Attachment 6 - Sample Task Orders.pdf

SAMPLE TASK ORDER A

INTERVENTIONAL AGENTS SAFETY AND PHARMACOKINETIC SERVICES (IASPS)

75N93024R00003

SAMPLE TASK ORDER A-01

Product Development Planning and Education

Associated with Task Area A

NOTE: The following Sample Task Order, indicated in this Attachment, is provided to assess the Offeror’s capabilities to conduct and fulfill the requirements of the Statement of Work, for projects of similar scope and size, to be issued under contracts awarded in response to this solicitation.

Although the Sample Task Order will NOT be executed, nor will awards be made for the Sample Task Order. Offerors are to include, in their proposals, a response that specifies the methods by which each Sample Task Order will be accomplished and the project management plan, with associated costs. Offerors should refer to the Additional Technical Proposal Instructions and Additional Business Proposal Instructions for guidance regarding preparation of their proposals.

STATEMENT OF WORK

I. BACKGROUND

The NIAID Division of Microbiology and Infectious Diseases (DMID) supports development of interventional agents against infectious diseases, including drugs directed against emerging and biodefense pathogens/agents. The activity to be supported under this Sample Task Order is to assess the status and overall scientific feasibility of the development of a novel therapeutic for Acute Flaccid Myelitis.

II. SCOPE

To assess the status and overall scientific feasibility of the development of a novel therapeutic for Acute Flaccid Myelitis and to develop a Product Development Plan for the specific Product.

III. TECHNICAL REQUIREMENTS

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

Assume the following:

1. The therapeutic is a small molecule

2. The investigator/product developer will provide information regarding:

a. Lead therapeutic indication

b. Proposed synthesis scheme for Active Pharmaceutical Ingredient (API)

c. Proposed drug product formulation and mode of delivery

d. Analytical and/or bioanalytical methods used to date

In addition to the General requirements included in the parent Statement of Work, the Contractor shall:

1. Prepare a Product Development Plan focused on the feasibility of development of a novel therapeutic for treatment Acute Flaccid Myelitis. Assess the development for clinical use as determined by current stage of development, bioavailability, potential toxicity, and manufacturing process. The Product Development Plan must include:

a. Preclinical development feasibility

b. Manufacturing

c. Pre-formulation studies and formulation development

d. Analytical and bioanalytical method development and validation

e. Metabolism and pharmacokinetic profiling

f. Calculation of PK parameters, including AUC, Cmax, Tmax, t1/2

g. Toxicology

h. Regulatory considerations, including regulatory documentation, manufacturing processes, non-clinical studies or the proposed clinical use

IV. PROJECT MANAGEMENT

There are no additional requirements to this Sample Task Order beyond those in the parent contract EXCEPT this Sample Task Order requires no Project Management Plan or updates.

V. QUALITY MANAGEMENT

There are no additional requirements to this Sample Task Order beyond those in the parent contract.

VI. FACILITIES, EQUIPMENT AND OTHER RESOURCES

Not applicable to this Sample Task Order.

VII. STORAGE AND SHIPPING

VIII. TRANSITION

End of Task Area A-01 Statement of Work

REPORTING REQUIREMENTS

In addition to those reports required by the other terms of this contract, the Contractor shall prepare and submit the following reports in the manner stated below. All reports shall include a cover page prepared in accordance with the following format:

Cover Page Format

• Contract and Task Order Number and Project Title

• Name and Sequence of Report (e.g., “Year 1, 2nd Study Report”)

• Period of Performance Being Reported

• Contractor’s Name and Address

• Author(s)

• Date of Submission

• Delivery Address

Deliverables

1. Teleconference Meetings and Minutes

The Contractor shall schedule and conduct a contract initiation meeting within two weeks of contract award. The contractor shall prepare and submit minutes for each teleconference. The minutes shall capture plans for future study designs, technical progress, issues affecting progress, changes in study designs and cumulative expenditures.

2. Monthly Update Reports

The Contractor shall submit to the COR a Monthly Update Report consisting of the draft Porduct Development Plan in its current state at the time of submission. These reports are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR.

The Contractor shall incorporate all recommended revisions subject to final acceptance by the COR.

3. Final Product Development Plan Report

The Contractor shall submit to the COR a Final Report consisting of the final version of the Product Development Plan. This report shall be comprehensive and of sufficient detail to describe the required items in Statement of Work 1a-h. This report is subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. The Contractor shall incorporate all recommended revisions subject to final acceptance by the COR.

4. Products

The Contractor shall submit any product of the Task Order, such as supporting data, raw data, results, and any electronic files to the Government or its designee (COR) as directed by the COR.

Delivery Schedule

Satisfactory performance of the completion of the Task Order shall be deemed to occur upon performance of the work described in the Statement of Work and upon delivery and acceptance by the Contracting Officer, or the duly authorized representative, of the following items in accordance with the stated delivery schedule. The items stated below, and as described in the Statement of Work and in the Reporting Requirements of this order, shall be delivered f.o.b. destination as set forth in FAR 52.247-35, F.o.b.

DESTINATION, WITHIN CONSIGNEES PREMISES (APRIL 1984), and in accordance with and by the date(s) specified below and any specifications stated in SECTION D, PACKAGING, MARKING AND SHIPPING, of this order:

Description Reporting

Requirement Location Delivery Schedule

Teleconference Minutes 1 Email to COR, Submit to eRDS

3 business days after meeting.

Monthly Technical Report

2 Email to COR, Submit to eRDS

Monthly on the 15th of each month following the calendar month of the report. No monthly report is due in the final month of the task order.

Final Report 3 Email to COR, Submit to eRDS

Draft to COR 10 business days before completion date of task order. Final due on the completion date of the task order.

Products 4 As instructed by

COR

As instructed by COR

All reports required herein shall be submitted in electronic format. The monthly report shall include a description of the activities during the reporting period, and the activities planned for the ensuing reporting period. The first reporting period consists of the first full month of performance plus any fractional part of the initial month. Thereafter, the reporting period shall consist of each calendar month.

The final report is to include a summation of the work performed and results obtained for the entire Task Order period of performance. This report shall be in sufficient detail to describe comprehensively the results achieved. The Final Report shall be submitted in accordance with the DELIVERIES Article in SECTION F of this task order.

SAMPLE TASK ORDER B

SAMPLE TASK ORDER B-01

Non-GLP in vitro Preclinical Safety Studies

Associated with Task Area B

NOTE: The following Sample Task Order indicated in this Attachment is provided to assess the Offeror’s capabilities to conduct and fulfill the requirements of the Statement of Work for projects of similar scope and size to be issued under contracts awarded in response to this solicitation.

Although the Sample Task Order will NOT be executed nor will awards be made for the Sample Task Order, Offerors are to include in their proposals a response that specifies the methods by which each Sample Task Order will be accomplished and the project management plan, with associated costs. Offerors should refer to the Additional Technical Proposal Instructions and Additional Business Proposal Instructions for guidance regarding preparation of their proposals.

The NIAID Division of Microbiology and Infectious Diseases (DMID) supports early phase development of interventional agents against infectious diseases, including drugs directed against emerging and biodefense pathogens. Preclinical safety data is a regulatory requirement for drugs to be accepted for an IND to begin clinical trials.

To perform a non-GLP Metabolite ID for two drug candidates in human liver microsomes.

Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities, not otherwise provided by the Government under the terms of the contract, as needed to undertake targeted research essential to translating basic research concepts into interventional agents.

In addition to the General requirements included in the parent Statement of Work, the Contractor shall:

Perform a Metabolite ID for 2 drug candidates in human liver microsomes.

1. Determine metabolites generated after incubation of 2 drug candidates in human liver microsomes and analysis of resulting metabolites by LC/MS.

2. Determine metabolites generated after incubation of 2 drug candidates in human hepatocytes and analysis of resulting metabolites by LC/MS.

3. Utilize industry standard software to predict structures for metabolites for each drug in microsomes and hepatocytes.

The Contractor shall provide facilities, equipment, space and other resources to conduct work in a manner to prevent cross-contamination with other materials.

All personnel, equipment and facilities shall be compliant with applicable regulatory agency requirements in effect throughout the entire period of performance. The Contractor shall maintain QA documentation to support adherence to these areas.

Storage of study materials and documentation under appropriate conditions as per US FDA regulations. Shipping shall be in accordance with US FDA regulation.

End of Task Area B-01 Statement of Work

In addition to those reports required by the other terms of this contract, the Contractor shall prepare and submit the following reports in the manner stated below. All reports shall include a cover page prepared in accordance with the following format:

• Period of Performance Being Reported

• Contractor’s Name and Address

• Author(s) award. The contractor shall prepare and submit to the COR minutes for each teleconference. The minutes shall capture plans for future study designs, technical progress, issues affecting progress, changes in study designs and cumulative expenditures.

2. Individual Study Plans

The Contractor shall submit a Draft Individual Study Plan within 5 business days after receiving an approved Service Request Form (SRF) to the COR for review and comment. The plans are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. Within 5 days of receipt of COR comments, the Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall consist of the following:

a) Purpose of Study

b) Study Objective

c) Compound Requirements

d) Experimental Design

e) Materials and Methods

f) Regulatory Compliance

g) Delivery Timelines

3. Individual Study Reports

The Contractor shall submit to the COR an Individual Study Report as described below for each completed study. These reports are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. The Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall be concise and consist of the following:

a) A report of all products, procedures and outcomes achieved; graphs and tables of data obtained, analytical data

b) A discussion and interpretation of the results

c) A budget report with cost justifications related to completing the study

d) Other information as may be required by the COR

4. Monthly Technical Reports

The Contractor shall submit to the COR a Monthly Study Progress Report, as described below. These reports are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. The Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall be concise and consist of the following:

a) A report of all products, procedures and outcomes achieved; graphs and tables of data obtained, analytical data

b) A discussion and interpretation of the results

c) A budget report with cost justifications related to completing studies underway

5. Task Order Final Report

The Contractor shall submit to the COR a Final Report that summarizes the results of the Task Order for the entire performance period. This report shall be comprehensive and of sufficient detail to describe the results achieved. The Final Report shall contain:

a) Cover Page as described above.

b) Introduction covering the purpose and scope of the Task Order effort.

c) Description of the overall progress, plus a separate description of each study protocol and subcontract, protocol or assay employed and its modifications and performance on the Task Order during the period of performance.

d) Descriptions shall include pertinent data in tables or graphs as appropriate to present significant results achieved, conclusions resulting from analysis, and a scientific evaluation of the data accrued under the Task Order.

6. Products

The Contractor shall submit any product of the Task Order, such as residual compounds, clinical material, prepared specimens, assays, protocols, raw data, results, and any electronic files to the Government or its designee (COR) as directed by the COR.

a) All drug products or chemical samples remaining from these studies

b) All files pertaining to this Task Order to include the synthesis scheme used and chemical characterization

c) Any documentation needed for regulatory submission.

Satisfactory performance of the completion of the Task Order shall be deemed to occur upon performance

Officer, or the duly authorized representative, of the following items in accordance with the stated delivery

Requirements of this order, shall be delivered f.o.b. destination as set forth in FAR 52.247-35, F.o.b.

DESTINATION, WITHIN CONSIGNEES PREMISES (APRIL 1984), and in accordance with and by the

Location Delivery Schedule

Teleconference Minutes 1 Email to COR, Submit to eRDS

3 business days after meeting.

Study Plan 2 Email to COR, Submit to eRDS

Draft to COR 5 business days after request. Final due 5 business days after COR comments.

Study Report 3 Email to COR, Submit to eRDS

Draft within 10 business days of study completion. Final due 5 business days after COR comments.

Monthly Technical Report

4 Email to COR, Submit to eRDS

Monthly on the 15th of each month following the calendar month of the report. No monthly report is due in the final month of the task order.

Final Report 5 Email to COR, Submit to eRDS

Draft to COR 10 business days before completion date of task order. Final due on the completion date of the task order.

Products 6 As instructed by

All reports required herein shall be submitted in electronic format. The monthly report shall include a description of the activities during the reporting period, and the activities planned for the ensuing reporting period. The first reporting period consists of the first full month of performance plus any fractional part of the initial month. Thereafter, the reporting period shall consist of each calendar month.

The final report is to include a summation of the work performed and results obtained for the entire Task Order period of performance. This report shall be in sufficient detail to describe comprehensively the

SAMPLE TASK ORDER C

SAMPLE TASK ORDER C-01

Non-GLP in vivo Preclinical Microbiological, Safety, Toxicology, and Pharmacokinetic Services

Associated with Task Area C

Offeror’s capabilities to conduct and fulfill the requirements of the Statement of Work for projects of similar scope and size to be issued under contracts awarded in response to this solicitation.

Although the Sample Task Order will NOT be executed nor will awards be made for the Sample Task Order, Offerors are to include in their proposals a response that specifies the methods by which each Sample Task Order will be accomplished and the project management plan, with associated costs. Offerors should refer to the Additional Technical Proposal Instructions and Additional Business Proposal Instructions for guidance regarding preparation of their proposals.

The NIAID Division of Microbiology and Infectious Diseases (DMID) supports early phase development of interventional agents against infectious diseases, including drugs directed against emerging and biodefense pathogens. Preclinical safety data is a regulatory requirement for drugs to be accepted for an IND to begin clinical trials.

To perform a non-GLP PK study of a monoclonal antibody cocktail.

Independently, and not as an agent of the Government, the Contractor shall furnish all necessary

Government under the terms of the contract, as needed to undertake targeted research essential to translating basic research concepts into candidate interventional agents.

In addition to the General requirements included in the parent Statement of Work, the Contractor shall:

1. Perform a pharmacokinetic Study of a mAb Cocktail, XYZ123, following a Single Intravenous Dose Administration to Male and Female Golden Syrian Hamsters.

2. Determine the plasma, lung, and bronchoalveolar lavage fluid (BALF) concentrations of a mAb cocktail in treated male and female Golden Syrian hamsters.

3. Perform a blood urea nitrogen (BUN) analysis on an aliquot of plasma and BALF.

manner to prevent cross-contamination with other materials.

The Contractor shall maintain Quality Assurance (QA) documentation to support adherence to these areas.

End of Task Area C-01 Statement of Work

In addition to those reports required by the other terms of this contract, the Contractor shall prepare and submit to the COR the following reports in the manner stated below. All reports shall include a cover page prepared in accordance with the following format:

• Period of Performance Being Reported

• Contractor’s Name and Address

• Author(s) approved Service Request Form (SRF) to the COR for review and comments. The plans are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. Within 5 days of receipt of COR comments, the Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall consist of the following:

a) Purpose of Study

b) Study Objective

c) Compound Requirements

d) Experimental Design

e) Materials and Methods completed study. These reports are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. The Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall be concise and consist of the following:

reports are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. The Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall be concise and consist of the following:

a) A report of all products, procedures and outcomes achieved; graphs and tables of data obtained, analytical data

b) A discussion and interpretation of the results

c) Description of the overall progress, plus a separate description of each study protocol and subcontract, protocol or assay employed and its modifications and performance on the Task Order during the period of performance.

d) Descriptions shall include pertinent data in tables or graphs as appropriate to present significant

Government or its designee (COR) as directed by the COR.

Satisfactory performance of the completion of the Task Order shall be deemed to occur upon performance

Officer, or the duly authorized representative, of the following items in accordance with the stated delivery

Requirements of this order, shall be delivered f.o.b. destination as set forth in FAR 52.247-35, F.o.b.

Location Delivery Schedule

Teleconference Minutes 1 Email to COR, Submit to eRDS

3 business days after meeting.

Study Plan 2 Email to COR, Submit to eRDS

Draft to COR 5 business days after request. Final due 5 business days after COR comments.

Study Report 3 Email to COR, Submit to eRDS

Draft within 10 business days of study completion. Final due 5 business days after COR comments.

Monthly Technical Report

4 Email to COR, Submit to eRDS

Monthly on the 15th of each month following the calendar month of the report. No monthly report is due in the final month of the task order.

Final Report 5 Email to COR, Submit to eRDS

Draft to COR 10 business days before completion date of task order. Final due on the completion date of the task order.

Products 6 As instructed by

All reports required herein shall be submitted in electronic format. The monthly report shall include a description of the activities during the reporting period, and the activities planned for the ensuing reporting period. The first reporting period consists of the first full month of performance plus any fractional part of the initial month. Thereafter, the reporting period shall consist of each calendar month.

The final report is to include a summation of the work performed and results obtained for the entire Task Order period of performance. This report shall be in sufficient detail to describe comprehensively the

SAMPLE TASK ORDER D

SAMPLE TASK ORDER D-01

GLP Preclinical Microbiological, Safety, Toxicology, and Pharmacokinetics Services

Associated with Task Area D

Offeror’s capabilities to conduct and fulfill the requirements of the Statement of Work for projects of similar scope and size to be issued under contracts awarded in response to this solicitation.

Although the Sample Task Order will NOT be executed nor will awards be made for the Sample Task Order, Offerors are to include in their proposals a response that specifies the methods by which each Sample Task Order will be accomplished and the project management plan, with associated costs. Offerors should refer to the Additional Technical Proposal Instructions and Additional Business Proposal Instructions for guidance regarding preparation of their proposals.

STATEMENT OF WORK

I. SCOPE

To perform standard GLP-toxicology on a single test article.

II. TECHNICAL REQUIREMENTS

services, qualified personnel, materials, equipment, and facilities, not otherwise provided by the Government under the terms of the contract, as needed to undertake targeted research essential to translating basic research concepts into candidate interventional agents.

In addition to the General requirements included in the parent Statement of Work, the Contractor shall:

1. Design and conduct a 28-day GLP toxicology study in rats with toxicokinetic assessment and recovery using a test article to be dosed once daily via IV bolus to rats. This study will be used to support an IND.

III. PROJECT MANAGEMENT

IV. QUALITY MANAGEMENT

However, this Sample Task Order requires typical industry practice quality/regulatory compliance appropriate for GLP.

V. FACILITIES, EQUIPMENT AND OTHER RESOURCES

The Contractor shall maintain QA documentation to support adherence to these areas.

VI. STORAGE AND SHIPPING

VII. TRANSITION

End of Task Area D-01 Statement of Work

In addition to those reports required by the other terms of this contract, the Contractor shall prepare and submit to the COR the following reports in the manner stated below. All reports shall include a cover page

• Period of Performance Being Reported

• Contractor’s Name and Address

• Author(s) approved Service Request Form (SRF) to the COR for review and comment. The plans are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. Within 5 days of receipt of COR comments, the Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall consist of the following:

a) Purpose of Study

b) Study Objective

c) Compound Requirements

d) Experimental Design

e) Materials and Methods completed study. These reports are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. The Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall be concise and consist of the following:

reports are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. The Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall be concise and consist of the following:

a) A report of all products, procedures and outcomes achieved; graphs and tables of data obtained, analytical data

b) A discussion and interpretation of the results

c) Description of the overall progress, plus a separate description of each study protocol and subcontract, protocol or assay employed and its modifications and performance on the Task Order during the period of performance.

d) Descriptions shall include pertinent data in tables or graphs as appropriate to present significant

Government or its designee (COR) as directed by the COR. The Contractor shall include:

a) All drug products or chemical samples remaining from these studies;

Satisfactory performance of the completion of the Task Order shall be deemed to occur upon performance

Officer, or the duly authorized representative, of the following items in accordance with the stated delivery

Requirements of this order, shall be delivered f.o.b. destination as set forth in FAR 52.247-35, F.o.b.

Location Delivery Schedule

Teleconference Minutes 1 Email to COR, Submit to eRDS

3 business days after meeting.

Study Plan 2 Email to COR, Submit to eRDS

Draft to COR 5 business days after request. Final due 5 business days after COR comments.

Study Report 3 Email to COR, Submit to eRDS

Draft within 10 business days of study completion. Final due 5 business days after COR comments.

Monthly Technical Report

4 Email to COR, Submit to eRDS

Monthly on the 15th of each month following the calendar month of the report. No monthly report is due in the final month of the task order.

Final Report 5 Email to COR, Submit to eRDS

Draft to COR 10 business days before completion date of task order. Final due on the completion date of the task order.

Products 6 As instructed by COR

All reports required herein shall be submitted in electronic format. The monthly report shall include a description of the activities during the reporting period, and the activities planned for the ensuing reporting period. The first reporting period consists of the first full month of performance plus any fractional part of the initial month. Thereafter, the reporting period shall consist of each calendar month.

The final report is to include a summation of the work performed and results obtained for the entire Task Order period of performance. This report shall be in sufficient detail to describe comprehensively the

SAMPLE TASK ORDER E

SAMPLE TASK ORDER E-01

Commercial Off-the-Shelf Screening for Absorption, Distribution, Metabolism, and Excretion (ADME), Safety, and Pharmacokinetics (PK)

Associated with Task Area E

Offeror’s capabilities to conduct and fulfill the requirements of the Statement of Work for projects of similar scope and size to be issued under contracts awarded in response to this solicitation.

Although the Sample Task Order will NOT be executed nor will awards be made for the Sample Task Order, Offerors are to include in their proposals a response that specifies the methods by which each Sample Task Order will be accomplished and the project management plan, with associated costs. Offerors should refer to the Additional Technical Proposal Instructions and Additional Business Proposal Instructions for guidance regarding the preparation of their proposals.

I. SCOPE

The scope of this Sample Task Order is to provide a suite of non-GLP standard, off-the-shelf in vitro ADME and safety screening assays plus standard in viv PK studies in rodents.

II. TECHNICAL REQUIREMENTS

Government as needed to perform the Statement of Work below.

In addition to the General requirements included in the parent Statement of Work, the Contractor shall:

1. Provide bioanalytical LC-MS/MS assays for a wide variety of chemotypes expected from the submitted compounds will be rapidly developed by using standard HPLC columns and generic gradients and mass spec conditions to provide compound detection in sample matrices appropriate for the in vitro and PK assays.

2. Perform in vitro ADME and physical property profiling in the assays as detailed below:

a. Aqueous Solubility – Turbidometric assay for kinetic solubility of test compounds diluted into an aqueous buffer (e.g., PBS at pH 7.5) at various target concentrations from concentrated DMSO stocks; <2 week turn-around requiring ~200 uL 10 mM compound in DMSO (or 1-2 mg).

b. Plasma Protein Binding – Rapid Equilibrium Dialysis (RED) plate (or similar) assay determining free/bound levels of a test compound in the presence of plasma dialyzed against PBS for >=4 hour incubation with LC-MS/MS quantitation of compound; each request will include testing in plasma from two species (selected from human, rat, mouse, dog, or NHP); reported data will include % protein bound and fraction unbound, as well as recovery levels; <2 week turn-around requiring ~100 uL 10 mM compound in dimethylsulfoxide (DMSO) or ~1 mg.

c. Microsomal Metabolic Stability - In vitro assay of stability of test compound in the presence of liver microsome extracts with LC-MS/MS quantitation of % parent compound remaining over a range of 6-time points to calculate t1/2 and intrinsic clearance (Clint) values; <2 week turn-around requiring ~50 uL 10 mM compound in DMSO (or ~1 mg).

d. Caco2 Permeability – In vitro, an assay using a monolayer of Caco-2 cells to assess the permeability of test compound across the gastro-intestinal tract; the test compound at a single concentration will be applied to the apical and basal sides of the monolayer in the presence and absence of a PGP inhibitor (e.g. verapamil) with LC-MS/MS quantitation of compound after 2 hours to determine the apparent permeability coefficient (Papp), efflux ratio and recovery of the test compound; <4 week turn-around requiring ~100 uL 10 mM compound in DMSO (or ~1 mg).

e. Cytochrome P450 Inhibition – In vitro screening assay measuring the potential for the test compound to inhibit cytochrome P450 enzyme activity in human liver microsomes;

test compound will be added at 5-7 concentrations to human liver microsomes, cofactors (NADPH and MgCl2), and specific probe substrates for multiple isozymes including CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, with LC- MS/MS quantitation of % inhibition relative to vehicle control and calculation of IC50 when possible; <2 week turn-around requiring ~100 uL 10 mM compound in DMSO (or ~1 mg).

f. Cytotoxicity – In vitro assay measuring the potential cytotoxicity to human hepatocyte

(or similar) cells using the MTT (or similar) assay for cell viability in the presence of test compound at a range of 5 non-zero concentrations relative to controls without a compound; <2 week turn-around requiring ~100 uL 10 mM compound in DMSO (or ~1 mg).

3. Perform in vitro safety profiling in the assays as detailed below:

a. Safety Panel Screen – In vitro assays against a panel of ~60 mammalian receptors and enzymes to assess potential off-target pharmacology that might lead to toxicity for test compound initially measured at a single concentration to determine % Inhibition relative to controls and follow-up IC50 analysis of hits using 5 concentrations of a test compound;

<2 week turn-around for initial %I screen plus 2 weeks for IC50 follow up requiring 30 mg (including sufficient supply for follow-up)

b. Cardiac Channel Inhibition – In vitro assay measuring the potential for the test compound to cause cardiac toxicity through inhibition of ion channels using ChanTest (or similar) rapid patch-clamp screening assay against 8 key target ion channels including hERG, hKCNQ1/hminK, hKir2.1, hKv1.5, hKv4.3/hKChiP2, hL-type Calcium (CAV1.2), hHCN4 and hNAV1.5 with % Inhibition determined from a range of test compound concentrations relative to controls and IC50 calculated when possible; <8 week turn-around requiring ~5 mg.

4. Perform assays screening pharmacokinetics properties as detailed below:

a. PK Screening – For each single-dose PK study, include two dose groups (varying dose and/or route) for a single test compound. Develop a fit-for-purpose LC-MS/MS bioanalytical method using standard HPLC columns and generic gradients and mass spec conditions to provide compound detection down to at least 1 ng/mL in the appropriate biological matrix (plasma or homogenized tissue). Compound requirements will vary with the study design but will typically require 20-75 mg for mice and 50-250 mg for rats, or hamster. PK with <=4 week turn-around of the study report, including raw data table, calculated PK parameters as possible (Cmax, Tmax, AUC, t1/2, apparent V, and Cl), and summary of results.

Assume the studies will be performed as follows:

Number of Compounds

ADMET Profiling Package 1 (Including Aqueous Solubility and Microsomal Metabolic/Plasma Stability three species selected from mice/rat/human/dogs/NHP)

ADMET Profiling Package 2 (Including Plasma Protein Binding, Caco-2 Permeability, Cytochrome P450 Inhibition and Cytotoxicity)

Cytotoxicity (stand-alone assay format) 1 CYP Induction

(Panel of 3 CYP enzymes with both qPCR and activity assessment)

Secondary Pharmacology Profiling (Panel of ~50 mammalian receptors/enzymes; Single-concentration inhibition screen and IC50 follow up of 5 hits)

Cardiac Channel Profiling (Panel of 8 assays with six ion channels; IC50 assessment using 5 concentrations of test compound)

Rodent PK Screening Package 1 (Including bioanalysis and PK parameters from each of 2 dose groups in mice or rats)

Rodent PK Screening Package 2 (Including bioanalysis and PK parameters from each of 2 dose groups in hamsters or guinea pigs)

Rodent MTD Package 1 (In mice or rats with up to 5 dose groups and max of 15 total animals per study; in-life observations for signs of acute toxicity and/or autonomic effects to establish MTD for future studies)

Rodent MTD Package 2 1

(In hamsters or guinea pigs with up to 5 dose groups and max of 15 total animals per study; in-life observations for signs of acute toxicity and/or autonomic effects to establish MTD for future studies)

III. PROJECT MANAGEMENT

No Project Management Plan or updates are required for this Sample Task Order.

IV. QUALITY MANAGEMENT

This Sample Task Order requires typical industry quality standards for screening assays and reporting to support projects in the LO phase of discovery.

VI. FACILITIES, EQUIPMENT, AND OTHER RESOURCES

The Contractor shall provide facilities, equipment, space, and other resources to conduct work in a

The Contractor shall maintain QA documentation to support adherence to these areas.

End of Task Area E-01 Statement of Work

In addition to those reports required by the other terms of this contract, the Contractor shall prepare and submit to the COR the following reports in the manner stated below. All reports shall include a cover page

• Period of Performance Being Reported

• Contractor’s Name and Address

• Author(s) approved Service Request Form (SRF) to the COR for review and comments. The plans are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. Within 5 days of receipt of COR comments, the Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall consist of the following:

a) Purpose of Study

b) Study Objective

c) Compound Requirements

d) Experimental Design

e) Materials and Methods

The Contractor shall submit an Individual Study Report as described below for each completed study.

These reports are subject to technical inspection and requests for clarification by the COR and may be edited by designees of the COR. The Contractor shall incorporate all recommended revisions subject to final acceptance by the COR. The Study Report shall be concise and consist of the following:

a) A report of all products, procedures and outcomes achieved; graphs and tables of data obtained,

4. Products

Government or its designee (COR) as directed by the COR. The Contractor shall include:

c) Any documentation needed for regulatory submission

Satisfactory performance of the completion of the Task Order shall be deemed to occur upon performance of the work described in the Statement of Work and upon delivery and acceptance by the Contracting Officer, or the duly authorized representative, of the following items in accordance with the stated delivery schedule. The items stated below, and as described in the Statement of Work and in the Reporting Requirements of this order, shall be delivered f.o.b. destination as set forth in FAR 52.247-35, F.o.b. DESTINATION, WITHIN CONSIGNEES PREMISES (APRIL 1984), and in accordance with and by the date(s) specified below and any specifications stated in SECTION D, PACKAGING, MARKING AND SHIPPING, of this order:

Location Delivery Schedule

Teleconference Minutes 1 Email to COR, Submit to eRDS

3 business days after meeting.

Study Plan 2 Email to COR, Submit to eRDS

Draft to COR 5 business days after request. Final due 5 business days after COR comments.

Study Report 3 Email to COR, Submit to eRDS

Draft within 10 business days of study completion. Final due 5 business days after COR comments.

Products 4 As instructed by

All reports required herein shall be submitted in electronic format. The monthly report shall include a description of the activities during the reporting period, and the activities planned for the ensuing reporting period. The first reporting period consists of the first full month of performance plus any fractional part of the initial month. Thereafter, the reporting period shall consist of each calendar month.

The final report is to include a summation of the work performed and results obtained for the entire Task Order period of performance. This report shall be in sufficient detail to describe comprehensively the