SOW-Deliverables.GTRP.Lentivirus.Core.Lab.Renewal.NHLBI-CSB-HV-2012-09.NIR.pdf

Gene Therapy Resource Program, Renewal Lentivirus Core Production Laboratory NHLBI-CSB-HV-2012-09-NIR (Formerly NIH-NHLBI-HV-12-09) February 22, 2011

STATEMENT OF WORK

I. BACKGROUND AND HISTORY

a. Background:

Over the years since the inception of gene transfer, a better understanding of the immunology and structural biology of vectors has emerged. Delivery systems with viral vector systems and non-viral vector systems continue to evolve, and in recent years a series of novel vectors and new viral serotypes have shown promise in preclinical studies.

Many diseases may benefit from gene transfer, including monogenic genetic diseases and acquired conditions, such as cystic fibrosis, hemophilia, alpha-1 antitrypsin deficiency, certain malignancies and immunodeficiencies, peripheral and cardiovascular diseases, and others.

Given the advances in the development of new gene delivery mechanisms, understanding of disease biology, and increase in the number of clinical trials conducted over the past several years, continued research in vector system development and clinical applications is critical to advancing the gene transfer field into the realm of medical practice. Gene transfer still holds promise for providing treatment options for millions of patients who are affected by challenging diseases.

Though great strides have been made in the field of gene transfer, the translation of gene transfer research from the bench to the clinic remains an arduous task requiring diverse areas of expertise. Expertise is needed in virology, vectorology, immunology, pharmacology, toxicology, animal model development and testing, regulatory science, clinical trials science, and medical expertise in specific disease areas, ranging from very common to very rare diseases.

b. History: In June 2005 the NHLBI convened an expert Working Group to better understand the impediments to clinical progress in gene therapy and to advise the NHLBI how to best direct its limited resources to facilitate translational research in the field of gene therapy. The NHLBI responded to these recommendations by establishing the NHLBI Gene Therapy Resource Program (GTRP) in March 2007. The GTRP consist of a clinical coordinating center (CCC) that oversees and coordinate the logistics of the core laboratories and provide regulatory assistance for clinical trials. In addition, the GTRP has four Core Laboratories; a preclinical-grade vector production core laboratory; a clinical-grade vector production core laboratory for adeno-associated virus (AAV); a clinical-grade vector production core laboratory for lentivirus; and a pharmacology/toxicology core laboratory. The current Lentiviral vector core has extensive experience producing and certifying retroviral vectors- from early murine-based vectors to novel HIV-1based Lentiviral vectors. The core has provided pilot production runs prior to large scale vector production, producing vectors tailored to investigators’ needs, release testing to certify vectors for clinical use, performing post-

NHLBI-CSB-HV-2012-09-NIR (Formerly NIH-NHLBI-HV-12-09) clinical-trial monitoring for replication competent viruses and assisting investigators with FDA-required documentation.

II. OBJECTIVES

The objective of the NHLBI Gene Therapy Resource Program (GTRP) renewal is to continue supporting the translation of basic research in gene therapy to clinical application in the areas of heart, lung, and blood diseases. The GTRP renewal will continue to provide resources in the areas of preclinical and clinical-grade vector production in accordance with Good Manufacturing Practices (GMP), and in the conduct of pharmacology/toxicology studies. In addition, the GTRP renewal will provide funds and regulatory assistance to investigators wishing to conduct gene therapy clinical trials. The GTRP renewal will consist of the following five components: 1) a clinical coordinating center that will oversee and coordinate the logistics of the core laboratories and provide regulatory and funding assistance for clinical trials; 2) a preclinical-grade vector production core laboratory; 3) a clinical-grade vector production core laboratory for adeno-associated virus (AAV); 4) a clinical-grade vector production core laboratory for lentivirus; and

5) a pharmacology/toxicology core laboratory.

The primary objective of the lentiviral vector production core laboratory is to provide large-scale, clinical-grade vectors (to NHLBI-funded investigators who are actively involved in gene transfer studies using large and small animal models.

III. SCOPE

The Lentiviral vector production core laboratory contract involves production of scalable clinical grade Lentiviral vectors, in accordance with Good Manufacturing Practices (GMP), as defined by the Food and Drug Administration (FDA), and applicable State and Federal regulations, for use by NHBLI funded investigators. It is expected that the contractor will produce an average of Twelve (12) vector batches per year for a minimum of three (3) batches for clinical studies or for safety and efficacy/dose/pharmacology/toxicology testing with large animal models.

The LCL will continue to 1) participate in the Steering Committee (SC), and subcommittees as necessary, and attend SC meetings and participate in teleconferences, 2) provide and maintain a Manual of Procedures (MOP), 3) update, in collaboration with the SC, a customer satisfaction survey for investigators to evaluate the quality and acceptability of the product and timeliness of the service provided, 4) update and maintain, in collaboration with the Clinical Coordinating Center (CCC), a secure and password protected web site page and provide updates to the CCC as needed, 5) produce scalable clinical grade lentiviral vectors, in accordance with Good Manufacturing Practices (GMP), as defined by the Food and Drug Administration (FDA), and applicable Federal and State regulations, for use by NHLBI-funded investigators,6) maintain, in a secure and confidential manner, an electronic database of all orders made for vector production

NHLBI-CSB-HV-2012-09-NIR (Formerly NIH-NHLBI-HV-12-09) and submit data, as defined and called for in the MOP, 7) prepare and ship vectors, in accordance with the MOP and state and Federal guidelines, upon completion of production and testing, 8) maintain product-related inventories in a secure and confidential manner, 9) monitor facilities to ensure quality control of vector production and accuracy and completeness of production data, and maintain and make available for review, as necessary, records of monitoring activities, and

10) prepare materials for and participate in site visits to the contractor’s facilities and ensure that up-to-date versions of all required certifications, inspections, and assurances are available for review during site visits.

IV. SPECIFIC REQUIREMENTS AND TASKS

a. Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government, as needed to perform the Statement of Work set forth herein.

b. The Contractor shall deliver the items specified in the Statement of Work and in ARTICLE C.2 to the destinations indicated in ARTICLE F.1.

c. Specifically, the Contractor shall:

1. Within the first 21 calendar days, develop, finalize, and implement a transition plan with a timetable of costs to smoothly transition the operations of the GTRP Lentivirus Vector Production Core Laboratory, should the existing GTRP Lentivirus Vector Production Core Laboratory be replaced. The transition plan shall be initiated upon contract award, with completion within 90 calendar days of contract award. This may include, but is not limited to the following: strategy and plans to complete transfer of all lentivirus studies that have not been started; strategy and plans to complete transfer of all lentivirus studies that have been completed; and plans for establishing communications with the existing or new GTRP CCC, vector core laboratories, NHLBI program members, Steering Committee members, program collaborators and colleagues. The transition plan shall be initiated upon contract award, with completion within 90 calendar days of contract award.

2. The Principal Investigator shall participate as a member of the GTRP Steering Committee (SC), and subcommittees as necessary, which will provide overall guidance for the GTRP.

The Principal Investigator shall also participate in conference calls and attend SC meetings.

3. Update and maintain a Manual of Procedures (MOP) describing methodologies to be employed and any new methodologies as they are developed. The MOP will describe processing of requests, production methods, a safety plan, quality assurance/quality control (QA/QC) procedures, methods for shipping materials, and procedures for maintaining records and reporting. Provide copies of the MOP amendments thereto.

NHLBI-CSB-HV-2012-09-NIR (Formerly NIH-NHLBI-HV-12-09)

4. Update, in collaboration with the SC, a customer satisfaction survey for investigators to evaluate the quality and acceptability of the product and timeliness of the service provided.

5. Produce scalable clinical grade lentiviral vectors, in accordance with Good Manufacturing

Practices (GMP), as defined by the Food and Drug Administration (FDA), and applicable State and Federal regulations, for use by NHLBI-funded investigators.

6. Evaluate and report to the CCC the feasibility of and approximate time required to fulfill each vector request.

7. Employ and maintain state-of-the-art vector production technology for small- and large-scale productions. This may require the contractor to develop or refine such technology (or technologies).

8. Maintain, in a secure and confidential manner, an electronic database of all orders made for vector production, including the name of the requesting investigator, the grant number (if applicable), name of the project and the vector provided, procedures adopted for GMP vector production, information on quality control and quality assurance methods, vector lot numbers, and dates of vector release. Submit data as defined and called for in the MOP.

9. Provide reports as described in Part V. Reporting Requirements and Deliverables and

ARTICLE C.2. Make available, for site visits, documents and data to support these reports.

10. Prepare and ship vectors, in accordance with the MOP and Federal and State guidelines, upon completion of GMP production and testing.

11. Maintain the GTRP web site page by providing updated information to the CCC for posting on the GTRP web site.

12. Maintain product-related inventories in a secure and confidential manner.

13. Monitor facilities to ensure quality control of vector production and accuracy and completeness of production data. Maintain and make available for review, as necessary, records of monitoring activities.

14. Provide a customer satisfaction survey to each investigator, upon completing production and shipment of the requested vector.

15. Prepare materials for and participate in site visits by NHLBI staff and outside experts to the

NHLBI-CSB-HV-2012-09-NIR (Formerly NIH-NHLBI-HV-12-09) contractor's facilities. Ensure that up-to-date versions of all required certifications, inspections, and assurances are available for review during the site visits by NHLBI and the

FDA.

16. Update and maintain the MOP, by amendments thereto, to reflect changes in operations and/or procedures during the life of the contract.

Gene Therapy Resource Program Lentivirus Vector Production Core Laboratory– Renewal NHLBI-CSB-HV-2012-09-NIR (Formerly NIH-NHLBI-HV-12-09) Reporting Requirements and Deliveries

V. REPORTING REQUIREMENTS AND DELIVERIES

In addition to those reports required by other terms of the contract, the contractor shall prepare and submit the following reports in the manner stated below and in accordance with the Statement of Work.

1.

Within the first 21 calendar days, develop, finalize, and implement a transition plan with a timetable of costs to smoothly transition the operations of the GTRP Lentivirus Vector Production Core Laboratory, should the existing GTRP Lentivirus Vector Production Core Laboratory be replaced. The transition plan shall be initiated upon contract award, with completion within 90 calendar days of contract award. This may include, but is not limited to the following: strategy and plans to complete transfer of all lentivirus studies that have not been started; strategy and plans to complete transfer of all lentivirus studies that have been completed; and plans for establishing communications with the existing or new GTRP CCC, vector core laboratories, NHLBI program members, Steering Committee members, program collaborators and colleagues. The transition plan shall be initiated upon contract award, with completion within 90 calendar days of contract award.

Transition Plan:

2.

Within the first 45 calendar days, the Contractor shall be responsible for developing and submitting a master spreadsheet and Gantt chart summarizing the key proposed activities and deliverables (including but not limited to those enumerated below) with timelines for the entire program using a separate chart for each year funded.

Comprehensive Program Summary and Timetable;

3.

The Contractor shall be responsible for augmenting and maintaining the existing manual of procedures containing all SOPs and policies governing the GTRP. This includes providing a description of all operations of the CCC, as well as any additions or revisions of procedures as necessary.

Manual of Procedures (MOP)

4.

Vectors and information related to the methodologies of vector production shall be provided to research investigators for whom specific requests have been filled. Biological specimens shall be shipped according to the procedures in the Manual of Operations.

Clinical-grade or Clinical-grade vectors

5.

Within 12 months of the contract’s expiration date, the Contractor shall begin working with the NHLBI COTR to develop a transition plan for either the phase out of the GTRP at the end of the contract period or for transition of the contract’s activities to another contractor should the GTRP be renewed. A draft of this transition plan is due to the NHLBI COTR within six (6) months of the contract’s expiration date and the final transition plan shall be submitted upon the contract’s expiration date. The transition plan is considered a contract deliverable and its due date(s) are set forth in Section F of this contract.

Technical and Business Transition Plan

6.

The contractor shall provide the CCC feedback on how to improve utility and access to the GTRP’s public and private website.

Website

7.

This narrative shall document and summarize all work results for the period covered on the monthly invoice. This narrative shall be attached to the copy of the monthly invoice sent to the Contracting Officer. Specifically, the report shall include the contract number, title, period of performance being reported, Contractor’s name and address, telephone and facsimile numbers, and date of submission. In addition, it shall include

Monthly Technical Narrative

a. A description of the work performed during the reporting.

b. A brief overview of any problems that occurred during the current reporting period and their resolution or status.

c. A summary of activities planned for the next reporting period.

d. A list of projects approved and initiated. A description of dissemination accomplished (e.g., abstracts submitted or approved, presentations by GTRP investigators) and a list of the manuscripts in preparation or submitted and publications resulting from the work of the Registry.

8.

The semi-annual technical reports, in a narrative form, shall be concise and informational.

They shall include but not be limited to: a cover page which includes the contractor’s name and address, the contract number, the name of the Principal Investigator; a description of overall progress, current problems which may impede performance, and proposed corrective actions; and activities planned for the next reporting period. Specific vector production information shall be in tabular format and include the following: the name of the requesting investigator, the grant number (if applicable), the name of the project and the vector provided, the procedures adopted for vector production, information on quality control and quality assurance methods, vector lot numbers, and date of vector release. The report shall also address administrative matters and staffing changes. A semi-annual technical report will not be due when the final report is due.

Semi-Annual Technical Progress Report

9.

Copies of manuscripts (published or unpublished) derived from research under the contract and copies of all abstracts, manuscripts, preprints, and publications that resulted from work conducted or any protocol or method developed specifically under this contract during the performance period.

Abstracts and Manuscripts

10.

This report shall include a summation of the work performed and results achieved for the entire contract period of performance. The report shall be prepared in the format described for “Monthly Technical Progress Reports” and be in sufficient detail to describe comprehensively the results achieved. The report shall also include a plan for future long-term support of the GTRP lentiviral vector core laboratory through additional funding sources other than the Government. A draft Final Report is due within ten (10) months of the

Final Technical Report contract’s expiration date for Contracting Officer and Contracting Officer’s Technical Representative’s review and approval to proceed with the Final Report. The Final Report shall be submitted on or before the last day of the contract performance period and shall be in sufficient detail to serve as a reference document.

11.

The Contractor shall prepare a Transition Plan within thirteen (13) months of the contract’s expiration date, detailing the contract close-out activities, with dated milestones by which Transition Plan activities will be completed. A comprehensive list of the final contract deliverables must be identified and included in the Transition Plan as well as made a part of the final report.

Transition Plan

12.

The contractor shall submit security information reports required by other terms of the contract.

Information System Security and Physical Access Reporting Requirements:

13.

The contractor shall submit an annual Section 508 report in accordance with the schedule set forth in the ELECTRONIC AND INFORMATION TECHNOLOGY ACCESSIBILITY Article in SECTION H of this contract. The Section 508 Report Template and Instructions for completing the report are available at:

Section 508 Annual Report http://www.hhs.gov/od under "Vendor Information and Documents."

14. Multiple Principal Investigators Leadership Plan

The Contractor shall submit a revised/updated Leadership Plan in the event of a change in any of the Principal Investigators named in the Key Personnel Article in SECTION G of this contract. The revised plan is subject to review and approval by the Contracting Officer.

15.

The Contractor shall submit an Annual Invention Report as required by FAR CLAUSE 52.227-11 including, but not limited to, the invention disclosure report, the confirmatory license, and the government support certification. The annual utilization report shall be submitted in accordance with Articles in SECTION F and H of the contract.

Invention Reporting Requirement and Annual Invention Report

16.

The Contractor will be required to prepare and submit, with the final report, a summary (not to exceed 200 words) of salient results achieved during the performance of the contract.

Summary of Salient Results

17.

Contractor shall submit monthly invoices as detailed in SECTION G of the contract.

Monthly Invoices

18.

The Contract shall submit Individual Subcontract Reports (ISR) and a Summary Subcontract Report (SSR) in accordance with Articles in SECTION F and H.

Subcontracting Reports http://www.hhs.gov/od�