Attachment 5 - Additional Technical Proposal Instructions.pdf

ATTACHMENT 5: ADDITIONAL TECHNICAL PROPOSAL INSTRUCTIONS, FORMAT FOR

TECHNICAL PROPOSAL and TABLE OF CONTENTS

INTERVENTIONAL AGENTS SAFETY AND PHARMACOKINETIC SERVICES (IASPS)

It is strongly recommended that offerors use the following template as the Table of Contents for the Technical Proposal. All information presented in the Technical Proposal should be presented in the order specified below.

These additional Technical Proposal instructions reflect the requirements of the solicitation and provide specific instructions and formatting for the Technical Proposal. While Section L of the solicitation provides a generic set of Technical Proposal instructions applicable to all NIH R&D solicitations, these instructions are tailored to the specific requirements of the RFP. The information requested in these instructions should be used to format and prepare the Technical Proposal, and should be used as a Table of Contents for your Technical Proposal. Offerors should follow the instructions in Section L of the solicitation, and include the information requested here.

Offerors are advised to give careful consideration to the Statement of Work, all reference materials, and attachments, the Technical Evaluation Criteria in Section M, and the solicitation as a whole in the development of their Technical Proposals.

Offerors proposing subcontracts to perform portions of the Statement of Work should clearly identify the specific tasks for which they plan to utilize subcontractors, as well as the method and level of integration/coordination between the prime Contractor and all proposed subcontractors, and the expected advantages of such an approach.

Offerors must refer to the solicitation Attachment entitled “Packaging and Delivery of the Proposal,” which details strict guidelines, including page limitations, formatting and layout of proposals, and prohibits the offerors use of links to internet web site addresses (URLs) to direct readers to alternate sources of information.

Include the Attachment “Packaging and Delivery of the Proposal”, with the SP.

TECHNICAL PROPOSAL – TABLE OF CONTENTS

Note: The Government has requirements in all Task Areas, however offerors are not required to propose to all Task Areas. Offerors must propose to Task Area F and at least one Task Area from Task Areas A -E. Offerors must submit one proposal per task area proposed. If submitting to all task areas, you are required to submit six proposals. Offerors should submit to Task Areas where they are capable to best meet the overall qualifications needed to fulfill the technical requirements of that Task Area. Proposals responding to the entire suite of services as well as those responding to only 2 or more are desired by the government. Each Technical Proposal shall address all elements of the proposed Task Area and detailed plans in response to the Sample Task Order matching the proposed Task Area; and all General Task Order Requirements described in the parent contract statement of work. Proposals will be evaluated independently for each Task Area proposed. If an Offeror proposes to both Task Area B and C, award may occur for either B or C, or for both B and C, in addition to the possibility of no award.

Task Area F will not be peer reviewed.

SECTION 1:

1) PROPOSAL TITLE PAGE. Include RFP title and number, name of organization, Unique Entity Identifier (UEI), and identify if the proposal is an original or a copy. Offerors that include in their proposals data that they do not want disclosed to the public for any purpose, or used by the Government except for evaluation purposes, shall also include the legend regarding Restriction on Disclosure and Use of Data prescribed by FAR 52.215-1(e)]

2) TABLE OF CONTENTS. In SECTION 3 of the Table of Contents, include the Task Area you are proposing on.

SECTION 2: TECHNICAL PROPOSAL OVERVIEW (suggested 6-page maximum, which will be included in the overall page limit set in the RFP)

The Offeror shall provide a brief overview of the Technical Proposal, including:

1) A brief description of the activities in the Task Area proposed by the offeror and all proposed subcontractors, including identification of all proposed subcontractors and a list of key personnel for the offeror and the proposed subcontractors with degrees, titles and role in the project.

2) By area of expertise, provide the total number of staff, the number available to be assigned to the contract for the offeror and all proposed subcontractors, and total number of additional staff to be hired and trained.

3) A brief description of the facilities and equipment to be made available by the offeror and all proposed subcontractors.

a. If Task Area D is proposed, a brief description of all facilities where GLP activities will be performed, including storage.

SECTION 3: TECHNICAL PLAN/APPROACH FOR EACH TASK AREA

GENERAL NOTES

The Offeror shall describe, in detail for each Task Area proposed, overall technical capabilities, approaches, methodologies, plans and procedures for providing services for interventional agent development described in the Statement of Work (SOW). Clearly specify the planned source (e.g. in-

Table of Contents Page

1. SECTION 1 1

2. SECTION 2: TECHNICAL PROPOSAL OVERVIEW – TASK AREA B x

3. SECTION 3: TECHNICAL PLAN/APPROACH x

4. SECTION 4: SCIENTIFIC AND TECHNICAL PERSONNEL x

5. SECTION 5: FACILITIES, EQUIPMENT, AND OTHER RESOURCES x

6. SECTION 6: PROJECT MANAGEMENT x

7. SECTION 7: QUALITY SYSTEM x

8. SECTION 8: OTHER CONSIDERATIONS x https://www.acquisition.gov/far/current/html/52_215.html#wp1144408 house, consortia partner, subcontract, etc.) for described technical capabilities (e.g. capable of performing synthesis or pharmacokinetic activities for therapeutic compounds in-house). If technical capabilities are to be obtained from a subcontractor, identify the subcontractor, if already known.

Regarding responses to the Sample Task Order(s) matching the Task Areas, the Offeror shall describe in detail the proposed approaches, methodologies, plans and procedures for completion of activities in the respective SOWs. The Offeror shall propose a timeline to complete the activities described in the Sample Task Order in the response and include a Gantt chart. The Offeror shall discuss relevant organizational experience, problems or obstacles encountered and approaches implemented to resolve or correct potential or identified problems.

1) Task Area A: Product Development Planning and Education

a. The Offeror shall describe demonstrated performance, usage, or implementation of technical capabilities, processes and procedures to implement and perform the scope of activities described in Task Area A as follows:

1. Describe technical capabilities, processes, procedures and methods for implementation and communication (i.e. reports) for assessing and advising on products for feasibility of design, development, manufacture, and for the development of Phase I and II clinical trial materials.

2. Describe technical capabilities, processes, procedures and methods for developing and writing Product Development Plans for specified products.

3. Describe technical capabilities for all classes of therapeutic small molecule products

b. The Offeror shall describe proposed plans, processes and procedures for the implementation and performance of the scope of activities described in Sample Task Order

2) Task Area B: Non-GLP in vitro Preclinical Safety Studies

a. The Offeror shall describe the demonstrated performance, usage, or implementation of technical capabilities, processes and procedures to implement and perform the scope of activities described in Task Area B as follows:

1. Describe any acquisition processes, procedures and anticipated timelines for obtaining any of the technical capabilities required to fulfill the SOW requirements.

b. The Offeror shall describe technical capabilities, processes, and procedures, to perform in vitro microbiological assays, to determine the candidates with properties considered most amenable to drug development, and to determine safety and metabolism in in vitro systems, e.g., metabolic, and permeability assays; dose response, and mechanism of action.

c. The Offeror shall describe technical capabilities, processes, ad procedures, to perform in vitro preclinical sudies, including:

1. Biotransformation assays conducted in vitro

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

3. All other in vitro safety and pharmacology assays and studies that may be required for a particular interventional agent candidate

d. The Offeror shall describe proposed plans, processes and procedures for the implementation and performance of the scope of activities described in Sample Task Order B.

3) Task Area C: Non-GLP in vivo Preclinical Microbiological, Safety, Toxicology, and

Pharmacokinetic Services

The Offeror shall describe the demonstrated performance, usage, or implementation of described technical capabilities, processes, and procedures to implement and perform the scope of activities described in Task Area C as follows:

a. Describe any acquisition processes, procedures, and anticipated timelines for obtaining any of the technical capabilities required to fulfill the SOW requirements.

b. Describe technical capabilities, processes, and procedures to prepare drug dosage forms for various routes of delivery (i.e., oral, IV, IP) to be used in the in vivo studies.

c. Describe technical capabilities, processes, and procedures to develop methods, and perform analytical tests to characterize interventional agents in various carriers in support of in vivo safety, pharmacokinetic studies, and other preclinical evaluations.

The Offeror shall describe technical capabilities, processes, and procedures to perform in vivo, preclinical safety, studies, including:

a. Determination of maximum tolerated dose and no observed adverse effect levels (NOAEL)

b. PK-Determination of relevant pharmacokinetic parameters: either, more than a single compound, and/or more than two dosages (either dose amount or route of delivery) for small animals; or at least a single dosage, in higher species

c. Single and repeated dose toxicity studies

d. Toxicokinetic parameters

e. Bioavailability studies

f. Behavioral pharmacology (e.g., functional observational battery, locomotor activity, convulsant activity, gastrointestinal motilities-time potentiation, etc.)

g. All other safety and pharmacology studies that may be required for a particular interventional agent candidate

The Offeror shall describe methods, processes, and procedures, to provide all data, information, and records to contribute to the writing and submission of the relevant sections of the Investigator’s Brochure, and all other documents related to IND submission, or FDA submission, such as SEND data, when requested, by the COR. Retain all records, samples, and histology/microscopy slides.

The Offeror shall describe proposed plans, processes and procedures for the implementation and performance of the scope of activities described in Sample Task Order C.

4) Task Area D: GLP Preclinical Microbiological, Safety, Toxicology, and Pharmacokinetic

Services

The Offeror shall describe the demonstrated performance, usage, or implementation of described technical capabilities, processes, and procedures to implement and perform the scope of activities described in Task Area D, as follows:

a. Describe any acquisition processes, procedures and anticipated timelines for obtaining any of the technical capabilities required to fulfill the SOW in Attachment 2.IV.

b. Describe technical capabilities, processes and procedures for the performance and documentation of in vitro microbiological assays to determine the candidates with the most “drug-like” properties and to help determine safety and metabolism in in vitro systems, e.g., AMES, metabolic, and permeability assays; dose-response; and mechanism of action.

c. Describe technical capabilities, processes and procedures for the performance and documentation for in vitro and in vivo Preclinical Safety, Toxicology, and Pharmacokinetics Studies, performed GLP when required, such as:

a. Determination of acute and subchronic toxicity

b. Single and repeated dose toxicity studies

c. Toxicokinetic parameters

d. Absorption, distribution, metabolism, and excretion studies

e. Genotoxicity testing

f. Carcinogenicity testing if relevant for therapeutic candidate

g. Reproductive toxicity studies

h. Biotransformation assays conducted in vitro

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

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

k. Behavioral pharmacology (e.g., functional observational battery, locomotor activity, convulsant activity, gastrointestinal motility, sleep-time potentiation, etc.)

l. Cell permeability

d. The Offeror shall describe proposed plans, processes and procedures for completing, directing and ensuring the successful technology transfer of all materials, assays, methods and procedures as required for the successful performance of contract activities.

5.) Task Area E: Commercial Off-the-Shelf Screening for Absorption, Distribution, Metabolism, and Excretion (ADME), Safety, and Pharmacokinetics (PK)

The Offeror shall describe the demonstrated performance, usage, or implementation of capabilities, processes, and procedures to implement and perform the scope of activities described in Task Area E as follows:

a. Describe technical capabilities, processes, and procedures for performing bioanalytical LC- MS/MS assays for a wide variety of chemotypes expected from submitted compounds 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.

b. Describe technical capabilities, processes, and procedures for performing standard, off-the-shelf non-GLP screening assays to assess compound physical properties and ADME and safety profiles.

c. Describe technical capabilities, processes, and procedures for performing standard, off-the-shelf Screening assays for pharmacokinetics (PK) properties in rodents or other small animals to assess plasma (and limited tissue) drug concentrations from standard routes of administration and a summary of results that will be provided.

d. Assume the assays will be performed on compounds as they are submitted in the order that they are received.

e. Assume generic study plans will be prepared prior to the initiation of work on submitted compounds to include details of the protocols for the requested assays, compound requirements for each requested assay, and delivery timings for each requested assay.

The Offeror shall 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 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 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 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 assay using a monolayer of Caco-2 cells to assess the permeability of test compound across the gastro-intestinal tract; 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 compound; <2 week turn-around requiring ~100 ul 10 mM compound in DMSO (or ~1 mg)

The Offeror shall 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 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

The Offeror shall perform assays for screening pharmacokinetic 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 study design but will typically require 20-75 mg for mouse and 50-250 mg for rat PK with <=4 week turn-around of study report, including raw data table, calculated PK parameters as possible (Cmax, Tmax, AUC, t1/2, apparent V, and Cl), and summary of results.

b. The Offeror shall describe proposed plans, processes and procedures for the implementation and performance of the scope of activities described in Sample Task Order E and compare and contrast when applicable to that planned/proposed for all product classes listed in the SOW.

SECTION 4: SCIENTIFIC AND TECHNICAL PERSONNEL

The Offeror shall provide information relevant to document individual training, experience, qualifications and expertise necessary for the successful completion of all proposed Task Area and Sample Task Order requirements. Limit CVs to 2-3 pages and provide selected references for publications relevant to the scope of the Task Order.

1) Principal Investigator (PI): Describe the experience, training, expertise, and qualifications, and level of effort of the proposed Principal Investigator to lead and direct the activities to be carried out under the Statement of Work.

2) Other Key Scientific and Technical Personnel: Describe the experience, training, expertise and qualifications, as well as the level of effort, for all proposed key scientific, technical, and regulatory where appropriate (Task Areas C and D) personnel.

Include the following:

• Project Manager

• Lead Scientific, Technical and/or Regulatory Personnel

SECTION 5: FACILITIES, EQUIPMENT, AND OTHER RESOURCES

The Offeror shall document availability and adequacy of facilities, equipment, space and other resources necessary to carry out the proposed Task Area and Sample Task Order requirements, including:

1) Location and features of facilities including a floor plan and a list of equipment and resources dedicated to the project for the prime contractor and any proposed subcontractors (lease or ownership information should be provided).

2) Identification and description of ALL support resources (including training programs, and computer and Information Technology systems) that will be required to effectively complete the functions specified in the Statement of Work.

3) Information on facility and equipment validation.

4) History and details of facility audits and/or inspections where applicable, and any relevant Master File information.

5) Description of plans and procedures to be utilized for compliance with all safety regulations and guidelines including training and monitoring of personnel for exposure to infectious and other hazardous materials.

6) Description of proposed plans and procedures for the receipt, storage, retrieval, packaging, and shipping of products, materials and reagents from domestic and international locations.

7) Description of registered biocontainment facilities, equipment and training programs and a clear description of biocontainment space, including square footage and intended use (i.e., cell culture, viral production, bacterial production, storage, etc.)

SECTION 6: PROJECT MANAGEMENT

The Offeror shall provide the Project Management approach for the overall project organization that addresses the planning, initiation, implementation, conduct, monitoring and completion of proposed tasks identified in the Statement of Work. If consultants and/or subcontractors are proposed, include the approach to solicit, select, award and manage the work performed by consultants and/or subcontractor(s).

The Offeror shall provide a Staffing Plan that describes roles, responsibilities, and level of effort for all scientific and technical personnel, including all proposed subcontractors and consultants. The Offeror shall provide an administrative and technical framework indicating clear lines of authority and responsibility for all proposed personnel. The Offeror shall include a chart of the proposed organizational/management structure for the project.

The Offeror shall describe the project management systems that will be used to track activities and to keep multiple activities on time and budget. The plan must include a description of the quality control methods that will be used to ensure the effective and efficient initiation, implementation, management, and oversight of contract requirements.

The Offeror shall provide an outline on how the PI and the Project Manager will communicate with the Contracting Officer’s Representative and Contracting Officer and how the PI and Project Manager will communicate, monitor, and manage the project both internally and externally (at subcontractor facilities).

SECTION 7: QUALITY SYSTEM

The Offeror shall describe the current model and operating procedures for implementing a QC/QA program for completion of the proposed Task Area and Sample Task Order requirements. As appropriate, include the following:

1) Complete description of the Quality System including QA and QC responsibilities.

2) Description of process to ensure the commitment of the offeror’s senior management support for the Quality Systems.

3) Quality System management of activities at subcontractor’s site that is appropriate for the phase of product development and within all applicable Regulatory regulations.

4) Relevant organizational experience, problems or obstacles encountered, and approaches implemented to resolve or correct identified problems.

SECTION 8: OTHER CONSIDERATIONS

This section of the Technical Proposal should document other resources not covered in Sections 1 through 7 above necessary to carry out the Task Order Statement of Work, including:

1) Biological Agents or Toxins

The Technical Proposal should include a plan for biohazard safety and security requirements.