BTF 2020 Statement of Work FINAL.pdf

Biological Testing Facility January 16, 2020 Version

STATEMENT OF WORK (SOW)

BIOLOGICAL TESTING FACILITY (BTF)

A. BACKGROUND AND INTRODUCTION

The National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is the lead Federal agency for the conduct of basic, clinical and epidemiologic research to develop new contraceptive methods and to evaluate existing methods of contraception and reproductive health. The Center for Population Research (CPR), within NICHD, was established in 1968 by the Secretary of Department of Health, Education, and Welfare, with the important goal of developing new contraceptive methods using contracts and grants. In 2017 the Contraceptive Development Program (CDP) was established within the Division of Intramural Population Health Research (DIPHR) to support clinical studies, preclinical contraceptive testing facilities as well as facilities for chemical and peptide synthesis.

Nearly half of all pregnancies in the United States are unintended. Thus, there is a critical need for contraception that fits the needs of women and men throughout their reproductive lives. The Contraceptive Development Program (CDP) supports research in the synthesis and testing of a broad spectrum of male and female contraceptive agents. Successful development of new contraceptive methods for men. and women has been a goal for many decades. From the inception of this program the CDP has had a continuing need for the discovery chemistry, optimization and subsequent development of the contraceptive agents.

The Biological Testing Facility (BTF) fulfills a unique role in bridging the discovery of contraceptive targets to the development and approval of the contraceptive products. To this end, the studies at the BTF will encompass discovery and optimization of compounds as anti-fertility agents. In addition, the BTF has an important role in enriching and providing the pre-clinical support services necessary to make progress toward the development of high quality, safe and effective male and female contraceptive products.

The purpose of this acquisition is to provide a state-of-the-art facility with the capability and capacity to carry out biological safety and efficacy evaluations of new entities with the goal of satisfying the regulatory requirements necessary to be able to introduce the new entities into clinical trials. This initiative will provide overall project management and the capabilities to support all phases of preclinical development of contraceptives, including process and product development, GMP clinical lot production, formulation, preclinical enabling studies and associated tasks leading to the filing of investigational new drug (IND) applications

B. SCOPE

The scope of this contract is for the Biological Testing Facility (BTF) to serve with the capability to carry out the in vitro enzymatic and cell based assays, in vivo studies, anti-fertility assessment, endocrine activity, toxicity, formulation, stability, Absorption Distribution Metabolism Excretion (ADME) profiling and Drug Metabolism Pharmacokinetics (DMPK) profiling of new chemical compounds, delivery systems, and devices and all activities related to preclinical development of products that can be tested in clinical trials for contraception and/or therapeutic indications.

C. TECHNICAL REQUIREMENTS:

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 maintain and operate a Biological Testing Facility and perform the Statement of Work below.

The Contractor shall perform work only as directed in Task Orders issued by the Contracting Officer in accordance with the procedures described in Article G of the Contract.

OVERALL AREAS OF EXPERTISE:

1. PRECLINICAL RESEARCH AND DEVELOPMENT SERVICES:

a. Bioinformatics and Website Services

b. Efficacy Evaluation Services

c. Safety and Toxicology Evaluation and ADME and DMPK Profiling Services

d. Formulation Services

e. GMP facilities for product preparation, stability and product release of steroids and other compounds and products to be used in clinical studies

f. Animal care and maintenance services

2. GENERAL SERVICES:

a. Project Planning, Initiation, Implementation and Management

b. Database, Data, Document, Product, Specimen/Reagent and Inventory Management.

c. Information and Physical Access Security(IPAS)

d. Receive, Format, Store, Ship and Record Compounds/Products and Biological Agents

e. Transition Plan

For each area of expertise, the Contractor shall provide services for, but not limited to:

1. PRECINICAL RESEARCH AND DEVELOPMENT SERVICES

Preclinical research and development services but not limited to the six (6) categories listed below. As requested and approved by TASK ORDER PROCEDURES, the Contractor shall validate assays and processes, conduct work under GMP/GLP when needed in accordance with FDA requirements, regulations, and standards in effect during the course of the project period, and provide predetermined complete Quality Assurance (QA) and Quality Control (QC) information for all services provided. The facility should have license for capability of working with controlled substances. For some services, with specific approval of the COR and Contract Officer, the contractor may subcontract for the requisite task. In addition, the Contractor shall evaluate the data resulting from the preclinical services and draw relevant conclusions specific to the objective of the service.

a. Bioinfomatics and Website Services

For this contract bioinformatics and website development and management should be in-house scientists, engineers and/or technicians.

The Contractor shall provide services for, but not limited to:

i. Bioinformatics

In-house Bioinformatcian for data mining of public databases and websites. The

Bioinformatician must be an expert in manipulating downloaded data for the purpose of interface with website development and content;

ii. Website

In-house web developer and day-to-day management of website, https://www.CITDBase.org. The website should be stand alone and cloud based on Amazon Web Services (AWS) server or as approved by the COR.

b. Efficacy Evaluation Services

For this contract, all animal work must be conducted in accordance with the Animal Welfare Act and Public Health Service Policy on Humane Care and Use of Laboratory Animals (https://olaw.nih.gov/policies-laws/phs-policy.htm), including the implementation of an animal care and use program and animal use protocol approval process under local, state and federal regulations. All animals shall be individually caged during all experimental studies except for those periods of cohabitation required for mating. Non-Human Primates (NHPs) may require paired caging at other times. Animal rooms for a given species will be maintained with separate controls for light, temperature and humidity appropriate for the species housed within.

For efficacy evaluation studies, contractor shall draw blood at specified periods and prepare serum or plasma samples for radioimmunoassay or other required assays of sex steroids (including but not limited to estradiol, total estrogens, testosterone, dihydrotestosterone, total androgens, and progesterone) and protein hormones (including but not limited to, FSH and LH). Assay of other drugs and biologics may be required for development activities.

i. Female Contraception

1) Primary Screen - rodent

2) Secondary Screen

a) Anti-ovulatory- rodent, rabbit, monkey

b) Luteolytic - rodent, monkey

c) Postcoital (studies to determine effect on sperm transport, fertilization, cleavage, zygote transport, intrauterine growth and development,

d) prenidatory changes and implantation) - rodent, rabbit

3) Duration of anti-fertility activity- rodent, rabbit, monkey

ii. Male Contraception

1) Primary Screen - rodent

2) Secondary Screen - rodent, rabbit, monkey

a. Effect on discrete stages of spermatogenesis

b. Effect on sperm maturation and storage

c. Effect on sperm transport

d. Effects on Leydig and Sertoli cells

e. Effect on sperm morphology and motility

f. Effect on capacitation

g. Effect on fertility

iii. Endocrine profile – ability to screen, assay and determine duration of action in appropriate species but, not limited to https://www.citdbase.org/ http://grants.nih.gov/grants/olaw/references/phspol.htm)

1) Androgen (Hershberger) - immature castrated male rodent

2) Anti-androgen - immature castrated male rodent.

3) Estrogen- immature female rodent and rabbit

4) Anti-estrogen - rodent and rabbitv

5) Progestational (Clauberg and McGinty) - immature female rabbit

6) Progestational (pregnancy maintenance)- rodent

a. Minimal effective dose

b. Optimal progestogen/estrogen ratio

7) Progesterone antagonist (Clauberg and Anti-McGinty) - immature female rabbit

8) Corticoid – rodent

a. Thymolytic

b. Glycogenic

c. Na/K excretion

d. Anti-inflammatory

9) Gonadotropic – rodent

10) Anti-gonadotrophic – rodent

iv. Spermicidal Activity – rabbit

v. Vaginal Irritation – rabbit

vi. Radioimmoassay - rodent, rabbit, monkey and human sera

1) Estradiol

2) Estrone

3) Total estrogens

4) Progesterone

5) Testosterone and dihydrotestosterone

6) Total androgens

7) Follicle stimulating hormone (FSH)

8) Lutinizing hormone (LH)

9) T3, T4

10) Thyroid stimulating hormone (TSH)

11) Inhibin

12) Cortisol

13) Adrenal corticotropic hormone (ACTH)

14) Experimental compounds but not limited to, e.g., DMA, 11β-MNT, 7α-MT, norethindrone, levonorgestrel, ethynylestradiol, medroxprogesterone acetate and all respective prodrugs.

vii. Receptor Binding Studies (various species derived)

1) Estrogen

2) Progesterone

3) Androgen

4) Glucocorticoid

viii. Transactivation Studies (various species derived)

1) Estrogen

2) Progesterone

3) Androgen

4) Glucocorticoid

5) Mineralcorticoid

c. Safety and Toxicology Evaluation and ADME and DMPK Profiling Services

Preclinical safety, toxicity and biokinetic pharmacology of anti-fertility and/or therapeutic candidates in vitro and in vivo in rodents, rabbits and non-human primates must be carried out under GLP guidelines. Clinical chemistry, urinalysis, hematology, and full pathology may be required for these and for other preclinical evaluation. This activity includes all such tests that are required to support clinical use in humans; testing must be sufficient to meet requirements for IND/NDA/BLA filing and must be performed under GLP requirements (21 CFR 58), unless otherwise specified by the NICHD Project Officer. The Contractor is responsible for acquisition, housing, care of animals and the services listed below. All animal work must be conducted in accordance with the Animal Welfare Act and Public Health Service Policy on Humane Care and Use of Laboratory Animals (http:/grants.nih.gov/grants/olaw/references/phspol.htm), including the implementation of an animal care and use program, and animal use protocol approval process.

i. Determination of maximum tolerated dose and no observed effect levels (NOEL);

ii. Determination of acute and sub chronic toxicity;

iii. Single and repeated dose toxicity studies;

iv. Determination of relevant pharmacokinetic/toxicokinetic parameters;

v. Bioavailability studies;

vi. ADME Profiling - Absorption, distribution, metabolism, and excretion studies;

vii. DMPK Profiling - Drug Metabolism Pharmacokinetics

viii. Genotoxicity testing;

ix. Carcinogenicity testing if relevant for anti-fertility and/or therapeutic candidate;

x. Reproductive toxicity studies (all segments);

xi. Biotransformation assays conducted in vitro;

xii. Cytotoxicity of compounds for actively dividing mammalian cells (e.g., IC50);.

xiii. Immunotoxicity studies to determine the toxicity of candidate compounds to the immune system or other specialized target organ systems;

xiv. All other safety and pharmacology assays and studies that may be required for a particular contraceptive and/or therapeutic agent or device; and

xv. Long term stability studies on drugs under clinical development.

d. Formulation Services

Drugs may be developed for a variety of administrations including oral, intramuscular injection, sub-cutaneous delivery, vaginal, transdermal, etc. Develop and perform analytical methods to characterize anti-fertility and/or therapeutic agents in various carriers in support of product characterization, product release, in vivo safety, pharmacokinetic studies, and other preclinical evaluations as required.

e. GMP facilities for product preparation, stability and product release of steroids and other compounds and products to be used in clinical studies

Encapsulation or other clinical formulation and stability studies as needed in preparation for batch release of materials for clinical trials

f. Animal care and maintenance services

All animal work must be conducted in accordance with the Animal Welfare Act and Public Health Service Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/phspol.htm). They include the implementation of an animal care, animal use program and animal use protocol approval process under local, state and federal regulations.

The Contractor should have in-house animal facility capable of housing and maintaining Non- Human Primates (NHPs).

2. GENERAL SERVICES:

a. Project Planning, Initiation, Implementation, and Management

The Contractor shall provide services for preclinical development of contraceptive agents identified through NICHD-funded grants and contracts, the private sector, or other sources selected by the NICHD COR. The specific services required will depend on the status of the individual candidate(s) as part of an overall product development plan and/or regulatory submission plan to the FDA. The Contractor shall be responsible for project planning, initiation, implementation, management and communication, including evaluation, selection, and management of subcontractors, as well as for all deliverables specified in this solicitation. The contractor/subcontractors will use state-of-the-art techniques and technologies in evaluating promising anti-fertility and/or therapeutics and will incorporate new and improved techniques and technologies into the contract activities.

The Contractor shall perform work only as directed in Task Orders issued by the Contracting Officer in accordance with the procedures described in Article G of the Contract (TASK ORDER

PROCEDURES)

i. Preclinical Development Planning and Evaluation Services

1) Develop an overall preclinical development plan for specified anti-fertility and/or therapeutic candidates and produce a Preclinical Development Plan Report.

2) Review and evaluate preclinical anti-fertility and/or therapeutic development activities/plans in terms of adequacy of potential regulatory submission within the context of an overall product development plan and produce a Preclinical Development Evaluation Report.

ii. Overall Project Management

Provide a technical and administrative infrastructure to ensure the efficient planning, initiation, implementation and management of all projects carried out under this contract and effective communications with the NICHD COR and the NICHD Contracting Officer. This infrastructure shall include a Principal Investigator with responsibility for overall project management and communications, tracking, monitoring and reporting on project status and progress, and recommending modifications to project requirements and timelines, including projects undertaken by subcontractors. This infrastructure shall also include Project Managers to coordinate and integrate all preclinical anti-fertility and/or therapeutic development activities conducted under this contract and administrative staff with responsibility for financial management and financial reporting on all activities conducted by the Contractor and subcontractors.

iii. Project Plan and Project Initiation

Upon written request from the NICHD Contract Officer and Contract Officer’s Representative, the contractor shall provide a Project Plan within 30 days that includes the following:

1) A determination regarding whether the work can be performed in-house by the

Contractor or if subcontracting is required.

2) Specification of the resources and services to be provided.

3) A description of the key development objectives

4) Delineation of project milestones and timelines for the accomplishment of milestones;

5) A description of the technical approach to carrying out the project and the physical facilities and other necessary resources to be made available;

6) A description of the project deliverables and a timeline for completion;

7) A list of proposed scientific and technical personnel and a description of their qualifications and relevant experience;

8) A plan for QA and QC of the project;

9) A detailed budget of all project costs.

Initiate the project plan with the written approval through Task Orders identified in Section G of the contract.

iv. Site visits

Each site visit will be held on a date designated by the NICHD COR in consultation with the Principal Investigator. The Principal Investigator shall be responsible for meeting arrangements/logistics. The Principal Investigator, Project Managers, Project Leaders, key subcontractor personnel and NICHD staff will attend these meetings. The agenda will be prepared by the NICHD COR and NICHD Contracting Officer in consultation with the Principal Investigator. Meetings shall be closed to the public and shall involve oral and electronic presentations including:

1) Updates to include results of studies completed since the prior meeting;

2) Interim reports on active protocols;

3) A description of any problem that may have arisen;

4) A discussion of potential future protocols influenced by evolving regulatory environment or other action items. Subcontractors may not be allowed to attend portions of the meeting in which potentially proprietary/confidential information will be presented/discussed.

v. Subcontract Execution, Management and Reporting

The Contractor shall manage the subcontracting activity and shall ensure that the award and management of subcontracts is in accordance with FAR Clause 52.244-2. Specifically, the

Contractor shall carry out the following for each project to be initiated under a subcontract:

1) Execute and manage subcontracts, oversee the technical, administrative and operational activities of subcontractors on a daily basis, including auditing subcontractor facilities, monitoring services and financial expenditures, and tracking deliverables and reporting requirements;

2) Include in the quarterly technical reports, an assessment of subcontractor performance and progress toward achievement of defined milestones; and identify and resolve problems with subcontractor performance;

3) Ensure that subcontractor personnel, equipment and facilities are compliant with regulatory requirements in effect throughout the contract period

4) Ensure the complete and effective transfer of technology by the subcontractors to the Contractor, the United States Government, or a third party as designated by the NICHD

COR

5) Perform all necessary transition and closeout functions on each subcontract.

vi. Biocontainment, Safety and Training

The Contractor shall:

1) Provide safe facilities and resources and conduct work in accordance with the Biosafety in Microbiological and Biomedical Laboratories guidelines, Centers for Disease Control and Prevention and the National Institutes of Health, third edition, HHS Pub. No. (CDC) 93- 8395 published by the U.S. Government Printing Office, May 1993, stock number 17- 0400-00523-7;

2) Provide adequate biocontainment facilities and staff with the required training, experience and expertise to operate the facilities and conduct the services, when appropriate, in accordance with Biosafety Level (BSL) 2 guidelines (http://bmbl.od.nih.gov/index.htm).

b. Databases, Data, Document, Product and Specimen/Reagent and Inventory Management

i. Provide, implement and maintain data management systems to support all contract activities described in the Statement of Work

ii. Provide, implement and maintain secure in-house data management capabilities and equipment to submit, compile, store, collate, analyze, track and retrieve data, structures, results, specimens, reagents, biological agents, product produced and released, documents generated in product development, and data received from other compound screening activities performed by third parties. This database will contain confidential proprietary information that cannot be used for data-mining purposes by the contractor or subcontractors.

iii. In-house database management of third party/vendor software for data mining by NICHD COR and others as approved by the COR. The third party/vendor software must have chemical structure search capability. Database management encompasses but, not limited to data entry of data generated by the Contractor, sub-contractors and other third pary data as approved by the COR. The third party/vendor software must be Collaborative Drug Discovery (CDD) or compatible with CDD for easy data transfer as approved by the COR http://bmbl.od.nih.gov/index.htm)

iv. Ensure secure electronic communications, including email, word processing and transmission of data files, between the Contractor, NICHD staff, subcontractors and consultants. Organize, maintain, and transfer information on protocols and test results and provide electronic copies of all reports to the NICHD Project Officer and designee if applicable.

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

Drug Master File, Investigator's Brochure, and all other documents related to IND/NDA/IBLA submission and maintenance to the NICHD COR or to a designated third party.

vi. Provide support in writing and preparation of manuscript for publication and abstracts as requested by NICHD COR.

vii. Provide an annual report summarizing the studies, tests, and procedures performed during the year and provide a study report after the completion of each study.

viii. Provide all equipment and operational systems to maintain the confidentiality of data received from the NICHD or third parties and data generated within the scope of the contract.

c. Information and Physical Access Security (IPAS)

IPAS is applicable to this solicitation and this information should be provided by the Contractor.

The Homeland Security Presidential Directive (HSPD)-12 and the Federal Information Security Management Act of 2002 (P.L. 107-347) (FISMA) requires each agency to develop, document, and implement an agency-wide information security program to safeguard information and information systems that support the operations and assets of the agency, including those provided or managed by another agency, contractor (including subcontractor), or other source.

d. Receive, Format, Store, Ship and Record Compounds/Products

The Contractor shall develop and maintain efficient and effective procedures sufficient to support contract activities for receiving, storing, shipping and recording compounds/products.

Transfer assays, processes, methods, SOPs, reagents, products or other materials, data and documentation developed under the contract to a third party designated by the NICHD COR or directly to the NICHD COR. The Technical Transfer packages shall include information (Technology Transfer Report}, material reagents and in-place training of others at the Contractor's or subcontractor's site or the site of a third party sufficient to completely and effectively transfer the technology.

i. Obtain the appropriate licenses and permits required by International, Federal, State and local authorities for the safe transport, storage, and distribution of compounds/products and biological agents;

ii. Provide for safe packing, labeling, and shipping of compounds/products and biological agents to sites designated by the NICHD COR so that shipments are coordinated for timely receipt;

iii. Pay costs for shipping from suppliers to the contract/subcontract site or to third parties, and from third parties to contract/subcontract site;

iv. Maintain stability of all shipments received by providing the appropriate temperature control in transit from the airport or other site to the Contractor/subcontractor facility;

v. Provide shipping containers for compounds/products and biological agents that comply with domestic and international postal regulations and pertinent International Air Transport Association (www.iata.org) and the International Civil Aviation Organization (www.icao.int) regulations. The shipping containers shall provide a sufficient margin of safety for maintaining appropriate environmental safeguards and desired refrigeration levels for specific products in transit, depending on the mode of transportation employed;

vi. Provide secure, safe and stable storage of reagents, products and biological agents under the required conditions (e.g., Biosafety Level, GMP, aseptic);

vii. Maintain a secure electronic record of all contraceptive and/or therapeutic and biological agents received, such as in an Excel spreadsheet or database compatible with Microsoft Office XP or software currently used and approved by NICHD, that includes searchable information such as compound identifiers, amounts available, storage locations, shipping data and other biological and chemical characteristics of the compounds

e. Transition Plans

The Contractor shall provide an orderly transition to a successor contractor or to the Government at the end of the contract. Thus, the Contractor shall:

i. Initial Transition Plan

Within 15 days of contract award the Contractor shall provide an Initial Transition Plan and timetable for the receipt storage and study (as necessary) of all of the items potentially being transferred from the out-going Contractor. This may include equipment, test agents, archived samples from completed studies, non-human primates, etc.

ii. Final Transition Plan

Ninety days before the expiration date of the contract, the Contractor shall provide a Final Transition Plan to the Project Officer for the orderly transition of contract-related materials to a successor contractor or to the Government. Materials may include equipment, tissues, slides, animals, reagents, therapies and data not already transferred to the Government. The Final Transition plan shall include an estimated cost of shipping materials to a successor contractor or to the Government.