SOW.Deliverables.GTRP.Renewal.Pharm-Tox.Feb.22.2011.pdf

Gene Therapy Resource Program Pharmacology/Toxicology Core Laboratory – Renewal RFP #NHLBI-CSB-HV-2012-06-NIR (formerly RFP NHLBI-HV-12-06) 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 consists of a Clinical Coordinating Center (CCC) and four Core Laboratories. The CCC is the linchpin of the GTRP and it is the only component of the GTRP whose work spans across all of the Cores and the NHLBI. The Pharmacology/Toxicology Core laboratory (PTC) works very closely with Investigators who request services to conduct pharmacology and toxicology studies on gene transfer agents being developed for clinical use. The PTC provides pharmacology and toxicology studies in small and large animal models. The PTC assists investigators with pharmacology/toxicology study design, participates with the investigator on pre-pre IND and pre-IND meetings with the FDA, conducts studies under Good Laboratory Practice Guidelines, performs clinical pathology and histopathology evaluations, conducts statistical analyses and prepares final reports for inclusion in IND submissions. Fulfilling the various service requests requires extensive interactions with all parties involved. Therefore, it is critical that the PTC have demonstrated experience in the conduct of complex research programs and knowledge of regulatory processes for animal testing as well as human gene therapy clinical trials.

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 (PCL); 3) a clinical-grade vector production core laboratory for adeno-associated virus (AAV); 4) a clinical-grade vector production core laboratory for lentivirus (LCL); and 5) a pharmacology/toxicology core laboratory (PTCL).

The primary objective of the pharmacology/toxicology core laboratory is to conduct preclinical vector toxicology testing and biodistribution studies using all types of gene therapy vectors in accordance with Good Laboratory Practices (GLP) in small and/or large animals, and applicable Federal and State regulations, for use by NHLBI-funded investigators.

III. SCOPE

The pharmacology/toxicology core laboratory is to conduct preclinical vector toxicology testing and biodistribution studies using all types of gene therapy vectors in accordance with GLP in small and/or large animals, and applicable Federal and State regulations, for use by NHLBI-funded investigators.

The PTCL will 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) develop, 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) develop, in collaboration with the Clinical Coordinating Center (CCC), maintain and update a secure and password protected web site page and provide updates to the CCC as needed, 5) conduct preclinical vector toxicology testing and biodistribution studies using all types of gene therapy vectors in accordance with Good Laboratory Practices (GLP) in small and/or large animals, and applicable Federal and State regulations, for use by NHLBI-funded investigators, 6) maintain an established facility to support rodent, non-human primate (NHP), and large animal pharmacology/toxicology and biodistribution studies 6) adhere to the treatment of animals in accordance with IACUC (Institutional Animal Care and Use Committee) guidelines, 7) monitor facilities to ensure quality control of pharmacology/toxicology studies and

February 22, 2011 that a regulatory framework is established to ensure consistent data quality. Develop plans to facilitate rapid communication of adverse toxicological results to the CCC and NHLBI and maintain and make available for review, as necessary, records of monitoring activities, and 8) 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 Pharmacology/Toxicology Core Laboratory, should the existing GTRP Pharmacology/Toxicology Core Laboratory be replaced. This may include, but is not limited to the following: strategy and plans to complete transfer of all pharmacology/toxicology studies that have not been started; strategy and plans to complete transfer of all pharmacology/toxicology 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. Provide and maintain a Manual of Procedures (MOP) describing methodologies to be employed and any new methodologies as they are developed. This MOP shall conform to Good Laboratory Practice (GLP) guidelines and include procedures for gene therapy pharmacological/toxicological studies in both large and small animals. Provide copies of the MOP, and any amendments thereto, as described in ARTICLE C.2.

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.

February 22, 2011

5. Conduct preclinical vector toxicology testing and biodistribution studies using all types of gene therapy vectors in accordance with Good Laboratory Practices (GLP) in small and/or large animals, and applicable Federal, State, and local regulations for use by NHLBI-funded investigators. Provide, in accordance with the MOP, written reports of the results of completed pharmacological/toxicological studies.

6. Employ and maintain state-of-the-art pharmacology and toxicology assays. This may require the contractor to develop or refine such technologies.

7. Maintain an established facility to support rodent, non-human primate (NHP), and large animal pharmacology/toxicology and biodistribution studies.

8. Adhere to the treatment of animals in accordance with IACUC (Institutional Animal Care and Use Committee) guidelines.

9. Evaluate and report to the CCC the feasibility of and approximate time required to fulfill each pharmacological/toxicological request.

10. Maintain, in a secure and confidential manner, an electronic database of all orders made for pharmacological and/or toxicological studies, including the name of the requesting investigator, the grant number (if applicable), the name of the project and the vector studied, the procedures adopted for toxicology studies, information on quality control and quality assurance methods, information on the vector used, the lot number, and all data pertinent to the pharmacological and/or toxicological study. These records shall be complete, accurate, legible, well-organized, and comprehensive. Submit data as defined and called for in the

MOP.

11. Provide reports as described in ARTICLE C.2. Make available, for site visits, documents and data to support these reports.

12. Monitor facilities to ensure quality control of pharmacological/toxicological studies and that a regulatory framework is established to ensure consistent data quality. Develop plans to facilitate rapid communication of adverse toxicological results to the CCC and NHLBI.

Maintain and make available for review, as necessary, records of monitoring activities.

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

GTRP web site.

14. Provide a customer satisfaction survey to each investigator, upon completing toxicological testing.

15. Participate as a member of the GTRP SC as described in Item1 and, as necessary, in teleconferences and meetings with the investigator requesting the toxicological study, NHLBI staff, and the FDA.

16. Prepare materials for and participate in site visits by NHLBI staff and outside experts to the contractor’s facilities. Ensure that up-to-date versions of all required certifications, inspections, and assurances are available for review during site visits and for cause audits by NHLBI and FDA.

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 Preclinical Vector Production Core Laboratory, should the existing GTRP Preclinical Vector Production Core Laboratory be replaced. This may include, but is not limited to the following: strategy and plans to complete transfer of all preclinical studies that have not been started; strategy and plans to complete transfer of all preclinical 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.

Information related to the methodologies of preclinical vector pharmacological and toxicology studies and biodistribution shall be provided to research investigators for whom specific requests have been filled.

Pharmacology/Toxicology

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

Final Technical Report comprehensively the results achieved. The report shall also include a plan for future long-term support of the GTRP preclinical vector core laboratory through additional funding sources other than the Government. A draft Final Report is due within ten (10) months of the 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 submit security information reports required by other terms of the contract

Information System Security and Physical Access Reporting Requirements:

12.

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."

13. 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.

14.

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

15.

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

16.

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

Monthly Invoices

17.

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�