Welcome, Introductions, and Overview

Welcome, framing of the meeting, and agenda overview

o   Michael McGinnis (Institute of Medicine)

o   David L. DeMets (Planning Committee Co-Chair, University of Wisconsin School of Public Health)

o   Richard E. Kuntz (Planning Committee Co-Chair, Medtronic)

Introduction to Large Simple Trials

Session chair: David L. DeMets (Planning Committee

Co-Chair, University of Wisconsin School of Public Health)

   Session Objectives:

   Set the vision for large simple trials (LSTs) as part of a learning health care system.

   Discuss the advantages of LSTs over current trial approaches.

   Discuss opportunities for LSTs as way to embed trials in growing digital infrastructure.

   Presentations:

   A vision for LSTs in the learning health system Michael S. Lauer (National Heart, Lung, and Blood Institute)

   Opportunities and challenges for LSTs Ralph I. Horwitz (GlaxoSmithKline)

   Session Questions:

1.   What is an LST?

2.   How would these trials fit into the larger clinical research ecosystem in a learning health care system?

3.   What need would this approach to clinical trials fill? (randomized controlled trial [RCT] cost, efficiency, generalizability)

4.   What are the advantages/disadvantages to this approach? (heterogeneity, subgroup analysis)

5.   How does the increased adoption of electronic health records (EHRs) provide an opportunity for LSTs?

6.   Are there modifications to the current design and conduct of LSTs that would enhance their value to a learning health system?

7.   What are some exampleas of the areas still in need of work to realize this vision (e.g., the culture shift needed to adopt potentially disruptive technologies)?

Highlighted Examples of LSTs

Session chair: James B. Young (Cleveland Clinic)

   Session Objectives:

   Highlight four examples of LSTs that each exemplify a different defining characteristic of LSTs.

   Emphasize trade-offs in trial design by discussing the pros and cons, giving examples of how these play out, and suggesting alternative approaches.

   Foreshadow the rest of the workshop by asking LST example speakers to address their experiences (successes and failures) with stakeholder engagement, infrastructure, and policy.

   Presentations:

   Very large, population-based trial with broad inclusion criteria, high cost-efficiency, and hybrid design (mail-based plus in-clinic component)

   VITamin D and omegA 3 triaL (VITAL) JoAnn E. Manson (Harvard University)

   Trial assessing role of waiving medication copayments for improving drug adherence and health outcomes, collaboration with health insurance company (Aetna)

   Post-Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) trial Niteesh K. Choudhry (Brigham and Women’s Hospital)

   Cluster randomized trial involving pediatric practices, utilization of EHR and decision support tools for obesity interventions

   High Five for Kids Trial/Study of Technology to Accelerate Research (STAR) Elsie M. Taveras (Harvard Pilgrim Health Care Institute)

   Industry trial for regulatory approval with global component

   Heart Outcomes Prevention Evaluation (HOPE) trial
P. J. Devereaux (McMaster University)

   Session Questions:

1.   Please give a very brief introduction on the specifics of the trial and why it is considered an LST.

2.   How does the trial address the issues of the generalizability of the evidence produced, simplification of research processes, and cost-effectiveness?

3.   In retrospect, what were the risks and trade-offs associated with the choice of an LST design (e.g., the risk of not collecting data that could be subsequently requested)? Please discuss the pros and cons, giving examples of how these play out and suggesting alternative approaches and any design changes that you would make on the basis of the lessons learned.

4.   What were your team’s experiences (successes and failures) with the following issues, which will be discussed in further detail during the course of the workshop:

a.   Stakeholder (health system leader, clinician, patient) engagement

b.   Infrastructure (research infrastructure, health information technology)

c.   Policy (privacy, consent, institutional review board issues, regulatory issues)

Session chair: Joe V. Selby (Patient-Centered Outcomes Research Institute)

   Session Objectives:

   Identify stakeholders relevant to the increased use of LSTs, focusing on patients, clinicians/health care systems, and payers, and the incentives that they face that could impede or advance uptake.

   Engage in the issues of the most importance to stakeholders and deliberate on what it will take from each of their respective points of view.

   Presentations:

   Patient perspective
Nancy Roach (Fight Colorectal Cancer)

   Health systems/clinician perspective
Alan S. Go (Kaiser Permanente)

   Payer perspective
Lewis G. Sandy (UnitedHealth Group)

   Session Questions:

1.   What are the top three issues for patients/clinicians/payers in considering the use of an LST approach to generate clinical evidence?

2.   What are the top three considerations for patients and clinicians in contemplating the greater integration of trials into routine care settings?

3.   What are the top three priorities for raising the awareness and participation of patients and clinicians in trials integrated into routine care?

4.   What are your priorities regarding the types of evidence that can be generated through LSTs?

5.   What are the roles for health systems and payers in (a) setting priorities, (b) dedicating staff support, and (c) providing funding for LSTs in routine care settings?

Welcome, framing of the meeting, and agenda overview

   David L. DeMets (Planning Committee Co-Chair, University of Wisconsin School of Public Health)

   Richard E. Kuntz (Planning Committee Co-Chair, Medtronic)

Session chair: John J. Orloff (Novartis)

   Session Objectives:

   Highlight infrastructure needs and barriers to the greater performance of LSTs.

   Discuss the needs and potential approaches to merge the goals of the health care system with research, focusing on the current state and future potential of the use of EHRs as platform for LSTs.

   Discuss establishment and sustainability of trial networks as an infrastructure to host and facilitate LSTs.

   Presentations:

   Aligning care and research to reduce burdens and improve integration
Richard Platt (Harvard Pilgrim Health Care Institute)

   Point-of-care trials using EHR platforms
Ryan E. Ferguson (VA Boston Healthcare System)

   Getting to comparable, computable data
Rebecca Daniels Kush (Clinical Data Interchange Standards Consortium)

   Building reusable research networks
Carole M. Lannon (Cincinnati Children’s Hospital Center)

   Session Questions:

1.   What are the current infrastructure needs for the more widespread performance of LSTs? Would you consider conducting LSTs on your network?

2.   What opportunities and challenges in the use of EHRs as a platform for LSTs currently exist? What are the priorities for change to maximize this potential going forward? How can disruption to the delivery of health care be minimized to incentivize more practicing physicians to engage in knowledge generation?

3.   What is the current state of the use of routinely collected clinical data for trials? What role will data standards play in the facilitation of LSTs? What are the priorities for change to maximize this potential going forward?

4.   What is the current state of reusable research networks in the United States? What is their role in LSTs? What are the major opportunities and barriers to the reusable network approach? Are there alternative community-based settings with lower infrastructure costs and greater access to patients that should be considered? Are existing research networks (including perhaps CTSA institutions or PBRNs) fit for purpose? What business models (e.g., hub and spoke) would be the most effective?

Policy Needs: Ethics, Trial Processes
Session chair: Robert M. Califf (Duke University)

   Session Objectives:

   Spotlight and differentiate real and perceived policy barriers to the greater use of LSTs.

   Highlight examples of ways in which these have been dealt with (or overcome).

   Anticipate potential policy issues as trials move to leverage electronic systems.

   Suggest components of a policy framework that would facilitate LSTs.

   Presentations:

   Policy overview
Robert M. Califf (Duke University)

   Ethical issues of bringing research and care closer together
Ruth R. Faden (Johns Hopkins University)

   Trial process challenges (privacy, institutional review boards)
Deven McGraw (Center for Democracy and Technology)

   Session Questions:

1.   What are the major policy barriers to the more widespread performance of LSTs? How have these barriers been overcome in the past? What are the priorities for change going forward?

2.   What are the important ethical issues to consider in bringing research and care closer together? What are the components of a new ethical framework to support a learning health system?

3.   What are the major privacy and human subjects research policy-associated considerations for LSTs? How have these challenges been overcome? What are the priorities for change going forward?

4.   What are the relevant ethical and policy considerations associated with randomization without additional consent in situations of equipoise?

Lunch Keynote

Randomized Evaluations of Accepted Choices in Treatment (REACT) trials

Tjeerd-Pieter van Staa (Clinical Practice Research Datalink, United Kingdom)

   Session Questions:

1.   What are the REACT trials? What was the impetus for these trials? How do they compare to LSTs?

2.   What are the stakeholder engagement-related challenges you have faced in setting up/running these trials? How have the relevant stakeholder groups responded?

3.   What are the infrastructure-related challenges and opportunities you have faced? What role has the level of EHR adoption placed in facilitating or inhibiting them? What are the most crucial non-information technology infrastructure resources?

4.   How have you addressed concerns about the accuracy and validity of data in the electronic medical record?

5.   What are the policy-related challenges that you have faced? What are the differences between the UK and

      U.S. systems that have facilitated or impeded these challenges?

6.   What lessons learned or best practices would you pass along to LST investigators? What would you do differently?

Policy Needs: Medical Product Regulatory Issues
Session chair: Richard E. Kuntz (Planning Committee Co-Chair, Medtronic)

   Presentations:

   Trial complexity
Kenneth A. Getz (Tufts University)

   Simplifying clinical trials
Christopher B. Granger (Duke University)

   FDA perspective
Rachel E. Sherman (Center for Drug Evaluation and Research, U.S. Food and Drug Administration)

   Session Questions:

1.   In general, what is the optimal role of LSTs in the medical products regulatory approval pathway? Are there areas of medical product development in which LSTs are not useful?

2.   How can an understanding of those policy/regulatory issues that drive complexity in traditional RCTs and the strategies to counteract them be applied to the adoption and use of LSTs in medical products regulatory contexts?

3.   What are the real and perceived regulatory barriers hindering the development of an enhanced LST capacity?

4.   What are some near-term strategies for accelerating progress in the uptake of LSTs in the United States?

5.   What is the current thinking from the U.S. Food and Drug Administration in terms of how and when LSTs might be used without jeopardizing the medical products development process?

Break

Strategies Going Forward
Session chair: David L. DeMets (Planning Committee
Co-Chair, University of Wisconsin School of Public Health)

   Session Objectives:

   Identify and discuss issues and key themes from the workshop.

   Consider strategies and priorities for accelerating progress in the uptake of LSTs in the United States.

   Brief Summaries and Key Stakeholder Perspectives from the Workshop:

   Representatives from key stakeholders groups will provide an overview of key themes and issues identified from their perspectives.

   Federal funders—Michael S. Lauer (National Heart, Lung, and Blood Institute)

   Nongovernmental funders—Robert E. Ratner (American Diabetes Association)

   U.S. Food and Drug Administration—Bram Zuckerman (Center for Devices and Radiological Health)

   Centers for Medicare & Medicaid Services (CMS)—Rosemarie Hakim

   Private payers—William H. Crown (Optum)

   Industry—Peter Held (AstraZeneca)

   Patients—Kate Ryan (National Women’s Health Network)

   Clinical researchers—Elizabeth A. Chrischilles (University of Iowa College of Public Health)

   Panel Questions:

1.   What are the themes of today’s presentations and discussions that have resonated most strongly with you?

2.   Where do you see the most opportunity for the application of LSTs? What do you see to be the biggest barriers?

3.   What will it take to seize these opportunities and overcome the barriers?

4.   Based on the presentations and discussions, can you identify issues that need to be resolved by others before progress can be made? For example, as the lead of the Ethics and Processes section, can you identify critical needs in infrastructure or regulatory issues that need to be resolved before you can achieve your goals?

5.   If you were granted one wish to move LSTs forward, what would that wish be?

Next Steps

   Session Description: The workshop will conclude with a brief discussion and summary of next steps.