A30 - STO 4 - BPN-Biologics PK and Tox Task Order.v2.pdf

Sample Task Order #4- Statement of Work

Pharmacokinetics and Toxicology Studies for NINDS NIH Blueprint Neurotherapeutics Biologics Network (BPN-Biologics) Project

Background

The National Institutes of Health (NIH) Blueprint Neurotherapeutics (BPN) network (https://neuroscienceblueprint.nih.gov/neurotherapeutics/blueprint-neurotherapeutics-bpn-network) is a consortium comprised of the NIH Office of the Director and 14 NIH Institutes and Centers (ICs) that support neuroscience research. BPN provides neuroscience researchers with funding and access to a full range of industry-style drug development services and expertise. The program, originally focused on small molecules, was launched for projects requiring medicinal chemistry optimization, pharmacokinetics (PK), pharmacodynamics (PD), drug manufacturing and formulation, Investigational New Drug (IND)-enabling toxicological studies support through Phase I clinical testing and it is now being expanded to include the development of biological therapeutics for neurological diseases (https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics).

Objectives The objective of this Task Order is for the Contractor and/or Subcontractor(s) to conduct all activities required to cover the performance of a series of rodent (rat and mouse) and non-rodent (dog and Non-Human Primate (NHP)) PK/PD, assay development, and toxicology studies to evaluate therapeutics (e.g. peptide and/or AAV9) for a neurological disorder.

TECHNICAL SPECIFICATIONS

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 a series of the following nonclinical studies under this Task Order:

The Task Order is comprised of the Base Task (Study 1) and eleven (11) Optional Tasks (Studies 2- 12). Optional Tasks may run concurrently or in sequence. Each study will be priced separately as a unit of work, including a final study report acceptable for inclusion in a regulatory submission to the U.S. Food and Drug Administration (FDA). Complete study costing should be provided separately for each study (Studies 1-12). The Business Proposal Template shows a tab for each study that should be completed.

1) GLP Rat Single Dose PK

2) GLP Mouse Single Dose PK

3) GLP Rat Multi-Dose PK

4) GLP Mouse Multi-Dose PK

5) GLP PD (Tissue Distribution in Mice)

6) Assay Development, and/or Qualification, and/or Validation, and/or Plasma and Tissue

Sample Analysis

7) GLP Dog Single-Dose PK

8) GLP NHP Single-Dose PK

9) GLP Dog Multi-Dose PK

10) GLP NHP Multi-Dose PK

11) GLP Rat Single-Dose Toxicology

12) GLP NHP Single-Dose Toxicology

Attachment #30 https://neuroscienceblueprint.nih.gov/neurotherapeutics/blueprint-neurotherapeutics-bpn-network https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics

The Contractor or subcontractor(s), during the period of performance of this Task Order, shall administer NIH-supplied Biologics to appropriate animal models such as rats, mice, dogs, NHPs, or other appropriate animal model and assess compound levels in blood and/or in tissues at various time points and calculate standard PK parameters, and/or PD and/or safety toxicology. Study outlines are presented below for the purposes of proposal development. It is expected that similar study designs will be used for each study to be completed, but minor, within scope modifications may be required during protocol finalization and may also depend on the biologic modality being evaluated.

The Contracting Officer’s Representative (COR) will initiate a study with the submission of a study request form, which will include a study outline and available information on the compound to be tested. The Contractor or subcontractor shall develop a study protocol and plan based on that outline, including a timeline for study initiation and completion. Upon COR approval of the protocol and study plan, the Contractor or subcontractor will initiate study activities. After completion of the in-life portion of the study, the contractor shall prepare a preliminary data report, to be submitted within 15 business days of the end of in-life. Within 1 month of submission of the data report, the Contractor will submit a full draft final report for review and comment by the COR and NIH Lead Development Team (LDT). After receipt of COR comments, a final study report shall be delivered, which incorporates all requested edits and modifications.

General Requirements for all Tasks

(1) Independently and not as an agent of the Government, Contractors shall be required to furnish all the necessary services, qualified personnel, materials, equipment, and facilities not otherwise provided by the Government as needed to provide the services described in this Statement of Work and subsequent TOs.

(2) All work under this contract shall be monitored by the Government COR, whose position is defined in Section G of the contract.

(3) Contractors shall, at the direction of the COR, submit any Standard Operating Procedures (SOPs), method descriptions, and references to be used in the implementation of the studies. Contractor SOPs will be treated as confidential, and how much detail is revealed and at what time can be discussed.

(4) Contractors shall provide project management for its own core team to ensure project planning, execution, delivery of reports, and accurate and timely communication with the COR, Contracting Officer (CO), and other stakeholders. The Contractor’s core team leader shall attend program team meetings on an as needed basis (no more than one meeting per week) either in person or via teleconferencing. During these meetings, the Contractor shall report project progress and provide input and feedback to the program team. The Contractor shall send the materials needed for these meetings to the COR at least 24 hours in advance of the meeting. The material needed shall include a status update on all ongoing studies, plans for the next reporting period, data generated and interpretations of data, any quality control issues, and the status of the budget when requested.

(5) Contractors shall arrange for site visits and independent audits, as requested by the COR.

Audits may be requested to assure Contractor and subcontractor facilities and all planned procedures meet FDA-required drug development Good Laboratory practice (GLP) standards. Contractors shall ensure all Contractor and subcontractor records and staff are available in response to site visits or study-specific audits, and provide interim and final audit reports to the COR.

(6) The Contractor shall immediately contact the COR if there are any adverse or problematic research results or difficulties with studies that would impact the development success of the project or endanger the timeline. The communications shall include proposed solutions according to the Contractor’s risk mitigation plan.

(7) Within 45 days of Task Order expiration, the Contractor shall provide the COR with a proposed Transition Plan for an orderly and complete transition/relocation of the Task Order resources to a successor Contractor or to the Government. The plan shall include details on the relocation/disposition of unused materials and supplies; manuals and directories developed by the Contractor; and all other government property not listed. Upon written direction by the Government, the Contractor shall transfer all Government property as directed, and fully cooperate with any successor Contractor and the Government to ensure an efficient transfer.

For studies involving animals, the Contractor is expected to have the following species available for use in the in vivo studies: rodents (rats or mice), dogs (purpose bred Beagle dogs), rabbits, NHPs, and other animal models (as appropriate). The animals shall be obtained from an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International-accredited registered breeder, as required by the U.S. Department of Agriculture (USDA).

For studies involving animals, the Contractor shall obtain, prior to the start of any work under this Task Order, an approved Animal Welfare Assurance from the Office of Extramural Research (OER), Office of Laboratory Animal Welfare (OLAW) (http://grants.nih.gov/grants/olaw/olaw.htm), Office of the Director, NIH, as required by Section I-43-30 of the Public Health Service Policy on Humane Care and Use of Laboratory Animals.

For studies involving animals only the Contractor shall maintain such assurance for the duration of this contract, and any subcontractors performing work under this contract involving the use of animals shall also obtain and maintain an approved Animal Welfare Assurance. The Contractor shall also be fully accredited by the AAALAC International. Information about AAALAC accreditation is available at www.aaalac.org. Additionally, the Contractor's Institutional Animal Care and Use Committee (IACUC) shall approve all animal procedures under this contract.

PK/PD and SAFETY TOXICOLOGY STUDY REQUIREMENTS

The Contractor and/or subcontractors shall conduct PK, PD, and/or safety toxicology studies, administering NIH-supplied biologics to appropriate animal models such as rats, mice, dogs and NHPs, etc., and assessing blood and brain concentrations (and other organs when deemed necessary, e.g., liver, lung, kidney, eye) of test compound at various time points and calculating standard PK parameters. Studies may be conducted by the Contractor or a suitable subcontractor.

Designs for several studies are presented below for cost proposal development purposes and as starting points for protocol development, subject to modification. It is anticipated that similar study designs will be used for the studies to be completed, but minor modifications may be needed based on individual project requirements. The mix of study types requested may also vary. The number of animals required to produce meaningful results may be determined with the support of a biostatistician. Dosing routes may include but are not limited to intramuscular (im), intravenous (iv), subcutaneous (sc), intrathecal (it), intracranial (ic), or oral (po).

Study 1: Single-Dose Rat PK Study (Base Task)

The Contractor shall conduct a non-GLP single-dose PK study, administering NIH-supplied biologic (e.g., AAV9) to a rat model and assessing blood or tissue concentrations of test compound at various time points and calculating standard PK parameters.

A design for a rat PK study is presented below, as a starting point for protocol development, subject to modification. It is anticipated that similar study designs will be used for the studies to be completed, but minor modifications may be needed based on individual project requirements. Dosing routes may include but are not limited to intramuscular (im), intravenous (iv), subcutaneous (sc), intrathecal (it), intracranial, or oral (po).

Group Test Article

Dose Route No. of Animals

Plasma Collection Brain Collection

1 A TBD iv 6 10 time points At final plasma collection

2 A TBD po 6 10 time points

3 A TBD iv 6 One time point At plasma collection

• Blood (plasma) collected via jugular catheters.

• Animals are to be perfused in situ with normal saline prior to brain (or other organ) removal.

• Dose levels will be determined at the time of protocol development based on available information on the compound.

• Collection and analysis of additional tissues may be requested

• Use of dual cannulated rats may be requested

• LC-MS/MS peptide quantitation in collected plasma and tissue samples will be conducted

• Assessment of test compound concentration at various time points and calculating standard PK parameters

Study 2: Single-Dose Mouse PK Study (Optional Task 1)

The Contractor shall conduct a non-GLP single-dose PK study, administering NIH-supplied biologic (e.g., AAV9) to a mouse model and assessing blood or tissue concentrations of test compound at various time points and calculating standard PK parameters.

A design for a mouse PK study is presented below, as a starting point for protocol development, subject to modification. It is anticipated that similar study designs will be used for the studies to be completed, but minor modifications may be needed based on individual project requirements. Dosing routes may include but are not limited to intramuscular (im), intravenous (iv), subcutaneous (sc), intrathecal (it), intracranial, or oral (po).

• Blood (plasma) collected.

• Animals are to be perfused in situ with normal saline prior to brain (or other organ) removal.

• Dose levels will be determined at the time of protocol development based on available

• information on the compound.

• Collection and analysis of additional tissues may be requested

• LC-MS/MS peptide quantitation in collected plasma and tissue samples will be conducted

Study 3: Multiple-Dose Rat PK Study (Optional Task 2)

The Contractor shall conduct non-GLP multi-dose PK studies, administering NIH-supplied biologic (e.g., peptides) to a rat model and assessing blood or tissue concentrations of test compound at various time points and calculating standard PK parameters.

A design for a multi-dose rat PK study is presented below, as a starting point for protocol development, subject to modification. It is anticipated that similar study designs will be used for the studies to be completed, but minor modifications may be needed based on individual project requirements. Dosing routes may include but are not limited to intramuscular (im), intravenous (iv), subcutaneous (sc), intrathecal (it), intracranial, or oral (po).

Group Treatment Number of Rats

1 Low 16 (8M/8F)

2 Mid 16 (8M/8F)

3 High 16 (8M/8F)

Dose

Route Sub-

Group No. of Animals

Plasma Collection

Brain Collection

A

TBD

iv

A 6 2 time points At final plasma collection

B 6 2 time points At final plasma collection

C 6 2 time points At final plasma collection

D 6 2 time points At final plasma collection

A

TBD

po

A 6 2 time points B 6 2 time points C 6 2 time points D 6 2 time points

• Blood (plasma) collected via jugular vein catheters

• Dose levels will be determined at the time of protocol development based on available information on the test article

• Route of administration will be determined at the time of protocol development. For the purposes of proposal development, assume po dosing.

• Dose administration once daily for 7 days; assume daily dose preparation

• Daily clinical signs

• Groups of 4M/4F animals evaluated at each time point

• Plasma and tissues (brain, heart, kidney, liver) will be collected on Days 1 and 7 after dose administration for 8 time points on each day; e.g., pre-dose, 15, 30, 60 min; 2, 4, 8, and 24 hr. after treatment. On intermediate Day 4, a pre-dosing blood sample will be collected.

• Collection and analysis of additional tissues may be requested.

• Assume a bioanalytical method is available to be transferred.

• LC-MS/MS peptide quantitation in collected plasma and tissue samples will be conducted

Study 4: Multiple-Dose Mouse PK Study (Optional Task 3)

The Contractor shall conduct non-GLP multi-dose PK studies, administering NIH-supplied biologic (e.g., peptides) to a mouse model and assessing blood or tissue concentrations of test compound at various time points and calculating standard PK parameters.

A design for a multi-dose mouse PK study is presented below, as a starting point for protocol development, subject to modification. It is anticipated that similar study designs will be used for the studies to be completed, but minor modifications may be needed based on individual project requirements. Dosing routes may include but are not limited to intramuscular (im), intravenous (iv), subcutaneous (sc), intrathecal (it), intracranial, or oral (po).

Group Treatment Number of Mice

1 Low 16 (8M/8F)

2 Mid 16 (8M/8F)

3 High 16 (8M/8F)

• Blood (plasma) collected via jugular vein catheters

• Dose levels will be determined at the time of protocol development based on available information on the test article

• Route of administration will be determined at the time of protocol development. For the purposes of proposal development, assume po dosing.

• Dose administration once daily for 7 days; assume daily dose preparation

• Daily clinical signs

• Groups of 4M/4F animals evaluated at each time point

• Plasma and tissues (brain, heart, kidney, liver) will be collected on Days 1 and 7 after dose administration for 8 time points on each day; e.g., pre-dose, 15, 30, 60 min; 2, 4, 8, and 24 hr. after treatment. On intermediate Day 4, a pre-dosing blood sample will be collected.

• Collection and analysis of additional tissues may be requested.

• Assume a bioanalytical method is available to be transferred.

• LC-MS/MS peptide quantitation in collected plasma and tissue samples will be conducted

Assessment of test compound concentration at various time points and calculating standard PK

Study 5: PD (Tissue Distribution in Mice) (Optional Task 4)

The Contractor shall conduct non-GLP PD studies, administering BPN-supplied biologics (e.g.

AAV9) to mice and assessing blood and tissue concentrations at various time points. A design for a tissue distribution study is presented below, subject to modification. It is anticipated that similar study designs will be used for the studies to be conducted, but modifications may be needed based on individual project requirements.

on available information on the test article

• Route of administration will be determined at the time of protocol development. For the purposes of proposal development, assume iv and po dosing.

• Collection and analysis of 4 tissues (e.g., brain, heart, kidney, skeletal muscle, etc.)

• Assessment of test compound concentration and/or vector gene product concentration at various time points

• Endpoints: Plasma/brain ratio, AUC, tissue drug levels, virus quantitation (qPCR) and anti-AAV9 antibody, and vector gene product (by LC-MS/MS) levels in collected plasma and/or tissue samples will be conducted

Study 6: Assay Development, and/or Qualification, and/or Validation, and/or Plasma and Tissue Sample Analysis (Optional Task 5)

Bioassays will be required to evaluate biological therapeutics characteristics such as in vivo activity, PK, PD, plasma and tissue concentration, etc.. Bioassays may already be developed and may need to be tech-transferred to the contractor or subcontractor facility to be qualified and/or validated.

Alternatively, bioassays may need to be developed de novo. For the purposes of proposal development, assume novel assay development will be required. The contractor shall conduct assay development studies (e.g., AAV9 qPCR viral quantitation; and anti-AAV ELISA antibodies), which will be used to analyze plasma and tissue samples to measure levels of the biologic being studied to support PK and PD and toxicology assessment. Samples will have been previously collected as a component of in vivo activity studies. For the purposes of proposal development, assume that bioanalytical methods including: 1) AAV9 qPCR and 2) AAV9 ELISA development, assay qualification, and assay validation will be required. The assays will meet or exceed FDA’s requirement on sensitivity and will be qualified and validated per ICH guidelines. For budget

Dose Group Route # of Mice Plasma Collection (min)

Tissue Collection

A iv 3M/3F per time point

9 time points At each plasma collection point

B iv 3M/3F per time point

9 time points At each plasma collection point development purposes assume a total of 48 plasma samples and 48 tissue samples (from 4 organs) will be tested using the qualified assays.

For purposes of proposal development, separate costing should be provided for each component of Optional Task 5, including: 1) assay development, 2) assay qualification, 3) assay validation, and 4) plasma and tissue sample analysis.

Study 7: Dog GLP Single-Dose PK (Optional Task 6)

The Contractor shall conduct GLP single-dose PK studies, administering NIH-supplied biologic (e.g., AAV9) to a dog model and assessing blood and/or tissue concentrations of test compound gene product at various time points and calculating standard PK parameters.

A design for a GLP dog (assume beagle for purposes of proposal development) PK study is presented below, as a starting point for protocol development, subject to modification. It is anticipated that similar study designs will be used for the studies to be completed, but minor modifications may be needed based on individual project requirements. Dosing routes may include but are not limited to intramuscular (im), intravenous (iv), subcutaneous (sc), intrathecal (it), intracranial, or oral (po).

• Dose levels will be determined at the time of protocol development based on available information on the test article

• Route of administration will be determined at the time of protocol development.

For the purposes of proposal development, assume iv and po dosing.

• Collection and analysis of 4 tissues (e.g., brain, heart, kidney, skeletal muscle, etc.) on last day

• Assessment of test compound gene product concentration at various time points out to 21 days

• Endpoints: Plasma/brain ratio, AUC, tissue drug levels, virus quantitation( qPCR), and anti-AAV9 antibodies and/or vector gene product (by LC-MS/MS) levels in collected plasma and/or tissue

Study 8: GLP NHP Single-Dose PK (Optional Task 7)

The Contractor shall conduct GLP single-dose PK studies, administering NIH-supplied biologic (e.g., AAV9) to an NHP model and assessing blood and tissue concentrations of test compound at various time points and calculating standard PK parameters.

A design for a GLP NHP PK (assume cynomolgus macaques for purposes of proposal development) study is presented below, as a starting point for protocol development, subject to modification. It is anticipated that similar study designs will be used for the studies to be completed, but minor modifications may be needed based on individual project requirements. Dosing routes may include

Group Test Article

Dose (mg/kg)

Route # of Animals

Plasma Collection

1 A TBD TBD 4 (2M/2F) 10 time points

2 A TBD TBD 4 (2M/2F) 10 time points

Dose (mg/kg)

Route # of Animals

Plasma Collection (hr.)

1 A TBD TBD 4 (2M/2F) 10 time points

2 A TBD TBD 4 (2M/2F) 10 time points

• Route of administration will be determined at the time of protocol development.

For the purposes of proposal development, assume iv and po dosing.

• Collection and analysis of 4 tissues (e.g., brain, heart, kidney, skeletal muscle) on last day

• Assessment of test compound gene product concentration at various time points out to 21 days

• Endpoints: Plasma/brain ratio, AUC, tissue drug levels, virus quantitation( qPCR), and/or anti-

AAV9 antibodies, and/or vector gene product levels in collected plasma and/or tissue samples will be conducted

Study 9: GLP Dog Multi-Dose PK (Optional Task 8)

The Contractor shall conduct GLP multi-dose PK studies, administering NIH-supplied biologic (e.g., peptides) to a dog model and assessing blood or tissue concentrations of test compound at various time points and calculating standard PK parameters.

A design for a multi-dose, GLP dog PK study (assume beagle for purposes of proposal development) study are presented below, as starting points for protocol development, subject to modification. It is anticipated that similar study designs will be used for the studies to be completed, but minor modifications may be needed based on individual project requirements. Dosing routes may include but are not limited to intramuscular (im), intravenous (iv), subcutaneous (sc), intrathecal (it), intracranial, or oral (po).

Group Dose # of Animals Plasma Collection

1 TBD – Low 4 (2M/2F) 10 time points

2 TBD – mid 4 (2M/2F) 10 time points

3 TBD - high 4 (2M/2F) 10 time points on available information on the test article

• Route of administration will be determined at the time of protocol development. For the purposes of proposal development, assume po dosing.

• Dosing may range from 1-5 days of daily or weekly dosing. For proposal development purposes, assume 3 days of daily dosing.

• Collection and analysis of 4 tissues (e.g., brain, heart, kidney, skeletal muscle, etc.)

on last day

• Assessment of test compound concentration at various time points out to 28 days

• Additional Endpoints: Plasma/brain ratio, AUC, tissue drug levels, virus quantitation( qPCR), and/or anti-AAV9 antibodies, and/or vector gene product levels in collected plasma and/or tissue samples will be conducted

Study 10: GLP NHP Multi-Dose PK (Optional Task 9)

The Contractor shall conduct GLP, multi-dose PK studies, administering NIH-supplied biologic (e.g., peptides) to an NHP model and assessing blood or tissue concentrations of test compound at various time points and calculating standard PK parameters.

A design for an NHP PK (assume cynomolgus macaques for purposes of proposal development) study is presented below, as a starting point for protocol development, subject to modification. It is anticipated that similar study designs will be used for the studies to be completed, but minor modifications may be needed based on individual project requirements. Dosing routes may include

Group Dose # of Animals Plasma Collection

1 TBD – Low 4 (2M/2F) 10 time points

2 TBD – mid 4 (2M/2F) 10 time points

3 TBD - high 4 (2M/2F) 10 time points

• Route of administration will be determined at the time of protocol development.

For the purposes of proposal development, assume po dosing.

• Dosing may range from 1-5 days of daily or weekly dosing. For proposal development purposes, assume 3 days of daily dosing.

• Collection and analysis of 4 tissues (e.g., brain, heart, kidney, skeletal muscle, etc.) on last day

• Assessment of test compound concentration at various time points out to 28 days

• Additional Endpoints: Plasma/brain ratio, AUC, tissue drug levels, virus quantitation( qPCR), and/or anti-AAV9 antibodies, and/or vector gene product levels in collected plasma and/or tissue

Study 11: Single-dose GLP toxicity study in rats (Optional Task 10)

The purpose of this study is to evaluate the potential systemic and local toxicity of the biologic therapeutic (e.g., AAV9) when administered as an intramuscular (IM) injection to male and female rats. The study design also includes a no-treatment recovery period to assess the persistence, reversibility, or delayed onset of any treatment-related effects. Animals will be dosed once on Study day 1. Dosing routes may include but are not limited to intramuscular (im), intravenous (iv), For purposes of proposal development, sample analysis costing should be provided separately.

Group Test Article Numbers of

Animals Injection (Days)

Necropsy (Days) Blood/Tissue Collection

(Days) Main Phase

Recovery Phase

M F M F Main Phase

Recovery Phase

1 AAV 10 10 10 10 1 30 60 -3, 15, 30, 60

2 Water for Injection

10 10 10 10 subtotal 20 20 20 20

Total 80

• Study endpoints will include the following:

• Cageside observations shall include observation for mortality, morbidity, general health and signs of toxicity.

• Clinical observations shall include evaluation of skin and fur characteristics, the injection site, eye and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, and somatomotor and behavior patterns, etc.

• The injection site shall be evaluated

• Collected blood samples shall be analyzed for clinical chemistry, including CRP, hematology and coagulation parameters.

• Animals shall be necropsied as soon as possible after the time of death or termination. A gross necropsy will be performed.

• The following organs shall be weighed after dissection at necropsies: adrenal glands, brain, heart, kidneys, iliac lymph nodes (left and right separately), liver, lung (with bronchi), ovaries (with oviducts), spleen, testes (with epididymides), thymus, and uterus (with cervix). All tissues shall be embedded in paraffin, sectioned, stained with hematoxylin and eosin, and shall be examined by a board-certified veterinary pathologist as required.

• Tissues (liver, brain, kidney, skeletal muscle) will be collected for bio-distribution analysis

• For purposes of proposal development assume qPCR and ELISA analysis will be conducted on

380 samples.

Study 12: Single-dose toxicity GLP study in NHPs (Optional Task 11)

The purpose of this study is to evaluate the potential systemic and local toxicity of the biologic therapeutic (e.g., AAV9) when administered as an intramuscular (IM) injection to male and female rats. The study design also includes a no-treatment recovery period to assess the persistence, reversibility, or delayed onset of any treatment-related effects. Animals will be dosed once on Study day 1. Dosing routes may include but are not limited to intramuscular (im), intravenous (iv), For purposes of proposal development, sample analysis costing should be provided separately.

Group Test Article Numbers of Animals

Injection (Days)

Necropsy (Days) Blood/Tissue Collection

(Days) Main Phase

Recovery Phase

M F M F Main Phase

Recovery Phase

1 AAV 6 6 6 6 1 30 60 -3, 15, 30, 60

2 Water for Injection

6 6 6 6 subtotal 12 12 12 12

Total 48

• Study endpoints will include the following:

• Cageside observations shall include observation for mortality, morbidity, general health and signs of toxicity.

• Clinical observations shall include evaluation of skin and fur characteristics, the injection site, eye and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, and somatomotor and behavior patterns, etc.

• The injection site shall be evaluated

• Collected blood samples shall be analyzed for clinical chemistry, including CRP, hematology, and coagulation parameters.

• Animals shall be necropsied as soon as possible after the time of death or termination. A gross necropsy will be performed.

• The following organs shall be weighed after dissection at necropsies: adrenal glands, brain, heart, kidneys, iliac lymph nodes (left and right separately), liver, lung (with bronchi), ovaries (with oviducts), spleen, testes (with epididymides), thymus, and uterus (with cervix). All tissues shall be embedded in paraffin, sectioned, stained with hematoxylin and eosin, and shall be examined by a board-certified veterinary pathologist as required.

• Tissues (liver, brain, kidney, skeletal muscle) will be collected for bio-distribution analysis

• For purposes of proposal development assume qPCR and ELISA analysis will be conducted on

380 samples.

Task Order Deliverables for all Tasks

Study Reports: The data and results from all protocols in which a given agent was evaluated, including microscopic pathology, shall be submitted to the COR as a separate draft report, due within the time frame specified in the Task Order. Each final Study Report shall be due as specified in the Task Order.

For GLP studies, the study report must be submitted in a format approved by the COR for submission of the report to the FDA for filing of an Investigational New Drug application or similar regulatory filing. Final Study Reports shall accurately and completely describe study design, procedures, and findings, and present an analysis and summary of the data followed by conclusions derived from the analysis. Data generated in the course of the studies should be separated by protocol and should be presented in an easily followed and understood tabular and graphic form.

a) The report shall include:

i. A cover page which shall include title, contract number, author(s), laboratory address, dates of initiation and completion, and sponsor;

ii. Comprehensive summary to be placed after the cover page;

iii. Data from each individual animal in each study, as well as a tabular summary of data for each treatment group, compared with a tabular presentation of ranges of historical control values presented in the context of individual control animals from the study;

iv. An evaluation of the meaning and significance of the data, particularly as they relate to potential effects of the agent in human therapy;

v. The signature of the Contractor's authorized representative and any others deemed necessary;

vi. A table of contents;

vii. A statement prepared and signed by the Contractor's Quality Assurance Unit, which will refer to all phases of the study and indicate where the raw data records, reports, and samples are stored.

The following items are examples of data that may be required for inclusion in the report.

b) Experimental Design and Methods

i. Drug/biologic compound information

• Identity data

• Lot number

• History (dates received, on test and study completed)

• Stability

ii. Animal history (source, sex, age, weight, immunization, procedure used for unique identification, etc.)

iii. Baseline data (pre-test)

iv. Control animals

v. Vehicle controls (if requested)

vi. Dose formulation information

vii. Route of administration

viii. Rate of injection

ix. Method of blood collection

x. Urinalysis data, if specifically requested

xi. Methodologies of all test procedures

xii. Days and method of sacrifice

xiii. Time period from death to necropsy

xiv. Rationale and documentation of all deviations from protocol

c) Results

i. Mortality

ii. Clinical Observations (appearance, behavior, signs of toxicity and pharmacologic effects)

iii. Body weights and food consumption

iv. Clinical laboratory studies

v. Gross and microscopic pathology

vi. Histopathology

vii. Ophthalmoscopic findings

viii. Organ weights and organ/body weight ratios

d) Statistical Analysis: Appropriate statistical analyses for comparing treatment groups to the control group as well as any other relevant statistical analyses needed to evaluate the data.

e) Statistical Evaluation

i. Cumulative mortality rate if appropriate

ii. Body weight and body weight changes

iii. Microscopic lesions if appropriate

iv. Clinical laboratory values

v. Total food consumption

vi. Organ weights and organ/body weight ratios

f) Tables

i. Cumulative mortality rates

ii. Mean body weights and food consumption

iii. Mean clinical laboratory values

iv. Summary incidence of gross pathology findings

v. Summary incidence of histopathology findings

vi. Summary of incidence of ophthalmoscopic findings

vii. Toxic, pharmacologic and behavioral effects for each test group to include a list of each sign and number of animals affected

g) Graphs

i. Mean weekly bodyweight and food consumption

ii. Survival if appropriate

h) Appendices

i. Toxic, pharmacologic and behavioral effect for each animal to include the date of observation of each sign, a description of each sign, and its subsequent course

ii. Clinical pathology reference ranges (when available)

iii. Individual ophthalmoscopic findings

iv. Analytical chemistry methods and results

v. Individual gross pathology findings

vi. References for clinical laboratory and statistical methods

vii. Week of death for each animal

viii. Individual clinical laboratory values

ix. Individual histopathology findings

x. Individual organ weights and organ/body weight ratios

i) Additional items may be required per Principal Investigator (PI)/COR discussions. In studies specified as GLP, all portions of the studies and reports must be in compliance with the GLP regulations. Corrections or additions to reports shall be submitted in form of an amendment clearly identifying the part of the report being added to or corrected, the reasons for addition or correction, and the dated signature of the person responsible.

The report shall be reviewed, assured for quality control, and contain a statement certifying that the studies were conducted in compliance with current GLP regulations, approved, signed, and dated by the Study Director.

(3) Report of Unexpected Event: This is a report of an unexpected adverse event, observed at any stage of the study, which would jeopardize the progress of the study. It shall be sent to the COR as soon as practicable after the adverse event.

b. Other Report Requirements

The Contractor shall also prepare and deliver the reports specified below. These reports, which are in addition to the “Technical Reports” specified above, are required by the Federal Acquisition Regulation (FAR) clauses that are applicable to and made a part of this Task Order.

The Contractor shall submit all reports in electronic format. All electronic reports submitted shall be compliant with Section 508 of the Rehabilitation Act of 1973 (29 U.S.C. 794d), as amended by the Workforce Investment Act of 1998 and the "Electronic and Information Technology Accessibility Provisions" set forth by the Architectural and Transportation Barriers Compliance Board (also referred to as the "Access Board") in 36 CFR part 1194. Additionally, 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 the contract. Additional information about testing documents for Section 508 compliance can be found at http://www.hhs.gov/web/section-508/.

Any paper/hardcopy documents/reports submitted under this contract shall be printed or copied, double-sided, on at least 30 percent post-consumer fiber paper, whenever practicable, in accordance with FAR 4.302(b).

Anticipated activities considered ancillary to the PK analysis of biopharmaceuticals include, but are not limited to, the following:

(1) Deliver study reports, including but not limited to weekly status update reports and summary development reports

(2) Conduct bi-weekly or weekly (as required) project update teleconferences

(3) Perform technology transfer from/to a third party when required

(4) Ensure compliance with GLP; and

(5) Maintain Quality systems to support GLP activities