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STATEMENT OF WORK

I. SPECIFIC AIMS

The “Recovery After an Initial Schizophrenic Episode” (RAISE) initiative seeks to fundamentally change the trajectory and prognosis of schizophrenia through coordinated and aggressive treatment in the earliest stages of illness. The specific aims of this initiative are:

1. To develop and refine a comprehensive and integrated treatment intervention that can be delivered in real world practice settings to promote symptomatic recovery, minimize disability, and maximize social, academic, and vocational functioning;

2. To test its feasibility, efficacy, and practical implementation in the community; and

3. To assess its overall clinical impact and cost-effectiveness as compared to currently prevailing treatment approaches.

II. BACKGROUND

The President's New Freedom Commission on Mental Health calls for transformation of the mental health system in the United States, envisioning “a future when everyone with a mental illness will recover.” Perhaps the greatest challenge to this new vision is schizophrenia, a devastating mental illness that impairs an individual’s ability to think, feel, and relate in a normal manner. Schizophrenia typically begins in late adolescence or early adulthood, thus derailing the interpersonal, academic, and vocational achievements that prepare a young person for adult roles and responsibilities. Recurrent episodes of psychosis are common, with multiple hospitalizations and gradual worsening of functioning. People with schizophrenia frequently drop out of school, lose the ability to work competitively, and become increasingly isolated from friends and family. Substance abuse often becomes a problem, further compromising function. Many patients end up in jail, homeless, or die by suicide. Once schizophrenia becomes established as a chronic illness, poor outcome is generally the norm.

Effective antipsychotic drugs have been widely available for half a century, and psychosocial interventions have been developed over the last thirty years that improve schizophrenia patients’ social and vocational functioning. Despite these advances, the overall prognosis for a person with schizophrenia remains grim, partly because available treatments are rarely applied early on, when clinical symptoms and functional impairments may be most responsive to vigorous intervention. For example, recent research suggests that many people with schizophrenia can achieve full symptomatic remission after the first psychotic break, often with lower doses of medication than those typically prescribed to persons with established illness. A number of psychosocial interventions are effective for boosting medication adherence, decreasing the number of subsequent psychotic episodes, and improving psychological and social adjustment among persons in early stage schizophrenia. Similarly, efficacy trials identify a number of promising approaches for achieving better outcomes in the early stages of illness. Yet, in the United States, current practice rarely involves proactive and coordinated intervention early in course of schizophrenia, and instead focuses treatment resources principally on the later chronic stages, when symptomatic and functional impairments are firmly entrenched.

The premise of RAISE is that this may be an ineffective and needlessly costly way to manage an illness that begins in early adulthood and persists for many decades. Recent research into the prodromal phase of schizophrenia suggests that cognitive impairments, interpersonal difficulties, and problems in role performance frequently precede positive symptoms, and that intervention during this period may delay or prevent the onset of psychosis. However, existing assessment instruments lack sufficient predictive power to identify which persons are at “true” risk for schizophrenia before psychotic symptoms appear, which has hampered testing of preventive interventions during the prodromal period. In contrast, the first episode of psychosis represents a readily identifiable event in the course of schizophrenia, and a unique opportunity for intervention. Given current knowledge of the earliest phases of schizophrenia, the best chance for altering the discouraging prognosis commonly associated with the illness is to intervene aggressively at the first episode of psychosis, before functional abilities are lost. The RAISE initiative will test this hypothesis by supporting the development, refinement, deployment, and testing of an early intervention model for schizophrenia that is relevant to the U.S. mental health system, in the sense that – if found to be effective in real world settings and relatively cost-effective – it could be deployed feasibly at a population level.

RAISE is innovative in two respects. First, RAISE will shift the focus of schizophrenia treatment away from managing end stage disease to early and aggressive treatment. The goal here is indicated prevention that pre-empts symptomatic and functional deterioration in the early years of illness. We hypothesize that effective early intervention may shift the long-term trajectory of illness away from chronic disability towards more normal functioning. Second, RAISE represents a coordinated effort to design and test an effective intervention for early phase schizophrenia that can be implemented on a wide, i.e., population-level, scale. From the earliest stages of development, this intervention will incorporate necessary features for rapid dissemination, adoption, and implementation in our communities, thus facilitating the transition from research to practice. The ultimate goal is to transform the current paradigm for treating schizophrenia in the United States by engineering rapid adoption and implementation of an effective treatment package on a broad scale. RAISE is a necessary first step in this process and will help to determine whether early identification and intervention programs situated in community-based settings can slow or halt clinical and functional deterioration in schizophrenia.

III. Objectives

To accomplish the goals outlined above, NIMH advocates a clinic-based, deployment-focused treatment development process. As its name implies, the clinic-based, deployment-focused model anticipates the clinical, economic, and logistical characteristics of the settings where an intervention will be delivered during development and pilot-testing, as well as the settings where it will ultimately be implemented in the "real" world. The model encourages collaboration among scientific content experts, services researchers, and “end users” to anticipate clinical and practical circumstances that can impede adoption and implementation of an effective intervention in community settings. These features include characteristics of typical patients, clinicians already available in target settings, training and supervision requirements necessary to introduce new approaches, space, time, and material resource constraints, and likely payment mechanisms for the new intervention. By attending to these issues early on it is more likely that health care providers, administrators, payers, and policy makers will be able and willing to adopt and implement any intervention(s) developed and tested in RAISE.

To maximize the chances for developing and testing a clinically relevant and transportable intervention for first episode schizophrenia, and to help ensure its eventual implementation, NIMH requires offerors to demonstrate working relationships with relevant stakeholder groups at the time the proposal is submitted. Examples of relevant stakeholders include members of consumer and advocacy organizations, representatives of real world delivery systems that regularly encounter individuals in the earliest phase of schizophrenia, and purchasers of health care and disability benefits at state and local levels. NIMH does not require applicants to possess established relationships with relevant Federal-level partners at the time the proposal is submitted. Examples of relevant Federal-level partners include the Substance Abuse and Mental Health Services Administration (SAMHSA), the Centers for Medicare and Medicaid Services (CMS), the Social Security Administration (SSA), the Health Resources and Services Administration (HRSA), and the Department of Justice (DoJ). Once an award is made, the offeror should expect to work closely with NIMH to establish active partnerships with one or more policy-making Federal stakeholders whose missions intersect with the care of persons with schizophrenia.

IV. APPROACH

From a scientific perspective, the RAISE initiative seeks to explore whether the early course of schizophrenia can be altered, from the first psychotic episode forward. However, when a patient first presents with psychotic symptoms, it is often unclear which DSM-IV diagnosis is most appropriate. Depending on the characteristics and duration of symptoms at the time of presentation, a variety of diagnoses are possible, including brief reactive psychosis, schizophreniform disorder, schizophrenia, schizoaffective disorder, and either bipolar disorder or major depression with psychotic features. Diagnostic uncertainty for newly ill individuals is encountered frequently in real world treatment settings, and it is unrealistic to expect that clinicians will withhold treatment until a definitive diagnosis is established. Consequently, NIMH requires that the scope of RAISE include all persons experiencing a first episode of psychosis that could plausibly lead to a diagnosis of schizophrenia. From this point forward the terms “first episode schizophrenia” and “first episode psychosis” are used interchangeably in the Statement of Work.

PROCESS

NIMH expects that the Initial Offer will present a well-developed conceptual model of the early post-psychosis stage of schizophrenia and describe a coordinated treatment approach that addresses the unique characteristics and needs of newly ill individuals. Once an award is made, NIMH envisions three subsequent phases to the project: (1) a period for refining the intervention based on input from stakeholders and investigators not involved in the contractor’s initial offer and iterative feedback from a small number of clinicians and patients, (2) a feasibility study to demonstrate that the intervention can be fielded in real world community treatment settings and can be evaluated in a randomized design, and (3) the implementation of a practical clinical trial built around the typical patients, clinicians, and payment mechanisms encountered in routine clinical practice. The offeror’s proposal must be structured according to the conceptual model, the coordinated treatment approach, and the three phases of intervention refinement and testing. The Initial Offer should address each of the goals, deliverables, and critical issues outlined in this section, section V, “SERVICES TO BE PERFORMED AND DELIVERABLES,” and section VII, “CRITICAL ISSUES.”

Once an award is made, NIMH envisions a 5-8-year timeframe to progress from the intervention refinement phase to completion of the practical clinical trial. The offeror’s proposal should describe the methods to be employed to achieve the goals of each phase and should estimate the time required to complete tasks within each phase. Proposals will be judged on the methods proposed for developing, refining, fielding, and evaluating the integrated treatment intervention, as well as efficiency in moving across the three post-award phases of the project.

Initial Offer: Conceptualizing the intervention. The four major goals for this phase are to: (1) summarize what is known about the natural history of the early post-psychosis phase of schizophrenia; (2) identify early events or processes that existing research associates with accumulating clinical and functional deterioration during this period; (3) review existing pharmacologic, psychotherapeutic, rehabilitative, and supportive treatments that have been applied to reduce morbidity in first episode schizophrenia and to maintain social, academic and vocational functioning; and (4) integrate all relevant information into a proactive, coordinated early intervention strategy that presents a coherent model of effective and efficient treatment delivery.

Examples of important questions that might be addressed in the conceptual model proposed in the Initial Offer include (but are not limited to):

1. What is the age distribution for first psychotic episodes?

2. What is the distribution of the duration of untreated psychosis, i.e., the period between onset of psychotic symptoms and the first presentation for treatment?

3. What is the distribution of symptom severity for first psychotic episodes?

4. Where do persons in the first psychotic episode typically present for treatment? What are the main financing mechanisms for first-episode care?

5. What are the major predictors of symptomatic and functional decline during the early phase of schizophrenia? Are these predictors fixed or malleable? Which short-term outcomes are most salient? How do we measure them?

6. Which pharmacologic, psychotherapeutic, and rehabilitation approaches have been tested with first episode patients? Have any tested treatments specifically targeted functional decline?

7. Which psychotherapeutic and/or rehabilitation approaches designed to improve functional outcome in persons with established schizophrenia are plausible for first episode patients?

8. Have other kinds of supportive services (e.g., housing, income support, transportation) been tested as methods for maintaining functioning?

9. What providers are typically employed to deliver each component of combined interventions? What knowledge and skills are required to deliver each component? What are the key outcomes that each supportive service would produce?

10. What difficulties have been encountered in developing, disseminating, and adopting multi-element treatment programs for first episode schizophrenia?

11. What algorithms are necessary at the patient level to determine appropriate intervention components for personalized care?

12. What is currently known about the optimal intensity and length of treatment for the initial phase of schizophrenia? What evidence exists on whether treatments can be tapered over time without risking symptomatic relapse?

All of these questions, although relevant, are perhaps not answerable at the present time. Nonetheless, hypotheses around these questions may figure into the design of a proactive, coordinated approach to first episode treatment. Taken together, already available information combined with hypotheses about the course and treatment responsiveness of the early post-psychosis phase of schizophrenia will help to define target populations for early and aggressive treatment, locations for fielding the intervention, and treatment modalities relevant to first episode schizophrenia.

At the time the proposal is submitted, the offeror will propose at least one intervention model that could plausibly meet the objectives of RAISE. The offeror will describe the rationale for the approach, the events or processes to be targeted for intervention, the content of the multi-element intervention, the target population and practice setting, the personnel and material resources necessary to implement the intervention in the practice setting (including training and supervision requirements), and financial mechanisms for supporting the intervention in the real world. NIMH expects that the proposed intervention will not merely consist of a collection of treatments and services; rather it will provide a model for effectively and efficiently delivering an integrated treatment package taking into account well known challenges in treating schizophrenia, such as individual patient variability in treatment needs, fluctuating levels of motivation, poor adherence, fragmentation of care, limited resources, etc. Finally, the offeror will identify primary treatment outcomes and discuss suitable methods for measuring clinical and functional outcomes.

The offeror will propose protocols for (1) refining the intervention through external feedback and practical experience, (2) testing the feasibility of delivering the intervention in real world settings, and (3) evaluating the impact of the intervention in a randomized practical trial. The offeror must identify an operations team capable of providing scientific protocol management as well as coordination and oversight of data acquisition at clinical sites. The operations team should possess adequate biostatistical expertise for analyzing data from complex effectiveness trials involving persons with serious mentally illness. The offer should clearly reflect the statistical difficulties that may be faced given potential design and randomization complexities. Comprehensive operational expertise, including proposed timelines, will be a critical selection factor.

First Episode Psychosis (FEP) research centers in the U.S. and abroad have developed effective strategies for identifying, recruiting, and retaining first episode subjects in treatment and longitudinal follow-up studies. A critical selection factor for RAISE is the offeror’s proven ability to recruit FEP persons into research studies and to retain them over time. As part of the response to this RFP, the offeror should document FEP research studies he/she has conducted over the past 2-5 years, the number of subjects recruited into each study, rates of attrition, whether the study remains active, and if so, the number of subjects needed to complete that study. The offeror should describe in detail how principles learned in FEP research clinics about identification, recruitment, and retention of subjects can be transferred and implemented in the community-based first episode treatment programs that will field the Phase 2 feasibility study and the Phase 3 clinical trial.

At the time of the initial offer, the contractor must provide evidence that a service delivery system partner has agreed to participate in the Phase 1 intervention refinement process and/or the Phase 2 feasibility study. The service delivery system partner’s level of commitment and ongoing involvement will be crucial to the success of RAISE and will be a critical selection factor. The service system delivery partner must help design the multi-element intervention, participate in its refinement and initial testing in Phases 1 and 2, and support its implementation in the Phase 3 field trial. It is expected that the service delivery system partner will make significant contributions to facility and personnel costs during the intervention testing phases. The randomized clinical trial in Phase 3 will compare the effectiveness of the proposed intervention to a scientifically and ethically defensible comparison condition; the offeror should specify the unit of randomization (e.g., by patient, clinic, county, etc.) in the proposal. NIMH may subject the proposed intervention and study designs for the feasibility testing and practical clinical trial phases to internal and external review.

Finally, the proposal should identify costs associated with completing Phase 1 of the project, and provide cost estimates for Phases 2 and 3. Other elements to be addressed in the Initial Offer are listed in section V, “SERVICES TO BE PERFORMED AND DELIVERABLES.”

Phase 1: Refining the intervention. The primary goal of this stage is to refine the multi-element intervention through external feedback and practical experience. Intervention refinement can be accomplished through a variety of methods, including consultations with foreign and domestic first episode schizophrenia experts, and focus groups involving mental health consumers, relatives, and clinicians. The aim is to incorporate feedback from key stakeholders outside of the investigative team to achieve broad-based consensus regarding the public health importance of the intervention and the scientific merit of the study design. An additional strategy for optimizing the multi-element intervention is to pilot the approach through an open case series design. In the open case series method, several clinicians try out a draft treatment manual in actual clinical practice and provide iterative feedback on their experiences working with patients. This feedback, combined with consumer satisfaction data from treated individuals, can be used to sharpen treatment procedures. During the intervention refinement phase of RAISE, the offeror may choose to test and modify the intervention package in the more controlled environment of a First Episode Psychosis research clinic. While this is acceptable to NIMH, the offeror must maintain a clinic-based, deployment focused approach while refining the intervention. Specifically, the offeror must illustrate how the practical realities of delivering the intervention in a community setting are accounted for in the iterative refinement process.

The second major objective for Phase 1 is to develop or adapt relevant measures of (1) diagnosis, clinical and functional outcome, and costs of providing care; (2) provider acceptance, competency, and adherence to the intervention protocol; (3) patient and family satisfaction with treatment; and (4) measures of subject attrition and adverse events. Whenever possible, the offeror should capitalize on data already collected during routine clinical care such as DSM-IV diagnosis, completed and missed treatment sessions, symptomatic recovery (defined as sustained remission), relapse episodes, hospitalizations, etc.

The final objective for Phase 1 is to lay the groundwork for the Phase 2 feasibility test. Necessary tasks include (1) identifying at least two non-academic, real world clinic sites to host the feasibility study; (2) documenting an adequate flow of first episode patients at these sites to support the feasibility study; (3) identifying clinical staff at those sites who will deliver the intervention; (4) establishing a training and supervision plan for study clinicians; (5) deciding on the comparison condition and the randomization plan; (6) initiating IRB approval for the feasibility trial; (7) specifying outcome variables, assessment instruments, and data collection/management procedures; and (8) lining up the operations personnel who will oversee day-to-day activities related to the feasibility test (see ORGANIZATION).

Deliverables for Phase 1 are listed in section V, “SERVICES TO BE PERFORMED AND DELIVERABLES.” At the conclusion of Phase 1, NIMH will decide whether to proceed to Phase 2 of the contract.

Phase 2: Conducting a feasibility study. Assuming that the revised intervention and assessment protocol presented at the close of Phase 1 is approved by NIMH, the major goals of Phase 2 are to demonstrate that the randomization plan proposed for the practical clinical trial is reasonable, that the multi-element treatment intervention can be delivered in non-academic, real world treatment settings, that patients and clinicians accept the experimental intervention, and that treatment process and outcome data can be collected for both experimental and control conditions. Tasks to be accomplished in Phase 2 include (1) obtaining IRB approval for the feasibility trial; (2) enrolling at least two non-academic, real world clinics in the feasibility trial; (3) training clinical staff to deliver the experimental intervention; (4) developing and testing recruitment, enrollment, and consent procedures in experimental and comparison sites; (5) establishing treatment quality assurance protocols across sites; (6) hiring operations personnel who will oversee day-to-day activities related to the feasibility study; and (7) testing the feasibility of the intervention on up to 40 patients treated for approximately 12 months across at least two treatment locations.

The second major objective for Phase 2 is to pilot test assessment measures of subject recruitment and enrollment, treatment delivery, clinician and consumer satisfaction, and clinical and functional outcomes (see Phase 1.) An important consideration for moving forward to the Phase 3 practical clinical trial is whether adequate baseline, treatment delivery, outcome, and cost data can be collected for both experimental and comparison conditions.

Based on results from the feasibility testing project, the contractor may propose further adjustments to the intervention package and assessment strategy, particularly if any new medications or evidence-based rehabilitation approaches are introduced into general clinical practice during Phases 1 and 2. Any adjustments should be incorporated into a draft protocol for conducting the practical clinical trial in Phase 3. While the exact size and duration of the Phase 3 trial will need to be determined based on work in Phases 1 and 2, it is broadly estimated that the trial will involve several hundreds of patients, will have a randomized design with an ecologically valid comparison group, will involve at least an18-month treatment duration for the latest enrolled patients, and will follow a significant number for 4 years or longer. To achieve these goals, a greater number of non-academic, real world clinic sites will be required for the practical trail; consequently, identifying appropriate service delivery system partners for the practical clinical trial is a crucial evaluation criterion for progressing to Phase 3. The offeror should document that the flow of first episode patients at selected sites is adequate to support the practical clinical trial and describe how field sites will be trained on research practices and maintaining steady enrollment of first episode patients. NIMH will subject both the feasibility study results and study design for the Phase 3 practical trial to internal and external review.

Deliverables for Phase 2 are listed in section V, “SERVICES TO BE PERFORMED AND DELIVERABLES.” At the conclusion of Phase 2, NIMH will decide whether to proceed to Phase 3 of the contract.

Phase 3: Conducting a practical clinical trial. Assuming that results from the Phase 2 feasibility trial are encouraging and a compelling RCT is designed, Phase 3 will involve a practical clinical trial that involves typical patients, real world clinicians, usual payment mechanisms, and longitudinal evaluation of clinical, functional, and economic outcomes. After the trial is completed, the contractor is expected to deliver a database and relevant analyses of the practical trial to demonstrate whether the innovative intervention is a clinically superior and cost-effective approach to treating first episode schizophrenia as compared with usual standard treatment.

Deliverables for Phase 3 are listed in section V, “SERVICES TO BE PERFORMED AND DELIVERABLES.”

Concurrent stakeholder engagement: Parallel to the tasks already outlined for Phases 1-3 is continuous engagement with relevant stakeholders across all phases of RAISE. The involvement and contributions of consumers, advocates, representatives of real world service delivery systems, and relevant Federal agencies will differ at each stage, but the contractor’s real world partners should play an active role in identifying who to treat as well as selecting treatment targets, interventions, practice settings, and reimbursement mechanisms relevant to the early post-psychosis stage of schizophrenia. Meaningful conversations with key scientific, community, and Federal stakeholders are critical across all stages of RAISE and will be monitored by NIMH throughout.

Timeframe: NIMH envisions a 5-8 year timeframe to progress from the intervention refinement phase to completion of the practical clinical trial. The length of the project will depend on how the contractor conceptualizes the overall process of developing and testing an intervention that is potentially deliverable in usual care settings, and how much time is devoted to each phase. For instance, a contractor might choose to extend Phase 1 if an open case series design is necessary to test and refine a newly developed multi-element intervention. However, if a contractor already has adequate experience with an appropriately comprehensive intervention, he or she may choose to compress Phase 1 and move quickly to the Phase 2 feasibility study. If problems are anticipated in fielding the intervention in real-world settings, additional time might be required for Phase 2. Alternately, if feasibility data already exist for a well-reasoned, multi-element intervention, more time might be allocated for the Phase 3 practical trial. As mentioned previously, proposals will be judged on the methods proposed for developing, refining, fielding, and evaluating the integrated treatment intervention, as well as efficiency in moving across the three post-award phases of the project.

Depending on the quality and diversity of proposals received in response to this RFP, NIMH may decide to make more than one award to carry out the first or the first and second phases of RAISE. The option to progress to subsequent phases for one or more awards will be determined based on the contractors’ success in achieving goals associated with prior phases and subject to availability of funding.

ORGANIZATION

From this point forward, the terms “Contractor” and “Principal Investigator” will be used interchangeably.

NIMH envisions a single Principal Investigator (PI) with overall responsibility for RAISE. At the time the contract proposal is submitted, the PI must provide evidence of a working relationship with relevant stakeholder groups, such as representatives of real world delivery systems that regularly encounter individuals in the earliest phase of schizophrenia and purchasers of health care and disability benefits at state and local levels. Other personnel include members of the PI’s Research Team, an External Advisory Committee, and the NIMH Government Project Officer (GPO). Assuming that the contractor is allowed to progress past Phase 1, a Data and Safety Monitoring Board will be required for Phases 2 and 3. NIMH expects at least annual meetings between representatives of the investigative team, the GPO, and the CO in Bethesda, MD to formally evaluate study progress and to determine future courses of action.

NIMH is open to other organizational models for RAISE, but successful proposals will include the following elements:

Principal Investigator (PI): There will be a single PI for RAISE, and he/she must be able to devote sufficient effort to complete the ambitious goals of this project. RAISE must be the PI's highest scientific priority. The PI must be a leader with expertise in first-episode psychosis research, as well as treatment development and clinical trials in schizophrenia. The PI must have substantial experience in leading complex scientific projects and motivating teams of investigators. He/she should possess a track record of working effectively with non-scientific partners from the community. He/she should have the ability to successfully and diplomatically resolve scientific and administrative conflicts and to maintain a high level of cooperation between all members of the RAISE project team.

Research Team: Members of the Research Team should bring expertise in first-episode schizophrenia research, intervention development, and intervention and services research: assessment and longitudinal monitoring of clinical symptoms; delivery and testing of pharmacologic interventions; assessment and modification of social, academic, and work functioning; clinic-based, deployment-focused intervention development; design, implementation, and analysis of clinical trials; real world implementation of effective interventions; and research ethics. To address the unique characteristics of a younger, acutely-ill population, additional expertise is required in developmental psychology perspectives on adolescence and young adult periods, health communication strategies, health behavior change, and treatment adherence research. To bridge the perspectives of clinical researchers, representatives of real world service delivery systems, and key stakeholders, the Research Team should also include expertise in policy matters surrounding mental health treatment financing and organization.

If the contractor is approved to move forward to Phases 2 and 3, a clinical trial Operations Unit will be required. The Operations Unit should possess sufficient expertise to oversee day to day activities related to the feasibility study and randomized practical trial, including obtaining IRB approval, recruiting and retaining first episode schizophrenia subjects, obtaining informed consent, assessing fidelity to treatment protocols, collecting outcome measures, monitoring study progress and adverse events, and interacting with clinical sites. The Operations Unit must have computer data entry and data management systems capable of accurate and efficient data capture, processing, editing, querying, and statistical file manipulation. The Operations Unit must include biostatistical expertise in effectiveness research and analyzing data and reporting results. The Operations Unit should possess prior experience in managing multi-site RCT projects, with procedures and outcomes acceptable to NIMH.

Service Delivery System Partner: At the time the contract proposal is submitted, the PI must provide evidence of a working relationship with one or more relevant real world service delivery system partner(s), or a purchaser of health care and disability benefits at the state or local level. The PI should explain why these stakeholder partners are relevant to developing and testing a state-of-the art real world intervention for first episode schizophrenia, and provide evidence of the partner’s commitment to implementing a novel therapeutic approach. NIMH recognizes that the service delivery partner may change over the course of RAISE depending on decisions about target populations, target problems, the content and setting of interventions, etc. However, having an appropriate partner(s) in place by end of Phase 1 is a crucial evaluation criterion for progressing to the Phase 2 feasibility trial.

Executive Committee: This committee will be the administrative and executive arm of RAISE. It will help make decisions on day-to-day operational issues; consider and adopt changes in study procedures as necessary; and review progress of the study in achieving its goals, taking whatever steps necessary to enhance the likelihood of success. In addition to the PI, the Executive Committee will include representatives of the Research Team, Operations Unit, and partnering service delivery system, as well as the NIMH Government Project Officer (GPO), ex officio, or other Federal staff as appropriate.

External Advisory Committee: This committee consists of outside scientific advisors, consumers of mental health services, and members of mental health advocacy organizations. The External Advisory Committee will provide consultation and guidance for RAISE, particularly during initial intervention design. Assuming that the contractor is allowed to progress past Phase 1, the External Advisory Committee will participate with the PI, the Research Team, and the NIMH GPO and CO in the annual review of study progress. The members of this committee will be named after contract award, in consultation with the GPO.

Data and Safety Monitoring Board: Assuming that the project progresses past Phase 1, a Data and Safety Monitoring Board (DSMB) will be required for Phases 2 and 3. The DSMB, comprised of independent experts in clinical trial design and operations, will be organized and appointed by NIMH and charged with ongoing review of the safety and progress of the feasibility study and the practical clinical trial.

V. SERVICES TO BE PERFORMED AND DELIVERABLES

RAISE consists of four distinct stages that focus sequentially on conceptualizing the intervention (Initial Offer), refining the treatment through expert feedback and practical experience (Phase 1), testing the feasibility of delivering the intervention in real world settings and the viability of a randomized treatment study (Phase 2), and conducting a practical clinical trial (Phase 3). Tasks associated with each phase are detailed below, as well as expected deliverables. Should NIMH decide to complete all three post-award phases of RAISE, we anticipate that the entire project will span 8 years.

Services and Deliverables

INITIAL OFFER: Conceptualizing the Intervention

Required Elements

· Summarize what is known about the natural history of the early post-psychosis phase of schizophrenia, identify early events or processes associated with accumulating clinical and functional deterioration during this period, and review existing pharmacologic, psychotherapeutic, and rehabilitative treatments that have been applied to reduce morbidity in first episode schizophrenia and maintain social, academic and vocational functioning.

· Document the offeror’s track record in recruiting subjects into first episode psychosis research studies and retaining them over time. The offeror should document relevant research studies he/she has conducted over the past 2-5 years, the number of subjects recruited into each study, rates of attrition, whether the study remains active, and if so, the number of subjects needed to complete that study.

· Describe in detail how principles learned in first episode psychosis research studies regarding identification, recruitment, and retention of subjects can be transferred to first episode treatment programs located in community settings.

· Provide evidence of a working relationship with one or more service delivery system partners who agree to participate in the clinic-based, deployment focused intervention development process. The offeror will provide evidence that the service delivery system partners have agreed to participate in the Phase 1 intervention refinement process and/or the Phase 2 feasibility study.

· Deliver a detailed manual that presents the integrated and comprehensive package of interventions, the actual model for delivering the intervention effectively, a credible comparison condition, and proposed strategies for evaluating treatment feasibility in Phase 2 and clinical effectiveness in Phase 3.

· Specify the unit of randomization (e.g., by patient, clinic, county, etc.) in the proposal and describe how randomization will occur in the Phase 2 feasibility study and the Phase 3 practical clinical trial.

· Identify costs associated with completing Phase 1 of the project; provide cost estimates for Phases 2 and 3.

NIMH determines whether or not to make the award.

PHASE 1: Refining the Intervention

Services

· Provide a list of parties that will provide external feedback regarding the proposed multi-element intervention, i.e., domestic and foreign experts in first episode schizophrenia research and clinical care, mental health consumers, relatives, advocates, etc. Describe how feedback will be acquired, e.g., independent manual review, meetings, focus groups, etc. Get GPO approval.

· Develop consent documents for patients and clinicians who will participate in the intervention refinement phase; pilot the multi-element intervention with a small number of real world clinicians and patients; obtain iterative feedback regarding the acceptability of treatment procedures.

· Develop or adapt measures of (1) diagnosis, clinical and functional outcomes, the cost of providing care; (2) provider acceptance, competency, and adherence to the intervention protocol; (3) patient and family satisfaction with treatment; and (4) measures of attrition and adverse events. Develop data collection and data management procedures for the feasibility study and practical clinical trial.

· Identify at least two non-academic, real world clinic sites to host the feasibility test; document that the flow of first episode patients is adequate to support the Phase 2 feasibility study; identify clinical staff at the real world clinics who will deliver the intervention, describe the training and supervision plan for study clinicians, describe the comparison condition and the randomization plan, and initiate IRB approval for the feasibility trial.

· Identify the operations personnel who will oversee day-to-day activities related to the fidelity test.

Deliverables

· Produce a revised treatment manual that reflects iterative feedback obtained in Phase 1; produce clinician training manuals for use in the Phase 2 feasibility study.

· Produce a manual that describes and operationalizes the comparison treatment.

· Produce memoranda of agreement with representatives of at least two real world service sites that agree to field the Phase 2 feasibility study. Document that the flow of first episode patients is adequate to support the Phase 2 feasibility study. Verify that clinicians selected for the feasibility trial are representative of clinicians normally found at well-staffed mental health clinics.

· Identifying appropriate service delivery system partners for the feasibility study is a crucial evaluation criterion for progressing to Phase 2.

· Provide the randomization plan; document that real world service sites agree to abide by the randomization plan.

· Produce consent documents for patients and clinicians who will participate in the Phase 2 feasibility study.

· Deliver a variable list, compile assessment instruments, and describe the data acquisition and data management plan for the Phase 2 feasibility study.

· Produce evidence that IRB review of Phase 2 protocol is underway.

· Identify costs associated with completing Phase 2.

NIMH determines whether or not to continue to Phase 2.

PHASE 2: Conducting a Feasibility Study

Services

· Obtain IRB approval for all participating sites.

· Obtain DSMB review of protocol; make necessary modifications.

· Develop the electronic database, data collection instruments, and operations manuals for the feasibility trial; conduct training on intervention delivery, protocol, and trial operations.

· Conduct the feasibility study involving ~40 patients across at least two non-academic, real world treatment sites treated for approximately 12-months with randomization to experimental and comparison conditions; include appropriate monitoring, reporting, and DSMB oversight.

· Analyze data from the trial; present results to GPO.

· Extend agreements with Phase 2 sites to continue to Phase 3 clinical trial; establish agreements with additional real world clinical sites to participate in Phase 3; establish that the flow of first episode patients is adequate to support the Phase 3 practical clinical trial.

· Design protocol for Phase 3 practical clinical trial based on results of Phase 2 feasibility trial.

Deliverables

· Deliver the database for ~40 representative patients treated with experimental or comparison interventions for approximately 12 months, together with the relevant statistical analyses for demonstrating feasibility (i.e., that the randomization plan is reasonable, that the multi-element treatment can be delivered in real world settings, that patients and clinicians accept the intervention, and that baseline, treatment delivery, outcome, and cost data can be collected for experimental and comparison subjects).

· An important consideration for moving forward to the Phase 3 practical clinical trial is whether adequate baseline, treatment delivery, outcome, and cost data can be collected for experimental and comparison subjects.

· If necessary, produce revised treatment and clinician training manuals that incorporate lessons learned during the feasibility study.

· Develop a draft protocol and recommendations for conducting the randomized practical trial in Phase 3.

· Produce memoranda of agreement with representatives of original and additional real world service sites that agree to field the Phase 3 practical trial. Document that the flow of first episode patients is adequate to support the Phase 3 practical clinical trial. Verify that clinicians selected for the RCT are representative of clinicians normally found at well-staffed mental health clinics.

· Identifying appropriate service delivery system partners for the practical clinical trial is a crucial evaluation criterion for progressing to Phase 3.

· Document that real world service sites agree to abide by the randomization plan.

· Produce consent documents for patients who will participate in the Phase 3 practical clinical trial.

· Deliver a variable list, compile assessment instruments, and describe the data acquisition and data management plan for the Phase 3 RCT.

· Produce evidence that IRB review of Phase 3 protocol is underway.

· Identify costs associated with completing Phase 3.

NIMH determines whether or not to continue to Phase 3.

PHASE 3: Conducting a Practical Clinical Trial

Services

· Obtain IRB approval for all participating sites.

· Obtain DSMB review of protocol; make necessary modifications.

· Register the study in the National Library of Medicine’s ClinicalTrials.gov database as required ( http://grants.nih.gov/grants/policy/hs/faqs_aps_clinical_trials.htm#q2).

· Finalize development of the electronic database, data collection instruments, and operations manuals for the RCT; conduct training on intervention delivery, protocol, and trial operations.

· Conduct RCT; include appropriate monitoring, reporting, and DSMB oversight.

· Analyze data from the trial; present results to GPO.

· Organize roundtable meetings for discussion and interpretation of results of RCT, policy decision impact, greater dissemination in health systems.

Deliverables

· Deliver a final de-identified electronic dataset (with end-user documentation) consisting of all data elements, summary scores, and derived variables from the randomized clinical trial.

· Submit for publication a report on the clinical and cost effectiveness of the innovative intervention as compared with an ecologically valid comparison treatment.

VI. REPORTING REQUIREMENTS

In addition to any ad hoc reports requested by the GPO or CO, the Contractor shall submit Technical Progress Reports covering the work accomplished during each reporting period as outlined below.

Monthly Study Reports: The GPO will provide a template to the Contractor for reporting study progress to NIMH. At a minimum this report will describe Clinical Site performance/compliance (i.e., subjects enrolled in the study and their demographic characteristics, subjects screened but not enrolled and reasons why not enrolled, subjects that have completed the study, and anticipated subject enrollment and completion schedules for the remainder of the study), gender, ethnic, and racial information for enrolled participants, listing of adverse reactions, complications and problems encountered and their resolution. The report shall present overall study information as well as data for each Clinical Site. Problems in recruiting and plans for correcting recruiting problems must be included. A brief description of any other impediments to achieving the goals of the contract, any factors having cost implications, and recommendations for resolution should be included.

Report to NIMH DSMB: The GPO will provide a template to the Contractor for reporting study progress to the NIMH DSMB. The Contractor shall submit one copy to the GPO and one copy to the NIMH DSMB of a report detailing study progress, subjects screened, subjects enrolled, adverse reactions, complications, data quality assurance, and any problems encountered and their resolution. The report shall present overall study information as well as data for each Clinical Site. The Contractor will be responsive to additional specific requests for data reports that may be requested by the DSMB. The Contractor should expect to report to the DSMB three times per year while the feasibility study or randomized clinical trial is ongoing.

Annual Progress Report: At the discretion of the GPO, the Contractor, Research Team, and External Advisory Committee shall meet with the GPO, and other NIMH staff annually to provide a detailed progress report for that year as well as plans for the next year. Continued funding for the next Contract year will be contingent on adequate progress and successful completion of milestones.

Final Data Sets and Other Materials: On or before the final date of the contract, the contractor shall prepare a final electronic dataset consisting of all data elements, summary scores, and derived variables from the randomized clinical trial. It is expected that the dataset will be made available to the wider scientific community at some time after the close of the randomized clinical trial in Phase 3. Therefore, the dataset and end-user documentation shall be prepared according to standard instructions provided to the contractor by the GPO. The instructions shall also include the steps necessary to de-identify the database to ensure the privacy and confidentiality of study participants.

VII. CRITICAL ISSUES

NIMH expects responses to the RFP to be organized around the Initial Offer and the three Phases described in IV. APPROACH. In addition to describing how he/she will organize to achieve the goals of the three phases, the offeror should describe methods that assure delivery of products listed in V. SERVICES TO BE PERFORMED AND DELIVERABLES. Finally, the Initial Offer should address each of the critical issues outlined below.

Recruiting First-Episode Subjects: The annual incidence of new cases of schizophrenia in the general population is estimated at 1 per 10,000 individuals (Hafner and an der Heiden, 1997). This means that even in large metropolitan areas, a relatively small number of first episode cases become available each year.