Rev_ATTACH 3 - NIH-NIMH-10-024- SOW_(FINAL2)121610_Amend1.pdf

Attachment 3 RFP# HHS-NIH-NIMH-10-024 Statement of Work Amendment 01 December 16, 2010

TITLE: New, Rapidly-Acting Treatments for Treatment-Resistant Depression

(RAPID)

SECTION C - STATEMENT OF WORK

A. Background

Depression is one of the most common and serious disorders treated by mental health practitioners. While there are many pharmacologic, psychotherapeutic, and combination treatment options available to clinicians, many patients with depression do not respond optimally to the initial treatment offered.

When initial treatment is limited to antidepressant medications, approximately 20-35% of patients do not respond. Even after multiple, sequential interventions only about 50% of patients achieve complete remission.

Because of the substantial mortality and morbidity associated with inadequate treatment, treatment-resistant depression is a major public health problem. The scope of this problem is vast both in terms of the numbers of affected individuals and the resultant societal and economic burdens.

Despite the enormous public health significance of this problem, systematic research on treatment-resistant depression has yielded only limited success. In particular, the timely and accurate identification of treatment-resistant patients has been problematic. It is generally accepted that there is a biologically-determined latency period that delays the onset of response to antidepressant treatment. This lag is believed to reflect the time required to reach therapeutic drug levels or to achieve adequate intensity of psychotherapy coupled with the time needed for the requisite biochemical and electrophysiological adaptations to occur.

Over the last decade, a series of studies has demonstrated the ability of novel approaches

– including ketamine and sleep deprivation therapy – to provide significant amelioration of symptoms within a few hours. However, symptoms typically return within a period of days after discontinuation of the acute intervention.

The exact mechanism(s) of action of these modalities is not clear. The pharmacologic effect of ketamine appears to involve blockade of glutamatergic NMDA receptors and facilitation of AMPA receptors. One research question concerns whether variations in dose levels might produce longer-lasting effects without a significant increase in adverse events (which, to date, have been minimal). Finally, while a recent study has shown that repeated administration of ketamine over several days is well tolerated, symptoms nevertheless returned within days of drug discontinuation for almost all patients. While recent research has increased understanding of the mechanism of circadian rhythms and the sleep-wake cycle, the rationale for an association between sleep deprivation and symptom relief also remains unclear.

The promising results of these Proof of Concept trials suggest that a more ambitious program of research might accelerate development of rapid-onset antidepressant treatment. This initiative aims to test new compounds (e.g. NMDA antagonists (other than Ketamine Hydrochloride), allosteric modulators of AMPA receptors, 5HT4 receptor compounds, Thyrotropin-Releasing Hormone (TRH)) or non-pharmacologic interventions other than sleep deprivation (e.g., TMS, ECT, MST).

As NIMH’s current portfolio includes research on both ketamine and sleep deprivation, proposals to study these interventions are not solicited.

The proposed initiative is envisioned to include the unique resources and expertise of NIMH’s Intramural Research Program (IRP). The outcome of this initiative could be expected to lead to an enhanced understanding of underlying mechanisms and development of innovative, rapidly-acting treatment approaches for treatment-resistant depression.

The general approach required for this initiative will be to first establish a small network of clinical trial sites and subsequently to test identified interventions (pharmacologic and/or non-pharmacologic) in adequately powered Proof of Concept trials in humans.

Trials will be initiated after promising interventions are identified by members of the network (including the NIMH Intramural Research Program), and approved by the RAPID steering committee and the NIMH Government Program Officer (GPO).

If any compound/intervention identified under this contract or in the field proves to be promising, the government may choose to conduct a larger efficacy trial with that compound/intervention in lieu of other smaller Proof of Concept trials (see Tasks 3 and 4).

Note: Guidance to offerors is provided in Attachment 5 to facilitate agreement regarding any Intellectual Property rights where the interventions proposed are to be acquired from third party sources (e.g. Pharmaceutical companies).

All efforts within each task area outlined below will be controlled by task order procedures outlined in more detail in the contract. These procedures require the issuance of a task order request by NIMH, the contractor’s response/proposal to a request (including a technical approach and budget), and final NIMH approval to begin the task order. Costs shall not be incurred or reimbursed until a task order has been approved. The approved total cost is a ceiling that cannot be exceeded without further authorization.

THE EMPHASIS AND OBJECTIVE IN THIS CONTRACT IS TO IDENTIFY AND

TEST THE MOST PROMISING INTERVENTIONS FOR TREATMENT RESISTANT

DEPRESSION (EITHER PHARMACOLOGIC OR NON-PHARMACOLOGIC).

HOWEVER, WHILE IT IS NOT A REQUIREMENT THAT OFFERORS HAVE THE

CAPABILITY TO CONDUCT BOTH PHARMACOLOGIC AND NON-

PHARMACOLOGIC INTERVENTIONS IN THE ESTABLISHED NETWORKS, THE

GOVERNMENT CONSIDERS IT ADVANTAGEOUS TO AWARD CONTRACTS TO

OFFERORS WITH THE CAPABILITY TO DO BOTH TYPES OF INTERVENTIONS.

THIS CAPABILITY COULD BE PROVIDED THROUGH THE INCLUSION OF

SITES WITH EXPERTISE IN A DIVERSITY OF INTERVENTIONS WHICH MIGHT

COMPLEMENT YOUR EXPERIENCE.

B. Purpose and Objectives

This initiative will leverage the development of rapidly-acting treatments (demonstrable clinical improvement within 72 hours of administration) for severe, treatment-resistant depression.

1. The primary objectives of this contract are:

• To establish a network of sites to study “Rapidly-Acting Treatments for

Depression” (i.e., the “RAPID-network”) that will focus on identifying and testing promising interventions (pharmacologic and/or non-pharmacological) that produce a substantial anti-depressant effect within 72 hours of initial administration.

• To perform randomized clinical trials testing such promising interventions (other than Ketamine Hydrochloride or sleep deprivation (total or partial)) in a well-characterized cohort of adult subjects (age 18-

60) diagnosed with treatment-resistant depression.

2. A secondary objective would be:

• To further study and evaluate interventions that showed efficacy in a

RAPID-network Proof of Concept trial in a larger clinical trial.

C. RAPID Organizational Structure (RAPID-network)

It is anticipated that the RAPID-network will consist of:

1. A Prime Contractor (i.e. The Offeror) that will function as a Coordinating Center (RAPID-CC) for the entire project.

2. The Contract Principal Investigator (Contract-PI), who must be a full-time employee of the Prime Contractor, will function as the lead investigator of the RAPID-Network and CC. The Contract-PI should be an established researcher in depression, actively publishing in the field, with strong leadership experience.

It is expected that the Contract-PI will devote at least 15% of her/ his full time effort to the contract.

3. Performance sites (“RAPID-sites”), which will be sub-awards. It is anticipated that the RAPID-CC will also be a performance site (RAPID-site), directed by a site Principal Investigator (Site-PI) who may be someone other than the Contract-PI.

THE RAPID-CC, under the direction of the Contract-PI, shall assemble a team of senior researchers to provide overall scientific leadership and direction to the RAPID-network consisting of up to five (5) (and preferably more than one) individual RAPID-sites, each directed by a site Principal Investigator (Site-PI).

The RAPID-CC shall manage and direct the contract-related activities performed at each RAPID-site. The Prime Contractor shall remain solely responsible for the overall contract and subcontractor performance.

4. Data Management Center (DMC): The RAPID-CC or one of the RAPID-sites may serve as DMC or the Contractor may subcontract the data management task to an independent DMC.

5. NIMH’s Intramural Research Program (NIMH IRP), directed by an NIMH IRP- PI, may periodically collaborate with the RAPID-network. The specific details of this collaboration will be determined on a case-by-case basis depending upon the nature of the individual clinical trials to be performed under this contract.

6. Network-wide Committees:

a. Steering Committee (RAPID-SC): The RAPID-SC shall consist of the Contract-PI, all Site-PIs, DMC-PI (if applicable), NIMH IRP-PI, and two other independent researchers (to be selected in consultation with the GPO). The GPO and at least one other NIMH extramural staff collaborator will serve as ex officio members of the RAPID-SC.

This committee is chaired by the Contract-PI and is the administrative and executive arm of the RAPID-network. The RAPID-SC shall direct and oversee the scientific aspects of the network activities and make recommendations to the GPO in reference to various aspects of contract research activities. The specific duties of this committee shall be determined by the Contractor in consultation with the GPO.

The RAPID-SC shall meet as necessary. The frequency of such meetings, initially estimated to be weekly, will be determined in consultation with the GPO.

b. Publication and Dissemination Committee: A subset of the RAPID-SC (which may include the Contract-PI and Site-PIs) will assist in the preparation and review of manuscripts produced by the RAPID-network, and should help coordinate the dissemination of results to the scientific and lay communities. In addition to published material, this may also include the development of a website for wider distribution of information related to this study. The GPO shall have the opportunity to comment on all publications prior to their approval by the committee and submission for publication.

c. Intervention Selection Committee: This committee, chaired by the Contract-PI or one of the Site-PIs, will consist of the Contract-PI, Site- PIs, NIMH IRP-PI, and the GPO. This committee will actively identify promising interventions for testing through the network in proposed clinical trials. This is an ongoing and crucial activity throughout the contract’s tenure intended to ensure a sufficient volume of trials to be conducted.

D. RAPID Infrastructure

1. RAPID-CC: The RAPID-CC shall have adequate staff with appropriate expertise to accomplish all the management and contract-related activities performed by the RAPID-CC.

2. RAPID-sites:

a. Facilities: Each RAPID-site shall have a Clinical Facility where the clinical research is to be performed. To allow optimal opportunities for conducting various research protocols, each RAPID-site should have both an inpatient and outpatient capability. Each RAPID-site shall provide the full range of services necessary to conduct clinical trials, including expertise in securing regulatory approval for clinical trials, access to an IRB, a pharmacy (AS APPLICABLE) experienced in the preparation of materials for randomized clinical trials, staff with experience in training, following, conducting research protocols, etc.

b. Staffing:

(1) Site Principal Investigator (Site-PI): Each site shall have a lead investigator who is an established researcher in depression and actively publishing in the field. It is expected that the Site-PI at each RAPID-site will devote at least 15% of her/his full time effort to the contract. The Site-PI will select and coordinate a team of investigators and support staff capable of conducting research on the safety and efficacy of antidepressant interventions in adults with treatment-resistant depression. The Site-PI shall coordinate the site’s efforts with the RAPID-SC and other RAPID-sites, and participate in the identification, evaluation, and prioritization of lead-interventions. The Site-PI shall attend the meetings of the RAPID-SC and participate in its deliberations.

The Site-PI shall hold final authority and responsibility for the scientific and clinical aspects of the site’s research activities.

(2) Other Site Staff: The site shall have staff (e.g., psychiatrists, clinical raters, nurses, research assistants), or access to staff, to accomplish all the research activities and relevant data management as described in the Statement of Work. Required expertise in adult psychiatry (especially depression and mood and anxiety disorders), clinical psychopharmacology AND/OR non-pharmacological interventions, should be available within the site’s research team or from external consultants.

c. DMC, if applicable: If the data management task is subcontracted, the DMC shall have a DMC Principal Investigator (DMC-PI) who is an established researcher with experience in multi-site clinical trials data management.

E. Contractor Requirements

Independently, and not as an agent of the Government, the Offeror shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, as described below, and not otherwise provided by the Government as needed to conduct intervention trials in treatment resistant depression. All work under the contract shall be conducted under the general guidance of the GPO (sometimes also referred to as the COTR).

1. The Contractor shall:

a. Establish the RAPID-network, including all sites, infrastructure, committees, and communications to perform this contract, including adding new sites or removing sites during the contract.

b. Conduct Trials

(1) Actively test, at a minimum, one promising rapidly-acting pharmacologic or non-pharmacologic intervention in a Proof of Concept trial for treatment-resistant depression.

(2) The first trial conducted under this contract shall be a Proof of Concept trial (with either drug or non-drug as the treatment).

(3) After the initial trial, subsequent trials may be additional Proof of Concept trials or larger scale trials.

(4) THE CONTRACTOR IS NOT REQUIRED TO HAVE THE

CAPABILITY TO PERFORM BOTH PHARMACOLOGIC

AND NON-PHARMACOLOGIC TRIALS, BUT MUST HAVE

THE CAPABILITY TO CONDUCT A LARGER-SCALE

TRIAL IF DIRECTED TO DO SO BY THE GOVERNMENT

COTR.

(5) Each clinical trial shall be an adequately controlled study in subjects with depression who have not responded to at least two adequate anti-depressant treatments.

(6) Depending on the available pilot data, each trial may be a single-or multi-site study with a number of subjects adequate to address the primary hypotheses with a minimum statistical power to show a study intervention-placebo difference in response rates of 0.80.

The Contractor shall propose a sufficient number of subjects to be enrolled in each study to establish Proof of Concept and/or inform judgment with respect to whether the particular intervention warrants more extensive evaluation in larger clinical trials.

(7) Interventions

(a) Interventions for all trials are to be provided by the

Contractor, although NIMH may periodically assist in identifying promising interventions. The Contractor is required to gain access to all approved interventions by directly negotiating terms with 3rd party suppliers - terms which do not conflict with the contract terms and conditions and which to the maximum extent practicable promote data sharing to advance research in this field.

The Contractor must demonstrate that access to proposed 3rd party interventions can be accomplished, and in a timeframe that will not cause delay in contract performance. Interventions will not be approved until access can be assured. (See offered guidance regarding intellectual property discussions with 3rd party suppliers, Attachment 4, Section J)

(b) When access has occurred, the Contractor shall submit a redacted copy of the signed agreement between the third party supplier and themselves as proof that the agreement is in place.

(c) All interventions studied under this contract must have appropriate Food and Drug Administration (FDA) approval prior to starting any clinical trial:

(i) All drugs must have FDA Investigational New Drug (IND) approval.

(ii) All devices must have FDA Humanitarian Device Exemption (HDE) approval.

The Contractor must provide evidence of IND/HDE approval, or if the intervention is exempted from IND or

HDE regulations, acknowledgement from the FDA of such exemption.

(8) The GPO shall approve all compounds, interventions, and studies to be performed under this contract.

c. Follow the NIH clinical practice regulations in performance of this contract: (http://grants.nih.gov/grants/policy/hs/index.htm;

http://clinicalresearch.nih.gov/ethics_guides.html).

d. Register each clinical trial in the National Library of Medicine’s ClinicalTrials.gov registry (http://www.clinicaltrials.gov/).

e. Arrange for the collection of biomaterials (e.g., DNA, blood).

(1) GENETIC DATA (E.G., DNA) SHALL BE COLLECTED AND

MADE PART OF A GLOBAL RESOURCE FOR THE GENETIC

STUDY OF MENTAL DISORDERS THROUGH THE NIMH HUMAN

GENETICS INITIATIVE (HTTP://NIMHGENETICS.ORG/) OR

OTHER PUBLIC DATABASE AND REPOSITORY FOR FUTURE

EXPLORATORY STUDIES BY THE RESEARCH COMMUNITY.

THE CONTRACTOR SHALL ENSURE THAT APPROPRIATE

PRIVACY AND DE-IDENTIFICATION PROCEDURES ARE IN

PLACE FOR THE COLLECTION OF BIOMATERIALS.

(2) FOR THESE TRIALS, THE NIMH GENETICS INITIATIVE

WILL BE USED, WHICH IS HOUSED AT THE RUTGERS

UNIVERSITY CELL AND DNA REPOSITORY (RUCDR). NO

SHORT TERM STORAGE IS EXPECTED AT THE CLINICAL

SITES.

(3) THE RAPID PI OR THE RESEARCH COORDINATOR WILL

REQUEST SHIPPING MATERIAL FROM RUTGERS THROUGH

THE RUCDR WEB PORTAL SYSTEM. AFTER THE BLOOD

SAMPLES HAVE BEEN COLLECTED, THEY WILL BE STORED

AT ROOM TEMPERATURE AND SHIPPED (VIA FED EX) FOR

OVERNIGHT DELIVERY.

(4) TWO LINKS ARE PROVIDED FOR THE INSTRUCTIONS:

• FLOW SHEET FOR BLOOD SAMPLE COLLECTION

FOR NIMH GENETICS INITIATIVE:

https://www.nimhgenetics.org/documents/Blood%20Sampl e%20Flow%20Sheet.pdf

• USER MANUAL FOR RUCDR WEB PORTAL

SYSTEM: http://rucdr.rutgers.edu/user%20manual.pdf http://grants.nih.gov/grants/policy/hs/index.htm� http://clinicalresearch.nih.gov/ethics_guides.html� http://www.clinicaltrials.gov/� http://nimhgenetics.org/� https://www.nimhgenetics.org/documents/Blood%20Sample%20Flow%20Sheet.pdf� https://www.nimhgenetics.org/documents/Blood%20Sample%20Flow%20Sheet.pdf� http://rucdr.rutgers.edu/user%20manual.pdf�

f. Respond to NIMH task order requests with timely proposals.

g. Manage, direct, and monitor the network and individual RAPID-site performance, including removal and replacement of non-performing RAPID-sites.

h. Review and monitor progress of each trial to optimize the likelihood of success.

i. Ensure that clinical trials initiated under this contract are completed in a timely manner and within budget costs.

j. Establish methods to effectively manage and communicate within the network, and with the NIMH, during the contract. This would include, but is not limited to, the following activities:

(1) Schedule and coordinate regular telephone conference calls with relevant parties involved in the studies, the GPO, and other NIMH extramural staff in order to discuss the progress of ongoing studies and other project related activities. The Contractor shall prepare minutes of these calls and send them to the GPO and other relevant parties within 4 working days after each call.

(2) Schedule, coordinate, arrange, participate in, and provide any information necessary for the RAPID-SC meeting calls. The Contractor shall prepare minutes of these meetings and distribute them to the GPO and other relevant parties within 7 working days after each meeting.

(3) Schedule, arrange, and coordinate meetings with RAPID-site staff with the purpose of training staff in all the relevant activities of the study.

(4) Arrange for site visits as needed to ensure the performance of individual RAPID-sites. Such site visit may include monitoring adherence to protocol, ensuring consistency with other RAPID-sites, and quality control of data collected, recorded, and entered in the database. The Contractor shall prepare a written report for the GPO on the results of each visit, which will be sent to the RAPID-site and the GPO within 15 working days after completion of the visit. Reports shall include descriptions of any problems identified at the site and recommendations and plans aimed at correcting them.

k. Submit all technical reports required under the contract to the NIMH in a timely manner.

l. Manage and direct all publications.

2. Estimated Workload Schedule:

a. The guaranteed minimum under this contract is the preparation effort for

Trial #1. If the final protocol is approved, a task order will be issued to conduct Trial #1, including final data analysis and dissemination of results to the research communities, i.e., peer-reviewed publication(s).

b. It is unknown how many additional trials will be performed under this contract, or the types of trials (e.g., drug/non-drug, Proof of Concept trials/Larger Scale trials.)

c. It is considered desirable by the Government to have a Contractor with the capability to identify and access more than one intervention, and conduct multiple, concurrent trials.

d. The total workload will be influenced by:

(1) The Contractor’s ability and effectiveness in identifying and accessing interventions. The Offeror should demonstrate that there is minimal risk in gaining access to the first proposed intervention so as to not delay performance under this contract.

(2) The ability of the Contractor to conduct and manage concurrent trials.

(3) Subject recruitment capability and the number of sites available.

(4) The results of on-going trials, which will influence the decisions to conduct Larger Scale trials.

(5) The time and effort needed for start-up activities to initially establish a network infrastructure, to add or remove sites for subsequent trials, and to finalize protocols and complete all regulatory requirements.

It is anticipated that some of the efforts to establish the initial infrastructure to begin Trial 1 may not be necessary for subsequent trials if essentially the same infrastructure is utilized.

Therefore, the start-up time for subsequent trials may be shorter.

3. Estimated Milestones

It is estimated that all preliminary activities required prior to initiating any of the trials will require at least six (6) but not more than ten (10) months for completion.

a. Trial #1 Milestones (first trial)

Contract Months Description Month 1 NIMH assigns Task (1)P-POC-1 (Preparations for initial Proof of Concept trial) at award Months 6-7 Execute subcontract agreements for the

RAPID-sites and, if needed, the Data Management Center (DMC)

Months 8-9 Complete all regulatory preliminary activities, finalize & submit the initial protocol to the GPO (including consent documents) and be ready to recruit subjects.

By month 10 NIMH approval of final scientific protocol and DSMB approval; begin recruitment

By month 40 (in contract year 4)

Complete Trial #1 (assumes a 30 month trial and 10 months for preparation/start-up)

b. Trial Metrics (Estimates)

(1) Proof of Concept (POC) Trials: Total 36-40 months to complete;

60 subjects each

(a) Trial #1 (total 40 months; 30 months to complete +10 months preparation)

(b) Trial #2 and on (total 36 months; 30 months to complete

+ 6 months preparation)

(2) Larger Scale (LS) Trials: total 48 months to complete (42 months to complete the trials + 6 months preparation); 200 subjects each

4. Sharing Research Data

a. The NIH endorses the broad sharing of final research data with the scientific and lay communities. This contract is expected to generate research data that must be shared with the public and other researchers.

NIH's data sharing policy may be found at the following Web site:

http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

b. NIH recognizes that data sharing may be complicated or limited, in some cases, by use of proprietary materials, institutional policies, and local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule (see HHS-published documentation on the Privacy Rule at http://www.hhs.gov/ocr/). The rights and privacy of people who participate in NIH-funded research must be protected at all times; thus, data intended for broader use should be free of identifiers that would permit linkages to individual research participants and variables that could lead to deductive disclosure of the identity of http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html� individual subjects.

c. The goal is for rapid and broad sharing of all de-identified clinical and other primary data generated in this project to permit analyses by the wider scientific community.

d. The clinical trials data generated in this project should be made available to the research community no later than one (1) year following the completion of the trial, defined as the date of the last protocol visit of the last protocol subject for each clinical trial funded under this contract. It is anticipated that public access to the clinical trials data will be accomplished by preparation of well-documented de-identified dataset(s) consisting of all data obtained as well as composite, computed, and/or derived variables constructed during the course of primary outcome analysis. It is anticipated that the DMC will be responsible for preparation of these dataset(s) according to guidelines provided by GPO for organization, documentation, and preservation of participant privacy. Prior to award, the Contractor and NIMH will develop and finalize a data sharing agreement that will specify timelines and criteria for: rapid disposition of data generated in this project; access to de-identified data; conditions for research use;

and procedures for vetting requests for access to primary data maintained in the data center and/or other NIH or public databases.

F. Tasks Areas

The major task areas of RAPID are depicted below. THE CONTRACTOR SHALL

HAVE THE CAPABILITY TO PERFORM ANY APPROVED TASKS IN ALL 4

TASK AREAS. A scheme for the designation and tracking of individual tasks under this contract is also presented, as follows:

TASK AREA

(1)

Preparations for Proof of Concept (POC) Clinical Trials (Drug or Non-Drug)

(1)P-POC-1 Preparations for POC Clinical Trial #1 (P-POC-1)

Establish the network infrastructure to begin POC Trial #1 and subsequent trials; finalize the protocol, obtain all clinical and regulatory (e.g., local IRB, NIMH Data and Safety Monitoring Board (DSMB)) approvals required to begin recruitment

(1)P-POC-2 Preparations for POC Clinical Trial #2 (P-POC-2)

Using the established infrastructure, obtain NIMH approval for the Trial #2 intervention; work to finalize the protocol and to complete all required preparations for this clinical trial (could include adding or removing sites)

(1)P-POC-3 Preparations for POC-3 (see above) (1)P-POC-4 Preparations for POC-4 (1)P-POC-5 Preparations for POC-5, etc.

TASK AREA

(2) Conduct Proof of Concept (POC) Clinical Trials (Drug or Non- Drug)

(2)C-POC-1 Conduct POC Clinical Trial #1 (C-POC-1) (2)C-POC-2 Conduct POC Clinical Trial #2 (C-POC-2) (2)C-POC-3 Conduct POC-3 (2)C-POC-4 Conduct POC-4 (2)C-POC-5 Conduct POC-5, etc

TASK AREA

(3) Preparations for Larger Scale (LS) Trials (i.e., Phase II/Phase III) (Drug or Non-Drug)

(3)P-LS-1 Preparations for LS Clinical Trial #1 (P-LS-1) (3)P-LS-2 Preparations for LS Clinical Trial #2 (P-LS-2) (3)P-LS-3 Preparations for LS-3, etc.

TASK AREA

(4) Conduct Larger Scale (LS) Clinical Trials (Drug or Non-Drug)

(4)C-LS-1 Conduct LS Clinical Trial #1 (C-LS-1) (4)C-LS-2 Conduct LS Clinical Trial #2 (C-LS-2) (4)C-LS-3 Conduct LS-3, etc.

TASK AREA 1 - Preparations for Proof of Concept Clinical Trials

General Description Proposed trials can be either drug or non-drug trials. For the first trial, this Task includes establishing the infrastructure of the RAPID-network, including individual RAPID-sites and staffing (see selection of RAPID-site, below), and for all trials completing the clinical and regulatory activities prior to beginning enrollment such as: protocol development, informed consent documents, forms development, development and testing of a data system, training of clinical and research staff, clinical exemptions, IRB, regulatory, and NIMH Data and Safety Monitoring Board (DSMB) approvals, certificate of confidentiality, etc. Subsequent trials may require less start up time since the basic infrastructure will be in place.

NOTE: A NIMH Data and Safety Monitoring Board will be established to review, monitor, and assess the clinical trials performed under this contract

1. Establish the Infrastructure.

Evaluate and propose high-quality sites and, upon approval from NIMH, establish formal subcontracts to perform the work under this contract.

a. At a minimum, sites should have:

(1) The demonstrated ability to recruit sufficient number of subjects with treatment resistant depression into clinical trials to achieve a minimum statistical power to show a study intervention-placebo difference in response rates of 0.80 and complete project recruitment within projected timeframes, have sufficient expertise in depression to reliably administer appropriate test batteries as a repeated measure in clinical trials, and have access to sufficient experience and expertise in adult psychiatry, psychopharmacology AND/OR non-pharmacologic interventions to contribute to the identification and evaluation of potential rapidly-acting interventions for the treatment of depression.

(2) A Site-PI who has the primary responsibility of identifying and recruiting eligible subjects at his/her center. The Site-PI will be responsible for the follow up, as specified in the study protocol, of each subject enrolled in the clinical trial and for submitting required data to the DMC. The Site-PI is also responsible for ensuring that site staff are adequately trained and certified to perform studies under this contract.

(3) The ability to participate and work cooperatively and effectively (including preparing for collaborative clinical trials of such interventions, and identification and evaluation of such interventions) with the other RAPID-sites, NIMH IRP, and NIMH staff.

(4) A setting where studies on various aspects of the safety (including standard procedures to identify, score, and report in an effective and timely manner all possible and actual adverse events), efficacy, and mechanism of action of such interventions can be conducted, using funds awarded directly through this contract.

(5) Data management capabilities that utilize specific procedures for data collection, quality assurance, storage, transfer, and analysis that meet good clinical trial practice criteria. The procedures shall ensure adequate protection of confidentiality of the research subjects.

b. Contractor’s evaluation of proposed RAPID-sites:

(1) The Contractor shall propose initial qualified sites/organizations, in accordance with the criteria below, including the plan for training site staff, and implementing data management.

(2) If the Contractor should need to add additional sites to ensure the ability to conduct specific clinical trials under this contract, the same criteria for selection and evaluation of such sites should be followed.

(3) All sites shall be approved by the GPO, and consented by the Contracting Officer, prior to enter into subcontract awards.

(4) The Contractor shall evaluate each proposed site in accordance with the following criteria:

(a) Access to a sufficient number of potential study participants to ensure the feasibility and successful enrollment of study subjects and timely completion of the study.

(b) Diversity of subjects including both sexes, a range of ages, ethnic diversity, and geographical dispersion (including a balance between urban and rural), as practicable and scientifically appropriate.

(c) Investigators experienced in conducting clinical trials involving the psychopathology and treatment modalities of the protocol.

(d) (AS APPLICABLE) SITES WITH EXPERIENCE IN

DIFFERENT TREATMENT MODALITIES WHICH

EXPAND YOUR OWN CAPABILITIES

(e) Availability of adequate experienced professional and technical staff to provide scientific and administrative coordination and support to the clinical trial, including site management and quality control expertise, appropriate clinical expertise, and capacity for subject recruitment and follow-up.

(f) Adequate facilities, equipment, and support staff to conduct clinical trials.

(g) Adequate computing resources and support staff, including necessary electronic communication capabilities.

(h) Adequate capabilities and staff for data collection, entry, editing, electronic transfer, quality control, database management (maintaining security and accessibility), and data backup (on site and off site)).

(i) Access to a standing IRB with a Federal wide Assurance from the United States Department of Health and Human Services Office for Human Research Protections.

(j) Agreement to participate as a site for this trial and to comply with the terms and conditions within the Statement of Work (with letter of support from the institution).

(k) If data management is to be subcontracted to a separate site (DMC), this site needs to have appropriate expertise and experience in data management and statistical analysis and experienced with a well-functioning, properly designed data acquisition, management, and processing system. Because some of the studies funded under this contract are likely to be multisite studies, the DMC shall ensure that data from the various sites can be appropriately merged and analyzed.

2. Protocol Development

a. The protocol development activities relevant to all studies performed under this contract include, but are not limited to:

(1) Human subject considerations (e.g., reporting of adverse events, rules for dealing with symptom exacerbations, hospitalizations, and treatment procedures, non-response, consent forms, consenting procedures).

(2) Plans for dealing with intellectual property, use patent, financial conflict of interest, etc.

(3) Plans to monitor and coordinate each site.

(4) Plans to arrange and coordinate training of clinical and research staff, in order to ensure reliability of evaluation, treatment, and assessment procedures.

(5) Plans to develop and implement a system for random treatment assignment and appropriate stratification of eligible subjects.

(6) Plan to monitor adverse effects of study interventions to maximize subject safety, including plans for prompt reporting of severe adverse events.

(7) Plans for overall quality control and monitoring the timeliness and adequacy of subject recruitment, including metrics for early identification and resolution of sites with deficient recruitment.

(8) Plans for terminating sites (e.g., should a site(s) not be able to maintain minimal recruitment goals) and for adding new sites.

(9) Plans/strategies for data sharing with the network, during the course of the contract, if appropriate.

(10) Plans for public access data set preparation for submission to NIMH after conclusion of the study-specific proprietary period.

b. Protocol activities relevant to individual protocols:

(1) The NIMH shall organize a scientific peer-review of each final protocol to be carried out by experts not otherwise associated with the trial. This review will be carried out within a reasonable time of submission of each final protocol by the Contractor and will result in recommendations to proceed with implementation or to revise and address specific issues.

(2) Final selection of protocols and specific interventions are subject to modification and recommendations by the GPO according to the needs of the field and feasibility of the proposed interventions.

(3) The protocols for these studies shall be developed by the RAPID- SC and should include, but are not limited to the following aspects:

(a) A review of the study objectives, public health significance, specific aims, and endpoints.

(b) A review of the intervention to be tested including preclinical studies, human safety data, pilot human efficacy data, mechanism of action, pharmacokinetics (if applicable), dosage and/or duration considerations, and rationale for dosage and/or duration of treatment.

(c) Study design (e.g., treatment specifications and length of treatment, subject selection criteria with rationale for limited exclusions, efficacy measures, randomization and stratification/blocking methods) and administrative structure.

(d) Submission of all materials necessary to obtain local IRB approvals at each site.

(e) Submission to the NIMH staff of all materials necessary to obtain NIMH DSMB approval to start subject enrollment.

(f) Submission to the GPO of all materials necessary to obtain approval of a clinical exemption from the NIH Clinical Exemption Review Committee before the start of subject enrollment into the protocol and all materials necessary to obtain approval of the Office of Management and Budget (OMB) if required.

(g) Recruitment Plan (e.g., enrollment of a diverse subject pool, including women and minorities, speed of subject accrual, subject retention).

(h) Provisions to adequately monitor, and appropriately intervene for, the safety of subjects who may exhibit suicidal ideation or behavior during their participation in a protocol.

(i) Statistical design considerations (including effect size, sample size, and power estimates, and rules for interim analysis and early termination of a treatment arm).

(j) Statistical analysis plan (including specification of primary outcome and statistical approach, and plans for follow-up of early study terminators, if appropriate).

(k) Clinical and laboratory monitoring procedures.

(l) Developing, preparing, and testing all study policies and procedures (including procedures for collecting all data needed on study subjects).

(m) The stopping rules and possible re-randomization rules, if appropriate.

(n) Obtaining and preparing (if applicable) drugs or necessary materials for the study interventions.

(o) Rules for possible dosage/duration adjustments (if applicable).

(p) Rules for pre-existing treatments as the subjects enter the trial and for adjunctive pharmacologic, psychotherapeutic, or other treatment during the trial.

(q) A plan for subject retention and a system for dealing with clinical emergencies, both acute and subacute (e.g., hospitalization, adjunctive medications).

(r) Plans for preventing, identifying, handling, and reporting protocol violations.

(s) Data management plans (e.g., data collection, monitoring, and safety, periodic data safety review, data sharing).

(t) Plans for disseminating findings from the trial.

(u) A timeline with milestones and evaluation criteria against which progress of the trial will be judged.

(v) Plans (if applicable) for insuring post-study access to study intervention for subjects who respond.

3. Design of database, computer system, and data management plans.

a. Database and computer system design should at minimum include:

(1) A centralized database that will include study data from all sites.

The design of the database should be operable across commonly used platforms (i.e., PC, MAC) and permit easy and efficient data entry.

(2) Standardized procedures for data entry and transfer to the centralized database and data verification. Data entry/verification procedures should minimize opportunities for human error and other incorrectly entered data. The Contractor will bear responsibility for the quality control of the data collection, subject tracking, and transfer of data to the DMC and will insure its uniformity.

(3) Internet access and capacity for electronic communications.

NIMH anticipates that the Contractor will develop a secure system of communication to facilitate interactions between RAPID-sites, RAPID-CC, DMC, and NIMH.

(4) A method to ensure security and confidentiality of all clinical records and information about any subjects enrolled in these research studies (including conforming to all HIPAA requirements).

(5) On-site and off-site backup of electronic data, as well as procedures to avoid data loss and down-time in case of equipment failure (e.g., hard disk crashes computer breakdowns, power outages).

(6) While not anticipated, if NIMH staff deems it necessary, the Contractor must be ready and able to close out data entry and transfer the complete database, along with complete supporting documentation, within 30 calendar days, to NIMH or to its designee.

b. Plans for data management activities should include but not be limited to:

(1) Procedures to receive, process, edit, correct, update, store, track, retrieve, and analyze all study data.

(2) Procedures and standards to measure and monitor how accurate, complete and up-to-date the database is, including a plan for resolving problems identified in the monitoring process.

(3) Quality control plan, as data are received from the RAPID-sites, where the DMC shall, as needed, check, enter (if received as hard copy), verify, process, monitor, correct, update, file, store, and inventory the data. Data received from the RAPID-sites shall be reviewed within one week from receipt for completeness, accuracy, consistency, out-of-range values, and overall quality.

Sites shall be informed promptly of any missing, incomplete, or erroneous data.

(4) Plan and methods for analyzing and presenting study data using appropriate statistical software.

(5) Plan for the DMC to develop and implement procedures to provide the RAPID-CC, RAPID-sites, and NIH with summary tables of the database for monitoring and tracking purpose throughout the course of the contract.

(6) The plan to allow the GPO to access data regarding serious adverse events (SAE), including SAE summaries, study ratings, and clinical source documents within 24 hours of the SAE.

(7) The plan to prepare and provide periodic study data and reports as requested by the GPO, the PIs, and the NIMH DSMB.

(8) The plan, upon completion of each clinical trial, to provide the GPO with a final, cleaned, edited, and documented database containing all study data and associated documentation, etc, in a format that is readily usable by NIMH or its designee. (See 4a –d/ Sharing Research Data.

(9) The plan, upon completion of each clinical trial, to provide the GPO with final statistical report of the outcomes of each clinical trial (format of the report to be determined for each trial).

4. Registration of each clinical trial in the National Library of Medicine’s

ClinicalTrials.gov registry (http://www.clinicaltrials.gov/).

5. Data Safety and Monitoring Board

The study protocol(s) and consent form(s) will be reviewed by the NIMH DSMB after IRB approval and prior to initiation of each clinical trial.

TASK AREA 2 - Conduct Proof of Concept Clinical Trials

General description

1. After all sites, regulatory aspects, final protocols, IRB and NIMH approvals have been obtained, begin recruitment and conduct Proof of Concept (either drug or non-drug) trials. The GPO shall approve all compounds, interventions and studies to be performed under this contract.

2. Conduct all trials in conformance with all other terms in this Statement of Work.

3. The Contractor shall manage and coordinate all clinical trials according to the protocols finalized and approved in TASK AREA 1; multiple trials may be required, with overlapping periods of performance.

4. The Contractor shall perform clinical monitoring, interim and final data analysis, and preparation of draft and final reports on each study.

5. Trial management and oversight shall include, but is not limited to:

a. Monitor sites for rate of recruitment, protocol adherence, data collection, and data entry and ensure quality performance at each site.

b. Ensure (if applicable) that adequate supply of study drug is available at each site.

c. Ensure adequate monitoring and prompt reporting of adverse medical events.

d. Ensure data transfer from the RAPID-sites to the DMC.

e. Assess the quality of the data received from the sites and verify (if needed) the database against any source documentation.

f. Prepare and submit to the GPO scheduled, regular progress reports

(including the status of enrollment at each site, study progress, and completion schedule) on each study.

g. Prepare and distribute required reports for the NIMH DSMB, the GPO, the PIs, and RAPID-SC.

6. NIMH Data and Safety Monitoring (NIMH will perform this function) http://www.clinicaltrials.gov/�

a. The GPO or other designated NIMH extramural staff collaborator will provide the Contractor with a template for reporting to NIMH DSMB and will provide oversight for such reporting.

b. All clinical trials performed under this contract will be reviewed by the NIMH Data and Safety Monitoring Board (DSMB) to help ensure the safety of participants and the integrity of the data. Study data will be reviewed by the NIMH DSMB according to the Board’s review schedule, currently three times per year, at approximately 4-month intervals.

c. The NIMH DSMB is an independent panel of experts in clinical trials who are appointed by NIMH to monitor trials that are conducted with NIMH funding. The NIMH DSMB will receive a report from the Contractor approximately 4-6 weeks before each review date. All clinical trials’ submissions to the NIMH DSMB are expected to follow the established reporting format and template that will be provided to the Contractor. In general, the report will include the major variables necessary for monitoring subject enrollment and retention, safety, quality of data collection, and integrity of the study.

Based on its review, the NIMH DSMB has the authority to prevent the study from starting or to stop the study after it has started.

TASK AREA 3 – Preparations for Larger Scale (LS) Clinical Trials

General description

1. Using the established infrastructure (or modifications thereto), provide clinical trial preparations to further study and evaluate, in a larger clinical trial, interventions that showed efficacy in a previous trial under the RAPID-network (i.e., Phase II/Phase III).

2. Complete the clinical and regulatory activities prior to beginning enrollment such as: protocol development, informed consent documents, forms development, development and testing of a data system, training of clinical and research staff, clinical exemptions, IRB, regulatory, and NIMH DSMB approvals, certificate of confidentiality, etc.

3. See Task Area 1 for detailed description of preparation activities required for all trials.

TASK AREA 4 – Conduct Larger Scale (LS) Clinical Trials

1. After all sites, regulatory aspects, final protocols, IRB and NIMH approvals have been obtained, begin recruitment and conduct larger–scale clinical trials

(either drug or non-drug trials). Manage and coordinate all clinical trials according to the finalized protocols. Perform all aspects of trial management and oversight, including clinical monitoring, interim and final data analysis, and preparation of draft and final reports on each study.

2. Conduct all trials in conformance with all other terms in this Statement of Work.

3. See Task Area 2 for more detailed description of activities for conducting all trials.

G. SAMPLE TASKS (6)

The sample tasks below include: 2 preparations for trials, conducting 2 proofs of concept trials, and conducting 2 larger-scale trials.

THERE ARE NO SAMPLE TASKS FOR TASK AREA 3 (PREPARATIONS FOR

LARGER-SCALE TRIALS), SINCE THE EFFORT FOR THIS IS LIKELY TO BE

ROUGHLY COMPARABLE TO THAT IN TASK AREA 2 (PREPARATIONS FOR

PROOF OF CONCEPT TRIALS).

NOTE: INSTRUCTIONS FOR COST PROPOSALS TO BE SUBMITTED FOR

THE SAMPLE TASKS BELOW ARE INCLUDED UNDER SECTION H.,

IMPORTANT NOTES TO OFFERORS.

SAMPLE 1: TASK AREA 1 - Prepare for proof of concept drug trial using

Ketamine

1. Description:

Establish the infrastructure of the RAPID-network, including individual RAPID-sites and staffing (see selection of RAPID-site), complete the clinical and regulatory activities prior to beginning enrollment such as: protocol development, informed consent documents, forms development, development and testing of a data system, training of clinical and research staff, clinical exemptions, IRB, regulatory, and NIMH DSMB approvals, certificate of confidentiality, etc.

2. See further description of pre-trial activities under Task Area 1, in Statement of Work.

SAMPLE 2: TASK AREA 1 - Prepare for proof of concept non-drug trial using sleep deprivation treatment

Establish the infrastructure of the RAPID-network, including individual RAPID-sites and staffing (see selection of RAPID-site), complete the clinical and regulatory activities prior to beginning enrollment such as: protocol development, informed consent documents, forms development, development and testing of a data system, training of clinical and research staff, clinical exemptions, IRB, regulatory, and NIMH DSMB approvals, certificate of confidentiality, etc. (http://grants.nih.gov/grants/policy/coc/)

SAMPLE 3: TASK AREA 2 - Conduct proof of concept drug trial using ketamine

Using the established infrastructure (or approved modifications thereto), and after all regulatory aspects and final protocols have been approved by the NIMH, begin recruitment and conduct Proof of Concept Ketamine trial.

Manage and coordinate all clinical trials according to the finalized protocols.

Perform all aspects of trial management and oversight, including clinical monitoring, interim and final data analysis, and preparation of draft and final reports on each study.

SAMPLE 4: TASK AREA 2 - Conduct proof of concept non-drug trial using sleep deprivation treatment after all regulatory aspects and final protocols have been approved by the NIMH, begin recruitment and conduct Proof of Concept sleep deprivation trial.

Manage and coordinate all clinical trials according to the finalized…