I. Introduction

Summary of Program

The Patient-Centered Outcomes Research Institute (PCORI) is launching this funding initiative to support patient-centered comparative clinical effectiveness research (CER) on the delivery of medication-assisted treatment (MAT) for pregnant women with Opioid Use Disorder (OUD). The study designs that PCORI will consider include large randomized controlled trials (RCTs) or well-justified observational studies. Each treatment program being compared should include two or more delivery models or components of delivery models that are documented to be efficacious or in common use, and should also be well characterized to facilitate replication and dissemination efforts. Through this PCORI Funding Announcement (PFA), PCORI seeks to fund studies with sufficient sample sizes to address the priority research questions. This program’s goal is to generate valid evidence that is readily generalizable to the broader population of pregnant women with OUD.

For this PFA, applicants should follow the definition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) for OUD: “a problematic pattern of opioid use leading to clinically significant impairment or distress.”

There is concern that using the term “MAT” suggests that medication is merely an ancillary part of the treatment rather than a central component. This PFA uses “MAT” because it is well defined, broadly used, and recognized. This PFA also uses “MAT” to distinguish it from approaches that focus on abstinence. If studies do not include maintenance medication, PCORI will consider them nonresponsive.

PCORI is particularly interested in large studies that can investigate potential Heterogeneity of Treatment Effects (HTEs) with respect to important sociodemographic and clinical characteristics (e.g., addiction severity, socioeconomic status, comorbid mental health conditions, or other clinical or patient/demographic characteristics proposed by investigators with an accompanying strong rationale).

Applications must address one or both of the priority research questions described in this PFA. Proposed studies should include comparison of two or more treatment models or components of treatment models. Treatment models should offer comprehensive treatment, including prenatal care, maintenance medication, and psychosocial services (on-site or by referral). Based on a 2016 Agency for Healthcare Research and Quality (AHRQ) systematic review by Chou et al.,[1] models of interest may include education and outreach and additional components.

If applicants propose comparing models or components of models that are in common use but without clear evidence of efficacy, they must document the extensiveness of their use and demonstrate how they will interpret study results.

Applicants must adequately define proposed comparators and describe how they will be measured. Proposed models must be evidence based or in current use.

Outcomes should include maternal measures, including illicit drug use, relapse, treatment entry, treatment retention, continuation of OUD care following delivery, patient quality of life, and anxiety/depression measures as well as perinatal and neonatal measures including pregnancy complications, preterm birth, birthweight, neonatal complications, and Neonatal Abstinence Syndrome. Studies should conduct periodic outcome assessments, including a follow-up period of three months or longer post-partum, to allow for the assessment of continuity of OUD care for the mother.

Background

The prevalence of OUD has increased dramatically among pregnant women in parallel with the current opioid epidemic. The largest increase in heroin use between 2002 and 2013 was in women, and the proportion of pregnant women who enter OUD treatment and report prescription opioids as their primary substance increased from 1 percent in 1992 to 19 percent in 2012. Incidence of Neonatal Abstinence Syndrome increased two-fold from 2009 to 2012.

OUD in pregnant women is associated with potentially serious maternal, fetal, and neonatal risks, including increased morbidity and mortality, decreased quality of life, complications during pregnancy, Neonatal Abstinence Syndrome in the baby, and potential longer-term cognitive and behavioral effects for the child.

MAT, which combines maintenance medication (methadone or buprenorphine) with psychosocial services, is an evidence-based, clinically effective treatment for pregnant women with OUD. Compared to methadone, buprenorphine has a more favorable safety profile and improved birth outcomes, including reduced incidence and severity of Neonatal Abstinence Syndrome.

Pregnancy might motivate women to seek treatment, but stigma such as treatment setting or methadone usage; lack of access to treatment; and, in some states, fear of legal consequences are important barriers. Unlike methadone, physicians might offer buprenorphine, and it does not have the associated stigma. However, buprenorphine is not as well-known and fewer than half the counties in the United States offer it; the need for treatment continues to exceed availability. Provider barriers include lack of expertise regarding the treatment (particularly in this patient population), lack of adequate support for its delivery, and lack of access to mental health providers or services necessary for evidence-based MAT.

There is evidence that pregnant women with OUD need comprehensive care, and some existing models deliver such care. These models are based on treatment models for the general population, and they can be characterized by the support offered to the provider who prescribes the maintenance medication.

Support can be provided in the care setting by integrating prenatal care, opioid treatment, and psychosocial services, or by co-locating prenatal care and opioid treatment with a collaboration with community psychosocial services. These models can be compared with the default option, “usual care,” in which a clinician provides prenatal care and then refers the patient to an opioid treatment center, or an opioid treatment center or office-based clinician provides OUD care and the patient is referred for prenatal care.

Support to the provider can also be offered remotely. In the “hub-and-spoke” model, the hub is an integrated center with addiction expertise that provides support remotely to spokes—offices located at some geographical distance from the hub, where clinicians offer prenatal care and opioid treatment to patients who live too far from the hub to receive care there. Further provider support to these spokes might include induction taking place elsewhere (e.g., in a hospital), psychosocial services delivered off-site by referral, or non-physician staff taking care of the logistics of treatment delivery.

Evidence Gaps

AHRQ recently commissioned a systematic review on MAT models in primary care settings that identified 12 models of MAT delivery currently in use, including one focusing on integrated prenatal care and MAT. As its main conclusion, AHRQ recommends research “to clarify optimal MAT models of care and to understand effective strategies for overcoming barriers to implementation.”

Comprehensive care for pregnant women with OUD includes prenatal care, maintenance medication for opioid addiction, and psychosocial services. Although there is a dearth of comprehensive treatment programs for pregnant women—according to recent data, only 19 states have treatment programs for pregnant women specifically—existing models do successfully treat pregnant women with OUD. These models vary by integration level and range from entirely separate care, in which the patient receives prenatal care and referrals to addiction care elsewhere or vice versa, to fully integrated, comprehensive prenatal and addiction care, in which a clinician or a team of clinicians provide prenatal and addiction care, and psychosocial services are on-site. In between nonintegrated and fully integrated care is co-located care, in which a prenatal care provider is co-located with a clinician providing Office-Based Opioid Treatment (OBOT), and the patient is referred to psychosocial services. There are also hub-and-spoke models, in which the hub is an addiction treatment center that provides support to clinicians offering OBOT at some distance from the center. These models vary by resource intensity for the spoke sites (e.g., induction in an addiction clinic or hospital versus in a provider’s office; on-site psychosocial services versus referral). Although these models might successfully treat pregnant and post-partum women with OUD, there are no studies comparing the effectiveness of these different approaches for pregnant and post-partum women.

To qualify for the buprenorphine waiver, which is required to be able to prescribe buprenorphine, clinicians must be able to refer patients to counseling services. Providers might organize weekly group counseling sessions on-site or provide brief counseling themselves, or they might refer to off-site services. Psychosocial services and referrals might also include mental health screenings and assessments, hepatitis C screening, contingency management, psychiatric care, and other specialty care. Although counseling is considered a key component of MAT, the format, frequency, and focus of counseling might vary, and its comparative clinical effectiveness for different subgroups of pregnant and post-partum women is unknown.

Research Topic Prioritization

The Medicaid Medical Directors Network identified the treatment of pregnant women with OUD as a priority in 2015 and 2016. PCORI met individually with representatives from key stakeholder groups, including midwives and obstetricians working in addiction treatment settings, addiction specialists, researchers who have focused on treatment of pregnant women with OUD, and individual Medicaid Medical Directors. PCORI also consulted the Advisory Panel on Improving Healthcare Systems, which consists of patient representatives, clinicians, researchers, payers, and purchasers.

Priority Research Questions

Applications should propose RCTs or well-justified observational studies that address the priority research questions noted below. The study should take place in clinical settings where pregnant patients with OUD typically receive care. The studies must be sufficiently large to be able to demonstrate differences in comparative clinical effectiveness in the study arms and to allow adequate power to detect the potential differences in treatment responses by patient clinical characteristics of interest. In considering approaches to their study design, conduct, and analysis, applicants should explicitly consider the tradeoffs of each element on the continuum while ensuring the validity of comparative clinical effectiveness findings. Interventions require some degree of flexibility in their use but must be sufficiently defined to be replicable in their dissemination and implementation in U.S. health care.

The priority research questions are:

1. What is the comparative clinical effectiveness of alternative models for comprehensive OUD treatment delivery on maternal and neonatal outcomes in pregnant and post-partum women with different levels of addiction severity?
   
   - Comprehensive care includes prenatal care, MAT for addiction, and psychosocial care.
    
2. What is the comparative clinical effectiveness, in terms of maternal and neonatal outcomes, of remotely supported OUD treatment delivery to pregnant women that includes more versus fewer resource-intense approaches to induction and psychosocial support for office-based opioid treatment?

Given the anticipated size and scope of proposed studies submitted under this funding initiative, applications should carefully consider and provide details supporting how the target sample size will be met across all study sites (e.g., expected eligible patients, recruitment capacity, integration of research and clinical workflow, etc.). Applicants should factor into target sample size calculations details such as anticipated attrition, informed by past studies by the investigative team and studies found in the extant literature. Similarly, recruitment timelines should include careful consideration of feasibility within the context of the proposed study. Furthermore, the proposed studies should have well-characterized interventions and comparators. Proposed treatment models or model components must address actual clinical choices faced by patients, caregivers, and clinicians in specific practice settings.

PCORI is interested in receiving applications that propose to conduct direct comparisons of models or model components that have a strong empirical or clinical rationale and/or are supported by published literature. Applicants should include sufficient details about the organization and components of treatment delivery. PCORI is always interested in studying populations with important disparities, important comorbidities, or difficult social conditions.

The characteristics that apply to these research questions include:

Population/Patient Problem: Pregnant women with OUD as defined by the DSM-5 and infants born to women with OUD. Although women with Medicaid insurance account for close to 50 percent of U.S. births, applications can include women with private insurance and uninsured women.

Intervention and Comparators:

The following treatment delivery models vary by spectrum of integration:

• Integrated prenatal care, OUD care, addiction medicine, and psychosocial service
• Co-located prenatal care, OBOT, and collaboration with community psychosocial services
• Prenatal care by clinician, referral to OUD treatment, or opioid treatment and referral to prenatal care (“usual care”)
• Models might offer remote support for providers, including hub-and-spoke models, in which the hub is a center with on-site addiction treatment expertise and spokes are office-based clinicians at geographical distance from the hub. The spokes serve women who live too far away from the hub. Core components of the spokes include prenatal care and office-based opioid treatment by the clinicians. The spokes might be more or less resource intensive regarding treatment delivery. For example, patient induction and stabilization might occur on-site or in a methadone clinic or hospital, and psychosocial services might occur on-site or by referral to community services. Specific psychosocial services, their format, and duration are important comparators. For example, both on-site and off-site services might vary by format and duration (e.g., medical management versus group counseling sessions on-site; referral to group versus individual counseling sessions).

Compared models need to be meaningfully different from each other and may include “usual care.” However, “usual care” is often ill defined, difficult to quantify, and subject to considerable geographic and temporal variations, which limits interpretability, applicability, and reproducibility. If an applicant proposes “usual care” as a rational and important comparator in the proposed study, then the applicant must described it in detail and include an explanation of how the care given in the “usual care” group will be measured in each patient (to the extent possible) and how appropriate inferences will be drawn from its inclusion.

Outcomes: Studies need to include addiction-specific outcomes (e.g., illicit drug use, relapse, treatment entry, treatment retention, post-partum treatment continuation, patient quality of life, and anxiety/depression) and pregnancy and neonatal outcomes (preterm birth, pregnancy complications, birthweight, neonatal complications, and Neonatal Abstinence Syndrome).

Time: Repeated assessments need to occur to measure maternal and neonatal outcomes during pregnancy. An assessment should also occur three months post-partum to assess continuity of care for the mother.

Setting: Focus on settings representative of locations where pregnant and post-partum women with OUD typically receive care.

Funds Available

PCORI has allotted up to $16 million in total costs under this PFA to fund high-impact studies related to treating pregnant and post-partum women with OUD. The proposed budget for all studies under this initiative may be up to $4 million in direct costs as appropriate, depending on the specific priority research questions the study proposes to address. The anticipated project period is three to four years; in no case should the project period exceed four years. For this solicitation, applicants should document that they have consulted with representatives from key stakeholder groups to identify the important decisional dilemmas and evidence needs that will drive development of the research questions or refer to previously documented decisional dilemmas. Because Medicaid covers close to 50 percent of U.S. births, partnerships and input from state Medicaid agencies, Medicaid Medical Directors, or other representatives is important. Successful applicants will collaborate with PCORI staff upon award of the proposed studies to establish a project Study Advisory Committee (SAC) or other appropriate engagement body that comprises national or regional organizations that represent—at a minimum—patients or families with lived experience; relevant clinicians; payers; and health plans. In collaboration with the applicant, PCORI might recommend other representation, including individual patients with lived experience and other relevant stakeholders, among them scientific and methodological experts. The SAC advises and assists the research team with further refining the study questions, outcomes, and protocol.

Given the significant treatment costs associated with some interventions, the applications must specifically address—in the context of the proposed studies—the support from payers, health plans, industry sponsors, or others in covering the study interventions and non-study, protocol-related clinical costs and services rendered in the care processes. This is important because the interventions should be immediately implementable on a large scale if the study results provide significant evidence. Of particular concern would be different levels of co-payment between two arms in a comparative study. Ideally, cost-sharing barriers will be eliminated in the study arms or equalized. If the study design does not allow for either option, the applicant should describe why and should also account for differences in co-payment costs in the analysis of the study’s findings.

PCORI expects that project budgets and duration will vary substantially, depending on the approach selected, needs for recruitment or primary data collection, length of follow-up, and analytic complexity. PCORI seeks efficient studies—such as those that take advantage of large populations already under observation, registries, and the supportive involvement of delivery systems or health plans—to enhance recruitment, data collection, and coverage of treatment-related costs. A prolonged recruitment period is not an acceptable rationale for longer studies.

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II. Guidance for Preparing Applications

Specific Requirements

The proposed study should strive to meet the following requirements:

• Focus on the priority research questions, with consideration of what is important to patients and other decision makers.
• Demonstrate consultation with patients and other stakeholders or their representative groups, or reference previously documented decisional dilemmas to determine if the study is answering a critical question—one that, if adequately answered, would substantially improve decision making.
• Receive endorsement by relevant patient organizations, clinician organizations, payer or purchaser consortia, and Life Sciences industry representatives as enough to potentially answer a critical question—one that, if adequately answered, would substantially improve decision making.
• Propose a sample size that is sufficiently large to allow for precise estimation of hypothesized effect sizes. The sample size must also support testing of a priori hypotheses related to potential differences in effectiveness, depending on sociodemographic and clinical characteristics (HTE). When determining anticipated effect sizes, pay attention to basing such estimates on efficacy results observed in prior and adequately conducted clinical studies.
• Examine diverse populations receiving care in real-world settings.
• Have strong interest and support from host delivery systems and clinical care settings.
• Specify broad and simple eligibility criteria that will allow for wide generalization of results while attending appropriately to any ethical concerns of excess risk in some patient subgroups.
• As applicable, compare interventions that can be implemented in real-world settings and are known to be efficacious, effective, or in common use.
• Include patient-reported outcomes (PROs) as primary outcomes, when appropriate.
• Provide preliminary evidence of the potential for efficient recruitment, high participation rates, and appropriate oversight by local or centralized Institutional Review Boards (IRBs), including plans for streamlining or waiving individual informed consent in cases of low-risk interventions (if applicable). PCORI believes that the intensity of oversight and the complexity of informed consent procedures should be closely related to the degree of risk from study participation. Applicants must address this issue and should present evidence that the study will not encounter significant recruitment or participation barriers.
• Adhere to all applicable PCORI Methodology Standards. The full application will require the applicant to identify the standards appropriate to the proposed study and to describe how the study team plans to address each standard.
• In the case of RCTs, also adhere to current best practices (standardized inclusion or exclusion criteria; proper randomization; techniques to minimize the potential for missing data; and appropriate safety monitoring, including establishing a Data and Safety Monitoring Board [DSMB] or indicating why such a board is unnecessary).

To carry out studies that allow for adoption of the findings in a real-world setting, and to maximize the efficient use of resources, take care to prevent these trials from becoming more complex and onerous than necessary. We encourage the applicant to be creative and consider the following innovative strategies, as appropriate and feasible:

• Identify and engage with major patient and stakeholder organizations that would implement study findings, as well as with existing local communities of patients and care providers to refine the research questions and study protocol, help monitor progress, and disseminate the findings.
• Consult with patients and other stakeholders on their decisional dilemma and evidence needs, or reference previously documented decisional dilemmas in preparation for submitting the Letter of Intent (LOI) and the full applications.
• Carefully describe pertinent evidence gaps and why the project questions represent decisional dilemmas for stakeholders (i.e., patients, clinicians, and policy makers). Similarly, applicants should document why project outcomes are especially relevant and meaningful endpoints for patients and their families. 
• Justify why the interventions you are comparing are viable treatment alternatives worthy of a significant PCORI investment to elucidate the best treatment delivery options for subgroups of pregnant patients with opioid use disorder.
• Minimize disruption to participants’ daily routines (e.g., minimize participant visits intended for study-assessment purposes and capture PROs during office visits, electronically, or via phone).
• Design the study so that you can conduct it using routine clinic or office operations.
• Use efficient methods to obtain participant consent while still meeting ethical and legal requirements.
• Capitalize on the existing electronic health records (EHRs) and other computerized information to identify and recruit eligible patients, monitor study conduct and patient safety, and collect study outcomes information.
• If data standardization and interoperability across study sites have not already been accomplished, develop methods that will enhance the standardization of data that are accessed from different EHR systems.

Nonresponsiveness

Applications will be considered nonresponsive to this PFA if the proposed research:

• Tests efficacy (or comparative efficacy) within a tight, protocol-controlled research setting (as opposed to a more real-world and pragmatic CER).
• Conducts a cost-effectiveness analysis in the form of dollar-cost per quality-adjusted life-year to compare two or more alternatives.
• Directly compares the costs of care between two or more alternative approaches.
• Measures the relative costs of care of two or more alternative approaches as the primary criteria for choosing the preferred alternative.
• Conducts studies of the natural history of disease, instrument development, pharmacodynamics, and fundamental science of biological mechanisms.
• Evaluates new or existing decision-support tools. This includes developing and evaluating a decision-support or shared-decision tool or system for patients, clinicians, or both.
• Develops clinical prediction or prognostication tools.

Applications that include studies of these issues may measure and report use of any or all health services, but may not employ cost-effectiveness analyses.

PCORI does have an interest, however, in studying conditions that lead to high costs to the individual or to society. Thus, PCORI is also interested in studies that:

• Address cost-related issues, such as the resources needed to replicate or disseminate a successful intervention.
• Address issues related to the cost burden on the patient (e.g., deductibles and co-payment).
• Evaluate interventions to reduce health-system waste or increase health-system efficiency.

PCORI considers applications that include studies of these issues without using cost-effectiveness analyses or comparing the costs of alternatives to be responsive.

PCORI discourages applications in the following categories and is likely to deem them nonresponsive:

• Study of the natural history of disease
• Instrument development
• Pharmacodynamics
• Fundamental science or study of biological mechanisms
• Establishing efficacy for a new clinical strategy
• Pilot studies intended to inform larger efforts
• Comparisons of patient characteristics rather than clinical strategy options

Features of Patient-Centered Outcomes Research (PCOR)

PCOR helps people and their caregivers communicate and make informed healthcare decisions, allowing their voices to be heard in assessing the value of healthcare options. This research:

• Assesses the benefits and harms of preventive, diagnostic, therapeutic, and palliative care to inform decision making, highlighting the choices that matter to people
• Is inclusive of an individual’s preferences, autonomy, and needs, focusing on outcomes that people notice and care about (including survival, functioning, symptoms, and health-related quality of life)
• Incorporates a wide variety of settings and diversity of participants to address individual differences and barriers to implementation and dissemination
• Directly compares clinical interventions that are available in the clinical settings
• Obtains stakeholder perspectives to address the burdens to individuals, availability of services, and requirements for technology and personnel

Leveraging Existing Resources

PCORI encourages investigators to propose studies that leverage existing resources, such as adding PCOR to an existing large clinical trial or analyzing existing large databases that contain valuable and relevant information that can be used to answer important CER questions. PCORI is interested in studies that leverage existing research networks or consortia that would facilitate the conduct of large, multi-site studies called for in this PFA.

Applicants proposing use of an existing research network infrastructure (e.g., the National Patient-Centered Clinical Research Network [PCORnet]); research consortia; or related data resources (e.g., electronic medical records data from healthcare delivery systems or administrative claims data from public or commercial insurers) should address the following in the Research Plan (as appropriate), with sufficient specificity:

• Identify and justify all participating research network entities (e.g., health plans, consortia projects and members, etc.) or, in the case of PCORnet, identify the names of the participating Clinical Data Research Networks (CDRNs), Patient-Powered Research Networks (PPRNs), and PCORnet Collaborative Research Groups that will be collaborating on the project. Also identify the affiliated study performance sites.
• Demonstrate that the data source can comprehensively capture the study variables needed to assess the interventions, covariates, and outcomes.
• Describe how you will manage data across study sites within the research network or the proposed research consortia, and whether you will use any dedicated data-coordinating functions or facilities.
• As applicable, demonstrate familiarity with the existing network governance policies or data-use restrictions. Provide a study management structure that identifies roles, responsibilities, and decision-making authority across the proposed research consortia.
• As applicable, provide a timeline for establishing data-use agreements.
• As applicable, describe the network infrastructure resource(s) used to conduct the study (i.e., core research-support facilities, streamlined IRBs, contracting, engagement and consenting processes, standardized data resources training, etc.). Indicate the percentage of sites that have previously used centralized versus localized IRBs.
• As applicable, provide documentation supporting the involvement of network leadership throughout the study (e.g., detailed Letters of Support, budgets, and Budget Justifications that cover the costs of the network’s efforts). You can obtain Letters of Support from PCORnet from the Coordinating Center by submitting a request via the PCORnet Front Door.

Preliminary Data and Use of Accepted Measures

PCORI encourages investigators to design their research using valid patient-centered outcomes measures. Include preliminary data that supports the proposed measures in the study population. We also encourage investigators to consider those measures described in the Patient-Reported Outcomes Measurement Information System (PROMIS).

Methodological Considerations

Regardless of study design, applications must adhere to all relevant PCORI Methodology Standards. These include 48 individual standards that fall into 12 categories. The first five categories are cross-cutting and are relevant to most PCOR studies. Researchers should refer to all of these standards when planning and conducting their research projects. These five categories are:

1. Standards for Formulating Research Questions
2. Standards Associated with Patient-Centeredness
3. Standards on Data Integrity and Rigorous Analyses
4. Standards for Preventing and Handling Missing Data
5. Standards for Heterogeneity of Treatment Effect (HTE)

In addition to these five sets of standards, the first standard listed under “Standards for Causal Inference Methods”—(CI-1)—is cross-cutting and applicable to all PCOR studies.

The seven other standards categories will be applicable to particular study designs and methods. Applicants should use the standards in each of these categories for guidance when they are relevant to a particular study. These categories are:

1. Standards for Data Registries
2. Standards for Data Networks as Research-Facilitating Infrastructures
3. Standards for Causal Inference Methods
4. Standards for Adaptive and Bayesian Trial Designs
5. Standards for Studies of Medical Tests 
6. Standards for Systematic Reviews
7. Standards for Research Designs Using Clusters

Most of these standards are minimal. The PCORI Methodology Standards reflect practices that applicants should follow in all cases, and all deviations need to be explained and justified. Applicants should address additional best practices—including relevant guidelines for conducting clinical trials developed by other organizations—in the application for PCORI funding. To help reviewers quickly identify adherence to a particular standard, applicants must cite each relevant PCORI Methodology Standard within the Methodology Standards Checklist, following the instruction in the checklist itself and in the Application Guidelines. Program staff use the checklist to evaluate applications.

Applicants should specifically discuss their capacity to measure such factors as differential adherence to chosen treatments (or participation in intervention programs) that could create or explain apparent differences in the effectiveness of the alternative interventions being compared in clinical populations.

Patient and Stakeholder Engagement

PCORI encourages all applicants to outline how patients and other stakeholders will participate as partners in various phases of the proposed research. Before completing this section of the Research Strategy, we encourage applicants to review the Engagement Rubric, which can be found in the PCORI Funding Center. Applicants should also review the PCORI Methodology Standards Associated with Patient-Centeredness and PCORI’s Sample Engagement Plans. The rubric and Sample Engagement Plans are not intended to be comprehensive or prescriptive; instead, they provide a variety of examples to incorporate engagement, where relevant, into the research process.

PCORI expects applicants to consult with patients and other stakeholders on their decisional dilemma and evidence needs, or to reference previously documented decisional dilemmas in preparation for submission. To describe the decisional dilemma, state the specific clinical decision(s) or treatment choice(s) the decision makers confront and explain how the findings from the proposed research will inform those decisions. State why this decision—such as choosing a specific medication, surgical approach, or care delivery strategy to treat a condition or manage a specific population—is important to patients. Document the uncertainty patients and other stakeholders face when making this decision. Identify the patients and other stakeholders you consulted when determining that the proposed study addresses their evidentiary needs for decision making, and indicate your commitment to continue engaging them actively in the study. Similarly, applicants should document how the project outcomes are especially relevant and meaningful endpoints for patients and other stakeholders.

For this PFA, applicants need not demonstrate that patients and other stakeholders are already engaged as research team members at the time of application. However, the Engagement Plan should outline how patients and other stakeholders will participate as partners in various phases of the proposed research, once awarded. Applicants should describe their plan to form a SAC, or other appropriate engagement body, to ensure that a broad spectrum of patients and other stakeholders advise and assist the research team with refining the study questions, outcomes, and protocols. These patients and other stakeholders must include national or regional organizations that represent—at a minimum—patients, caregivers, clinicians, policy makers, and other healthcare system stakeholders. PCORI might recommend additional representation in collaboration with the applicant, including individual patients with lived experience and other relevant stakeholders, such as scientific and methodological experts. The SAC or other appropriate engagement body should meet in person at least two times per year, and the budget should account for these engagement costs.

PCORI understands that engagement structures and approaches vary widely. Other engagement approaches, such as forming stakeholder groups, panels, task forces, working groups, and other bodies or involving individual patient and other stakeholder partners in various ways, are also permissible to employ—either in addition to or instead of—the formation of the SAC. For clarification in your application materials and for merit review purposes, please indicate which body or structure is filling the SAC requirements, including the requirements for in-person meetings at least two times per year and appropriate budgeting.

Populations Studied

PCORI seeks to fund research that includes diverse populations with respect to age, gender, race, ethnicity, geography, or clinical status, so that possible differences in CER can be examined (otherwise known as HTE). PCORI recognizes that some proposed studies might represent important PCOR opportunities, even in the absence of a broadly diverse study population. However, the burden is on the applicant in such cases to justify the study’s importance in the absence of diversity and to discuss which subgroups are most important and how they will analyze them, including whether there will be power to examine the question of effectiveness in subgroups. PCORI is interested in including previously understudied populations for whom effectiveness information is needed, such as hard-to-reach populations or patients with multiple conditions. Thus, comparisons should examine the impact of the strategies in various subpopulations, with attention to the possibility that the effects might differ across subpopulations. PCORI has developed the following list of priority populations to guide our research and engagement efforts:

• Racial and ethnic minority groups
• Low-income groups
• Women
• Children (age 0–17 years)
• Older adults (age 65 years and older)
• Residents of rural areas
• Individuals with special healthcare needs, including individuals with disabilities
• Individuals with multiple chronic diseases
• Individuals with rare diseases
• Individuals whose genetic makeup affects their medical outcomes 
• Patients with low health literacy or numeracy and/or limited English proficiency
• Lesbian, gay, bisexual, and transgender persons (LGBT)
• Veterans and members of the Armed Forces and their families

Project Budget and Duration

PCORI has devoted up to $16 million in total costs to this PFA. Applicants may request up to $4 million in direct costs for a research project period not to exceed four years (not including peer review). The maximum budget includes all research and peer-review-related costs. (Please refer to the Application Guidelines for further details.) At the time of contract execution, PCORI sets aside all of the funds associated with an awarded project to be made available throughout the contract’s period of performance. Obligated funding is available for the duration of the project period. Note that PCORI will not cover costs for interventions that are being compared in the proposed study. (See Appendix 2: Allowable and Unallowable Costs in the Application Guidelines for details.)

Applicants should propose realistic budgets, project durations, and associated timelines. For those rare circumstances in which the estimated direct cost exceeds the maximum direct costs outlined in this PFA, please provide a detailed justification in your LOI that ties the extra expense to the project’s success. PCORI will not approve all requests for additional funds. We will deny any request for a project period longer than five years. For further information regarding PCORI’s policies about allowable and unallowable costs, refer to Appendix 2 in the Application Guidelines. Note that although subcontractor indirect costs are included in the prime applicant’s direct-cost budget, these costs are not considered when determining adherence to the PFA’s direct-cost limit.

A contract is the funding mechanism for this program. Total project funding is contingent upon successful programmatic and budget performance (e.g., meeting recruitment targets). Milestones and targets—as well as possible pilot phases for the sole purpose of assessing recruitment feasibility—should be included in the budget and will be negotiated at the time of the award. PCORI will expect awardees to provide corroborating evidence to receive continual funding support. Some of the activities that will be considered during negotiations include:

• Developing a study protocol and procedure manual for the intervention
• Assigning roles and responsibilities to study team members for project implementation
• Forming a SAC or other appropriate engagement body
• Obtaining clearances from all institutional and community partners, including IRB approvals
• Establishing a DSMB or providing a clear description of why one is unnecessary
• Executing all subcontractor agreements
• Agreeing on eligible patient populations for study recruitment
• Identifying barriers to patient recruitment in the study and addressing these barriers effectively
• Demonstrating successful recruitment during a pilot phase (if indicated)

Refer to the Application Guidelines for a list of additional PFA-specific project milestones.

Collaboration

PCORI is particularly interested in applications involving community and commercial organizations that can help researchers design, implement, disseminate, and sustain effective interventions. We encourage applications that include novel collaborations with accreditation organizations, credentialing bodies, educational enterprises, patient advocacy groups, industry, professional societies, and subspecialty societies.

Protection of Human Subjects

This component (up to five pages) is included in the Research Plan Template. Describe the protection of human subjects involved in your proposed research. PCORI follows the Federal Policy for the Protection of Human Subjects (45 CFR part 46), including the Common Rule. For more detailed information, please see Section 5, titled “Human Subjects Research Policy” in the Supplemental Grant Application Instructions for All Competing Applications and Progress Reports, which is issued by the U.S. Department of Health and Human Services. PCORI does not require that applicants comply with sections of this policy referring to requirements for federal-wide assurance or to standards for including women, minorities, and children. Awardees must also comply with appropriate state, local, and institutional regulations and guidelines pertaining to the use of human subjects in research.

PCORI requires awardees to ensure that there is a Data and Safety Monitoring Plan, which might include the need to appoint a DSMB, as provided in the PCORI Policy on Data and Safety Monitoring Plans for PCORI-Funded Research.

PCORI merit reviewers will examine plans for protection of human subjects in all applications and may provide comments regarding the plans (see How To Evaluate Human Subjects Protections). Reviewers’ comments on human subject research are not reflected in the overall application score, but PCORI staff might use them during potential funding negotiations. Final determinations about the adequacy of human subject protections rest with the IRB or international equivalent that has jurisdiction for the study.

The Awardee Institution, whether domestic or foreign, bears ultimate responsibility for safeguarding the rights and welfare of human subjects in PCORI-supported activities.

Required Education of Key Personnel on the Protection of Human Subject Participants

PCORI requires all applicants to adhere to the National Institutes of Health (NIH) policy on education in the protection of human subject participants in the conduct of research. This applies to all individuals listed as key personnel in the application. The policy and FAQs are available on the NIH website.

Data Management and Data-Sharing Plan

PCORI encourages openness in research and making research data available for purposes of replication and reproducibility. Although not required to be submitted as a component of the research application, if an award is made, the awardee must develop and maintain a plan addressing data management and data sharing of research project data in a manner that is appropriate for the nature of the research project and the types of research project data. This must be done in a manner that is appropriate for the research project, and in a manner consistent with applicable privacy, confidentiality, and other legal requirements.

Peer Review and Release of Research Findings

PCORI has a legislative mandate to ensure the scientific integrity of the primary research it supports and to make study findings widely available and useful to patients, clinicians, and the general public within a specific timeframe. Accordingly, the PCORI Board of Governors (Board) adopted the Process for Peer Review of Primary Research and Public Release of Research Findings.

In summary, Awardee Institutions are required to submit to PCORI for peer review a draft final research report that provides the methodological details, describes the main study results, and interprets the findings in clinical or other decisional contexts. Subject matter experts (SMEs); individuals with expertise on research methodology or biostatistics; and patients, caregivers, and other healthcare stakeholders will review the draft final research report. After Awardee Institutions have responded to reviewers’ comments to PCORI’s satisfaction, the report will be accepted and considered final. PCORI will then prepare a 500-word abstract summarizing the study results for patients and the general public, which the Awardee Institution will review and approve.

PCORI will post the following materials on its website no later than 90 days after the draft final research report is accepted: (1) a 500-word abstract for medical professionals; (2) a standardized summary of the study results for patients and the general public; (3) a link to the study record on ClinicalTrials.gov (as applicable); and (4) ancillary information, including conflict-of-interest disclosures. The final research report, along with anonymized reviewer comments, will be made publicly available on the PCORI website no later than 12 months after its acceptance, except by prior mutual agreement with the Awardee Institution.

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III. How To Submit an Application

Letter of Intent (LOI)

Applicants should download the Cycle 2 2017 Medication-Assisted Treatment (MAT) Delivery LOI Template from the PCORI Funding Center. They must complete the document and convert it to a PDF with a three-page limit. PCORI suggests including all references as in-text citations using American Medical Association citation style, but we do accept other citation styles. Do not upload additional documents as part of your LOI, such as Letters of Endorsement or Support, because they are not requested at this stage. Their inclusion will result in LOI rejection without review. Please visit the PCORI Funding Center for additional applicant resources, including the FAQ and required templates.

Please answer all of the questions in the LOI Template. This includes the question on brief justification for the proposed cost of the study. Providing the answer “costs not to exceed $4 million” is not sufficient. Upload your document to PCORI Online. The deadline for LOI submission is July 25, 2017, by 5 p.m. (ET).

LOI Review

PCORI evaluates LOIs based on the following criteria:

• Whether the proposed topic addresses the priority research questions identified in this PFA
• Importance of the specific research questions (comparison), as evidenced by critical gaps identified by clinical guidelines developers or recent relevant systematic reviews
• A size or scope sufficient enough to have a significant impact on patient outcomes or healthcare practice
• Clarity and credibility of applicants’ responses to the LOI questions, as well as their justification of the proposed study size, citing published estimates, including effect sizes, standard deviations, and the need for rigorous comparative analysis of important subgroups
• Prior relevant experience
• Programmatic fit and balance, considering whether the research study question and design comply with requirements in this PFA
• Adherence to the administrative and formatting requirements listed in the Application Guidelines, specifically the three-page limit for the LOI

Only applicants whose LOIs are deemed most responsive to this PFA will be invited to submit a full application. Notification of denial or approval to submit an application will occur no later than August 22, 2017. Please refer to the Application Guidelines for information on how to submit your LOI via PCORI Online.

You are invited to submit an application based on the information provided in the LOI. Any changes to the following require PCORI approval:

• Research questions
• Specific aims
• Study design
• Comparators
• Principal Investigator (PI) (Contact PI and PI #2)
• Institution

You may email requests for changes or questions to [email protected].

Note: A PI can only submit one LOI per PFA. However, an individual listed as a PI on one LOI can be listed as and serve in another non-PI role (e.g., co-investigator or consultant) on other LOIs within the same PFA during the same cycle. A PI may submit multiple LOIs to different program PFAs in a cycle, but the PI must ensure that the research topics and projects are not similar. If a PI submits an LOI to multiple program PFAs, LOIs that exhibit scientific overlap or that appear to be duplicate submissions will be disqualified. PCORI will contact the PI and provide him or her with an opportunity to choose the PFA to which he or she would like to apply. This applies to single- and dual-PI submissions.

Submission Dates

LOIs and applications must be submitted in accordance with the published dates and times listed in the Overview section of this PFA and in the PCORI Funding Opportunities.

PCORI Online System

To submit an application, you must register with PCORI Online and submit both an LOI and an application for each cycle in which you are applying.

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IV. Applicant Resources

• Medication-Assisted Treatment Application FAQs (Cycle 2 2017)
• Medication-Assisted Treatment FAQs (Cycle 2 2017)
• Targeted PFA Application Guidelines (Cycle 2 2017)

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V. Merit Review

PCORI’s merit review process is designed to support the following goals:

• Identify applications that have the strongest potential to help patients, caregivers, clinicians, policy makers, and other healthcare system stakeholders make informed decisions to improve patient outcomes.
• Implement a transparent, fair, objective, and consistent process to identify these applications.
• Elicit high-quality feedback that reflects a diversity of perspectives to ensure that the PCORI-funded research reflects the interests and views of patients and other stakeholders and those who care for them, and that it meets the criteria for scientific rigor.
• Fund projects that fill important evidence gaps and have strong implementation potential.
• Regularly evaluate and continually improve the merit review process and policies in support of PCORI's mission.

PCORI merit review is a multiphase process that includes PFA development; staff evaluation of LOIs; the review panel’s preliminary review of full applications; an in-person panel discussion of a subset of full applications (identified by PCORI’s Research Priority Area Program staff and based on the preliminary review and program priorities); the Selection Committee’s recommendation of applications for funding; and, finally, Board award approval.

Preliminary Review

PCORI conducts rigorous merit review of the full applications it receives. Note that PCORI may eliminate applications from the review process for administrative or scientific reasons (e.g., non-responsiveness). An application may be administratively withdrawn if it is incomplete; submitted past the stated due date and time; or does not meet the formatting criteria outlined in the Application Guidelines, in the PCORI templates, and in PCORI Online. An application can be scientifically withdrawn if it is not responsive to the guidelines described in this PFA, describes research that is not comparative, includes a cost-effectiveness analysis, or otherwise does not meet PCORI programmatic requirements.

PCORI Merit Review Officers (MROs) recruit each panel based on the number of and topic areas represented by invited LOIs. MROs recruit the Panel Chair, scientist reviewers who are SMEs, patient representatives, and representatives of other stakeholder groups. All panel members receive training during the review cycle to ensure that they understand the programmatic and organizational goals of review.

We designed the table below to help applicants understand how the PCORI merit review criteria align with criteria from other funding organizations with which applicants might be familiar (e.g., NIH). Though PCORI’s criteria do map to most NIH criteria, there are areas where we ask for different information (i.e., PCORI does not include a criterion that tracks to NIH’s innovation criterion, but does include criteria evaluating patient-centeredness and engagement), reflecting PCORI’s unique approach.

Application Merit Review

Below are PCORI’s merit review criteria. PCORI’s merit review panels use these criteria during the preliminary and in-person review phases to evaluate and score all submitted applications and to ensure consistency and fairness in application evaluation.

Criterion 1. Potential for the study to fill critical gaps in evidence:

The application should address the following questions:

• Does the application convincingly describe the clinical burden?
• Does the application identify a critical gap in current knowledge as noted in systematic reviews, guideline development efforts, or previous research prioritizations?
• Does the application identify a critical gap in current knowledge, evidenced by inconsistency in clinical practice and decision making?
• Would research findings from the study have the potential to fill these evidence gaps?

Criterion 2. Potential for the study findings to be adopted into clinical practice and improve delivery of care

The application should describe how evidence generated from this study could be adopted into clinical practice and delivery of care by others. The application should also address the following questions:

• Does the application identify who will make the decision (i.e., the decision maker) or use (i.e., the end-user) the study findings (not the intervention) this study produces, such as local and national stakeholders?
• Does the application identify potential end-users of study findings—such as local and national stakeholders—and describe strategies to engage these end-users?
• Does the application provide information that supports a demand for this kind of a study from end-users?
• Would this study’s research findings have the potential to inform decision making for key stakeholders? If so, provide an example. How likely is it that others could reproduce positive findings, resulting in improvements in practice and patient outcomes? Identify the potential barriers that could hinder others from adopting the intervention.
• Does the application describe a plan for how to disseminate study findings beyond publication in peer-review journals and at national conferences?

Criterion 3. Scientific merit (research design, analysis, and outcomes)

The application should show sufficient technical merit in the research design to ensure that the study goals will be met. The application should also address the following questions:

• Does the application describe a clear conceptual framework anchored in background literature which informs the design, key variables, and relationship between interventions and outcomes being tested?
• Does the Research Plan describe rigorous methods that demonstrate adherence to the PCORI Methodology Standards?
• Is the overall study design justified?
• Are the patient population and study setting appropriate for the proposed research question?
• Does the application provide justification that the outcome measures are validated and appropriate for the population?
• Are each of the comparators (e.g., active intervention arm and comparator arm) described clearly justified? If “usual care” is one of the arms, is it adequately justified and will it be sufficiently measured?
• Are the sample sizes and power estimates appropriate? Is the study design (e.g., cluster randomized design, RCT, or observational study) accounted for, and is the anticipated effect size adequately justified?
• Is the study plan feasible? Is the project timeline realistic, including specific scientific and engagement milestones? Is the strategy for recruiting participants feasible? Are assumptions about participant attrition realistic, and are plans to address patient or site attrition adequate?

Criterion 4. Investigator(s) and environment

This criterion should assess the appropriateness (e.g., qualifications and experience) of the investigator(s)/team and the environment’s capacity (e.g., resources, facilities, and equipment) to support the proposed project. It should not be an assessment of the institution’s quality.

The application should also address the following questions:

• How qualified are the PIs, collaborators, and other researchers to conduct the proposed activities? Is there evidence of sufficient clinical or statistical expertise (if applicable)?
• Does the investigator or co-investigator have demonstrated experience conducting projects of a similar size, scope, and complexity?
• If the project is collaborative or dual-PI, do the investigators have complementary and integrated expertise? Are the leadership, governance, and organizational structures appropriate for the project?
  • (Dual-PI Option Only) Does the Leadership Plan adequately describe and justify PI roles and areas of responsibility?
• Is the level of effort for each team member appropriate for successfully conducting the proposed work?
• Does the application describe adequate availability of and access to facilities and resources (including patient populations, samples, and collaborative arrangements) to carry out the proposed research?
• Is the institutional support appropriate for the proposed research?

Criterion 5. Patient-centeredness

The application should demonstrate that the study focuses on improving patient-centered outcomes and employs a patient-centered research design (i.e., a design informed or endorsed by patients). (Note: The study can be patient-centered even if the end-user is not the patient, as long as patients will benefit from the information.)

The application should also address the following questions:

• Does the application include a thorough description about which outcomes (both benefits and harms) are important to patients, and are those outcomes included in the study plan?
• Does the application provide information that indicates that closing the evidence gap is important to patients and other stakeholders?
• Are the interventions being compared in the study available to patients now, and are they the best options for comparison (including whether patients and their healthcare providers would choose them for managing the condition being studied)?

Criterion 6. Patient and stakeholder engagement

The application should demonstrate the engagement of relevant patients and other stakeholders (e.g., patients, caregivers, clinicians, policy makers, hospitals and health systems, payers [insurance], purchasers [business], industry, researchers, and training institutions) in the conduct of the study. Quality of engagement should be evaluated based on scope, form, and frequency of patient and stakeholder involvement throughout the research process.

The application should also address the following questions:

• Does the application provide a well-justified description of how the research team incorporates stakeholder involvement? Does the study include the right individuals (e.g., researchers, patients, caregivers, clinicians, policy makers, and other healthcare system stakeholders) to ensure that the projects will be carried out successfully?
• Does the application show evidence of active engagement among scientists, patients, and other stakeholders throughout the research process (e.g., formulating questions, identifying outcomes, monitoring the study, disseminating, and implementing)? Are the frequency and level of patient and stakeholder involvement sufficient to support the study goals?
• Is the proposed Engagement Plan appropriate and tailored to the study?
• Are the roles and the decision-making authority of all study partners described clearly?
• Are the organizational structure and resources appropriate to engage patients and stakeholders throughout the project?

In-Person Review

During preliminary review, all administratively and scientifically compliant applications are evaluated and scored based on PCORI’s merit review criteria, including evaluating adherence to the PCORI Methodology Standards. After PCORI completes the preliminary review, PCORI program staff members evaluate panel scores and critiques to identify a subset of applications for merit reviewers to discuss at the in-person review meeting. Not all submitted applications move forward to in-person review.

During the in-person review, merit reviewers meet to discuss applications and to clarify the merits of the proposed research. They also identify areas for improvement. Each application is re-scored based on the content of discussion. The Panel Chair and PCORI MRO lead the in-person panel meeting and ensure that all applications receive a fair and thorough review according to the standards outlined in the PFA.

Post-Panel Review

After the in-person meeting, PCORI program staff evaluate final merit review panel scores and comments, identify duplication or synergy among funded projects, and consider the fit of applications within the programmatic vision. Program staff members then recommend projects to a Selection Committee, which includes members of the Board. The Selection Committee considers recommendations and works with staff to identify a slate of applications for possible funding based on merit review scores, programmatic balance and fit, and PCORI’s strategic priorities. This slate then goes to the Board for consideration and approval.

In addition, PCORI evaluates applicant risk before issuing an award. Factors considered include financial stability, quality of management systems, audit findings, and past performance on PCORI awards (e.g., compliance with PCORI reporting requirements, conformance to PCORI terms and conditions on previous awards, and timely achievement of milestones). Based on the risk assessment, PCORI may impose special terms and conditions on awardees or withhold contract issuance until such business risks are mitigated. PCORI will not award new contracts to current awardees with overdue reports (progress, interim, final, etc.) until the awardees have submitted the overdue reports.

Summary Statements and Funding Recommendations

Applicants receive summary statements approximately two weeks before funding decisions are announced. If an application progresses to in-person discussion, the applicant will receive a summary statement that includes:

• In-person panel discussion notes
• Final average overall score
• Preliminary reviewer critiques
• Application quartile, which provides information for applicants to understand how they did relative to other discussed applications

Summary statements for applications that do not progress to in-person discussion include only the preliminary reviewer critiques.

PCORI makes funding recommendations by identifying meritorious applications that fit the programmatic needs and satisfactorily address the merit review criteria while adhering to the PCORI Methodology Standards. PCORI also considers the funds allotted for the current PFA when deciding which applications to recommend to the Board for approval. Applicants to this current cycle’s PFA will receive summary statements and notification of the funding status of their application no later than May 2018.