Center for Cardiovascular Health Services Research

The Johns Hopkins University-Tufts Trial Innovation Center (JHU-Tufts TIC) was established in 2016 to provide Clinical and Translational Science Award (CTSA) investigators across the country with world-leading expertise in state-of-the-art trial design and execution of multisite studies. The JHU-Tufts TIC is one of three TICs nationally that provides a framework for excellence in clinical trial practice to allow new treatments and drugs to reach patients faster and more cost-effectively.

The TICs, at JHU-Tufts, Utah and Duke-Vanderbilt, along with a Recruitment Innovation Center (RIC) at Vanderbilt, and the 64 CTSA Program Hubs, make up the NCATS Trial Innovation Network, which will support investigators with protocol development, implementing central institutional review boards (IRBs) and recruitment plans while also developing and disseminating sustainable innovative practices across the network.

The Trial Innovation Network has established a new model of collaboration in multisite clinical trials by linking local resources at the 64 national NIH-supported CTSA Hubs and their more than 500 affiliated clinical institutions spanning all domains of healthcare, with the centralized expertise at the TICs and RICs. This will ultimately transform how clinical trials are conducted.

The JHU-Tufts TIC will lead two innovation projects: 1) the development and implementation of clinical trial performance metrics, and 2) novel trial design such as ‘efficacy to effectiveness’ (E2E) to generate evidence for optimal use of new treatments.

Principal investigators will jointly lead the JHU-Tufts TIC from both institutions, Harry P. Selker, MD, Executive Director of ICRHPS and Dean of the Tufts CTSI at Tufts University, Daniel F. Hanley, MD, the Jeffrey and Harriet Legum Professor of Neurology and Director of BIOS and Daniel Ford, MD, MPH, the David M Levine Professor of Medicine and Vice Dean for Clinical Research in the Johns Hopkins School of Medicine.

Tufts MC, led by researchers at the CCHRPS is one of 15 ‘Hub’ sites in a new national emergency medicine clinical trials network. The NIH-sponsored national SIREN Network will develop and conduct large-scale clinical trials to test new treatments in areas such as traumatic brain injuries, seizures, spinal cord injuries, cardiac arrest, heart attacks, congestive heart failure, pulmonary embolism, blood transfusion and more.

The SIREN Network is an NIH cooperative 5-year award that will nationally bring together 15 ‘Hub’ institutions and their local ‘spoke’ sites, to provide a national infrastructure for conducting large multi-site clinical trials.

Tufts Medical Center, together with partners from the Tufts Medical Center Clinical and Translational Science Institute (CTSI), Clinical Research Network (Maine Medical Center, Central Maine Medical Center, Eastern Maine Medical Center, Baystate Medical Center, and Lahey Hospital and Medical Center), form the Tufts SIREN Hub and Spokes and will act as a coordinated network to develop and execute emergency medicine trials. The Tufts CTSI Clinical Research Network encompasses an urban quaternary care academic health center and large community-based hospitals in urban, suburban and rural areas, a mix that reflects much of the range of the 5,000-plus hospitals in the U.S., allowing for greater generalizability of research findings to clinical practice.

For more information, read our press release.

The IMMEDIATE Trial, funded by the National Heart, Lung and Blood Institute (NHLBI) from 2006-2011, was a clinical effectiveness, multisite randomized control trial to assess the use of glucose-insulin-potassium (GIK) for acute coronary syndromes (ACS). This was the first double-blind placebo-controlled study of GIK for ACS, and the first to assess the use of GIK in the pre-hospital setting as administered by paramedics. The IMMEDIATE Trial demonstrated that very early administration of GIK by emergency medicine services (EMS) personnel reduced the incidence of cardiac arrest or mortality by 50% for individuals with ACS, and by 60% for those with a more severe form of myocardial infarction known as STEMI (ST-elevation myocardial infarction).

The IMMEDIATE Trial used ACI-TIPI and TPI predictive instruments, embedded into electrocardiographs to help to maximize the identification of eligible participants in the pre-hospital setting by paramedics. While the results of the IMMEDIATE Trial were very encouraging, because prior GIK studies had not been positive — even though they gave GIK later than would be expected to work and had not been double-blind placebo studies such as IMMEDIATE, FDA has requested a confirmatory trial (IMEMDIATE-2).

The IMMEDIATE-2 Trial design is very similar to the original IMMEDIATE Trial, with some notable exceptions. Firstly, enrollment will occur in both the emergency department and EMS settings, as opposed to only EMS settings for the IMMEDIATE Trial. This more accurately reflects the typical clinical distribution of patients with ACS, where up to 50% come directly to the emergency department and will help to increase the enrollment opportunities. Secondly, the primary endpoint will be a Finkelstein-Schoenfeld hierarchical endpoint of the combination of all-cause 30-day mortality, in-hospital cardiac arrest and infarct size.

Efficacy to Effectiveness (E2E) is an approach to clinical trial design that addresses the effectiveness and safety gaps often in standard randomized controlled trials. E2E trials are designed prospectively, whereby an effectiveness trial would commence seamlessly upon completion of the efficacy trial. This approach offers an opportunity for an improved understanding of how a treatment will work in more usual real-world clinical settings.

Reasons for adopting an E2E trial design:

• To provide a broader understanding of the treatment
• To allow understanding of heterogeneity of treatment effects for special patient groups
• Greater evidence for physicians, payers, providers and patients
• Better translation of research results into an impact on the public
• Potential for a broader target population

The JHU-Tufts Trial Innovation Center (JHU-Tufts TIC) wants to work with interested CTSA investigators nationally to develop the E2E concept and understand the challenges and potential solutions for better-linking efficacy and effectiveness trials. Through consultations and workshops, we will work with investigators to design the logistics and features of a specific intervention, including site selection, inclusion and exclusion criteria, data issues, industry engagement and regulatory matters related to approval for marketing.

The team working on this project includes highly experienced comparative effectiveness researchers, trialists, clinical epidemiologists, statisticians, pharmacologists and experts in drug development and testing experts, from academics, industry and the FDA.

The JHU-Tufts TIC, in collaboration with MIT’s NEWDIGS program, is hosting a series of Design Labs, the next of which will take place in May 2018 in Boston. This interactive multi-stakeholder event will provide a venue to discuss the considerations and challenges of designing a Phase 2 or Phase 3 E2E multi-site clinical trial that supports generating robust efficacy and effectiveness data. These DesignLabs are an opportunity to bring together physicians, payers, industry, regulatory agencies and patient groups for structured and open conversation under strict confidentiality agreements. One of the earliest projects that the NEWDIGS team helped bring to fruition was adaptive licensing, which is now part of the regulatory pathway in Europe.

For more information on NEWDIGS, visit their website.

Investigators are invited to apply for an Initial Consultation at the Trial Innovation Network website here.

Read more about E2E here:

• Integrated Efficacy to Effectiveness Trials
• Nature of E2E Clinical Trials
• Efficacy to Effectiveness Clinical Trial Design: Generating Evidence for Optimal Use of New Treatments. Listen to the webinar.

The JHU-TIC, in collaboration with the Tufts Center for the Study of Drug Development (CSDD), is leading a project to define a set of common, generalizable trial performance metrics and associated benchmark values.

Using both prospective landscape scan and retrospective regression analysis, we will identify a set of metrics that predict specific performance outcome measures. These metrics will be developed and disseminated within the Trial Innovation Network to allow sites to measure and improve performance.

Training materials outlining metric collection and analysis and operational guidelines for each metric will be developed before a pilot of these metrics in the Tufts MC CTSI Clinical Research Network.

The JHU-Tufts team will work closely with the CTSA Common Metrics Initiative as they roll out the new Accrual Metric. JHU and Tufts are two of the sites included in the Accrual pilot.

More updates will be posted here as the project progresses.

Harry P. Selker, MD, MSPH
Director, CCHSR and Professor of Medicine

Denise Daudelin, RN, MPH
Assistant Professor of Medicine

Dorothy Dulko, PhD
Project Director

Manlik Kwong, BSEE, BSCS
Adjunct Instructor of Medicine

Marisha Palm, MSc, PhD
Assistant Professor, Program Director

Cortney Wieber, MS
Research Associate