomized controlled trials and present the potential of observational studies based on big data. Third, we cover several obstacles related to the use of observational (retrospective) data in clinical studies. We conclude that randomized controlled trials are not at risk for extinction, but innovations in statistics, machine learning, and big data analytics may generate a completely new ecosystem for exploration and validation.

Responding to the Marketplace: Workforce Balance and Financial Risk at Academic Health Centers.

Elsewhere in this issue, Welch and Bindman present research demonstrating that academic health centers (AHCs) continue to disproportionately comprise specialists and subspecialist faculty physicians compared with community-based physician groups. This workforce composition has served AHCs well through the years-specialists fuel the clinical engine of the major tertiary and quaternary missions of AHCs, and they also dominate much of the clinical and translational research enterprise. AHCs are not alone-less than one-third of U.S. physicians practice primary care. However, health reform has prompted many health systems to reconsider this configuration. Payers, employers, and policy makers are shifting away from fee-for-service toward value-based care. Large community-based physician groups and their parent health systems appear to be far ahead of AHCs with a more balanced physician workforce. Many are leveraging their emphasis on primary care to participate in population health initiatives, such as accountable care organizations, and some own their own health plans. These approaches largely assume some element of financial risk and require both a more balanced workforce and an infrastructure to accommodate the management of covered lives. It remains to be seen whether AHCs will reconsider their own physician specialty composition to emphasize primary care-and, if they do, whether the traditional academic model, or a more community-based approach, will prevail.