Amendment_00001_04-19-19.pdf

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AMENDMENT #00001

NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

REQUEST FOR PROPOSALS (RFP) NUMBER: NIH-NINDS-75N95019R00027

PROJECT TITLE: Screening of Investigational Agents through the “NINDS Preclinical Screening Platform for Pain” (PSPP)

AMENDMENT NUMBER: 00001

DATE OF ISSUANCE: April 19, 2019

The above numbered RFP is amended as set forth below. The hour and the date specified for receipt of proposals remains unchanged. Offerors must acknowledge receipt of the amendment prior to the hour and the date specified in the RFP or as amended, by one of the following methods:

I. By acknowledging receipt of this amendment on each copy of the proposal submitted. Please note that this is the preferred method.

II. By separate letter or email which includes a reference to the RFP and amendment number.

FAILURE OF YOUR ACKNOWLEDGMENT TO BE RECEIVED AT THE PLACE DESIGNATED FOR

THE RECEIPT OF PROPOSALS PRIOR TO THE HOUR AND DATE SPECIFIED MAY RESULT IN

REJECTION OF YOUR PROPOSAL. If by virtue of this amendment you desire to change a proposal already submitted, such change may be made by letter, provided each letter makes reference to the RFP and this amendment, and is received prior to the opening hour and date specified.

The purpose of this amendment is to 1) provide responses to questions received concerning the above numbered RFP and 2) make changes to the above numbered RFP.

A. This amendment provides repsonses to questions received concerning the above numbered RFP as stated below.

INTERESTED OFFEROR QUESTIONS GOVERNMENT REPSONSES TO

INTERESTED OFFEROR QUESTIONS

INTERESTED OFFEROR QUESTION #1:

Section D.1 Animal facilities, in page 133, as ___________ is not AAALAC accredited, can you please confirm that we can submit a RFP regardless as long as we are registered at OLAW (we are not yet registered at OLAW but can apply).

GOVERNMENT RESPONSE TO INTERESTED OFFEROR

QUESTION #1:

The Contractor and any subcontractor shall be fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International or equivalent and maintain that accreditation for the duration of the contract. Please refer to the following solicitation sections and/or attachments for information concerning this requirement.

• PART III, SECTION J, SOLICITATION

ATTACHMENTS, Attachment 3: Statement of Work, 04/19/2019, D.I. ANIMAL FACILITY.

• PART III, SECTION J, SOLICITATION

ATTACHMENTS, Attachment 22: Sample Task Order Request For Proposal (TORFP) #1, Enclosure Number 1 – Sample Task Order #00001 Statement of Work (SOW), 04/19/2019, D.I. ANIMAL FACILITY.

• SECTION M - EVALUATION FACTORS FOR

AWARD, 4. MANDATORY QUALIFICATION

CRITERIA, C. ANIMAL WELFARE

INTERESTED OFFEROR QUESTION #2:

Is a biosketch be equivalent to submit in lieu of resume?

QUESTION #2:

A biosketch is commonly used to highlight each individual's qualifications for a specific role in a proposed project and the National Institutes of Health (NIH) requires a biosketch for senior/key persons applying for or renewing NIH grants not contracts. For resume requirements, please refer to RFP SECTION L, b. TECHNICAL PROPOSAL INSTRUCTIONS, 1. Technical Discussions, b. Personnel,

4. Resumes.

INTERESTED OFFEROR QUESTION #3:

The Offeror must submit its Small Business Subcontracting Plan, Travel Policy, Total Compensation Plan and Annual Report with the initial Business Proposal. Are URL’s ok to submit?

QUESTION #3:

Offeror may opt to include URL’s in its proposal submission.

However, Offerors shall refer to SECTION L of the RFP for all proposal instructions concerning the submission of the Small Business Subcontracting Plan (2.c.6.), Travel Policy (2.c.14.), Total Compensation Plan (2.c.9.), and Proposer’s Annual Financial Report (2.c.13.).

INTERESTED OFFEROR QUESTION #4:

Are there a format for the Resumes of the PIs that is required if we would like to use subcontractors do they need to be US based or can they be based outside the US?

QUESTION #4:

Please refer to the above Government Response to Interested Offeror Question #2 for resume requirements.

The Government shall comply with FAR Part 25 and the NIH Policy Manual at 6325-1 - Clearance of Foreign Contracts, Foreign Subcontracts, and Domestic Contracts or Subcontracts with a Foreign Component.

INTERESTED OFFEROR QUESTION #5:

We were wondering about the structure for testing: when compounds are sent to contractor will there be indication of what area of pain they want to test in or any particular assay or should the contractor

QUESTION #5:

Guidance will be provided by the NIH COR to the Contractor about the testing structure scheme for each participant’s agent.

provide a testing flow scheme and make recommendations?

INTERESTED OFFEROR QUESTION #6:

Is testing in Non-Human Primates required for the RFP or is rodent sufficient?

QUESTION #6:

Testing in non-human primate models can be requested by participants to the PSPP program; subsequently, the contractor should be in a position to run the non-human primate model in-house or demonstrate capability to subcontract it. Please refer to C.I.a.b) of the Statement of Work (Section J, Attachment 3).

INTERESTED OFFEROR QUESTION #7:

Is there a page limit for the proposal?

QUESTION #7:

There is no page limit for the proposal.

INTERESTED OFFEROR QUESTION #8:

There was a request to provide a list of the last 3 contracts completed during the past three years and all contracts currently being performed that are similar in nature to the solicitation work scope. Does this mean you wish the contractor to disclose their clients or can this be provided in a blinded way as we have confidentiality agreements with our clients?

QUESTION #8:

Proposals submitted to this RFP will only be disclosed to authorized personnel in accordance with FAR 3.104, specifically 3.104-4 Disclosure, Protection, and Marking of Contractor Bid or Proposal Information and Source Selection Information. Offerors may submit past performance information regarding predecessor companies, key personnel who have relevant experience or subcontractors that will perform major or critical aspects of the requirement when such information is relevant to the instant acquisition. Please refer to the requirements for Past Performance Information in Section L of the RFP (2.a.14.).

INTERESTED OFFEROR QUESTION #9:

For the behavioral assays are both genders required or will those be on a case by case basis?

QUESTION #9:

For the behavioral assays genders will be on a case by case basis, as indicated in D.II.1. Animal Sources and Strains of the Statement of Work.

INTERESTED OFFEROR QUESTION #10:

In many behavioral tests particularly in the neuropathic pain models, animals can be reused and thus one can test several compounds in one cohort of animals. Will this be acceptable or does each compound need to be tested in a new cohort of animals

QUESTION #10:

Each agent needs to be tested in a new cohort of animals.

Please refer to C.I.a.f), of the Statement of Work.

INTERESTED OFFEROR QUESTION #11:

Given the complex nature of the effort described ________________ respectfully requests that the due date be extended to Friday, May 31, 2019. We believe the additional time will be needed to allow us to coordinate with subcontractors.

QUESTION #11:

The hour and the date specified for receipt of proposals remains unchanged.

INTERESTED OFFEROR QUESTION #12:

Please consider two related questions concerning the verification of investigational agents identity and/or purity within RFP 75N95019R00027

We recognize the PSPP statement “Contributors with a promising non-addictive therapeutic for pain (Contributors) will be invited to submit bioactive investigational agents to the PSPP for testing. These investigational agents will be evaluated to determine if they are non-opiate, metabolically stable compounds that show promise in established and newly developed models of pain.”

1. Does PSPP think it is reasonable to expect the contributor to provide investigational agents that are characterized for purity (typically ≥95%) and identity? We certainly expect that basic level of test article qualification from a contributor in our work. We ask this because in our experience at this non GxP discovery/pre-IND phase it would be unusual for the Contractor to be tasked with this requirement.

We recognize the PSPP statement “The Contractor shall be required to confirm and/or determine the purity of investigational agents when applied using reasonable standard analytical tools including melting point, nuclear magnetic resonance (NMR), infrared (IR), and potency and report any discrepancy between batches to ensure continuity of different batches of candidate

GOVERNMENT RESPONSE TO INTERESTED OFFEROR

QUESTION #12:

The purity of agents is expected to be equal or higher than 95%. The Contractor shall be required to confirm and/or determine the purity of investigational agents when applied using reasonable standard analytical tools including melting point, NMR, IR, and potency and report any discrepancy between batches to ensure continuity of different batches of candidate investigational agents. Noted discrepancies shall be reported to the COR who will attempt to find resolution.

Please refer to D.IV.1) and 2), of the Statement of Work.

investigational agents. Noted discrepancies shall be reported to the COR who will attempt to find resolution.”

2. Is this characterization of the investigational agent, be it identity and/or purity, to be conducted on every investigational agent received prior to the testing for the aim of this RFP or, is the Contractor to utilize the characterization phase by request ONLY of the COR in the event the test results for the agent(s) is/are challenged. If it is the latter would PSPP consider suggesting a percentage of total agents ( to be qualified) for the sake of Task Order cost analysis.

INTERESTED OFFEROR QUESTION #13:

Reference: Section L.1.d Level of Effort (Page 91)

Question: The hours provided in the Level of Effort (LOE) table indicate the Principal Investigator (PI) expend 1800 hours per year, which is essentially 100% commitment.

Is it the Government’s intent to require a single PI to be 100% committed to this program? It seems unlikely that a single experienced expert in the field would give up all currently funded research programs in order to manage this program.

QUESTION #13:

It is the Government’s intention is for a Single PI with expertise in the pain field who can manage and oversee all prime and subcontractor activities.

INTERESTED OFFEROR QUESTION #14:

Reference: Section L.1.d Level of Effort (Page 91)

Question: Committing a PI to 1800 hours for Task Order 1, does not provide any additional time to support forthcoming Task Orders. Is it the Governments intent to have the offeror commit all the PI time to Task Order 1, and not reserve time to commit to other task orders planned or expected over the IDIQ Period of Performance?

QUESTION #14:

The Government intends to issue the first task order upon award of the Contract, which shall include four option years.

The Government has anticipated that should there be a need to issue a second task order on a completion type basis in year 5 that the flexibility to so is available.

INTERESTED OFFEROR QUESTION #15:

Reference: Section L.1.d Level of Effort (Page 91)

Question: See Question 1 above. We consider it unlikely that any qualified individual would abandon his/her research programs to commit full time to this contract.

Would the Government consider a combination of a PI, Co-PIs, and Program Management expertise to meet the duties that contribute to the 1800 hours per year estimate?

QUESTION #15:

The Government may consider a combination of personnel to meet the duties that contribute to the 1800 hours per year estimate. The Offeror shall propose the best solution they feel is necessary for this procurement. Please refer to 8.B.

QUALITY OF PERSONNEL AND EXPERIENCE (Principle Investigator, Other Scientific and Technical Personnel, and Staffing Plan and Organizational Support) in Section M of the RFP.

INTERESTED OFFEROR QUESTION #16:

Reference: Section L.2.b.6 Enhancing Reproducibility through Rigor and Transparency

Question: Section L.2.b.6 sates “Specifically, the offeror shall describe in its technical proposal the information described below:”

then does not provide additional information within the section. Can the Government provide the information we must address, or state that there is no need to respond to this section in the proposal?

QUESTION #16:

The offeror shall describe in its technical proposal the information described in D.III Rigor in the Statement of Work.

INTERESTED OFFEROR QUESTION #17:

Reference: Section M.8.B. Quality of Personnel and Experience, Principal Investigator

Question: The evaluation factor for the Principal Investigator includes “Suitability and adequacy of the PI's expertise in the Pain field”. Is it the Government’s intent to require a PI with a background in pain? For example, would a management team that includes a pain expert, but the PI may have expertise in Task Areas #2 or #3 be considered acceptable?

QUESTION #17:

Offerors proposals will be evaluated in accordance with Section M evaluation criteria of the RFP. Please refer to the Governments Response to Interested Offeror Question #15 above.

INTERESTED OFFEROR QUESTION #18:

QUESTION #18:

Will there be any exposure or PK data on the compounds when contractor receives them to allow them to make recommendation on dose ranges, pretreatment time prior to testing.

The Contractor shall conduct in-vitro and/or in-vivo ADME and formulation studies as well as PK studies to assess blood and tissue (including brain) levels of novel investigational agents supplied by the PSPP to support in-vivo efficacy studies testing. Please refer to the objective for Performance Area 3: ADME AND FORMULATION

STUDIES AS WELL AS PK ASSESSMENT AND

BIOANALYTICAL TESTING OF SAMPLES in the Statement of Work.

INTERESTED OFFEROR QUESTION #19:

Is there a preferred route of administration or will it be compound dependent?

QUESTION #19:

Oral or intra-peritoneal dosing are the preferred routes;

however, the PSPP participant and the PSPP program director will decide the best administration route for the agent of interest.

INTERESTED OFFEROR QUESTION #20:

Reference is made in the RFP to bioanalytical assays which are being performed in addition to PK and ADME measures. Would it be possible to get a further description of the bioanalytical work desired and the purpose of these bioanalytical assays. For example are they additional screens or are they intended as proofs of agent efficacy.

QUESTION #20:

The Contractor should be able to run in-house or through a subcontractor. Please refer to a) - d) in Performance Area 3:

ADME AND FORMULATION STUDIES AS WELL AS PK

ASSESSMENT AND BIOANALYTICAL TESTING OF

SAMPLES of the Statement of Work.

INTERESTED OFFEROR QUESTION #21:

Regarding subcontractors, can we receive more clarification on the limitations regarding US vs. non-US contractors. For example if the latter is head quartered outside the US but they perform the work in their US labs is that acceptable.

QUESTION #21:

The Government shall comply with FAR Part 25 and the NIH Policy Manual at 6325-1 - Clearance of Foreign Contracts, Foreign Subcontracts, and Domestic Contracts or Subcontracts with a Foreign Component.

INTERESTED OFFEROR QUESTION #22:

We propose to submit our total pricing for the RFP based on combined total costs of the following;

a. Performance Area 1 (In Vivo studies)

– Price for the stated required 16 models/tests multiplied by the

GOVERNMENT RESPONSE TO INTERESTED OFFEROR

QUESTION #22:

The Government cannot advise as to how an offeror approaches their proposed response concerning the technical or business approach to the solicitation requirements. Offerors shall be evaluated in accordance with SECTION M - EVALUATION FACTORS FOR AWARD of the RFP.

number of agents NIH has estimated for each of the five years.

b. Performance Area 2 (In Vitro studies)

– Price for the stated required 2 test areas multiplied by the number of agents NIH has estimated for each of the five years.

c. Performance Area 3

(ADME/Formulation/Others Tests) – Price for the stated required 3 test areas multiplied by the number of agents NIH has estimated for each of the five years.

We will provide the unit pricing as background information.

The pricing per year as indicated in the RFP will be a combined total of all the above.

Please confirm if the above is in order.

INTERESTED OFFEROR QUESTION #23:

Is AAALAC accreditation mandatory?

QUESTION #23:

Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) is mandatory. Please refer to the Governments Response to Interested Offeror Question #1 above.

INTERESTED OFFEROR QUESTION #24:

Can we apply/provide a proposal for one area of performance only (out of the 3 requested)?

QUESTION #24:

The Government cannot advise as to how an offeror approaches their proposed response concerning the technical or business approach to the solicitation requirements. Offerors shall be evaluated in accordance with SECTION M - EVALUATION FACTORS FOR AWARD of the RFP. Please refer to the Government response to Interested Offeror Question #22 above.

INTERESTED OFFEROR QUESTION #25:

Within the area of performance 1 (in vivo testing in pain conditions, abuse liability and side effect models) can we submit a partial proposal? (excluding 4-5 tests/models out of

GOVERNMENT RESPONSE TO INTERESTED OFFEROR

QUESTION #25:

The contractor may consider subcontracting as an alternative to address the missing models, but the Government cannot advise as to how an offeror approaches the 16 listed that we do not carry at this point).

their proposed response concerning the technical or business approach to the solicitation requirements. Offerors shall be evaluated in accordance with SECTION M - EVALUATION FACTORS FOR AWARD of the RFP. Please refer to the Government response to Interested Offeror Question #22 above.

INTERESTED OFFEROR QUESTION #26:

I have a quick question for this contract. In the RFP description, it said the subcontractor needs to provide a complete cost proposal in the same format as the offeror's cost proposal on page 125. Could you please clarify if this cost proposal refers to the "Breakdown of Proposed Estimated Costs (plus fee) w/Excel Spreadsheet"? Are there anything else needed for the cost proposal?

QUESTION #26:

A complete cost proposal in the same format as the offeror's cost proposal is required for all subcontractors proposed as specified in 12. of the RFP. Please refer to SECTION J, BUSINESS PROPOSAL ATTACHMENTS, Attachment 12:

Breakdown of Proposed Estimated Costs (plus fee) w/Excel Spreadsheet.

(End of Answers to Questions to the RFP)

B. This amendment revises the above numbered RFP as stated below.

1. SECTION C, ARTICLE C.1. STATEMENT OF WORK, a., is replaced in its entirety as follows:

Independently and not as an agent of the Government, the Contractor shall be required to furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government, as needed to perform the Statement of Work, dated 04/19/2019, attached hereto and made a part of this Solicitation (See SECTION J - List of Attachments).

2. SECTION J, SOLICITATION ATTACHMENTS, Attachment 3: Statement of Work, 04/19/2019, 13 pages, C.I.a. is revised to add the following.

f) Each agent needs to be tested in a new cohort of animals.

3. SECTION J, SOLICITATION ATTACHMENTS, Attachment 3: Statement of Work, 04/19/2019, 13 pages, D.IV.1) is deleted and replaced in its entirety as follows.

The supply and purity of the investigational agents shall be the responsibility of the COR and the Contributor sources of test submissions. The purity of agents is expected to be equal or higher than 95%. The COR shall supply the Contractor with available information on storage and physico-chemical properties of the investigational agents when it is available from owners

(PSPP Contributors) of the investigational agents. In addition, any available toxicological data concerning handling of investigational agents shall be made available to the Contractor.

4. SECTION L, b.2.6. Enhancing Reproducibility through Rigor and Transparency, first paragraph is deleted and replaced in its entirety as follows:

The offeror shall demonstrate compliance with the NIH Policy on enhancing Reproducibility through Rigor and Transparency as described in NIH Guide Notice NOT- OD-15-103.

Specifically, the offeror shall describe in its technical proposal the information described below:

Please refer to SECTION J, SOLICITATION ATTACHMENTS, Attachment 3: Statement of Work, 04/19/2019, 13 pages, D.III. RIGOR.

5. PART III, SECTION J, SOLICITATION ATTACHMENTS, Attachment 3: Statement of Work, 01/04/2019, 13 pages, is deleted and replaced in its entirety as follows:

Attachment 3: Statement of Work, 04/19/2019, 13 pages

6. PART III, SECTION J, INFORMATIONAL ATTACHMENTS, Enclosure Number 1 – Sample Task order #00001 Statement of Work (SOW) in Attachment 22: Sample Task Order Request For Proposal (TORFP), is deleted and replaced in its entirety as follows:

Enclosure Number 1 – Sample Task Order #00001 Statement of Work (SOW), 04/19/2019, 15 pages

(End of Summary of Changes to the RFP)

Attachment 3: Statement of Work, 04/19/2019, 13 pages

STATEMENT OF WORK

04/19/2019

PROJECT TITLE: Screening of investigational agents through the “NINDS Preclinical

Screening Platform for Pain” (PSPP)

A. BACKGROUND INFORMATION AND OBJECTIVES

The National Institutes of Neurological Disorders and Stroke (NINDS) is establishing the Preclinical Screening Platform for Pain (PSPP) in response to the National Institutes of Health (NIH) Helping to End Addiction Long-term (HEAL) initiative. The HEAL initiative (https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative) is a trans-NIH effort to fast-track basic, translational, and clinical research in the field of addiction and pain to address the national opioid crisis. The goal of the PSPP is to foster the development of opioid alternatives to treat all types of pain conditions.

As part of this HEAL Initiative, the PSPP will provide pain researchers from the academic and industry community with a centralized resource for testing compounds, biologics, natural products, and devices for their potential as opioid alternatives. Researchers with a promising non-addictive therapeutic for pain (here and after Contributors) will be invited to submit bioactive investigational agents to the PSPP for testing. These investigational agents will be evaluated to determine if they are non-opiate, metabolically stable compounds that show promise in established and newly developed models of pain.

The Contractor shall provide screening of potentially viable investigational agents submitted through the PSPP. NINDS will send investigational agents to the Contractor in a blinded fashion (without structures), and the Contractor shall perform progressive testing funnel established in collaboration with NINDS staff and the External Consultants Board for the PSPP (ECB.) The testing will include in-vitro evaluation, including opioid receptor activity, followed by testing in a series of acute and chronic pain models. Selected testing models of tolerability and/or side effect liability shall also be performed to determine therapeutic index. Additional testing in models of abuse liability shall also be investigated to evaluate the test agents for addictive potential.

The Contractor shall provide resources and expertise in not only the execution of existing models available in the labs presently but also in establishing new in-vivo pain models to create a standardized panel of preclinical pain models and behavioral tests that shall be used to evaluate potential efficacy as well as the side effects and abuse liability of Contributor-submitted investigational agents. The Contractor shall evaluate the efficacy, pharmacokinetics, side effects and abuse liability of new investigational agents, perform in-vitro pharmacological profiling and determine target selectivity, execute formulation research studies and establish Absorption, Distribution, Metabolism and Excretion (ADME) profiles of candidate agents submitted to the NINDS by Contributors. The Contractor in their own facilities or through subcontractors shall also provide the complete array of in-vitro and in-vivo assays to evaluate the potential side effects (in-vitro and in-vivo), drug abuse liability, in-vitro pharmacological profiling and target selectivity, ADME (in-vitro and in-vivo) profiling, formulation research studies and pharmacokinetic studies of the investigational agents.

https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative

The goal of the NIH programs served by this contract is to bring new drugs to market. To this end, the NIH has been granted a Determination of Exceptional Circumstances (DEC) to the Federal Acquisition Regulation (FAR) for this contract. The DEC enables the Contributors to retain control of the intellectual property for investigational agents evaluated through the PSPP.

B. SCOPE

The Contractor shall provide screening of Contributor’s investigative agents, including compounds, biologics, natural products, and devices for their potential as opioid alternatives. The PSPP will evaluate investigational agents in-vitro and in-vivo to determine they are non-opiate, metabolically stable compounds that show promise in established and newly developed models of pain. The scope of the contract also includes activities focused on interpretation of efficacy data including the evaluation of abuse liability and potential motor or sensory side effects. Other activities include in-vitro target selectivity profiling assays, ADME profiling, formulation research and pharmacokinetic studies. The Contractor shall demonstrate in-house expertise in the in-vivo evaluation of investigational agents using animal models related to a variety of pain conditions including but not limited to headache. In addition, the Contractor shall be able to adapt, develop, validate and establish new models to support the PSPP mission to sustain the changing priorities of the program and the state of the art for existing models.

C. TECHNICAL REQUIREMENTS AND PERFORMANCE AREAS

C.I. TECHNICAL REQUIREMENTS:

The Government will be responsible for providing the following:

• NIH staff. The NINDS Contracting Officer (CO) and Contracting Officer Representative (COR) will oversee the PSPP contract. The COR will approve platform design, investigational agent testing progression and provide feedback to the Contractor on PSPP strategies and project design, in consultation with the Contributors and NIH-External Consultant Board (see below).

• Contributors with bioactive investigational agents (compounds, biologics, natural products, and devices) will be the source of the test agents. All interactions between the Contractor and Contributors will be mediated and managed by the COR.

• Access to reports of pharmacokinetic (PK) and PD assays if available.

• Additional scientific information on the analogs as needed to execute the services under this contract.

• ECB. The NIH will utilize external consultants to assist the COR in reviewing proposals, reports, and data produced by the Contractor.

• Information Technology (IT) system. The NIH will establish a SQL database for entering, searching, downloading, the data under this contract. The Contractor shall be responsible for entering the data that they generate into this database. NINDS will provide training on how to use the IT system and technical support.

The Contractor shall be required to demonstrate a platform of a wide-range of established and validated models of pain conditions and in-house expertise for testing new investigational agents and devices in models of pain conditions. The Contractor shall provide a platform of in-vivo testing in models to cover the broad spectrum of pain conditions to measure efficacy, abuse liability and sensory or motor side effects of investigational agents (small molecules, biologics, natural products, and devices). The Contractor shall also demonstrate capabilities in the areas of supportive in-vitro pharmacological screening against opioid receptors and other molecular targets associated with off-target effects, ADME profiling, formulation research and pharmacokinetic and bioanalytical studies (in animal model species) established exposures in the proposed efficacy studies. Evaluation of new investigational agents will be conducted under the following three performance areas:

1) In-vivo testing in pain conditions, abuse liability and side effects assessment models, including supporting studies or establishing new pain-related models to support the evolving requirements of the PSPP as needed;

2) In-vitro pharmacological profiling against opioid receptors and/or other molecular target(s) of safety; and

3) ADME and formulation studies as well as PK assessment and bioanalytical testing of samples.

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 conduct services in the following Performance Areas.

C.I.a. PERFORMANCE AREAS

PERFORMANCE AREA 1: IN-VIVO TESTING IN PAIN CONDITIONS, ABUSE LIABILITY AND

SIDE EFFECTS MODELS

Objective: The Contractor shall establish, through the use of existing and proposed models, a testing platform and conduct in-vivo studies by administering PSPP-supplied investigational agents to assess efficacy, abuse liability and side effects.

Technical requirements:

The Contractor shall furnish all necessary services, qualified personnel, materials, equipment, and facilities to perform the following in-vivo testing studies:

a) A battery of in-vivo testing studies to assess efficacy including but not limited to models of acute, inflammatory and neuropathic pain and/or unspecified pain condition-related model(s) which have been established and validated in rodents or non-rodent species.

b) In-vivo abuse liability testing studies established and validated in rodents and/or non-rodent species including but not limited to non-human primates.

c) In-vivo testing to assess efficacy in pain conditions-related models that can be tissue and/or organ and/or system and/or condition and/or disease specific pain models, including but not limited to headache, fibromyalgia pain, post-surgical pain, visceral pain, osteoarthritis pain, diabetic pain, bone cancer pain, chemotherapy-induced pain, post-herpetic neuralgia pain, established and validated in rodents and non-rodent species including but not limited to non-human primates.

d) In-vivo side effects testing studies in an established and validated model in rodents or non-rodent species including but not limited to non-human primates to assess confounding sensory and motor neurons-related activities.

e) Demonstrate the ability to create, modify, validate, and implement additional in-vivo testing models in rodents and non-rodent species including but not limited to non-human primates as requested

f) Each agent needs to be tested in a new cohort of animals.

The Contractor in coordination with the NINDS data management representative should coordinate a seamless transfer of detailed information on material and methods, experimental design and rationale supporting the proposed studies, raw data and analyzed data (% inhibition, dose response curves, ED50 or any measurement of agonist or antagonist activity), mathematical and statistical method(s) of analysis into the NINDS database.

PERFORMANCE AREA 2: IN-VITRO PHARMACOLOGICAL PROFILING

Objective:

The Contractor shall provide in-vitro pharmacological profiling of proposed investigational agents to evaluate molecular interaction with opioid receptors and other biological molecular targets known to elicit adverse events or induce off-target liabilities.

Technical Requirements:

The Contractor shall furnish all necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government, as needed to perform the following in-vitro profiling of the investigational interventions submitted:

a) Binding and function at opioid receptors including Mu-opioid, Delta-opioid, and Kappa-opioid receptors.

b) Binding or functional assays of other biological targets. The assays available should include but are not limited to the following:

a. Adenosine receptor A2A,

b. α1A-adrenergic receptor, α2A-adrenergic receptor, β1-adrenergic receptor, β2-adrenergic receptor,

c. Cannabinoid receptor CB1, Cannabinoid receptor CB2,

d. Cholecystokinin A receptor,

e. Dopamine receptor D1, Dopamine receptor D2,

f. Endothelin receptor A,

g. Histamine H1 receptor, Histamine H2 receptor,

h. Muscarinic acetylcholine receptor M1, Muscarinic acetylcholine receptor M2, Muscarinic acetylcholine receptor M3,

i. 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT3,

j. Vasopressin V1A,

k. Acetylcholine receptor subunit α1 or α4,

l. Voltage-gated calcium channel subunit α Cav1.2,

m. GABAA receptor α1 Benzodiazepine site,

n. Potassium voltage-gated channel subfamily H member 2; hERG, Potassium voltage- gated channel KQT-like member 1,

o. NMDA receptor subunit NR1,

p. Voltage-gated sodium channel subunit α Nav1.5,

q. Acetylcholinesterase,

r. Cyclooxygenase 1; COX1, Cyclooxygenase 2; COX2,

s. Monoamine oxidase A,

t. Phosphodiesterase 3A, Phosphodiesterase 4D,

u. Lymphocyte-specific protein tyrosine kinase,

v. Dopamine, Noradrenaline, and Serotonin transporters,

w. Androgen receptor and Glucocorticoid receptor.

The in-vitro assays above can utilize purified preparations of cell-membrane or protein from recombinant or tissue sources that expresses the molecular target of interest at a single test concentration (for example: 10-100 μM final concentration in duplicate) and/or multiple concentrations establishing concentration–response curves.

The Contractor shall provide detailed information on material and methods, experimental design and rationale supporting the proposed studies. The Contractor shall coordinate a seamless transfer of raw and analyzed data (% inhibition, concentration response curves, inhibitory binding affinity, EC50 or any measurement of agonist or antagonist activity), mathematical and statistical method(s) of analysis into the NINDS database.

PERFORMANCE AREA 3: ADME AND FORMULATION STUDIES AS WELL AS PK

ASSESSMENT AND BIOANALYTICAL TESTING OF SAMPLES

Objective:

The Contractor shall conduct in-vitro and/or in-vivo ADME and formulation studies as well as PK studies to assess blood and tissue (including brain) levels of novel investigational agents supplied by the PSPP to support in-vivo efficacy studies testing.

Technical requirements:

The Contractor shall furnish all necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government, as needed to perform the necessary ADME and formulation as well as PK studies.

As requested by the COR the Contractor shall develop a study protocol including a timeline for study initiation and completion and plan and execution of the following studies:

a) In-vitro and/or in-vivo ADME studies including but not limited to solubility, permeability assessment, P-glycoprotein efflux, CYP profiling, clearance in rodents and/or non-rodent species including but not limited to non-human primates’ liver microsomes and hepatocytes.

b) Formulation studies to identify best suitable formulation for dosage in animals via a specified route of delivery including intravenous, intraperitoneal, oral and other route of administrations.

c) Single dose and multiple dose pharmacokinetic studies in rodents, dogs, non-human primates, and/or other species.

d) Plasma and tissue sample analysis for test agent.

The Contractor in coordination with the NINDS data management representative should coordinate a seamless transfer of material and methods, experimental design, bioanalytical methods, formulation methods, all raw data, analyzed data, statistical data and method(s) of analysis pertaining to the outlined studies into the NINDS database.

C.2. SPECIAL REQUIREMENTS

a. CONFIDENTIALITY All data provided to the Contractor and developed by the Contractor under this contract must be treated confidentially. The data to be treated confidentially is associated not only with the certain “discreet” investigational agents which are not available to the public, but with all agents (Materials) submitted for testing through the program. Under no circumstances are chemicals or drugs or any information associated with these chemicals or drugs, including the data generated under this contract, to be released or divulged without prior written approval of the NINDS Contracting Officer’s Representative (COR).

The Government requires that all data accumulated under the contract be immediately available for its review and that provisions are made to maintain confidentiality of all data. Authority to release data may be granted only by the CO together with the COR and must be in writing.

The Contractor shall use Materials supplied by Contributors under this contract only for contract-related research. The Contractor shall not publish any data generated from Contributor’s Materials submitted for testing under the contract, without written approval of the COR and Contributor. Toxicity and safety data for compounds shall be disclosed only to the COR and may only be disclosed to other parties at the direction of the COR.

b. INTELLECTUAL PROPERTY The testing of agents in the PSPP may result in intellectual property. To facilitate the Contributors’ further development and eventual commercialization of their investigational agents, the NIH has sought a Determination of Exceptional Circumstances (DEC) to the Federal Acquisition Regulation (FAR) for this contract. The DEC enables the Contributors to retain control of the intellectual property created related to their investigational agents through the PSPP, thereby increasing the likelihood of commercializing of potential new therapy alternatives to opioids. The intellectual property policies established under the DEC are described in detail in HHSAR 352.227-11 Patent Rights—Exceptional Circumstances (Sept. 2014) and HHSAR 352.227-14 Rights in Data—Exceptional Circumstances (Sept. 2014) hereby made a part of any resultant contract in Section I.

To summarize:

Class 1: Subject Inventions that require use of the Material.

Class 2: Subject Inventions that could utilize the Material but are not limited to the Material.

Class 3: Subject Inventions that do not fall into Class 1 or Class 2 above.

The DEC contains the clause HHSAR 352.227-14 Rights in Data-Exceptional Circumstances (Sept. 2014), also made a part of any resultant contract under Section I, to ensure that proprietary data provided to the Contractor are used only for the purpose of the contract, and that data generated under the contract are not disclosed until there has been reasonable time for the applicable party to prepare and file a patent application, if appropriate.

D. ADDITIONAL REQUIREMENTS

D.I. ANIMAL FACILITY - shall be accredited by or registered as follows:

1. The Contractor and any subcontractor shall be fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International or equivalent and maintain that accreditation for the duration of the contract. Information about AAALAC accreditation is available at www.aaalac.org.

2. The Contractor shall submit an approved Animal Welfare Assurance for 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. 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.

3. The Contractor and any subcontractor shall comply with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/phspol.htm) and conduct work in compliance with recommendations established in the Guide for the Care and Use of Laboratory Animals (http://www.nap.edu/openbook.php?record_id=5140).

4. The Contractor’s Institutional Animal Care and Use Committee (IACUC) shall approve all animal procedures under this contract.

D.II. ANIMAL REQUIRMENTS:

The Contractor shall comply with the HHSAR clause 352.270(5)(b), Care of Live Vertebrate Animals (Oct 2009). All available animal handling and safety assurances and related laboratory inspections shall be provided to the COR on an annual basis throughout the period of the contract and such assurances must also be accessible when required. Any violations of protocol resulting in issues, warnings or the need for corrective measures shall be reported immediately in writing to both the COR and Contracting Officer. All relevant explanations related to the nature of the violation as well as planned remedy or actions need to accompany the report.

1. Animal Sources and Strains:

Animal species and strains shall be specified by the COR for each investigational intervention http://www.aaalac.org/ http://grants.nih.gov/grants/olaw/olaw.htm http://grants.nih.gov/grants/olaw/references/phspol.htm http://www.nap.edu/openbook.php?record_id=5140 and should be used from the same supplier throughout this contract. Testing in female animals shall also be required on specified investigational agents as specified by the NINDS COR.

2. Data Integrity and Controls:

The Contractor shall establish controls to ensure consistency of the data. Source of animal supplies shall not be changed without advanced permission of the COR and validation of appropriate drug standards.

3. Animal Facility Treatments:

No insecticides, such as chlorinated hydrocarbons or methylenedioxyphenyl compounds shall be used in animal facilities because of their effects on hepatic drug metabolism enzymes.

Bedding for animal cages shall not contain any substances that alter the animal's microsomal enzymes or that produce other adverse effects.

D.III. RIGOR:

The Contractor shall refer to Article H.2., of the Contract and the NIH Rigor and Reproducibility webpage (https://www.nih.gov/research-training/rigor-reproducibility) for guidance on implementing enhanced rigor in study designs and data reporting as appropriate or as directed by the NINDS COR.

D.IV. SUPPLY AND PURITY OF THE INVESTIGATIONAL AGENTS:

1) The supply and purity of the investigational agents shall be the responsibility of the COR and the Contributor sources of test submissions. The purity of agents is expected to be equal or higher than 95%. The COR shall supply the Contractor with available information on storage and physico-chemical properties of the investigational agents when it is available from owners (PSPP Contributors) of the investigational agents. In addition, any available toxicological data concerning handling of investigational agents shall be made available to the Contractor.

2) The Contractor shall be required to confirm and/or determine the purity of investigational agents when applied using reasonable standard analytical tools including melting point, nuclear magnetic resonance (NMR), infrared (IR), and potency and report any discrepancy between batches to ensure continuity of different batches of candidate investigational agents. Noted discrepancies shall be reported to the COR who will attempt to find resolution.

3) The Contractor must be licensed by the Drug Enforcement Administration (DEA) to receive and handle schedule II-V compounds. In addition, the Contractor must either possess, or demonstrate the ability to obtain a DEA registration for Schedule I controlled substances.

4) Investigational agents will usually be submitted to the Contractor blinded for testing to maintain rigor and protect intellectual property rights of the PSPP Contributor. For DEA scheduled investigational agents that cannot be shipped blinded it shall be the Contractor’s responsibility to establish a procedure for blinding the technical staff that will conduct testing.

5) Contractor shall be responsible for proper storage of investigational agents as directed by the COR. Most investigational agents shall be stored at 4°C but some shall require - 20°C, -80°C and/or in a desiccator.

https://www.nih.gov/research-training/rigor-reproducibility

6) At the end of the end of requested studies the Contractor shall transfer any stored investigational agents to a location designated by the COR or shall dispose of it in an approved manner based on industry standards when directed by the COR to do so.

D.V. DATA SECURITY, STORAGE, ACCESS AND TRANSFER TO NINDS

D.V.1. Test Data and Programmatic Information Storage, Access and Data Transfer.

NINDS shall maintain a Structured Query Language (SQL) database that can be accessed by authorized contract personnel using NINDS assigned individual passwords. Pertinent information about the database and its operation follows.

1) The database shall store all test data generated by Contractors and any sub-contractors.

Test sites can access the database using current versions of commonly used web browsers such as IE, Mozilla, and Chrome.

2) Test sites are required to upload raw data and test results contemporaneously within 5 days of completion of tests ordered by the COR.

3) Enable the COR to communicate with test site to provide Test Orders.

4) Test sites shall not be able to edit historical data. Historical data can be edited by contacting the COR providing reasons for the edit, and the nature of the edits needed.

COR will respond in a timely manner, within 5 calendar days, to Edit requests. Once COR approves an edit, he / she shall task appropriate NINDS staff to make the changes in the database.

5) The database shall also store programmatic information deemed useful by NINDS.

D.V.2. Data Security:

1) Access to all investigational therapy, data or other materials provided by the Government as well as all reports, summaries, data descriptions, generated tables and/or testing results derived in performance of this contract shall be restricted pursuant to the terms of HHSAR 352.227-14 Rights in Data—Exceptional Circumstances (Sept. 2014) not this FAR clause. The Contractor is not allowed any internal use or through outside contract to study, manipulate, copy, remove, publish and/or release any information on any data provided by the Government and/or generated under this contract without the prior written approval of the NINDS Contracting Officer and the COR. Further, any such approvals must be submitted in writing by the Contractor to the COR and Contracting Officer. When the data are not at the contract site, e.g., when data are being securely transmitted, mailed or delivered to NIH, the Contractor must ensure that the data are covered with the statement, "Privileged Communication of Data -- Property of the U.S. Government” and take appropriate measures to assure safe transmission. The contract number and title shall also be included on such transmissions. Any unexpected or notable observation discovered during evaluation of investigational compounds or resultant from reviews or other summary data collected must be immediately reported to the COR. All such information and conclusions, raw data are deliverables and therefore the sole property of the U.S. Government.

2) All computers, software and databases used by the Contractor in the performance of this Contract shall be FISMA compliant. Computers shall have the latest operating system, web browser, anti-virus software, and security patches installed with automating updating enabled.

3) The Contractor shall store all raw data (i.e. laboratory notebooks, data storage media, etc.) for the performance period of the contract. At the end of the performance period of the contract the Contractor shall transfer program data to a location designated by the NINDS COR.

E. DELIVERABLES

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 this contract.

The Section 508 Report Template and Instructions for completing the report are available at:

https://www.hhs.gov/web/section-508/contracting/technology-products/product-accessiblity-template/index.html under "Vendor Information and Documents."

Additionally, when submitting electronic reports and forms the offeror shall ensure they fully conforms to the applicable Revised 508 Standards prior to delivery and before final acceptance.

E.I. TECHNICAL DELIVERABLES

1) Protocol manual describing established and validated in-vivo pain models in any animal species. This shall be due within 60 days after contract award in an electronic format.

2) Protocol manual describing in-vitro and or in-vivo methods, test preparations, relevant mathematical calculations and formula derivations. This shall be due within 60 days after contract award in an electronic table format.

3) Protocol manual describing newly established and validated in-vivo pain models in any animal species. This shall be due within 30 days after completion of the validation of the experimental study according to the COR specifications.

4) Preliminary Data Reports - After completion of the in-life portion of the study, the Contractor shall prepare a preliminary data report, to be submitted within 5 calendar days from the end of in-life portion of the study. Within 10 calendar days of submission of the data report, the Contractor shall submit a full draft report for review and comment by the COR. After receipt of COR comments, raw data and a final study report shall be delivered and /or transferred to a specified NINDS-Data base.

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