A collaborative, academic approach to optimizing the national clinical research infrastructure: The first year of the Trial Innovation Network

Abstract

Inefficiencies in the national clinical research infrastructure have been apparent for decades. The National Center for Advancing Translational Science (NCATS) –sponsored CTSA program is able to address such inefficiencies. The Trial Innovation Network (TIN) is a collaborative initiative with the CTSA Program and other NIH Institutes and Centers (ICs) 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: three Trial Innovation Centers (TICs), the Recruitment Innovation Center (RIC), and the individual CTSA institutions that have identified TIN Liaison units. The TIN has launched a national scale single (central) IRB 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 ICs 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.

1. Introduction

Clinical trials are costly and challenging to complete. A recent analysis found that the average cost to develop and gain marketing approval for a drug is $2.56 billion;¹ a single phase of a clinical trial can range from $22.2M to $71.3M, depending on therapeutic area² and worse, most fail. In addition to the financial barriers for conducting clinical trials, other hurdles include inefficiencies in developing a study design, duplicative review processes (e.g. Institutional Review Board), non-standard contracting language, recruitment challenges, inefficient study site selection and training and cumbersome research data monitoring. Problems extend beyond study completion; approximately half of results across many types of studies published in biomedical journals are overstated or are altogether incorrect.³ An overhaul of the way clinical trials are designed and conducted is essential if the academic research infrastructure is to increase its impact on health and healthcare.

1.1. The early Clinical and Translational Science Award (CTSA) program

The CTSA program’s goal in 2006 (under the National Center for Research Resources) was to propel institutions to create a “novel, and integrative academic home for clinical and translational science.” In Dr. Elias Zerhouni’s early and pioneering vision, CTSAs were intended to advance the assembly of institutional academic “homes” that can provide integrated intellectual and physical resources for the conduct of original clinical and translational science.⁴ Thus, during the first funding cycles, CTSAs were established across the country and served as the singular homes for translational research at their respective institutions. Dr. Zerhouni also envisioned that the assembled consortium of CTSA sites would provide a research environment that is more nimble, conducive to, and responsive to the demands of modern translational and clinical research.⁴ The early CTSAs did just that, and transformed an ineffective clinical and translational science infrastructure through two primary methods: development of metrics to assess the length of the processes at individual institutions, and by creating common approaches to contracts and shared Institutional Review Board (IRB) considerations, thereby avoiding redundancy in multicenter studies and accelerating the start-up phase of clinical research.⁵ Strategic goals were subsequently formalized which included enhancing the national capability for clinical and translational research⁶. Consortium-wide efforts around recruitment, Good Clinical Practice qualifications, competencies and training, data management, IRB streamlining and contract streamlining ensued; these were collaborative initiatives led by CTSA Program investigators that supported the formation of, and are now being leveraged in and tested by, the newly formalized “Trial Innovation Network”.⁷

1.2. The new CTSA Trial Innovation Network

The Trial Innovation Network (TIN) is a new collaborative initiative within the National Center for Advancing Translational Science (NCATS) CTSA Program that leveraged the prior work of the CTSA program and brought in new capability from clinical trial intensive groups. Clinical trialists with decades of experience in conducting large scale, multi-site regional, national, and international clinical trials that recruit and engage challenging populations comprise TIN leadership. Through innovation, the Network will address critical roadblocks in clinical trials and accelerate the translation of novel discoveries and interventions to real world clinical practice. For example, in clinical trials, numerous approvals must be in place before patients can be enrolled; removing one bottleneck (e.g., IRB review) simply shifts the bottleneck to another process. The novelty of the TIN is to synchronously address all potential bottlenecks by systematizing and streamlining approvals and processes. Through experience gained by conducting hundreds of trials, we have identified these bottlenecks and developed approaches to streamline all approvals to achieve maximally efficient study initiation, including: confidentiality agreements, sponsor contracts and site subcontracts, trial registration, protocol finalization, investigator meetings, Data & Safety Monitoring Board operations, Investigational New Drug Application/ Investigational Device Exemption, budgets, and IRB review. The TIN is also unique in its ability to “right-size a Network” for any given proposal, rather than relying on pre-identified existing Networks. The ultimate mission of the TIN is to execute highest quality trials more quickly, and in a cost-efficient manner. The TIN awardees are composed of three key organizational partners: three Trial Innovation Centers (TICs), the Recruitment Innovation Center (RIC), and the individual CTSA institutions that have identified TIN Liaison units. Short- and long-term key metrics for the TIN are still being developed and refined, but the focus is directed on decreasing complexity, increasing efficiency and productivity, and accelerating translational research to get new treatments to patients faster.

1.2.1. Trial Innovation Centers (TICs):

The TICs develop, demonstrate, and disseminate innovative ways to increase the quality and efficiency of multi-site clinical research. The TICs provide collaborative support for a broad range of multi-site clinical studies that include trials across the human life span, trials for diagnostic testing or development of therapeutics such as drugs, biologics, and devices, as well as behavioral interventions. TICs also are actively exploring innovative approaches aimed at streamlining trial implementation, promoting high quality multi-site trials, and the dissemination of successful advances in process and approach. The TICs are charged with supporting Central IRB (CIRB), contracting, regulatory, protocol and consent development as well as performance and quality monitoring. The three TICs (Utah, Duke/Vanderbilt and Johns Hopkins/Tufts) are all experienced in supporting these activities.

1.2.2. Recruitment Innovation Center (RIC):

The RIC strives to increase the likelihood of success for multi-site clinical trials by developing informatics-driven approaches to assess the site-specific availability of potential participants during trial planning and by developing community driven approaches to participant recruitment and retention. The RIC is already achieving these expectations by optimizing electronic health record (EHR) and cohort discovery tools using a multi-modal approach to enable broad participation in site feasibility assessments, conducting targeted community engagement studios⁸ and other service lines designed to promote recruitment, retention and return of value to participants. The RIC is also involved in building relationships with external stakeholders, establishing a diverse Community Advisory Board as well as creating resources to educate and train local recruitment specialists. The RIC (at Vanderbilt) is experienced in these activities.

1.2.3. CTSAs within the TIN

Each CTSA has—or soon will have—an established group dedicated to the activities associated with the TIN. Although the resources for this function vary by CTSA size, the roles for the TIN Liaisons at each CTSA are the same. These TIN Liaisons include staff with legal, IRB, budgeting, or project management expertise to work with TIC activities, and staff with data, informatics, analysis, privacy protection, study recruitment, communications or project management expertise to work with the planned RIC activities. The multi‐disciplinary TIN Liaisons will lead scientific, training, and implementation aspects of the TIN. They will use their experience and knowledge of the local environment to innovatively operationalize the Network at their Institutions, tailoring general Network plans into more specific action plans best suited for their Sites. In addition, the named liaisons will encourage investigators at their Institutions to generate ideas for multi-center trials and studies that encompass a wide-range of disciplines, provide input prior to protocol implementation, encourage investigators to take advantage of existing CTSA resources, and recognize the essential contributions and efforts of their local teams in executing multi-center clinical trials. Local CTSA PIs will provide a first review and approval of any proposals from their Institution to the Trial innovation Network. Local resources to enhance study design and recruitment will continue to benefit Investigators. CTSA PIs will be included on initial TIN communications with Investigators to ensure a collaborative relationship between the Investigator, the CTSA, and the TICs and RIC. While CTSA institutions are the frontline of the TIN, the TIN will engage many types of additional sites including non-CTSA academic institutions, community hospitals, physician practices, and others.

2. One Year Results to Date

2.1. Trial Innovation Network resources

Structurally, the TIN features a national scale single (central) IRB system, master contracting agreements, quality-by-design approaches, novel recruitment support methods, and a focus on evidence-based strategies to recruitment and patient engagement, as well as other components critical to trial conduct. These offerings are shared and set in place, meaning they do not need to be recreated for future studies. In addition, the TIN has established its decision-making process and communication format as well as all policies, procedures, staff support, and manuals of operation. Its core resources/services are in place (Appendix 1 and 2). Notably, these procedures have been harmonized among long-standing and large-scale academic clinical research organizations such as Duke Clinical Research Institute, Utah and Hopkins.

The TIN provides support and resources in a multi-pronged approach. Specifically, study investigators can request an initial consultation with the TIN or specific services depending on the funding status of the proposal. Unlike some other research networks, the TIN supports clinical trial teams who have been funded by a sponsor other than the TIN for the conduct of the trial. Projects that are already funded or are pending funding may request discrete services (Appendix 1). Projects that are early in the development phase request an initial consultation (Appendix 2). These initial consultations usually consist of several scheduled meetings (in person or web conferences) to discuss applicable topics such as study design, budget, CIRB, timelines, recruitment and retention, study feasibility, study design support, and statistical analysis support. Given that poorly designed studies can place participants at risk with little likelihood of providing an answer to the central question of the trial, an important emphasis of the TIN is optimized study quality. Recognizing that that national clinical research infrastructure must include and embrace performance sites more broadly, already more than 150 unique health systems/organizations are involved as sites in TIN related multisite studies. There are 12 different NIH Institutes and Centers (ICs) involved (See Figure 1).

Figure 1:

Multiple NIH I/Cs are associated with studies using the TIN.

NIH IC involvement has been in several different ways. NIH ICs are often introduced to the TIN via the many NCATS presentations and training opportunities. In addition, once a project is submitted to the TIN, the NIH IC PO is often invited to attend the consultations and conversations whenever appropriate and agreed to by the involved parties. This inclusive approach has been an effective technique in facilitating dialogues and embracing opportunities for synergy within the project and other prospects associated with the funding agency. Additionally, individual investigators with connections to the CTSA Consortium and access to the TIN approach ICs independently, and then a joint process can ensue.

2.2. TIN innovation

One of the defining features of the TIN is the charge to embrace and apply innovation in all activities by leveraging the Network as a learning laboratory. The TIN is charged with using novel concepts, approaches and methodologies directed at improving the quality, safety, efficiency and timely completion of multi-site clinical trials. Some innovative opportunities underway within the TIN include:

• Creative use of EHR data to deliver more accurate counts of eligible patients.

• Involving underrepresented/minority groups in research design/development of materials to determine impact on enrollment and retention more broadly.

• Testing training approaches for researchers who seek to engage underrepresented and marginalized communities.

• Creating a medical device-based cohort participant monitoring/retention system

• Formalizing and testing e-consent models.

• Assessing whether early budget consultation through the TIN results in more accurate prediction of site costs.

• Testing a new clinical trial model to streamline the process for bringing on clinical trial sites within a 90-Day cycle

• Assessing whether an in-person site initiation visit results in improved protocol adherence and trial efficiency compared to a remote site initiation visit.

• Establishing evidence to support a common activity in studies such as site initiation visits.

• Establishing a service that supports efficacy to effectiveness (E2E) trial designs that works with the investigator and study team to design a study that includes seamless transition from an initial efficacy trial component to a generalizable effectiveness trial component.⁹

• Conducting clinical trials within a registry population.

• Service lines designed to support the workflow of leveraging clinical systems.

• Ensuring the use of sophisticated methods such as adaptive trial design, sequential studies, futility analyses through simulation, early termination of trials using frequentist pre-specified or unlimited Bayesian interim analyses for the quality of the studies and the increased protection of human subjects.

2.3. TIN communications and coordination

The TIN has created a web portal (https://trialinnovationnetwork.org/) to support communication for the multiple individuals and sites who have a role in the program. The general method of providing resources, best practices and webinars is gaining traction among users through the website. Currently approximately 300 users signed up to be notified of new updates and webinars. Communications resources include a RIC toolkit, Trials Today, newsletters such as the RIC Download, and frequent recruitment webinars, all designed to share best practices and enhance the sustainability of recruitment initiatives at local sites. The TIN CIRB provides resources, tools, and a fully functional web-based platform (https://trialinnovationnetwork.org/smart-irb-exchange/) to operationalize and coordinate the CIRBs activities.

The TIN offers frequent education and training opportunities via its Collaboration webinars and liaison-Network meetings. Recognizing the need to support the CTSA Site liaisons, the TIN holds monthly meetings to discuss current topics, identify needs and describe lessons learned. In addition, there are monthly “Open Forums” focused on various topics that allow the liaisons and CTSA researchers to ask questions in an informal, open dialogue session. A smaller working group with members from 11 Institutions has been identified and have volunteered to partner with other liaison members across the CTSA to help champion the TIN and address identified gaps and concerns. These members serve as Peer Advisors to Liaison Team members across the consortium to provide access to sharing local barriers and challenges as well as best practices, beneficial materials and resources.

2.4. TIN ‘Hardwiring’ through legal agreements

Clinical trial contracting is a major barrier to clinical trial start-up.¹⁰ Data show that an average negotiation of contract terms of 55 days (exclusive of budget and IRB approval) could be reduced to 22 days if a “master agreement” was used.¹¹ Several years ago this barrier prompted CTSAs to develop a standardized contract that could help reduce delays in trial start-up. With support from NCATS, the Accelerated Clinical Trial Agreement (ACTA) was developed by 25 CTSAs in collaboration with the University Industry Demonstration Partnership, and with input from several pharmaceutical companies. Leaders from the institutions’ contracts and legal offices volunteered for consensus building work over 2 years. Over 300 unique organizations, including a variety of institution types as well as most CTSAs, have legal sign-on acceptance of the terms of the ACTA. CTSAs then developed an adoption of the Federal Demonstration Partnership Clinical Trials Subaward Agreement (FDP-CTSA) for NIH sponsored trials. The FDP-CTSA was recently accepted, with minor updates, for use by the TIN. A total of 73 institutions have signed on to the FDP-CTSA. The contract is now being used in 4 TIN studies and data are being collected to determine the rate of acceleration to study start-up.

2.5. Decisions made

The TIN has received 113 requests for support from 39 different CTSA institutions and 8 non-CTSA Institutions (See Figure 2). Requests for TIN infrastructure can be communicated in menu format to be adaptable to researcher needs, depending on the funding status of the proposal. Requests are assessed on use of the TIN infrastructure and scientific merit of each protocol as follows: Importance of the question to be addressed; Merit of experimental design, including appropriate controls; and Safety and welfare of participants. Requesting these services and consults involves submitting an application through the TIN intake system. The system is a web-based, logic flow tool that is designed to only require responses to questions necessary for the types of projects and needs a researcher might consider. Once a proposal is submitted, a member of the Proposal Assessment Team (PAT) assigns the proposal to a TIC and/or RIC. A TIC/RIC Project Manager will personally contact the researcher within 5 business days of proposal submission. PAT procedures are in place to rapidly evaluate and provide initial guidance on use of TIN resources. On average the TIN teams have initiated efforts on the projects within 2 days of proposal submission. Snapshot of the 98 of 113 projects receiving support to date are included in Figure 3. A description of the types of support are described in Appendix 1 and 2. The landscape of support being provided varies between projects with some applications receiving one element of support with other projects receiving up to 5 (Figure 4). Support to date represents a diversity of disease areas (Figure 5). Fifteen projects submitted to the TIN did not receive support. These were early submissions that either were not ready for network involvement, had not engaged their CTSA, or were considered to be out of scope according to the funding agency.

Figure 2. Stakeholder engagement.

As of May 18, the Network has received proposals from 39 different CTSA institutions. Note: These numbers do not include the pilot testing/demonstration projects (total of 11) conducted among the TIC sites as systems and services were being established.

Figure 3. Support provided.

As of May 18, 113 proposals have been submitted and 98 of those are or have received support from the TIN.

Figure 4.

Landscape of resources supporting projects

Figure 5.

Therapeutic areas represented in submissions.

2.6. Outcome

To date, 59 projects have completed an initial consultation. On average it has taken 71 days from submission to completion of the consultation, with times ranging from 1 day to 160 days. Satisfaction surveys have been sent to research teams that have completed an initial consultation with 16 responses to date. Of these, 85% strongly or somewhat agreed that they were satisfied with the overall experience with the TIN. There were two respondents who indicated they were not satisfied with their overall experience with the TIN; one indicated displeasure with the TIN CIRB’s inability to work with the Veterans Affairs (VA) IRBs, which is limited by VA policy. The other respondent reporting dissatisfaction on the Likert scale for this topic also included wholly positive and complimentary questions in the qualitative response opportunities, suggesting that this individual may have incorrectly scored the satisfaction question. See Figure 6 and Table 1 for breakdown of satisfaction results and comments.

Figure 6.

Satisfaction related to the initial consultations.

Table 1.

Comments related to most valuable aspect of the initial consultation.

What did you find most valuable about the Initial Consultation?
Outstanding input from experts across multiple disciplines.
I felt the TIC team was committed to helping me and my team improve our project. It seems the tools they can bring to the project re IRB, DCC, CCC could help a lot.
Suggestions for outreach to referring doctors Approval of the CIRB
The comprehensive approach to addressing our study requirements, the excellent communication, the excellent organization, the high level of expertise, and last but not least, the genuine interest in our study.
They clarified some of the challenges in working with a central IRB
Statistical consult
This is an invaluable resource and a wonderful team. The guidance surrounding planning for a quick start-up was fantastic.
The initial consultation increased my understanding of the role of the central IRB as we move forward with my grant application. In addition it was reassuring to interact with such pleasant and thoughtful individuals. It gives me confidence that our work together going forward will progress smoothly.
Prompt and helpful staff, they were amazing.
The recruitment innovation center's proposal of services/ideas were excellent!!
The conciseness and professionalism of those at the TIC.
A detailed explanation of the process.
Many people together in the same room may make the process more streamlined.
Information on recruitment services I was not aware of
Defining the specific aims of the project.

3. Future plans and conclusions

3.1. Budget tools

One report indicates that budget negotiations and approval lead to up to 49% of study delays.¹² If we could harness the collective expertise of the CTSA institutions to develop tools to improve clinical trial budget creation, the aggregate impact on time and cost savings could be enormous, as studies indicate that sponsors may lose an astonishing $600,000 to $8 million for each day that a trial delays launch.¹³ The TIN is in the process of developing a “go/no go” tool that will be able to assist sites in quickly determining budget feasibility. These types of tools will be developed and made freely available for use by institutions collaborating with the TIN.

3.2. Recruitment infrastructure support service

Recruitment challenges continue to plague the national clinical trial system. To solve this problem, the RIC leverages clinical data to support cross-network phenotyping queries to determine site feasibility such that planning numbers can be data driven and realistic. Next innovations will include cataloguing and building technical infrastructure models for using the clinical system to improve workflow related to recruitment of participants such as EHR query and alert tools. Tools and processes will also be implemented to obtain input from (potential) participant communities on study inclusion and exclusion criteria for studies. Developing and making available training approaches for researchers to engage underrepresented and marginalized communities will help with better engagement of these important groups. Finally, enhanced tools for e-consent will be provided.

3.3. Hardwiring through legal agreements

New efforts will involve other contracting processes including Umbrella Confidentiality Agreements, Data Use Agreements and Material Transfer Agreements. Importantly, these initiatives require the engagement, collaboration, and agreement of all CTSA institutions as well as other major research- oriented institutions to be maximally effective in streamlining and efficiency.

3.4. Increased awareness and utilization by NIH Institutes and Centers

Some NIH ICs have well established clinical and data coordinating centers to support multi center trials. Other, smaller organizations may be lacking in this capability and effort and therefore will be more interested in engaging the TIN. As these engagement opportunities grow, we will create dashboards and mechanisms to enhance transparency regarding study activities such as real time participant enrollment, procedural completion and milestone achievements that will be paramount for reporting to constituents and stakeholders.

3.5. Further engagement with TIN Liaisons

The TIN Liaisons are integral to the success of the TIN by encouraging faculty and investigators to generate ideas for studies, review submissions to the network and leverage their local sites’ expertise to optimize studies prior to TIN submission. As part of the “value add” to these members, we are working to create access to a Network Dashboards that enhance transparency and provide a task list for individual study activities. For example, we have developed a Network Dashboard that displays high-level information about submitted proposals, enables the user to contact the assigned TIC/RIC, and displays progress indicators that allows the user to monitor Network Support progress (See Figure 7).

Figure 7.

Design of Network Dashboard (All Proposals Tab)

Furthermore, in an effort to centralize the requests the Trial Innovation Network sends out to the CTSA sites, the Network has developed additional tabs, such as the EHR Cohort Assessment tab, which allows the TIN Liaison Teams to keep track of the work they are doing. Similar to other tabs, the EHR Cohort Assessment tab allows the user to drill down and see metrics related to the request, and centralizes actions for the user (see Figure 8).

Figure 8.

Design of Network Dashboard (EHR Cohort Assessment Tab)

4. Conclusions

The Trial Innovation Network is functional and has begun early operations. To ensure the TIN achieves its full potential, the interest of Institutes and Centers (ICs) across NIH in leveraging the infrastructure will be critical, as well as support from other sponsors. Many ICs may be reluctant to adopt the newly available TIN services due to issues related to credibility, lack of awareness, and perception of cost inefficiency. The TIN will only overcome these barriers by providing evidence of the value of this centralized, shared, and non-redundant infrastructure. To that end, the TIN will capture data and metrics that quantify increased efficiency and quality improvement. Fortunately, the TIN itself provides a national laboratory to study, understand, and innovate the process of conducting clinical trials in the course of its operations. In this way, the process can be continually improved. The TIN intends to accelerate these metrics over time.

Appendix

Appendix 1:

Key structural service elements and capabilities within the TIN have been established in Year 1 by the TIN awardees.

Services	What TIN Customers Can Expect
Operationalize Standard Agreements	With this service, we will provide recommendations on how to use the FDP-CTSA Standard Agreement. This Standard Agreement can be used by each of the participating institutions in your multi-site study.
Operationalize Central IRB	The TIN has established three Central IRBs (CIRBs), which are based on the SMART IRB Authorization Agreement, to provide CIRB services to a funded multi-center clinical trial. For each study, the TIN CIRB provides resources, tools, and a web-based platform (IRB Reliance Exchange) to operationalize the CIRB. With this service, we will ensure all site investigators understand the process for initiating the use of a CIRB at their local institution, as well how to submit and report to the CIRB from initial submission to study closeout.
Recruitment Plan	An effective recruitment plan includes strategies to identify and engage specific population(s) of relevance for a trial including how to communicate and market a study in order to engage potential participants and meet realistic enrollment and retention goals. The recruitment plan service includes providing advice and recommendations on recruitment strategies. Key features of this TIN Service include: Comprehensive review of study and existing recruitment plan Assistance with identifying stakeholders and recruitment partners (such as providers and community organizations), as well as locations for participant recruitment Guidance on understanding unique needs and preferences of potential participants, and barriers and facilitators to recruitment and retention Tailored advice and recommendations on the most appropriate recruitment and retention strategies to deploy when engaging participants from any community
Recruitment Feasibility Assessment	Recruitment feasibility assessment is the process of evaluating the possibility of recruiting an adequate number of participants with the appropriate range of characteristics (such as age, gender, race/ethnicity, and health status) to meet enrollment goals on the projected timelines and cost. The recruitment feasibility assessment considers environmental (such as location, competition, prior success recruiting, potential participant pool) strengths and weakness as well as logistical, motivational and behavioral barriers to recruitment and retention. Key features of this TIN Service include: Comprehensive review of study Assessment of the likelihood study will meet predefined recruitment and retention goals Environmental scan and assessment of barriers Review budget for recruitment and retention Tailored advice to enhance recruitment feasibility
Recruitment Materials	Recruitment materials may include any written or verbal communication delivered through a range of multimedia channels and platforms to increase enrollment. Key features of this TIN Service include: Reviewing recruitment material needs including any dissemination plans Providing advice, recommendations and templates in order to improve the recruitment of potential participants for specific studies Sharing best practices Tailoring materials to specific populations, when appropriate
Community Engagement Studio8	A Community Engagement Studio is a consultative method that allows meaningful involvement of diverse groups of stakeholders in the planning and implementation of research. The Studios can be used to facilitate project-specific input including guidance and recommendations on identifying and addressing barriers to participation and how to develop or refine recruitment materials and messages. Key features of this TIN Service include: Assessing whether a studio might be appropriate based on the needs of a study and if so, where a studio has the potential to be most valuable Identifying community and/or patient stakeholders for studio Convening community engagement studio Summarizing recommendations on how to develop and refine recruitment plan, study messaging and materials.
EHR-Based Cohort Assessment	The TIN will help consider ways that Electronic Health Record (EHR) data may be leveraged to inform study design and potential site selection. Investigators can expect expert clinical and technical review of a study’s goal recruitment population and high level assessment of computable phenotyping. Projects may also request and receive support required to organize distribution of phenotype algorithms to potential CTSA institutions and collation of results.
Data Management	Consultation and potential implementation concerning the most efficient collection of study data. Investigators can expect rigorous discussion about eliminating extraneous “curiosity” data points, and emphasis on the proper risk based monitoring to assure the quality of data required for the primary and secondary endpoints of the study.
Statistical Assistance	CTSA institutions have statistical resources and expertise; with this service, the TIN will work with these teams to confirm statistical assumptions and calculations, as requested. This may be particularly relevant for preparation and presentation of Data Safety Monitoring Board (DSMB) reports.
Study Design	Collaborative assistance with statistical design respects the statistical expertise at each collaborating institution. Investigators can expect TIC statistical teams to be complimentary to the PI’s existing resources, and during study implementation (if indicated). TIC statisticians will keep the investigator’s local statistical experts involved with the study.
Efficacy-to-Effectiveness (E2E) Trial Design	The E2E Team works with investigators and teams to support trials that seamlessly transition from a trail that shows efficacy of a treatment in selected participants and settings to an effectiveness trail that shows impact in the wide span of patients and settings in which the treatment will ultimately be used. The objective is to be sure that effectiveness is formally tested, which often is not the case, but to also minimize the cost and time of the additional trial. Thereby, regulatory requirements are met for marketing approval but also other stakeholders have evidence to support wide use in clinical practice. Besides the elements of study design and operationalization, an E2E Consultation will allow the study team to think through the evidence required by various stakeholders, and prospectively design a study that will allow regulators, payers, patients, healthcare providers and physicians to make informed decisions and thus maximize the impact of the trial.

Appendix 2:

Projects that are early in the development phase may request an initial consultation and receive input on any of the described activities.

Initial Consultations	What Customers Can Expect
Study Design	The TIN will review submitted study material and discuss the proposed design. The discussions may involve the study goals and aims, the methodology, statistical and regulatory considerations, participant recruitment, schedule of assessments, study interventions, or other components of the study. The goal of these discussions is to help work through potential barriers to successful study completion.
Study Budget	The TIN will provide recommendation on the budget as it relates to the proposed protocol. At the conclusion of an initial consultation, an estimated budget based on the protocol design will be generated. The budget will include estimates for the overall study budget, site/participant budget, and a recruitment budget, if applicable.
Projected Timelines	The TIN will provide a recommendation on timelines for submission of the application as well as timelines for the overall conduct of the study. This review includes planning, study start-up, conduct, close-out, and final publication.
Recruitment	The TIN will assess recruitment strategies. At the conclusion of an initial consultation, an assessment of study recruitment will be provided.
Assessment of Study Feasibility	The TIN will assess the feasibility of the study being successfully completed within the proposed timelines and budget and note any potential barriers. The TIN will provide recommendation to optimize successful completion of the study within the proposed timelines and budget.