Redacted_JOFOC_Contract_HHSN272201100021I.pdf

Statement of Work April 7, 2015 ATTACHMENT A

ATTACHMENT 1 - BASE CONTRACT STATEMENT OF WORK

NIAID PRECLINCAL DEVELOPMENT SUPPORT

HHSN272201100021I

STATEMENT OF WORK

A. BACKGROUND AND INTRODUCTION

The development of vaccines and any other mucosally deliverable to prevent the spread of HIV infection is among the National Institute of Allergy and Infectious Diseases (NIAID) highest priorities.

In addition, vaccines administered to infected individuals have potential for inducing immune control of the infectious agent. While advances in immunology and molecular biology continue to offer an expanding array of approaches for the development of new vaccines/products, there is limited capacity to move promising concepts through the development process. In order to supplement limited industry involvement in developing vaccines, NIAID requires a nontraditional, proactive and developmentally-oriented program to provide preclinical development support for promising products when such products emerge from investigator-initiated research studies. NIAID will use this contract to more rapidly and efficiently close development and production gaps.

The Contractor shall carry out, either directly or through subcontractors and/or consultants, tasks in the following areas:

• Essential Core Activities

• Feasibility Assessments

• Audits

• Regulatory Documentation

• Process development and cGMP manufacture

• Safety and Immunogenicity Testing

NIAID utilizes advisory groups for guidance in identifying emerging opportunities and in selecting areas of emphasis for the Contractor to pursue. However, activities carried out by the Contractor will also assist NIAID in identifying these emerging opportunities. An Advisory Committee, formed by NIAID to include experts not involved with the operation of the contract, will evaluate and prioritize projects to be undertaken. Upon determination of a specific need that is appropriate to be fulfilled by the Contractor, NIAID will issue a task order. This action will initiate work on a project.

B. SCOPE

The Contractor shall provide NIAID with a broad and flexible range of nontraditional, proactive and developmentally-oriented capabilities to provide preclinical development support for promising products when such products emerge from investigator-initiated research studies. These capabilities will allow NIAID to more rapidly and efficiently close development and production gaps. The Contractor shall assist NIAID staff in providing all support needed for small-scale production, preclinical testing and documentation leading to Investigational New Drug (IND) submission for Phase I, II, and III clinical testing.

C. GENERAL DESCRIPTION OF TASK AREAS

1. Essential Core Activities: This task area includes essential activities that shall be performed by the

Contractor on a regular basis and consists of the following:

a. Project Management

b. Quality Assurance/Quality Control

c. Information Technology and Data Management

d. Storage and Shipping

e. Personnel and Physical Infrastructure

f. Reporting Requirements/Deliverables

g. Transition

2. Feasibility Assessments: Under this task area, the Contractor shall assess products for feasibility of design, development, manufacture, potency assay development and stability for the development of phase I-III clinical trial materials.

3. Audits: Under this task area the Contractor shall conduct, review and evaluate audits. Types of audits to be conducted include, but are not limited to, technical and/or facilities audits.

4. Regulatory Documentation: Under this task area, for products produced and/or tested for use in

NIAID-sponsored research, in collaboration with the product supplier, the Contractor shall develop a Master File, Investigator’s Brochure, and compile an IND application, including a clinical trial protocol (provided by NIAID) appropriate for submission to the U.S. Food and Drug Administration (FDA). [Guidance on regulatory requirements can be obtained through the FDA Center for Biologics Evaluation and Research website (www.fda.gov/cber).]

5. Process Development and cGMP Manufacture: Under this task area the Contractor shall produce vaccines, any other mucosally deliverable inhibitory agents of HIV preventative technologies and research-grade products as requested by the COTR, including process development and production of cGMP pilot lots suitable for early phase human clinical trials, and perform the necessary characterization tests required for release for clinical use.

6. Safety and Immunogenicity Testing: Under this task area the Contractor shall perform pre-clinical testing of products as required for regulatory compliance prior to initial human clinical trial evaluation.

D. GENERAL REQUIREMENTS FOR ALL TASK ORDERS

The following requirements shall apply to every task order issued in each of the respective task areas:

a. Within 30 days of initiation of a task order, provide a project plan to the COTR that includes key development objectives and milestones, proposed timelines for achieving task objectives and milestones.

b. Develop a plan for how intellectual property will be handled, as well as the disposition of data/materials developed under task orders. This includes any intellectual property that may pre-exist or be developed during performance of work. Included in the plan shall be the assignment of such rights and obtaining concurrence from the interested parties, including maintenance of security for confidential and/or proprietary data. A copy of the plan shall be provided to the COTR within 30 days of initiation of the task order. The Contractor shall also consult and coordinate with the third-party providers of proprietary materials or data throughout the development process and complete a material transfer agreement third-party provider, if needed. Attachment 6, Advance Understandings, includes a provision entitled “Intellectual Property Option” that requires the Contractor and all subcontractors/consultants to provide access to any Subject Inventions made using third-party proprietary materials or data and to maintain the confidentiality of proprietary data http://www.fda.gov/cber) provided to them during the conduct of the contract.

c. The Contractor shall provide within 30 days after initiation of the task order a “Quality Management Plan” consisting of at a minimum the following:

• acceptance criteria for each deliverable

• procedures and process controls for each deliverable

• roles and responsibilities of personnel involved

• assurance that the established procedures and process are followed

E. GENERAL REQUIREMENTS FOR TASK AREAS

1. ESSENTIAL CORE ACTIVITIES

Immediately upon award of the base contract, NIAID anticipates issuing a single task order for the Essential Core Activities task area. The general requirements for the Essential Core Activities are included in the Task Order that is included as Attachment 2.

2. FEASIBILITY ASSESSMENTS

The Contractor shall assess products for feasibility of design, development, manufacture, potency assay development, and stability for the development of phase I-III clinical trial materials. Specifically, the Contractor shall:

a. organize and attend a site visit with the investigator/developer and their staff to determine the current status of the project, including progress to date

b. assess the capabilities of the investigator/developer staff, laboratory and supporting institution

c. assess the current status and overall scientific feasibility of the project

d. review all relevant documents related to the project’s history including all current scientific documents related to the project, including laboratory notebooks, publications, and any ancillary documentation, plus all regulatory documentation

e. assess financial feasibility of the project

f. assess the manufacturing feasibility

g. assess the traceability of all reagents

h. provide the COTR with a final feasibility report and recommendations for a go/no go decision.

3. AUDITS

a. arrange for audits of foreign and domestic sites, such as facilities audits or technical audits as requested by the COTR, for the purpose of evaluating compliance with domestic and non-domestic laws and regulations and FDA regulations and guidance, including those required to meet GLP, cGMP, and GCP standards, NIAID policies, and the terms of the contract

b. ensure the audit process is in compliance with the Quality Management Plan

c. conduct audits in compliance with the Task Order’s Statement of Work and appropriate regulations; prepare an audit report, and distribute the report to the COTR. Upon approval of the report by the COTR, distribute a copy to the audited organization’s representative.

d. ensure that appropriate staff and all necessary records are available for audits.

e. For audits of investigators/developers, monitor compliance with corrective and remedial actions by following up to ensure appropriate actions have been taken. Provide interim and final audit reports to the COTR and the CO on implementation of corrective and remedial actions and the resolution of all issues identified during the auditing process. Ensure the confidentiality of this information and prohibit it from being released inappropriately to third parties.

4. REGULATORY DOCUMENTATION

The Contractor shall obtain and compile in consultation with the COTR, product sponsors, subcontractors or consultants, the nonclinical data, Investigator’s Brochure, final product trial protocol and other appropriate documentation for submission to either the Center for Biologics Evaluation & Research (CBER) or the Center for Drug Evaluation and Research (CDER), FDA (for an IND application), or non-domestic regulatory authorities as applicable and when requested by the COTR. Specifically, the Contractor shall:

a. obtain and review preclinical and clinical information needed for the IND or other regulatory submissions, by contacting appropriate individuals, other contractors, performing literature research, and accessing various databases (e.g., MEDLINE, PDQ, or TOXNET)

b. compile and submit to the FDA all data and other information required for the pre-IND meeting

c. participate in discussions with the FDA during preliminary, pre-IND and IND meetings

d. prepare, update and distribute Investigator’s Brochures as described in 21 CFR 312.23 (e.g., product description and formulation, summary of preclinical and clinical safety, immunogenicity, activity data, risks and side effects), and distribute at the request of the

COTR

e. prepare and/or arrange for transfer of Master Files to regulatory agencies as required for

IND submission

f. assemble and submit the required documentation for the original IND submission (e.g., chemistry, manufacturing, control, in-process/release testing data, pharmacology, toxicology and previous human experience)

1) the IND study protocol utilizing information provided by the COTR or third party as identified by the COTR

2) edit, paginate and index the original IND submission to be forwarded to the COTR or third party as identified by the COTR

3) obtain authorization for cross-filing of information when appropriate

4) provide additional submissions and amendments as necessary for successful filing of the IND, or comparable non-U.S. approval documents. Prepare an environmental assessment as described in 21 CFR 25.31 if required

g. Coordinate with and provide regulatory assistance to the manufacturer, any subcontractors performing safety and immunogenicity testing, and all others involved in the production and preclinical testing of a product throughout the process of IND submission to the FDA.

h. Upon completion of any Task Order the Contractor shall deliver to the COTR the following:

1. all files pertaining to this contract at the request of the COTR

2. copies of all FDA submissions

5. PROCESS DEVELOPMENT AND cGMP MANUFACTURE

For vaccines and any other mucosally deliverable inhibitory agents of HIV preventative technologies, facilities shall include but not be limited to those with the capability to produce one or more of the following vaccine types: a) DNA plasmids, b) bacterial vectors, c) viral vectors, d) yeast vectors, e) recombinant proteins, f) peptides, g) inactivated virus or bacteria, and h) attenuated virus or bacteria.

The Contractor shall be responsible for the overall management and conduct of process development and production activities. The Contractor shall produce products as requested by the COTR, including production of lots suitable for IND-enabling safety and activity testing, and performance of the necessary characterization tests required for release for clinical use. The Contractor shall also be required to explore alternative adjuvants, delivery vehicles and routes of administration of vaccine immunogens. Specifically, the Contractor shall:

a. In consultation with the COTR, develop a detailed project plan and budget for early-to-late-stage process development and manufacture for each product designated prior to undertaking reagent grade or cGMP production. The project plan shall include written standard operating procedures for all steps in the production and purification process that are used in pilot production.

b. Provide infrastructure, facilities, and resources for performing production of an optimized product under cGMP conditions. Perform audits, as needed or as requested by NIAID COTR, to assure facilities and all planned procedures meet the FDA-required GLP and cGMP standards. Meet, or subcontract all requirements for reagent grade and cGMP production, vialing or pre-filled device preparation, filling, finishing, packaging, labeling, storage and shipping of material.

c. Manufacture vaccines and related products under cGMP conditions. Establish master viral or master cell stocks. Fill and finish including packaging and labeling. Perform all release testing and provide a certificate of analysis. Establish and maintain a stability testing program. Provide documentation for an IND and Master File.

d. Establish and maintain an inventory of test and pilot lots of products that have been produced, and make arrangements for the appropriate storage of such lots in a manner that meets regulatory guidelines. Maintain and operate controlled storage of samples at appropriate temperatures with appropriate monitoring for equipment failure (Room temperature through -90°C.) Liquid nitrogen storage may be required for some products.

Receive, store, ship and record products, master cell banks, biological agents, reagents, records, and any other materials associated with the products.

e. Receive, store and manipulate biohazardous materials under appropriate Biosafety Level procedures and maintain facilities that provide aseptic and/or sterile conditions as appropriate. For the safety and protection of workers provide protective garments, training, equipment and sufficient monitoring to assure safe handling of potentially hazardous materials, including radioactive materials. Conduct tasks in accordance with all applicable and current Federal, state, and local laws, codes, ordinances and regulations, as well as all PHS Safety and Health provisions.

f. Prepare and document cell-line or clone history for master stocks, cell banks, bacterial or viral clones. Prepare, where applicable, cGMP-grade master stocks, cell banks, bacterial or viral clones. Specific services to be provided include, but are not limited to, expansion of research cell banks and their characterization to meet lot regulatory requirements, including GMP DNA sequencing, restriction analysis, plasmid stability, host stability, host identity, auxotrophy/prototrophy, purity (non-host contamination). For mammalian and other eukaryotic cells, appropriate safety assessment studies shall be performed, including but not limited to in vivo and in vitro viral and non-viral adventitious agent detection, tumorigenicity, and karyotyping. The Contractor shall provide and appropriately store characterized research-grade reagent stocks (e.g. cell banks, bacterial or viral clones).

g. Develop and provide Quality Assurance/Quality Control assays for products in-process, including methods for monitoring the sterility, safety, identity, potency, quality, and immunogenicity of products, evaluation of purity, identification of contaminants, and production, acquisition, or improvement of specific reagents necessary for such characterization and evaluation.

h. Produce products specified as reagent grade or cGMP, under appropriate Biosafety Level

(BSL). For cGMP production, products shall be produced in quantities sufficient for early-stage clinical trial testing. Production lots shall include sufficient product for all pre-clinical studies, including stability testing, toxicity testing, biodistribution, etc.

i. Prior to use of a manufactured product in clinical studies, perform final lot release testing as described for biologics and drugs in the regulations for General Biological Product Standards

(21 CFR 610).

j. Acquire, identify, and evaluate the activity/potency of any adjuvants, immunostimulatory cytokines or co-stimulatory molecules or their genes, or other products that may be necessary to enhance or otherwise improve the immunogenicity of the product. Produce or acquire any reagents necessary for testing or evaluating the immune responses to products.

k. Develop plans for and perform stability testing of products including examination of titer or potency at appropriate intervals.

l. The Contractor shall deliver any initial product of the contract, such as a vaccine, adjuvant, assay, or other deliverable, including the product’s associated data, to the Government upon request.

m. The Contractor shall deliver to the Government or its designee by the completion date of the

Task Order, the following items:

1) VACCINES and PRODUCTS

(a) all vaccines and products including master cell banks, vaccine substance, bulk product, and any other product made under the task order

(b) cGMP quality pilot lots of products and adjuvants

(c) all vaccines, products, and adjuvants in various stages of production with attached detailed manufacturing information

(d) a complete list of accurate and updated information regarding design, development and production, including pertinent Contractor activities, , computerized data files, original data, and any related information such as CMC section for IND, cross-reference to BMF

(e) a complete list of accurate and updated information on subcontract activities

(f) labeled and inventoried paper files and computer files covering all aspects of production

(g) government-owned equipment and property

2) PRECLINICAL STUDIES

(a) all data obtained from safety, biodistribution, and immunogenicity trials

(b) all vaccine, products, adjuvants, or other materials remaining from these studies

6. SAFETY AND IMMUNOGENICITY TESTING

The Contractor shall test the product, as appropriate, for safety, potency and immunogenicity (both cellular and humoral) in vitro and/or in small animals, and if necessary in non-human primates. When products require additional testing such as reproductive toxicology, the Contractor shall arrange for these tests to be performed. The Contractor shall integrate production and testing activities and perform all tests as required by the FDA, or as requested by the COTR, prior to human administration and IND or Master File submission. As required, all studies shall be performed in accordance with Good Laboratory Practice (GLP) regulations (21

CFR 58).

a. Perform preclinical immunogenicity evaluation of vaccines. Preclinical studies shall be designed to assess the immune response including, but not limited to antigen-specific antibody levels, neutralizing antibody levels, and cell mediated immune responses in immunized animals. Testing shall be conducted consistent with relevant FDA guidelines.

b. Perform preclinical safety and toxicity studies as required by the FDA or as requested by the

COTR.

1) For vaccines/products, perform preclinical safety evaluation including:

a) Systemic toxicity. Preclinical studies shall include dose-ranging studies of systemic toxicity as well as toxicity to potential target organs, including hematopoietic and immune systems.

b) Local site reactivity studies to include detailed clinical observations and histological evaluation of tissue at the injection or application site, or other visible lesions from biopsies or term necropsy samples

c) Biodistribution/Integration. In the case of DNA and some vector-borne vaccines, studies may have to be performed to determine the biodistribution of the product.

If the product persists above threshold levels in a tissue an integration analysis shall be performed.

d) Genetic toxicity. In the case of DNA and vector-borne vaccines, a pivotal GLP preclinical study shall focus on assessment for the potential of the nucleic acid vaccine to recombine with endogenous host DNA sequences and integrate into host chromosomes. Studies designed to address the potential for integration shall use the most sensitive methods available.

e) Tumorigenicity studies. Tumorigenicity studies may be appropriate under certain conditions; for example, if the preclinical genetic testing demonstrates evidence of integration activity and/or broad tissue distribution.

f) Reproduction toxicity studies. Reproduction toxicity studies shall be performed prior to the use of products in pregnant women. Such studies shall include but are not limited to fertility, general reproductive performance, teratogenicity and developmental toxicity.

g) Evaluation of the safety of adjuvants included in product formulation

c. Provide all data, information and records required for the writing and submission of the

Master File, Investigator’s Brochure, and all other documents related to IND submission or for submission to other non-U.S. regulatory authorities to the COTR or to a COTR-designated third party. Provide information pertaining to the composition, manufacture, and quality control of the product as appropriate for particular investigations carried out under an IND.

d. Retain all records, samples, and histopathological slides, as indicated under GLP and cGMP guidelines, and provide them to the COTR upon request.

e. Upon completion of each Task Orders, the Contractor shall deliver to the COTR:

1) data obtained from safety, biodistribution, and immunogenicity trials

2) all products, adjuvants, or other materials remaining from these studies

3) any initial product of the contract, such as vaccine, adjuvant, or assays, including associated data

(END OF STATEMENT OF WORK for the BASE CONTRACT)