This Funding Opportunity Announcement (FOA) encourages UG3/UH3 phased cooperative research applications to conduct an efficient, large-scale pragmatic trial to evaluate the impact of, and strategies to best implement, acupuncture treatment of older adults (65 years and older) with chronic low back pain (CLBP). This FOA requires that the intervention under study be embedded into health care delivery system, “real world” settings. Awards made under this FOA will initially support a one-year milestone-driven planning phase (UG3), with possible transition to an implementation phase (UH3). UG3 projects that have met the scientific milestone and feasibility requirements may transition to the UH3 phase. The UG3/UH3 application must be submitted as a single application, following the instructions described in this FOA.
This FOA is part of the NIH HEAL (Helping to End Addiction Long-term) Initiative – an aggressive trans-agency effort to speed scientific solutions to stem the national opioid public health crisis.
Trials must be conducted across two or more health care systems (HCS) and will become part of and work with the NIH HCS Research Collaboratory supported through the NIH Common Fund. (See https://commonfund.nih.gov/hcscollaboratory). The NIH HCS Research Collaboratory Program has established a CCC that is providing national leadership and technical expertise in all aspects of research with HCS. After awards are made by NIH, the CCC (http://rethinkingclinicaltrials.org/about-nih-collaboratory/) and the NIH will work with awardees from this FOA to facilitate the planning and rapid execution of high impact trials that conduct research studies with partnering health care delivery systems.
Background
Low back pain is an important US public health concern as it is commonly associated with high levels of disability and is one of the most common reasons for primary care visits. The prognosis for acute back pain is generally favorable, with many patients improving after one to three months. The predominant population effected by low back pain is the group with CLBP and have pain that lasts 3 months or longer. As the prevalence of chronic conditions increases with age, older adults (65 years and older) with CLBP are likely to also have other comorbid medical conditions. As older adults develop more chronic conditions, they are more likely to use healthcare services and suffer outcomes such as unnecessary hospitalizations, adverse drug reactions, declining functional status and mortality. The use of opioids for pain relief in older adults is therefore particularly concerning, in view of the complexity of their medical management. Successful non-pharmacologic pain management options for CLBP in older adults are critically needed. Such options must address not only pain symptoms, but also address patient levels of functioning to prevent or reduce subsequent disability.
In 2011, the Institute of Medicine (IOM) and the National Pain Strategy (NPS) recommended developing evidenced-based strategies for treatment of chronic pain that incorporates the biopsychosocial nature of the condition. The recent Centers of Disease Control (CDC) guideline for prescribing opioids for chronic pain states that “nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain” and has prompted research into nonpharmacological treatments for pain conditions.
In response to the U.S. opioid crisis, HHS is focused on preventing opioid addiction and providing more non-pharmacologic treatment options for chronic pain. AHRQ, CMS and NIH are collaborating in this effort. The Agency for Healthcare Research and Quality published a systematic review of noninvasive, nonpharmacological treatment for chronic pain in June 2018 (https://effectivehealthcare.ahrq.gov/sites/default/files/cer-209-evidence-summary-non-pharma-chronic-pain.pdf). This review included assessment of several nonpharmacological interventions, including exercise, acupuncture, spinal manipulation, and multidisciplinary rehabilitation that have been associated with modest benefits in CLBP. This review noted that acupuncture improved function and/or pain for at least one month after treatment ended for chronic low back pain.
Acupuncture efficacy trials data included in the review reported durable slight to moderate improvements in function and pain for CLBP patients that were <60 years of age. An acupuncture and chronic pain meta-analysis (Acupuncture for Chronic Pain: Update of an Individual Patient Data Meta-Analysis) reported results from an individual level patient data meta-analysis that found that acupuncture was effective for chronic pain with only minimal diminishing of effects one year after the treatment was complete. However, similar compelling data on the improvements in meaningful health outcomes of acupuncture for CLBP in older adults (65 or more years) are currently lacking; such studies are critically important for expanding non-opioid pain management options for older adults who frequently suffer with high levels of disease burden.
For health care policy makers or payers, such as the Center for Medicare & Medicaid Services (CMS), this evidence gap must be addressed to inform coverage determinations on nonpharmacologic interventions, including acupuncture, in older adults with CLBP. CMS is interested in generating evidence on promising items and services for Medicare patients and has several mechanisms to cover and pay for items and services in the context of a clinical study, including coverage with evidence development (CED) through a national coverage determination (NCD). CMS has published a guidance document for the Public, Industry and CMS staff, to help understand CMS’ implementation of CED through the NCD process (https://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=27 ). Section VI of this guidance document, entitled Requirements for CED under Section 1862(a)(1)(e), provides a list of general requirements for clinical studies that must be included (with occasional minor modifications) in the coverage determination. The guidance document relates that CMS would not anticipate approving a study that does not meet the listed requirements.
By addressing gaps in the literature on the benefits and harms of acupuncture in individuals 65 years and older, it is anticipated that evidence on improvements in health outcomes derived from this initiative would assist CMS in determining Medicare coverage for acupuncture in CLBP. To this end, applicants may wish to consider how their model would translate into the Medicare Fee for Service model of coverage and payment (e.g., sites where acupuncture is furnished, types of practitioners that can bill Medicare).
Additional language:
This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative will bolster research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative.
Research Goals
This Funding Opportunity Announcement (FOA) encourages UG3/UH3 phased cooperative research applications to conduct an efficient, large-scale pragmatic trial or implementation science study to evaluate the impact of acupuncture treatment in people age 65 or older (Medicare population) with chronic low back pain (CLBP) in a way that is integrated into health care delivery, as there is insufficient evidence of the benefits in the Medicare age population. The largest U.S. study to date of acupuncture for CLBP was in patients up to age 65 with a median age 47 years ( 2009).
Awards made under this FOA will initially support a one-year, milestone-driven, planning phase (UG3), with possible transition to an implementation phase (UH3). UG3 projects that have met the scientific milestones and feasibility requirements may transition to the UH3 phase. The UG3/UH3 application must be submitted as a single application, following the instructions described in this FOA. Trials must be conducted across two or more health care systems (HCS) and must be conducted as part of the NIH HCS Research Collaboratory. After awards are made by NIH and the NIH HCS Collaboratory Coordinating Center (http://rethinkingclinicaltrials.org/about-nih-collaboratory/) will work with awardees from this FOA to facilitate the planning and rapid execution of high impact trials that conduct research studies with partnering health care delivery systems.
For the purpose of this FOA, embedded pragmatic clinical trials are studies that are conducted within the health care delivery setting and are “primarily designed to determine the effects of an intervention under the usual conditions in which it will be applied”, which is in contrast with explanatory trials that “are primarily designed to determine the effects of an intervention under ideal circumstances” (http://www.bmj.com/content/350/bmj.h2147). “There are “three key attributes of pragmatic clinical trials (PCTs): (1) an intent to inform decision-makers (patients, clinicians, administrators, and policy-makers), as opposed to elucidating a biological or social mechanism; (2) an intent to enroll a population relevant to the decision in practice and representative of the patients or populations and clinical settings for whom the decision is relevant; and (3) either an intent to (a) streamline procedures and data collection so that the trial can focus on adequate power for informing the clinical and policy decisions targeted by the trial or (b) measure a broad range of outcomes (http://rethinkingclinicaltrials.org/chapters/pragmatic-clinical-trial/what-is-a-pragmatic-clinical-trial-2/).”
Awards supported by this initiative will utilize the existing coordinating center of the NIH HCS Research Collaboratory. The overall goal of the NIH HCS Research Collaboratory program is to strengthen the national capacity to implement cost-effective large-scale research studies that engage health care delivery organizations and patients as research partners. The NIH HCS Research Collaboratory Program established a CCC led by Duke University in 2012 (http://rethinkingclinicaltrials.org/about-nih-collaboratory/), which is providing national leadership and technical expertise. Awardee(s) from this FOA will work with the NIH and CCC for both the planning and implementation of their pragmatic clinical trial or implementation study. All Projects must conduct research studies in partnership with at least two health care delivery systems, and work with the NIH and the CCC to ultimately make available data, tools, resources and lessons learned from Collaboratory research projects to facilitate a broadened base of research partnerships with HCS.
Embedded pragmatic clinical trials of acupuncture in older Americans with CLBP supported by this initiative will be expected to provide innovative approaches to address and overcome important barriers to research in the setting of HCS. Research conducted in partnership with health care systems is essential to strengthen the relevance of research results to ‘real world’ health practice. Successful approaches and best practices established through this initiative should have a major impact on the management of CLBP in older adults in the US. (See http://commonfund.nih.gov/hcscollaboratory/).
Although the importance for biomedical research and strengthened partnerships with organizations that deliver health care is clear, many challenges exist, both cultural and practical. Many ethical and regulatory issues must be addressed to perform research in the health care delivery setting. Technical challenges to accessing and aggregating quality-controlled data from health care systems in understandable ways are not trivial. Research studies have frequently used endpoints that are not part of the normal evaluation of patients during a routine visit and interventions that are impractical in most care delivery settings. Education and engagement of providers and patients on the value of research in the care setting, and of researchers on the relevance of their work to health systems, are urgently needed for optimizing the care in all people. The NIH HCS Research Collaboratory program has created a broad framework to tackle some of these major challenges.
This UG3/UH3 will fund a one-year, milestone driven, start-up phase in preparation for a three-year randomized pragmatic clinical trial embedded delivery in two or more health care systems to assess the effectiveness of a minimum of 12 weeks of acupuncture treatment for addressing clinical significant changes in pain intensity, pain interference and/ or function in older Americans (age 65 or greater) with chronic low back pain (CLBP). Subject selection must be based on definition of chronic low back pain that will be consistent with definitions in guidelines and be sufficient to be amenable to improvement with an effective intervention. Acupuncture treatment should be compared to usual care or another known effective intervention for treatment of CLBP.
The proposed projects must address the following criteria:
Research studies must include the following:
- Must be done in a CLBP population that is 65 years or older, who meet guideline definition of CLBP. The project must enroll patients based on broad eligibility criteria to maximize diversity, and minimize intentional or unintentional exclusions based on risk, multi-morbidity, age, health literacy, demographics, or expected adherence.
- Must provide a minimum 12-week acupuncture intervention versus usual care or other intervention for chronic low back pain.
- Primary endpoint must be measured at 12 weeks, 6 months, and 12 months after randomization to treatment, with comparison to usual care, or other planned comparator arm. The study must be powered for primary endpoint assessment at 6 months. Important health outcomes to CLBP patients include improvements in pain and function, as noted in the systematic review.
- The project must leverage opportunities made available through integrated health care systems and use of outcomes that can be captured by passive follow-up by electronic health records, and with minimal need for adjudication. Augmentation of the electronic health record is allowable for patient reported data and outcomes, although this should be streamlined and collected only at necessary time points.
- Proposed analytic plans for projects that propose cluster-randomized trials must address adequacy of sample size and study power and employ analytic strategies relevant for such pragmatic trial designs. Applicants are strongly encouraged to consult Collaboratory Biostatistical Guidance documents (http://sites.duke.edu/rethinkingclinicaltrials/biostatistical-guidance-documents/) when developing pragmatic trial analytic plans.
- The project design must incorporate rigorous controls, prospectively identified, preferably by randomization. The design may incorporate novel randomization approaches, such as by cluster or timing of implementation. If another method is used to generate the comparison group, perhaps by staged assignment or staged implementation of the intervention, it should provide comparable rigor.
- Project must be done within at least two health care systems.
Research studies may include but are not limited to the following:
- Randomizing participants in the acupuncture arm to a maintenance phase for acupuncture versus no maintenance phase between 12 weeks and 24 weeks.
- Randomizing participants in the comparator arm to a maintenance phase or no maintenance.
- Collecting information from subjects on preference of interventions prior to, during and at end of study.
- Implementing cost-effective delivery methods for acupuncture such as group interventions with single provider versus other strategies.
- Including a cost-effectiveness evaluation.
- Evaluating different methods of implementing acupuncture into health care delivery to identify which is most efficient, cost-effective, and minimizes barriers.
Partnerships with health care delivery organizations will be critical in conducting this work. It is anticipated that the research will generally be performed with high volume electronically-supported integrated HCS to establish efficiencies. The HCS partnership must facilitate access to all data sources relevant to the project, which may include inpatient, outpatient, imaging, clinical laboratory, pharmacy and community data. Applicants, who may be from academic institutions or other organizations, must demonstrate experience in successful conduct of clinical or implementation research in partnerships with HCS. Applicants must identify at least two HCS as partners for the proposed Project. Applicants are encouraged to use as many health care systems as needed to assure that the results of the study are generalizable to the US population of patients age 65 or older who suffer from chronic low back pain.
These projects will be funded as phased awards with a one-year planning phase (UG3) and up to three-year implementation phase (UH3). Activities in both phases will depend on the specific study (e.g. disease domain, interventions, experimental design, randomization strategy and proposed outcome measures).
During the UG3 or planning phase activities will generally include, but are not limited to:
- Identify project staff that will participate in the Collaboratory Work Groups (see Section I.5 Additional Information http://rethinkingclinicaltrials.org/cores-and-working-groups/), which will develop guidelines and practices to be implemented across projects.
- Work with the Collaboratory 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 HCS 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.
- Assess adequacy and finalize clinically relevant outcome measures with other Collaboratory investigators. It is anticipated that successful applicants will work with other Collaboratory investigators and NIH to identify and harmonize common outcome measures (pain severity, pain interference, and pain functioning, as well as others). It is also anticipated that successful applicants will work with the CCC and NIH to develop metrics for resource utilization for planning and implementing Collaboratory pragmatic trials. If an award is made, NIH and CCC staff will work with the Program Directors/Principal Investigators to facilitate this aspect across Projects.
- Refine estimates of requirements with guidance from NIH and the CCC, for sample size, numbers of sites, site to site heterogeneity, and implementation timetable based on data derived from the partnering HCS.
- All studies must use at least two HCS for implementation.
- Develop detailed plans for site implementation, including site staff, method of identification, randomization (as applicable) and participant recruitment and acquisition and administration/implementation of the intervention if applicable.
- Address all ethical issues and issues related to human subject safety oversight for the Project, including development of informed consent documents or opt-out consent if applicable, and finalizing site of IRB review. Applicants must propose a consolidated or centralized IRB approach for trial oversight, to facilitate both appropriate and timely study implementation.
- Address all potential regulatory elements of the proposed trial (if applicable).
- Develop a detailed budget for conduct and completion of the Project, including preparation of a final study report.
- Finalize detailed plans for data coordination and quality control for the UH3 phase. It is not anticipated that the CCC will provide these functions for the acupuncture study. Data coordinating activities for individual Projects must be separately budgeted as part of the UH3 budget.
Project Implementation Phase (UH3): The objective of the up to three-year UH3 implementation phase is to actually conduct the Project in accordance with activities planned in the UG3 phase. Implementation activities will depend upon the study, but in general the following goals should be achieved:
- It is expected that the project will implement all aspects of the proposed pragmatic trial, including the identification and recruitment of proposed sample sizes of patients, practice sites, and clinicians, the execution of the intervention and its implementation, and the assessment of outcomes.
- The project is expected to provide complete assessment of all issues related to patient, clinician and site identification, and EHR tools used in these steps.
- The project is expected to provide definitive information about the execution of the intervention at all sites.
- The project is to provide detailed and definitive testing of the validity of methods used for monitoring and outcome assessment.
Milestones and UG3/UH3 Transition
Utilization of milestones is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. This FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a start-up phase of up to one year (UG3) and a full enrollment and clinical trial execution phase (UH3). Projects should include well-defined milestones for the planning phase (UG3) and annual milestones for the implementation phase (UH3). It is understood that the proposed milestones for the UH3 phase will be revised as activities in the UG3 phase progress. In the event of an award, the PD/PI, NIH staff and the Coordinating Center will negotiate a final list of milestones for each year of support.
At the completion of the UG3 planning phase, the applicant will be required to submit a detailed transition request for the UH3 implementation phase. UH3 transition requests will undergo an administrative review to determine whether the project will be awarded the implementation phase (UH3). All regulatory approvals should be obtained prior to the end of the UG3 award. Training of intervention providers, comparison group providers, or other resources should be planned at the start of the UH3 award to allow for the successful launch and execution of the proposed pragmatic trial in the UH3 phase. Prospective applicants should note that initial funding of the UG3/UH3 Phase Innovation cooperative agreement does not guarantee support of the UH3 Project implementation phase. Applicants should understand that transition to the UH3 phase of the project will occur only if an administrative review process recommends that the UG3 planning milestones have been successfully met, that the UH3 phase can proceed with confidence of success, and availability of funds. Continuation of the award is conditional upon satisfactory progress and subject to availability of funds. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NIH will consider ending support and negotiating an orderly phase-out of the award and retains, as an option, periodic external peer review of progress. NIH staff will closely monitor progress at all stages, milestones, accrual, and safety.
Types of Clinical Trials Not Responsive to this FOA
The following types of clinical trials are not responsive to this FOA and applications proposing such activities will be deemed non-responsive and not reviewed:
- Phase I (first-in-human) trials whether single or multi-site
- Single site trials
- Studies to understand the mechanism of the intervention
- Studies to assess initial feasibility of an intervention
- Drug or device safety trials
- Studies that propose to conduct studies in animals or in vitro studies
- Studies that do not propose a trial of acupuncture in humans
- Studies that proposes a sham or time and attention control
Additional Information
Governance: The awards funded under this FOA will be cooperative agreements (see Section VI.2 Cooperative Agreement Terms and Conditions of Award). Close interaction with the NIH staff and with the CCC will be required to accomplish the goals of this program.
HCS Research Collaboratory Work Groups have been established by the CCC and the NIH as the core collaborative activity of this program. The Work Groups provide a forum for discussion of challenges and solutions across projects. Harmonized and standardized policies and processes will be vetted in these groups. Work Groups have been established in the following areas: Electronic Health Records, Regulatory /Ethics, Biostatistics & Study Design, Health Care Systems Interactions, and Patient Reported Outcomes (http://rethinkingclinicaltrials.org/cores-and-working-groups/). Additional Work Groups may be identified as the HCS Research Collaboratory expands with this initiative and other new projects. Work Groups will comprise individuals from each of the Projects, the Coordinating Center, and staff from the NIH. PDs/PIs must identify study staff or investigators that will participate in Collaboratory Work Groups.
A Steering Committee has been established by the CCC to address issues that span all projects, provide input into the policies and processes of the HCS Collaboratory, and assist in dissemination of policies and processes that enable research in healthcare systems, involving their patients, and practitioners. At a minimum, the Steering Committee will have one representative from each of the Projects, one representative from each Work Group, one representative from the Coordinating Center, NIH Program Officers and Project Scientists for the CCC and Projects. All members are expected to actively participate in all Steering Committee activities. The combined vote of NIH membership may never exceed 40 percent.
Deadline: March 15, 2019 (letters of intent due 30 days prior to the deadline)
Filed Under: Funding Opportunities