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In 2016, the National Center for Advancing Translational Science launched the Trial Innovation Network (TIN) to address barriers to efficient and informative multicenter trials. The TIN provides a national platform, working in partnership with 60+ Clinical and Translational Science Award (CTSA) hubs across the country to support the design and conduct of successful multicenter trials. A dedicated Hub Liaison Team (HLT) was established within each CTSA to facilitate connection between the hubs and the newly launched Trial and Recruitment Innovation Centers. Each HLT serves as an expert intermediary, connecting CTSA Hub investigators with TIN support, and connecting TIN research teams with potential multicenter trial site investigators. The cross-consortium Liaison Team network was developed during the first TIN funding cycle, and it is now a mature national network at the cutting edge of team science in clinical and translational research. The CTSA-based HLT structures and the external network structure have been developed in collaborative and iterative ways, with methods for shared learning and continuous process improvement. In this paper, we review the structure, function, and development of the Liaison Team network, discuss lessons learned during the first TIN funding cycle, and outline a path toward further network maturity.
Improving the quality and conduct of multi-center clinical trials is essential to the generation of generalizable knowledge about the safety and efficacy of healthcare treatments. Despite significant effort and expense, many clinical trials are unsuccessful. The National Center for Advancing Translational Science launched the Trial Innovation Network to address critical roadblocks in multi-center trials by leveraging existing infrastructure and developing operational innovations. We provide an overview of the roadblocks that led to opportunities for operational innovation, our work to develop, define, and map innovations across the network, and how we implemented and disseminated mature innovations.
New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or “hybrid” trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.
One challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities. This communication draws on the experience of the National Center for Advancing Translational Science (NCATS) Trial Innovation Network (TIN) to develop approaches for enhancing the informativeness of clinical trials. We distilled this information into three principles: (1) assemble a diverse team, (2) leverage existing processes and systems, and (3) carefully consider budgets and contracts. The TIN, comprised of NCATS, three Trial Innovation Centers, a Recruitment Innovation Center, and 60+ CTSA Program hubs, provides resources to investigators who are proposing multicenter collaborations. In addition to sharing principles that support the informativeness of clinical trials, we highlight TIN-developed resources relevant for multicenter trial initiation and conduct.
Given the convergence of the long and challenging development path for medical devices with the need for diagnostic capabilities for mild traumatic brain injury (mTBI/concussion), the effective role of public–private partnership (PPP) can be demonstrated to yield Food and Drug Administration (FDA) clearances and innovative product introductions. An overview of the mTBI problem and landscape was performed. A detailed situation analysis of an example of a PPP yielding an innovative product was further demonstrated. The example of PPP has led to multiple FDA clearances and product introductions in the TBI diagnostic product category where there was an urgent military and public need. Important lessons included defining the primary public and military health objective for new product introduction, the importance of the government–academia–industry PPP triad with a “collaboration towards solutions” Quality-by-Design (QbD) mindset to assure clinical validity with regulatory compliance, the development of device comparators and integration of measurements into a robust, evidence-based statistical and FDA pathway, and the utility of top-down, flexible, practical action while operating within governmental guidelines and patient safety.
Inefficiencies in the national clinical research infrastructure have been apparent for decades. The National Center for Advancing Translational Science—sponsored Clinical and Translational Science Award (CTSA) program is able to address such inefficiencies. The Trial Innovation Network (TIN) is a collaborative initiative with the CTSA program and other National Institutes of Health (NIH) Institutes and Centers that addresses critical roadblocks to accelerate the translation of novel interventions to clinical practice. The TIN’s mission is to execute high-quality trials in a quick, cost-efficient manner. The TIN awardees are composed of 3 Trial Innovation Centers, the Recruitment Innovation Center, and the individual CTSA institutions that have identified TIN Liaison units. The TIN has launched a national scale single (central) Institutional Review Board system, master contracting agreements, quality-by-design approaches, novel recruitment support methods, and applies evidence-based strategies to recruitment and patient engagement. The TIN has received 113 submissions from 39 different CTSA institutions and 8 non-CTSA Institutions, with projects associated with 12 different NIH Institutes and Centers across a wide range of clinical/disease areas. Already more than 150 unique health systems/organizations are involved as sites in TIN-related multisite studies. The TIN will begin to capture data and metrics that quantify increased efficiency and quality improvement during operations.
Computerized tomography scans are rapid, readily available, and relatively inexpensive. Volume of hemorrhage on computerized tomography (CT) is an important predictor of mortality and functional ability after intracerebral hemorrhage (ICH). Computerized tomography angiography (CTA) offers many clinical advantages over cerebral digital subtraction angiography (DSA) for the evaluation of intracranial vascular abnormalities in cases of ICH. CTA must be shown to have similar sensitivity and specificity as DSA in the detection of secondary causes of ICH. The use of non-contrast CT in the initial evaluation of patients presenting with suspected ICH is well established and universally accepted. Recently, advances in CTA have enabled this modality to gain wide acceptance in evaluating possible secondary causes of ICH, such as aneurysm or vascular malformation. As scanner technology and software rendering capabilities continue to improve, CTA appears poised to replace DSA and become the new gold standard for such evaluations.
This chapter reviews the epidemiology of non-traumatic intracerebral hemorrhage (ICH) in light of modern neuroimaging and discusses the incidence, etiology, clinical presentation, and natural history of this condition. Risk for ICH appears to be marginally greater in men than in women, driven by an excess of deep hemorrhages. Incidence rates increase dramatically among persons older than 60. Hypertension is the most important and prevalent modifiable risk factor for ICH. The clinical features used to define ICH are presentation with a gradual progression (over minutes or days) or sudden onset of focal neurological deficit, usually accompanied by signs of increased intracranial pressure such as vomiting or diminished consciousness. A variety of reports have examined clinical and radiographic factors associated with prognosis after ICH. Primary intraventricular hemorrhage (IVH) is rare among adults, comprising 2-3% of ICH admissions. Signs and symptoms of IVH frequently include headache, vomiting, and altered level of consciousness.
Clinical outcomes prediction in rudimentary form began as clinical observations of associations between single characteristics and pertinent outcomes. Multivariate modeling in intracerebral hemorrhage (ICH) has focused on determining outcomes and examining the independent effects of specific characteristics (e.g., intraventricular hemorrhage (IVH)) that could help explicate pathophysiological mechanisms and identify potential targets for intervention. Prognostic models have fostered the development of prognosis-based clinical trial methodology in which prognostic models are used to stratify patients. Models can be used to provide a sophisticated historical comparison for data collection in observational studies. Models are also used to define patient groups suitable for specific clinical trials and help to define relevant endpoints that can be prespecified for a particular group according to their expected outcome. Finally, mathematical outcome models have been used to identify specific findings or other characteristics that may affect outcome and be targets for intervention.
Acute hypertensive response is the elevation of blood pressure above normal and premorbid values that initially occurs within the first 24 hours of symptom onset in patients with intracerebral hemorrhage (ICH). Hypertension is the most frequent and most important risk factor for ICH. Hypertensive patients suspected of primary intraparenchymal hematoma died and were subsequently autopsied in order to assess the alterations of extraparenchymal and intraparenchymal vascular structures. Stroke patients with a history of hypertension are at risk of critical hypoperfusion for mean arterial pressure levels usually well tolerated by normotensive individuals. Drugs recommended for use in lowering blood pressure in acute stroke include labetalol, hydralazine, nicardipine, and nitroprusside. The Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) trial is a prospective, open label phase I safety and tolerability study started in 2005 that plans to study 60 patients.
Perihematomal brain edema (PHBE) plays an important role in secondary brain injury after intracerebral bleeding. Perihematomal brain edema is commonly observed during the acute and subacute phases in patients with intracerebral hemorrhage (ICH). In human studies, early CT scans demonstrate that PHBE develops within three hours of symptom onset. Magnetic resonance imaging is playing an evermore important role in the evaluation of hyperacute cerebrovascular disease. Several mechanisms are implicated in the development of neurological deterioration in patients with ICH. Single-photon emission computerized tomography (SPECT) is useful in the study of PHBE evolution. Several drugs have demonstrated their benefit in PHBE treatment in animal models, and in the future may block PHBE development in clinical practice. Deferoxamine and other iron chelators attenuate brain edema in ICH, and may be potential therapeutic agents for treating ICH, reducing the oxidative stress caused by the release of iron from the hematoma.
This chapter discusses the basic principles of management of intracerebral hemorrhage (ICH), including initial stabilization, the prevention of hematoma growth, and hemodynamic goal-setting. It also talks about the treatment of potential complications such as cerebral edema, herniation and seizures, and identification of the underlying etiology. The occurrence of ICH is strongly related to premorbid blood pressure; however, the relationship between the growth of hematoma and uncontrolled blood pressure remains to be clarified. The medical management of acute ICH revolves around the concept of hematoma stabilization. Recently published research may help identify patients that are at greater risk of hematoma expansion by the presence of tiny enhancing foci following CT angiography. Amyloid angiopathy is a common etiological factor in older patients, especially those older than 65 years who have multiple lobar hemorrhages. In hemorrhages in patients who are on anticoagulation, a risk-benefit ratio needs to be established before restarting anticoagulation.
Intracerebral hemorrhage (ICH) presents clinically in a variety of ways, depending primarily on the location and size of the hematoma. Several studies have correlated the anatomical location of putaminal hemorrhages with their clinical presentation. Caudate hemorrhage presents with sudden onset of headache, vomiting, and altered level of consciousness, resembling subarachnoid hemorrhage (SAH) from ruptured cerebral aneurysm. Behavioral and neuropsychological abnormalities can be a prominent part of the clinical picture of caudate hemorrhage. Lobar ICHs occur in any of the cerebral lobes, generally favoring the parietal and occipital areas although some series have reported a predominance of frontal or temporal locations. Primary hemorrhage into the medulla oblongata is the least common of all brain hemorrhages. The most consistent clinical profile in medullary hemorrhage has been with sudden onset of headache, vertigo, dysphagia, dysphonia or dysarthria, and limb incoordination.