MTEC Pre-Announcement: Department of Defense Posttraumatic Stress Disorder Adaptive Platform Trial Regulatory Sponsor Partner

The Medical Technology Enterprise Consortium (MTEC), in support of the US Army Medical Materiel Development Activity (USAMMDA), is excited to post this pre-announcement for a Request for Project Proposals (RPP) with the objective to identify organizations who are willing and able to fulfill responsibilities as the regulatory sponsor of active clinical trial protocol S-21-02 entitled, “A Phase 2, Multi-Center, Multi-Arm, Randomized, Placebo-Controlled, Double-Blind, Adaptive Platform Study to Evaluate the Safety, Tolerability, and Efficacy of Potential Therapeutic Interventions in Active-Duty Service Members and Veterans with Posttraumatic Stress Disorder” (NCT05422612). The Department of Defense (DOD) is funding and has established this posttraumatic stress disorder (PTSD) adaptive platform trial (APT). The team is now seeking interested partners to serve as the regulatory sponsor and holder of the existing Master Protocol Investigational New Drug (IND) application to the U.S. Food

and Drug Administration (FDA).____________________________________________________________________________________CLINICAL PROBLEM:PTSD is a chronic and disabling psychiatric disorder with a lifetime prevalence of approximately 7% in the United States. PTSD is characterized by intrusive thoughts, nightmares and flashbacks of past traumatic events, avoidance of reminders of trauma, hypervigilance, and sleep disturbance, all of which lead to considerable social, occupational, and interpersonal dysfunction. While patients suffering from PTSD all exhibit some element of the cardinal features as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, there is significant heterogeneity in clinical presentation. Certain symptoms may be more prominent in some patients than others, and most patients have at least one additional psychiatric comorbidity such as insomnia, depressive disorders, anxiety disorders, or substance use disorders. Efforts have been made to categorize patients based on clusters of symptoms and comorbidities, but the utility of such subtypes for diagnosis, prognosis, or for treatment guidance is not yet validated.PTSD symptoms can persist for years or decades after the traumatic event; only one-third of patients recovered at the one-year follow-up and one-third remained symptomatic 10 years later. PTSD is associated with poor social support, higher healthcare utilization, and may be associated with increased mortality.Therefore, the goal of the DOD’s PTSD-Drug Treatment (DT) program, led by the U.S. Army Medical Materiel Development Activity’s (USAMMDA) Warfighter Brain Health Project Management Office (WBH PMO), is to increase the medical readiness of U.S. Warfighters by developing drug therapies for the treatment of PTSD.BACKGROUND ON THE DOD PTSD APT:Since 1987 there have been over 130 clinical trials conducted in PTSD with more than 48 drugs or drug combinations, encompassing more than 30 mechanisms of action, with little to no return on investment. Most of these trials studied one drug at a time, without the use of biological information to define the sample of patients with PTSD most likely to respond to the drug’s mechanism of action either prospectively or retrospectively. Given that PTSD is biologically complex with multiple integrated, dysregulated biological systems leading to clinical presentation, a different approach to the development of drug treatments is necessary. Innovative clinical trial designs, such as master protocols and adaptive protocol elements, are efficient, cost-effective, and have increasingly been used in other indications to address complex disorders, with U.S. FDA support.An APT is a type of master protocol with adaptive protocol elements. The master protocol describes default procedures and analyses for all therapies within the trial. Specific cohorts of the trial are described in appendices and provide details specific to each cohort. These might include, but are not limited to, deviations in the default trial population or additional safety analyses specific to a cohort that might need to be conducted.The DOD PTSD APT is a unique trial that utilizes an adaptive platform design to answer multiple scientific questions simultaneously and more efficiently. The framework allows for the evaluation of multiple potential treatments for PTSD, and interrogation of the biological and environmental factors that underpin drug effectiveness in PTSD biomarker subtypes. The first three drugs to be tested in the DOD PTSD APT are fluoxetine, vilazodone, and daridorexant. All three drugs are currently FDA-approved for non-PTSD indications. In the future, additional drugs that will be tested (pending funding availability) may include generic drugs, drugs under marketing exclusivity, or new molecular entities.In addition to the efficiencies gained by simultaneous testing of multiple treatments, this study aims to address the clinical and biological heterogeneity of PTSD in military populations and develop a precision medicine approach through the identification, characterization, and validation of candidate biomarkers to identify the most effective therapy for each patient’s unique biological or clinical characteristics. These biomarkers, whether evaluated together or individually, within or across biomarker modalities, may be diagnostic of PTSD subtypes, predictive of treatment response, surrogate/monitoring markers of clinical efficacy, or pharmacodynamic markers of intervention effects. DOD PTSD APT GOVERNANCE STRUCTURE AND CURRENT PARTNERS:LEAD ORGANIZATION: USAMMDA is the funding and management organization of the DOD PTSD APT. The USAMMDA WBH PMO PTSD-DT program Product Manager (PdM) is responsible for the cost, schedule, and performance of the DOD PTSD APT and all technical decisions. The WBH PMO PTSD-DT program partnered through a variety of agreements with a team of experts in operational excellence, platform trial statistical methodology, drug development, and PTSD clinical assessment and pathophysiology to design and execute the DOD PTSD APT study. The team of experts that support the study through various committees and working groups are outlined below. NOTE: The Government does not indemnify its partners.CURRENT REGULATORY SPONSOR: The current regulatory sponsor is The Surgeon General, Department of the Army. The U.S. Army Medical Research and Development Command (USAMRDC) Office of Regulated Activities (ORA) provides regulatory-sponsor support and oversight for the trial. USAMMDA has partnered with USMRDC ORA for their support through an interagency agreement. It is the intent that this upcoming RPP would seek a new performer to replace the current USAMRDC regulatory sponsor through the MTEC OTA.EXECUTIVE COMMITTEE: The study’s central governance body is the APT for PTSD Executive Committee (APEC). The APEC is chaired by the DOD PTSD WBH PMO and includes leads from each of the study partners and working groups. The APEC provides expert insight and advice on major study design elements to the PdM. The APEC optimizes the study design and executes operational tasks to meet the study objectives.MTEC: MTEC is a biomedical technology consortium collaborating with multiple government agencies under a 10-year renewable Other Transaction Agreement (OTA), Agreement No. W81XWH-15-9-0001, with the U.S. Army Medical Research Acquisition Activity (USAMRAA). Through MTEC and the OTA, USAMMDA has partnered with Berry Consultants, Citeline, and Pharmaceutical Product Development (PPD) to perform the following functions in support of the DOD PTSD APT. The period of performance for the MTEC partners started in 2020 and has a current end date of November 2025, however pending funding availability, it is possible the end date may be extended.STATISTICAL MODELING: Berry Consultants, LLC is responsible for operationalizing and executing the statistical simulations and calculations, and developing key documents (e.g., statistical sections of the master protocol, statistical analysis plan, operational plan) to inform the DOD PTSD APT design, initiation, and execution.DRUG SELECTION: Citeline is responsible for operationalizing and executing the drug selection process in consultation with the Drug Selection Working Group, and for providing input to the APEC for initial and continual assessments of interventions to be tested in the DOD PTSD APT.CLINICAL RESEARCH ORGANIZATION (CRO): PPD, LP is responsible for operationalizing the DOD PTSD APT design by establishing the clinical trial infrastructure and executing the DOD PTSD APT in alignment with guidance from the APEC.SPONSOR’S OFFICE TECHNICAL REPRESENTATIVE (SOTR): The WBH PMO PdM serves as the SOTR for all MTEC partners working on the DOD PTSD APT, including Berry Consultants, Citeline, and PPD. The SOTR’s responsibilities include verifying that MTEC partners perform the technical requirements outlined in their scope of work in accordance with the terms, conditions, and specifications of their awards; acceptance for the Government of services performed, i.e., approval of deliverables; invoice review and approval; and monitoring compliance with MRDC Office of Human Research Oversight requirements. The SOTR will serve the same function for future MTEC awards working on the DOD PTSD APT, such as the regulatory sponsor (subject of this upcoming RPP).ADVISORY TEAM AND WORKING GROUPS: One steering committee and three Working Groups (WGs) include DOD expertise to ensure the testing design and execution align with active-duty military requirements. The WGs operate at both the strategic and tactical levels and provide subject matter expertise in PTSD clinical trials. All WGs review and provide input into the master protocol, drug appendices, and related key study documents.The Joint Steering Committee operates at a strategic level to provide consultation to the PdM to ensure a successful program and to facilitate coordination across government entities, as well as connections to individuals or organizations who may be helpful. The members are from the DOD, the US Department of Veterans Affairs, the FDA, and several National Institutes of Health components.The Drug Selection WG is comprised of subject matter experts in clinical pharmacology, and PTSD drugs, who review and provide feedback on the deliverables from the MTEC Drug Selection Vendor (via DOD coordination). This WG provides input to the APEC for their recommendations to the PdM for drugs and doses to be tested in the DOD PTSD APT. During study execution, the DSWG will work with the APEC to inform their drug selection recommendations beyond the initial set of drugs to be tested. USAMMDA has partnered with the San Francisco Veterans Administration through an interagency agreement for contracting with the Drug Selection WG members.The Clinical WG members have significant expertise in developing, validating, and implementing clinical assessments, including cognitive, functional, and Quality of Life assessments, primarily in military samples. This WG provides input to the APEC for their recommendations on key protocol elements and development of key study documents during the design and execution of the trial that align with the study objectives, including inclusion/exclusion criteria, inclusion of clinical assessments, and identification of clinical endpoints. The CRO, PPD, has subcontracted with individual consultants for the Clinical WG.The Biomarker WG has expertise in a variety of specific biomarker modalities. This group provides input to the APEC for their recommendation of key protocol elements that align with the study objectives, including an integrated approach to optimal collection and analysis of PTSD-relevant multi-modal biomarker data. This WG will also review emerging biomarker data from main stage analyses to inform precision medicine objectives, potential diagnostic development, and work with the APEC to inform their drug selection recommendations beyond the initial set of drugs to be tested. The CRO, PPD, has subcontracted with individual consultants for the Clinical WG.SCOPE OF WORK:This upcoming RPP focuses on identifying an organization capable of serving as the regulatory Sponsor to hold the existing Master Protocol IND application to the U.S. FDA for the DOD PTSD APT, scheduled to begin enrollment the second quarter of 2023. The DOD WBH PMO requires a partnership with a regulatory Sponsor who will include the WBH PMO as part of the Sponsor Organization.[1],[2]The replacement regulatory sponsor organization will work closely with the WBH PMO PTSD-DT PdM, and must be willing and able to interact with the other partners described above, with the exception of the current regulatory sponsor, in coordination with the WBH PMO. It is the intent that a contractual relationship with the new regulatory sponsor would be executed under the MTEC OTA. Interested parties are encouraged to review the MTEC Base Agreement, which includes the overarching terms and conditions from the OTA for prototype projects between the Government and MTEC that all Research Project Awardees are expected to agree to. The MTEC Base Agreement can be found on the MTEC Website (within the Documents Library: https://www.mtec-sc.org/documents-library/).POTENTIAL FUNDING AVAILABILITY AND PERIOD OF PERFORMANCE:The U.S. Government (USG) currently has funds available for this effort. Offerors are expected to propose budgets they believe are reasonable for the scope of the Regulatory Sponsor role based on the expectations described within this upcoming RPP. MTEC expects to make a single award to a qualified Offeror to accomplish the scope of work.ACQUISITION APPROACH:This upcoming RPP will be conducted using the Enhanced White Paper approach. In Stage 1, Offerors are invited to submit Enhanced White Papers using the mandatory format contained in this upcoming RPP. The Government will evaluate Enhanced White Papers submitted and select those that best meet their current priorities using the evaluation criteria described in the upcoming RPP. Offerors whose proposed solution is selected for further consideration based on the Enhanced White Paper evaluation will be invited to submit a full cost proposal in Stage 2. Notification letters will contain specific Stage 2 proposal submission requirements.This upcoming RPP will be posted to the MTEC website (mtec-sc.org) and SAM.gov to notify interested parties. The RPP is expected to be released as soon as possible and will have a short proposal preparation period (approximately 30 days). MTEC membership is required for the submission of an Enhanced White Paper in response to this upcoming MTEC RPP. To join MTEC, please visit http://mtec-sc.org/how-to-join/.MTEC:The MTEC mission is to assist the U.S. Army Medical Research and Development Command (USAMRDC) by providing cutting-edge technologies and supporting life cycle management to transition medical solutions to industry that protect, treat, and optimize Warfighters’ health and performance across the full spectrum of military operations. MTEC is currently recruiting a broad and diverse membership that includes representatives from large businesses, small businesses, “nontraditional” defense contractors, academic research institutions and not-for-profit organizations.POINT OF CONTACT:For inquiries regarding this pre-announcement, please direct your correspondence to Dr. Lauren Palestrini, MTEC Chief Science Officer, lauren.palestrini@mtec-sc.org.[1] 21 CFR 312.3 indicates a “Sponsor” may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization.[2] FDA’s Guidance for Clinical Trial Sponsors (March 2006) is relevant to parties who participate in leadership roles in a clinical investigation other than sponsors, including funding organizations and/or others who share decision-making authority for a trial. The guidance indicates Sponsor (see 21 CFR 312.2 definition of Sponsor) interaction with the DSMB to provide important information regarding goals, plans, schedule, and resources, and to address DSMB questions when reviewing interim comparative data, has significant advantages.