Pragmatic Clinical Trials: NCCIH Funding Opportunities for RM-16-019

April 25, 2017

2:30 p.m. to 3:15 p.m. ET

Purpose of the Webinar:

On Tuesday, April 25, 2017, the National Institutes of Health (NIH) National Center for Complementary and Integrative Health (NCCIH) hosted a webinar to provide information about a request for applications (RFA) for pragmatic clinical trials.

The webinar conveyed important information about the NIH Health Care Systems Research Collaboratory and the type of research it funds, the specific funding opportunity currently available, and NCCIH’s involvement in this funding opportunity. The webinar also provided an opportunity for participants to ask questions of the webinar speakers.

Webinar Speakers:

Robin Boineau, M.D., M.A., Medical Officer, Division of Extramural Research and Office of Clinical and Regulatory Affairs, NCCIH
Catherine Meyers, M.D., F.A.H.A., Director, Office of Clinical and Regulatory Affairs, NCCIH
Wendy J. Weber, N.D., Ph.D., M.P.H., Branch Chief, Clinical Research in Complementary and Integrative Health Branch, Division of Extramural Research, NCCIH

Additional NCCIH Staff Present:

Anita McRae-Williams, M.A., Outreach Program Manager, Division of Extramural Research, NCCIH (Webinar Moderator)

This report summarizes information provided during the webinar about (1) the Collaboratory, (2) the goals and objectives of the current Request for Applications (RFA), (3) the nature of pragmatic clinical trials, (4) NCCIH’s priorities for the current RFA, and (5) details of the application and review process.

The NIH Health Care Systems Research Collaboratory: A Common Fund Program

The NIH Health Care Systems Research Collaboratory is a program supported by the Office of the Director of NIH and co-chaired by two Institute or Center (IC) directors, one of whom is NCCIH Director Dr. Josephine Briggs. NCCIH staff have played key roles in overseeing the Collaboratory.

The objectives of the Collaboratory are to

Establish a coordinating center to provide national leadership and technical expertise in all aspects of research with health care systems.
Support high-impact demonstration projects that involve research studies in partnership with health care systems.
Make available data, tools, and resources from Collaboratory projects to facilitate a broadened base of research partnerships.

The Collaboratory website provides a wealth of information, including resources for planning and implementing pragmatic clinical trials in cooperation with health care systems.

The Collaboratory coordinating center, located at Duke University, provides the overall administrative structure for the entire program. Nine Collaboratory pragmatic trials, funded through two previous RFAs, are in progress across the country. Each trial has its own data coordinating plan. The RFA to be discussed in this webinar is the third issued by the Collaboratory, and 11 NIH ICs are involved in it.

RFA-RM-16-019 Goals and Objectives

The current funding opportunity, RFA-RM-16-019, will fund milestone-driven phased cooperative agreements for large-scale pragmatic trials that include a 1-year planning phase (UG3, direct cost cap $500,000) and a 2- to 4-year implementation phase (UH3, direct cost cap $1 million/year) in a single application.

Projects funded under this RFA must include at least three partnering health care systems, which must be identified in the application, unless a strong justification for fewer systems is provided.

The projects must be pragmatic trials rather than explanatory trials. The differences between these two types of trials are explained below. Projects must be responsive to the specific research areas listed in the RFA for 1 of the 11 participating ICs. This is a change from the previous two rounds of Collaboratory funding.

Pragmatic vs. Explanatory Trials

The Collaboratory supports pragmatic trials. A pragmatic trial is primarily designed to determine the effects of an intervention under the usual, real-world conditions in which it will be applied. The approach, including study design, is kept as simple as possible without sacrificing scientific rigor.

In contrast, an explanatory trial is designed to increase the probability of obtaining the maximal effect from an intervention in a controlled setting. The results show how the intervention works in ideal patients under ideal circumstances (i.e., they demonstrate efficacy).

The design of pragmatic trials differs from the design of explanatory trials in a variety of ways:

The eligibility criteria for explanatory trials are strict, while those for pragmatic trials include all patients with the condition.
In explanatory trials, the intervention is delivered in an inflexible way, with strict instructions for all aspects; in contrast, delivery is highly flexible in pragmatic trials.
In explanatory trials, both the experimental intervention and any comparison interventions are delivered by seasoned practitioners in specific settings, but in pragmatic trials, they are delivered by the full range of practitioners in a variety of settings.
Explanatory trials have restricted flexibility in the choice of comparison interventions, and placebos or time and attention control conditions may be used. In pragmatic trials, practitioners follow their usual practice with high flexibility.
In explanatory trials, there is regular followup with data collection, beyond usual care. In pragmatic trials, there are no formal follow-up visits; data collected in the normal course of practice are used.
In explanatory trials, the primary outcome is directly related to the intervention and may be a surrogate marker; in pragmatic trials, a clinically meaningful outcome is used.
In explanatory trials, participant compliance and practitioner adherence are closely monitored; in pragmatic trials, they are monitored unobtrusively or not at all.
Explanatory trials use intent-to-treat analysis and may include per-protocol analysis to evaluate the primary outcome. Pragmatic trials use intent-to-treat analysis.

NCCIH Priorities for This RFA

NCCIH’s mission is to define, through rigorous scientific investigation, the usefulness and safety of complementary and integrative interventions and their roles in improving health and health care. In general, our interests include both natural products and mind and body interventions. However, for this RFA, we are interested only in trials of mind and body or integrated approaches.

Like the other ICs that are participating in this RFA, we have established specific areas of interest. Through this RFA, NCCIH is interested in funding studies of a mind and body or integrated approach to address:

Symptom management, particularly for chronic pain syndromes
Reduction of prescription drug (opioid) use or abuse in patients with chronic pain
Medication adherence
Post-traumatic stress (disorder) or traumatic brain injury
Sleep disorders or disturbances
Anxiety or depression
Promotion of psychological resilience
Weight loss and weight loss maintenance
Smoking cessation
Promotion of healthy eating and physical activity

For example, high-priority topics that could be addressed by pragmatic trials under this RFA could include (1) determining whether integrating a complementary approach into the treatment algorithm for pain management could reduce the use of opioids, (2) finding out which of several complementary health approaches for low-back pain is most effective and most easily used in health care systems, and (3) testing whether adding a complementary approach to an effective smoking cessation intervention improves outcomes.

Issues to keep in mind regarding submission of pragmatic trial applications to NCCIH include the following:

Trials of regulated products (dietary supplements, devices, or biologics) require U.S. Food and Drug Administration approval or clearance for the indication studied in the trial.
Strong preliminary data (a positive efficacy study or studies) must be available for the intervention for the specific clinical condition to be studied.
NCCIH priorities for pragmatic trials are:
- The trial must address questions of major public health importance.
- The intervention must be well-characterized and available so that it can be delivered within existing systems.
- Trials should leverage passive collection of outcome data via existing systems such as electronic health records.
- Trial design must incorporate rigorous controls, preferably via randomization.

Application and Peer Review

Eleven ICs are participating in this funding opportunity. If your proposed study doesn’t fit NCCIH’s areas of interest, consider the other ICs. Their contact people are listed in the RFA.

Important RFA details include the following:

The budget limits are $500,000 in direct costs for up to 1 year of planning for the UG3, followed by $1 million in direct costs/year for up to 4 years of implementation for the UH3.
Multiple principal investigators (PIs) are allowed, and PIs are required to devote a minimum of 20 percent effort to the study.
The applicant institution must be domestic, and no foreign components are permitted.
Applicants must submit both the UG3 and UH3 phases in a single application. The research plan must include specific aims, the research strategy, rationale and plans, and milestones for both stages.
Applicants must include letters of support from each of the health care system partners, as well as resource and software sharing plans.

Review criteria for this RFA are not standard. They are specific to this funding opportunity, as stated in the RFA. Factors such as the milestones and software sharing plan will influence the “overall impact” score of the application.

Letters of intent are due on May 2, 2017, and applications are due on June 2, 2017. Late applications will not be accepted, and the continuous submission policy does not apply. The review meeting will be held in October or November 2017, and award decisions will be announced in March 2018.

Resources

Extensive information on pragmatic trials is available on the Collaboratory website, including a knowledge repository—a living textbook on pragmatic clinical research.

The NCCIH contact for this RFA is Dr. Robin Boineau, who can be reached at rb@nih.gov.

Summary of Questions and Answers

How can I decide if NCCIH is the best fit for my proposal vs. another NIH IC?

We strongly encourage you to review the NCCIH Strategic Plan, including the top scientific priorities listed in the plan, as well as our active funding announcements, to see whether your interests align with ours. Also read the RFA; it includes specific information about our areas of interest for this funding opportunity. We encourage you to discuss your proposed study with Dr. Robin Boineau at rb@nih.gov. If you send a short summary of the specific aims of your proposed study, that would help start the conversation.

Why is partnering with health care delivery organizations so important?

It’s anticipated that much of the data collected in the demonstration projects funded under this RFA will come from electronic health records from high-volume health care systems. Applications will be accepted from academic institutions or other organizations, but these organizations must have health care systems as clinical research partners. Applicants must identify at least three such systems as partners or provide a strong scientific rationale for partnering with fewer than three.

Two current Collaboratory-funded trials involve fewer than three health care systems. In one instance, the single participating health care system has a very wide geographic distribution of hospitals. In the other, the two dialysis providers involved in the trial represent a large proportion of outpatient dialysis in the United States. These are the kinds of justifications that would be needed to warrant the inclusion of fewer than three health care systems in a trial.

Do all data used in the pragmatic trials need to be from electronic health records?

No. You can augment the electronic health record by doing some additional data collection. For example, you might want to obtain data on patient-recorded outcomes. However, as many aspects of your trial as possible should be pragmatic and done simply, in the course of routine practice.

Do you anticipate another funding cycle of this funding mechanism?

At this point, we don’t have plans. Our current plan is just to offer this RFA.

We have noticed that many ICs are now interested in supporting pragmatic research in health care systems. This is a growing area of interest at NIH. Therefore, future RFAs for pragmatic trials may be issued by individual ICs or groups of ICs, but not necessarily come from the Common Fund. In fact, NCCIH just issued a separate FOA that allows the submission of pragmatic trials. If your idea is specific to NCCIH, there are other FOAs that might be of interest to you after this RFA expires. However, the trials would not be conducted within the Collaboratory program.

Is a letter of intent required?

No, it is not required and not binding. However, we encourage you to submit a letter of intent because it helps us prepare for review. It will also help us determine whether there is an IC that matches your priorities. So please talk to us and send in your letter of intent in May. There are specific elements that we ask you to provide in your letter, as explained in the RFA.

Are there new review criteria that will affect our score?

Yes. There are specific review criteria for this RFA. We recommend that you focus on and address all the specific criteria that are listed. This will affect your score.

Why are pragmatic trials so important to NCCIH?

For two reasons.

First, this RFA specifically solicits them. If you respond to this RFA, it is critically important that you propose a pragmatic trial because a pragmatic trial design is part of the review criteria.

Second, and more generally, one of the reasons that the Collaboratory began as a Common Fund initiative was the recognition that traditional explanatory trials weren’t providing health care systems and policymakers with the most informative data. Therefore, the Common Fund took this on as a methodologic challenge and developed methods for pragmatic research and ways of soliciting this work to learn to perform this type of trial and partner with health care systems. The nine demonstration projects the Collaboratory is currently funding include a number of different disciplines. The program focuses on developing methods and best practices. Pragmatic trials answer different kinds of research questions than explanatory trials, and provide a lot of information on the effectiveness of interventions. The new emphasis on pragmatic trials represents a significant paradigm shift at NIH. There is a growing community of ICs that are interested in this type of research.