Research Proposal Questions

1. Should I apply for the RFA-AT-22-004 or RFA-AT-22-005 funding opportunity?

Title HEAL Initiative: Sickle Cell Disease Pain Management Trials Utilizing the Pain Management Effectiveness Research Network Cooperative Agreement (UG3/UH3, Clinical Trial Required) RFA-AT-22-005 HEAL Initiative: Pragmatic and Implementation Studies for the Management of Sickle Cell Disease Pain (UG3/UH3, Clinical Trials Optional) RFA-AT-22-004

Appropriate types of studies

  • Effectiveness research trials.
  • Studies need to randomize participants individually, collect in-person measures for research purposes (such as specified clinical laboratory tests, observed studies of mobility or other measures of function), or deliver an intervention in a standardized fashion.
  • Embedded pragmatic trials or implementation trials.
  • Interventions under study must be embedded into health care delivery systems in real-world settings.
  • Pragmatic trial models collect most data needed for analysis of the research question as part of clinical care, and it is expected that these data will be obtained primarily through the electronic records of the health care system.
  • Implementation trials have implementation-focused main outcomes that are most likely at a system or individual provider level. Patient-level implementation outcomes may be possible if they are not focused on health but on use of the targeted intervention.

Infrastructure

  • Clinical trials will be conducted within the infrastructure of the HEAL Pain Management Effectiveness Research Network (HEAL ERN).
  • Awardees will work with the National Center for Advancing Translational Sciences (NCATS) Trial Innovation Network (TIN, trialinnovationnetwork.org) for clinical, biostatistical, and recruitment support.
  • Clinical trials will be conducted within the infrastructure of the NIH HEAL Initiative Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM) Program Coordinating Center.
  • Awardees will work with the Health Care Systems (HCS) Research Collaboratory Coordinating Center (CCC, rethinkingclinicaltrials.org) to facilitate further planning and refinement of the proposed trial in partnerships with health care delivery systems.

2. Is my research question ready for a pragmatic trial?

Patients, providers, and researchers all want the best available clinical evidence to inform decisions about which approaches or therapies to provide or recommend. If you are considering a pragmatic or implementation trial design, is there sufficient efficacy information on the intervention to warrant further testing in a large-scale pragmatic or implementation trial across multiple health care systems? Can the intervention be implemented across health care systems?

4. Does my project need to include implementation outcomes?

This FOA will support either pragmatic trials or implementation trials. Applications proposing pragmatic intervention trials are not required to include implementation outcomes; however, investigators proposing these studies may improve their ability to deliver the intervention in their trial by utilizing effective implementation strategies or by measuring implementation outcomes. The UG3/UH3 funding opportunity will accept pure implementation trials of effective interventions with the goal of understanding how to get effective interventions into health care delivery with good adoption, implementation, and sustainability. This expanded call is consistent with multiple efforts across NIH to advance dissemination and implementation research (e.g., PAR-19-274).

5. To what degree can pilot work be conducted during the UG3 phase, and can any pilot work be done during the first year of the UH3 phase?

In the context of pragmatic trials, “piloting” usually refers to the work investigators do during the planning phase to test their ability to successfully get the intervention into clinical sites, extract needed data from electronic medical records, and assess methods for identifying eligible participants and methods for collecting data from participants to augment the electronic health record. Investigators can pilot the intervention and assess its uptake so that when they get to the trial conduct phase, they are prepared for trial startup. For implementation trials, the planning phase can be used to collect site-specific context data and test the ability to measure implementation outcomes based on electronic health or administrative records. It is expected that efficacy data for the intervention already exist. The piloting work should be complete before beginning the UH3 phase, as the investigators are expected to launch the trial at the start of the UH3 phase.

6. Do all software tools needed for implementation need to be developed during the planning phase, or can these be developed after a project is selected for transition to the UH3 (trial conduct) phase?

By the start of the UH3 phase, the study team should have all methods, tools, and software needed to conduct the pragmatic or implementation trial. Tools can be modified as needed during the UH3 phase.

7. Will sharing plans require sharing preexisting proprietary software currently used by partnering health care systems?

Applicants will not be required to share preexisting proprietary software that is currently used by partnering health care systems. Applicants will be encouraged to share resources and software whenever possible.

8. Is the UG3/UH3 intended to support work of clinicians or interventionists?

The interventions should be delivered as part of routine health care delivery. Thus, funds from the award typically are not used to directly pay for delivery of the intervention.

9. Should the pragmatic or implementation clinical trials in the UG3/UH3 enroll patients at more than one institution/center?

Trials should be conducted across three or more health care systems that provide care to SCD patient populations. Clinical trials will be conducted within the infrastructure of the NIH HEAL Initiative PRISM Program Coordinating Center, which has dedicated pain, implementation science, and pragmatic clinical trial design. Awarded applicants will work with the PRISM Program Coordinating Center (rethinkingclinicaltrials.org) to facilitate further planning and refinement of the proposed study’s partnerships with health care delivery systems. Trials should include a diverse patient population that approximates the U.S. population of patients with the condition being studied. Investigators who propose fewer than three health care systems must provide justification that there is adequate geographic, provider, and racial diversity within the proposed systems and that the trial will be generalizable to other health care systems.

10. What activities should be carried out in the UG3 phase?

During the UG3 or planning phase, activities will generally include but are not limited to:

  • Identifying project staff who will participate in the PRISM Program work groups (see https://rethinkingclinicaltrials.org/cores-and-working-groups/, which will develop the guidelines and practices to be implemented across projects.
  • Working with the PRISM Program to implement approved guidelines and practices for electronic data extraction and quality control methods and tools, as well as for electronic data sharing. In the planning phase, this will include developing and validating all electronic data methods and tools within the health care systems needed for the project (e.g., electronic health records, electronic methods for patient identification and outcomes assessment, patient-reported data, biospecimens, images, high-throughput genomic data, family history data, data abstraction, and survey instruments) and complete quality control testing at all sites.
  • Assessing adequacy and finalizing clinically relevant outcome measures with other PRISM Program investigators. Awarded applicants will work with other PRISM Program investigators and NIH to identify common outcome measures (e.g., pain severity, pain interference, pain functioning, and others) and will work with the CCC and NIH to develop metrics for resource utilization for planning and implementing PRISM Program pragmatic trials. If an award is made, NIH and CCC staff will work with the program directors/principal investigators to facilitate coordination among projects, if appropriate.
  • Refining estimates of requirements with guidance from NIH and the CCC for sample size, numbers of sites, site-to-site heterogeneity, and the implementation timetable based on data derived from the partnering health care systems.
  • Using at least three health care systems for trial conduct, unless a specific rationale for limiting this aspect of the project is provided.
  • Developing detailed plans for site implementation, including plans for site staff, the method of identification, randomization (if applicable), participant recruitment and acquisition, and administration/implementation of the intervention (if applicable).
  • Addressing all ethical issues and issues related to human subject safety oversight for the trial, including development of informed consent documents or opt-out consent (if applicable) and finalizing the site of Institutional Review Board (IRB) review. Applicants must propose a consolidated or centralized IRB approach for trial oversight to facilitate both appropriate and timely study implementation.
  • Addressing all potential regulatory elements of the proposed trial (if applicable).
  • Developing a detailed budget for conduct and completion of the trial, including preparation of a final study report.
  • Finalizing detailed plans for data coordination and quality control for the UH3 phase. The CCC will not provide these functions for individual trials. Data coordinating activities for individual projects must be separately budgeted as part of the UH3 budget.

11. Given the two stages—UG3 and UH3—how should the aims and research strategy sections of the application be structured?

Page 1 of the research plan must include specific aims for each of the two stages. Typically, investigators divide the remaining pages into two discrete descriptions, first for the UG3 and then for the UH3. The FOA has a list of activities that must occur during each phase. You can use this as a guide. Information already described for the UG3 does not need to be repeated in the UH3 section; you can just refer to it. If your project meets the definition of a clinical trial, you can provide additional details, such as inclusion/exclusion criteria and details of the protocol, in the study record.

12. Do applications need to include a complementary health approach?

Applications do not need to include complementary health approaches. Applications must fit the mission of one of the participating Institutes or Centers and the goals specified in the FOA.

13. How much evidence is needed for an intervention to justify a primary focus on implementation rather than intervention effectiveness?

The amount of evidence needed to justify implementation often depends on the volume of evidence suggesting a health benefit and the relevance of that evidence to the context and the intended target population. If there are still key questions about the link between the intervention and targeted health outcomes, investigators can consider using a hybrid effectiveness-implementation design, in which questions of both effectiveness and implementation can be addressed.

14. For implementation trials, should my project include a relevant conceptual framework?

While the FOA does not require use of a dissemination and implementation theory, model, or framework, investigators may find that using an existing model (e.g., dissemination-implementation.org) can help clarify causal relationships in the implementation process, determine relevant implementation strategies to test, or identify implementation outcomes to measure.

15. Must all three health care systems be participating members of the PRISM Program?

No, organizations that have not previously participated in PRISM Program projects are welcome. The PRISM Program has worked with organizations that provide health care but might not be considered typical health care systems, such as dialysis providers and corporations that provide health care.

However, all participating health care systems must be large-scale health care delivery organizations with electronic records, and investigators must have ready access to the electronic records needed to assess study outcomes. The FOA’s definition of a health care system was intentionally broad so investigators can propose ideas that may not have been anticipated. If you are unsure whether an organization is acceptable, please contact a program officer.

Note that for this FOA, results must be generalizable and applicable to a broad patient population. Typically, sites from multiple regions around the country would be included in a study. No foreign sites can be included, although foreign consultants are acceptable.

16. Is it necessary to budget for a biostatistician or will one be provided by the CCC?

You definitely need a doctorate-level biostatistician for both the design stage of your trial and the development of the analytic plan. The CCC is a resource center, not a data coordinating center for your trial. It will not collect, store, or analyze your data. You need to budget for a biostatistician because your application needs to include full information about how you will obtain and analyze your data.

17. Can NIH provide additional guidance on including milestones in the application?

Milestones are intermediate steps toward the completion of concrete goals and must include clear and quantitative criteria for success. Yearly quantitative milestones are required to provide clear indicators of a project’s continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of noncompeting award years. The application must include clearly specified, well-defined milestones; quantitative go/no-go decision points; and timelines for assessing progress. Applicants must provide a timeline and detailed annual quantitative milestones spanning the funding period. If selected for funding, applicants will work with NIH staff to develop more granular quarterly milestones for each year of funding.

18. What are some examples of quantitative milestones?

Examples of quantitative milestones include but are not limited to enrollment numbers, completion of enrolled patient follow-up, and publication of results. Note that prior to an award, NIH staff and the applicants will finalize an agreed upon set of milestones that will be included in the notice of grant award.