attach-01-sow-2020-05-15_final.pdf

ATTACHMENT 1

May 15, 2020 Page 1 of 8

STATEMENT OF WORK (SOW)

Title: Clinical Research Support and Collaboration for NHGRI Protocols

BACKGROUND

The National Human Genome Research Institute (NHGRI) Division of Intramural Research plans and conducts a broad program of laboratory and clinical research to translate genomic and genetic research into a greater understanding of human genetic disease, and to develop better methods for the detection, prevention, and treatment of heritable and genetic disorders. To support this mission, the NHGRI’s Office of the Clinical Director (OCD) focuses on finding new and better ways to help patients affected by genetic disorders. To that end, the office provides oversight and guidance to NHGRI scientists working to develop better diagnostic methods, innovative therapeutic approaches and improved medical management strategies for genetic disorders.

The NHGRI, through the OCD, conducts a number of different types of research studies related to genetic conditions and the way that genes affect health, including natural history studies and therapeutic trials on rare diseases; statistical expertise has been found to be essential in determining the number of patients needed to discern a difference among groups, selecting an appropriate study design, and helping perform ongoing and final analyses. Conducting studies in the current and planned NHGRI protocol requires meticulous protocol monitoring, data management services, regulatory support of new and existing Investigational New Drugs (INDs) specializing in project oversight for vector management in order to remain compliant with established regulatory guidelines. Also essential is administrative assistance to run the Institute’s Data Safety and Monitoring Board (DSMB).

SCOPE

The NHGRI requires a contractor that offers a full range of (1) clinical research services, including clinical research management, statistical design and analysis, protocol development and data management, clinical site management, pharmacovigilance services, quality assurance, and regulatory affairs support; (2) specialty services, including DSMB services; (3) analytical solutions, including bioinformatics, and (4) integrated clinical trial management through an organized system of tracking clinical trials. The contractor should be able to comprehensively apply these services to provide leadership and support for the current request for protocol monitoring and data management support services and further scope as applicable after protocols are finalized. The contractor should be able to assign a dynamic team of qualified personnel who have experience in clinical trial design and regulatory expertise, especially as relates to studies of rare diseases, genetic conditions, gene therapy (including via AAV9 vectors), including as relevant to pediatric as well as adult conditions.

The OCD requires senior level statisticians to assist in the development and execution of clinical research protocols. Some pre-clinical studies also require statistical expertise provided by this contract. Issues to be addressed include power analyses, sample size, group analyses, trends, and

May 15, 2020 Page 2 of 8 stopping rules, as well as more complex topics.

Finally, the OCD requires administrative assistance to run the Institute’s DSMB. This committee serves the NHGRI Institutional Review Board (IRB) by reviewing clinical protocols in which there is an intervention, including if a placebo is involved. Contract support is needed for arranging meetings, recording minutes, and communicating with members of the DSMB. The contractor also provides formal, written reports to the Director, NHGRI, and to the NHGRI IRB, as required by the DSMB charter. A member of the Contractor’s staff shall serve as Executive Secretary of the DSMB.

NHGRI requires a contractor that is equipped with all the required resources to provide the requested services. All the tasks related to this project require the entity to have in place the necessary network and personnel to successfully achieve all deliverables which allows for continuity in the completion of the work and the final product.

Task Area 1: Protocol Monitoring and Data Management Support Services

Scope:

Under this task area, the contractor shall provide protocol monitoring and data management support services in order to remain compliant with NIH’s established regulatory guidelines.

The company should be uniquely equipped with all the required resources to provide the requested services, preferably via one vendor to ensure efficiency, cost-efficacy, and optimal communication. This allows for continuity in the completion of the work and the final product.

The contractor shall utilize pre-set systems such as the Clinical Trial Database (CTDB) or REDCap, and comply with the current set of Standard Operating procedures (SOPs). The contractor shall provide project management oversight that includes conference calls with the sponsor to discuss study status, operational and analytic issues, as needed; Assure compliance with corporate requirements; Coordination and tracking of all study-related responsibilities;

Coordination and management of internal staff activities and timelines; and participation in conference calls with study leadership, as needed. Contract staff shall primarily work off-site and travel to the NHGRI as needed.

***NOTE: For cost purposes estimate eight (8) days per month that the Contractor (one staff member) shall be required to work on-site at NHGRI in Bethesda, MD.

Tasks:

Under this task order, the contractor shall independently provide expert support services to satisfy the overall operational objectives of the NHGRI. The primary objective is to provide services and deliverables through performance of support services including but not limited to the following tasks:

• Manage the NHGRI Clinical Director’s intramural monitoring and quality assurance program.

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• Establish, update and implement the SOP for protocol monitoring and quality assurance.

• Prepare and enforce corrective and preventative action (CAPA) plans.

• Review the status of all ongoing clinical trials currently in progress with respect to monitoring needs, including the past frequency of visits and issues encountered and create a Site Monitoring Plan which may include the following: overall project objectives; primary and secondary study end points; brief synopsis of the study;

objectives for each monitoring type visit (assessment, Initial, Routine, Site Closeout Visit, or For-Cause); Frequency and scope of source document verification [to include eligibility criteria, primary outcome criteria, Adverse Events (AEs)/ Serious Adverse Events (SAEs)]; specimen collection, inventory, and shipping process, test article audit;

and timeline for completion of monitoring reports and follow-up items.

• Assume responsibility for managing the clinical trials assurance schedule for audits and track visit action items.

• Lead NHGRI clinical staff training for FDA-regulated clinical trials; prepare informational materials for training; educate clinical staff on human research protection policy updates.

• Conduct on-site source document verification for intramural studies. Evaluation of study performance will be examined on an ongoing basis throughout a clinical research team’s participation in studies, including observations regarding performance in site visit monitoring reports and other measures defined with the developed SOP documents.

• Document protocol non-compliance and unreported safety events as described in the clinical protocol and as outlined in the monitoring SOP.

• Conduct investigational product and study supply accountability from receipt, storage, and dispensation to return or destruction.

• Support clinical investigators by preparing and maintaining the investigator regulatory file.

• Verify data from NHGRI intramural clinical trials; verify NIH Clinical Center Pharmacy inventory records.

• Prepare regulatory documentation and official binders for NHGRI intramural clinical trials.

• Manage the NHGRI Clinical Director’s program for submitting data to the national registry and results database of clinical studies of human participants (clinicaltrials.gov ).

• Perform data and statistical analysis to prepare clinical trial data for submission to clinicaltrials.gov ; prepare informational materials on clinical trials for use on clinicaltrials.gov.

• Serve as liaison to regulatory offices and agencies, including the NIH Office of Human Subjects Research Protections, the NIH Office of Intramural Research, the NHGRI Institutional Review Board, the NHGRI Bioethics Core, the National Library of Medicine and the NIH CC Office of Protocol Services.

• Contribute to and participate in OCD policy activities for human research protection and clinical trial management.

• Prepare recommendations to the Clinical Director for updates to the corresponding SOPs and quality management guidelines used for monitoring support based on policy group participation.

• Perform data management for small NCI-CTEP-sponsored study:

https://clinicaltrials.gov/ https://clinicaltrials.gov/ https://clinicaltrials.gov/

May 15, 2020 Page 4 of 8 o Create and submit quarterly report to CTEP (via CDUS) o Extract and summarize trial data from clinical records o Work with staff on tracking and reporting of adverse events o Complete case report forms o Create and maintain spreadsheets for data analysis o Maintain regulatory-compliant study database in pre-configured applications in use by NHGRI o Work with staff on data for regulatory reporting (sponsor, FDA, DSMB)

• Perform data management for other NHGRI clinical protocols o Work with staff on database creation for NHGRI protocols, primarily in the

NICHD-based Clinical Trials Database (CTDB) o Enter old study data into CTDB (back-data entry) o Act as intermediary between investigators and CTDB staff for creating, modifying and maintaining study databases

Deliverables:

Upon request, the contractor shall provide requested deliverables, including, but not limited to, the following:

• Status reports shall be provided upon the start of a new Protocol Monitor within 7 calendar days of the start or at an agreed upon date with the Contracting Officer’s Representative (COR).

Task Area 2: Regulatory Support for IND and IDE Submissions

The required activities involve regulatory support for intramural studies conducted by the NHGRI. There have been variations in current practice regarding who holds IND applications and Investigational Device Exemptions (IDEs) at NIH. As such it is now required that individual principal investigators no longer hold existing and new INDs and IDEs but rather they are held by the Institute. The mechanism for implementing this will vary by IC and could be fulfilled by an IC entity (e.g., CTEP), a central shared service center sponsored by an IC or ICs, the Office of the IC Clinical Director, an extramural office, etc. It will be the responsibility of the IC to establish how it conducts business and to document its practice to the Clinical Director, NHGRI as the NIH Institutional Official. NHGRI has determined that a third party will need to provide the regulatory support for existing and new INDs and IDEs.

The NHGRI requires that a contractor provide regulatory support for intramural studies related to existing and new INDs applications and Investigational Device Exemptions (IDEs) as it has been mandated that individual principal investigators can no longer hold INDs or IDEs in their name.

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Tasks:

The contractor shall provide expert support services including but not limited to the following tasks:

• Submit IND Applications, the transfer of these applications to Pharmaceutical partners, and any upcoming IND applications.

o Note: All submissions are to be made to the Food and Drug Administration (FDA) in electronic common technical document (eCTD) format.

• Support for new Sponsor-Investigator INDs will include drafting of the Introduction and General Investigational Plan, cover letter, and administrative forms (Forms FDA 1571 and 1572).

o Note: These documents will be drafted in conjunction with the clinical study team utilizing the final clinical protocol and consent documents provided by the Investigator. Finalized documents will be compiled with any applicable letters of cross- reference for submission in eCTD format. Prepare and submit two routine submissions a year to each application – an IND Annual Report (Clinical data update) and a single Safety Report (MedWatch).

• Conduct a review of each IND prior to its transfer to a Pharmaceutical Partner to ensure that the application is complete and that all obligations associated with the application applicable during the reporting period have been met. A submission to transfer the IND and all associated obligations, including reporting requirements, to another party will be drafted and submitted to the FDA upon transfer to the other party.

• Review each open IND be performed to ensure that the application is up to date and there are no outstanding reports or commitments to the FDA which require follow-up and/or further contact. Review serious adverse event reports (draft MedWatch or other documentation) and, upon review of the Investigator’s Brochure, Protocol, or other applicable documentation, provide a medical assessment regarding the causality and expectedness of the event, and therefore advise on the applicability of expedited reporting requirements. NHGRI staff will forward self-identified events to the contractor for review.

• For the IND Gap Analysis and review of the IND documentation that is not available electronically, the contractor may need to be on-site at NHGRI. All other tasks will be performed at the contractor’s site.

***NOTE: For cost purposes estimate 3 times per year that the Contractor (one staff member) shall be required to work on-site at NHGRI for 1 day.

Deliverables:

• Application-specific conference calls with the sponsor shall be scheduled one month prior to the IND Anniversary date, to discuss study status, upcoming reports, and other issues, as needed, which can impact submission timelines. Calls will be as needed to meet submission timelines.

• IND Annual Reports will be drafted and compiled from source data provided by the Sponsor-Investigator, including IRB submissions, clinical data tables, and other

May 15, 2020 Page 6 of 8 information, as appropriate, from the reporting period. The Contractor’s Regulatory Specialist will review the NHGRI IRB database on an annual basis and construct the list of events reported to the IRB for inclusion in the annual IND Report.

o For each Annual Report an eCTD Table of Contents will be used to drive submission drafting and to compile all required elements. Summaries of relevant clinical and nonclinical data will be drafted by the contractor from data provided by the Sponsor- Investigator. The report shall be provided by the contractor on an annual basis. The Government will review and recommend changes and return to the Contractor within 30 days of contract expiration for e-submission.

• Assembly of IND Annual Reports and Safety Reports in eCTD format, including drafting cover letter and completion of appropriate administrative forms.

• A review of all current INDs for completeness and to ensure that all regulatory obligations associated with the application have been met shall be completed within 30 days of award. This gap analysis will ensure that at the initiation of the contractor support all applications are complete and would withstand a regulatory or Pharmaceutical partner inspection. A plan to address any deficiencies found shall be provided as the deliverable from this task.

• For e-submission support, the currently available legacy submissions will be transferred over to PeC to allow appropriate cross references to past submission to be made in new submissions.

Task Area 3: Statistical Expertise and DSMB Support

The NHGRI, IRP, through the OCD, conducts a variety of research investigations related to genetic health and disease; these include natural history studies and therapeutic drug trials on rare diseases as well as other study types. For these studies, specific statistical expertise and experiences is needed for a variety of research requirements, including (but not limited to):

determination of the number of patients needed to discern a significant difference among groups, choice of appropriate study design, including length, number, and types of subjects, and the design and application of methods of conducting data analysis prior to, during, and after study completion. Importantly, the nature and implementation of these activities may have specific requirements according to regulatory entities; others may depend on the specific study question being asked. The OCD, NHGRI needs contract assistance for statistical expertise that can flexibly meet a range of needs for a variety of types of planned, ongoing, and completed genetic studies. The statistical expertise must include knowledge and experience with genetic and rare disease studies in particular (as well as experience providing support for broader clinical trials).

The Contractor shall provide consultation by senior level statisticians to assist in the development and execution of clinical research protocols. Some pre-clinical studies also require statistical expertise provided by this contract. Issues to be addressed include power analyses, sample size, group analyses, trends, and stopping rules, as well as more complex topics, the nature of which will depend on the study design and research hypotheses.

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The Contractor shall provide the NHGRI OCD with administrative assistance for the Institute’s DSMB. This committee serves the NHGRI Institutional Review Board (IRB) by reviewing clinical protocols in which there is an intervention, especially if a placebo is involved. The DSMB advises on issues such as study design, power estimates, stopping rules, interim analyses, and adverse event reporting. Members of the DSMB also assess objectively the seriousness of unexpected adverse events. The Contractor shall arrange meetings, record minutes, and communicate with members of the DSMB. The Contractor shall provide formal, written reports to the Director, NHGRI, and to the NHGRI IRB, as required by the DSMB charter. A member of the Contractor’s staff shall serve as Executive Secretary of the DSMB.

Tasks:

The contractor shall provide expert support services including but not limited to the following tasks:

• The Contractor shall provide timely statistical consulting, including reports of sample size, power analysis, stopping rules, etc., which are required to be delivered by the Contractor to the NHGRI physician or scientist seeking the consultation.

• The afore-mentioned reports may include, depending on the study design, research hypotheses, and reporting needs and requirements of a particular study, detailed statistical methods, results, and graphical presentations of the application of the statistical models and queries used.

• As with other research endeavors, statistical support is anticipated to be iterative; that is, the Contractor may anticipate that multiple versions and statistical reanalyzes may be required for the completion of any stage of a study.

• The Contractor shall arrange DSMB meetings and conference calls, and the preparation of minutes of the meetings, agendas, certificates of compliance with Conflict of Interest rules, and reports of deliberations.

• The Contractor shall provide minutes, agendas, which must be certified by the Director of NHGRI and delivered to the NHGRI Institutional Review Board and the NHGRI Clinical Director, in a timely fashion as stipulated by the DSMB Manual of Operations.

• The Contractor shall attend the annual DSMB meeting which will be held at the NIH campus in Bethesda, MD or may be conducted teleconference.

***NOTE: For cost purposes estimate one person traveling one time per year for one day for the annual DSMB meeting to be held in Bethesda, MD.

TRANSITION PLANS

The contractor shall accomplish a smooth, efficient, and orderly transition for the contract work at both the start and end of the contract. In order to accomplish this, the contractor shall develop a Transition Plan for (1) the start-up of contract services and (2) for the closeout of the contract upon completion of the contract effort and transition to any successor contractor. All electronic material, including, but not limited to, , status reports, regulatory materials, monitoring data, statistical models and results, and other documentation, developed through this contract must be

May 15, 2020 Page 8 of 8 in a non-proprietary format to permit ease of transport and use to Government staff and future contractors.

A. Transition and Startup

The Government requires that there be no disruption to services to be continued under this proposed contract. The contractor shall cooperate fully with the incumbent contractor. The contractor shall participate in meetings and telephone conversations with the COR and the incumbent contractor in which current procedures and activities are discussed in detail. Among the details that shall be addressed in the Transition Plan are staff training and orientation; transfer of all relevant documents including status reports, data analyses, and results developed during the contract period. The successor contractor shall provide the COR a list of all the steps and materials needed to carry out the transition and phase-in the various requirements of the contract per the SOW. This plan shall be developed in conjunction with the COR within the first 10 calendar days of contract award.

B. Contract Expiration

The contractor shall submit a transition plan that identifies a delivery schedule for transferring all of the materials identified to the successor contractor. The transition plan shall be developed in consultation with the COR.

The contractor shall perform the following activities for transition:

1. The contractor shall cooperate fully with the successor contractor.

2. The contractor shall participate in meetings and telephone conversations with the COR and the successor contractor in which current procedures and activities are discussed in detail.

3. The contractor shall provide a detailed list of all task orders currently in progress.

4. The contractor shall deliver to the successor contractor the following in accordance with the delivery schedule provided in the approved transition plan: electronic versions of all relevant documents developed under this contract.

5. The contractor shall be responsible for transportation of any equipment and materials and other costs required for the transition.

Scope: