A8_Additional Technical Proposal Instructions.pdf

ADDITIONAL TECHNICAL PROPOSAL INSTRUCTIONS

The Offeror shall submit a proposal that addresses the two (2) task areas and contract management requirements described in the Statement of Work (SOW). Only proposals from prospective offerors who demonstrate the capability to perform all aspects of the SOW (either in-house or through subcontracts) will be considered for award.

Task Area 1 - Manufacturing

Offeror must demonstrate (either through in-house capacity and/or subcontracts) that it has the technical staff and expertise, manufacturing facilities, equipment, and Quality Systems to handle capacity for concurrent manufacturing related requirements to perform the following types of manufacturing activities within a performance period of 12 months:

i. Conduct technology transfer, process development, analytical methods development studies for a variety of biologics including, but not limited to, ASOs and AAV vectors.

ii. Conduct small-scale manufacturing runs for ASOs and AAV vectors under GLP compliant and/or cGMP compliant conditions.

iii. Conduct ASO and AAV vector full-scale engineering and/or manufacturing runs for biologics under GLP compliant and/or cGMP compliant conditions to support clinical studies.

iv. Conduct studies to support the development of formulations and dosage form manufacture of candidate therapeutics including ASOs and AAV vectors.

v. Conduct fill-finish, label, store, and ship activities for manufactured biologics per year.

vi. Conduct phase appropriate validation studies to support preparation of active pharmaceutical ingredients (API) and dosage form manufacture of candidate therapeutics. The validation studies shall support documentation of the identity, strength, quality, purity, potency and stability of drug substances and drug products.

vii. If any work will be subcontracted, demonstrate that the subcontractor(s) has the appropriate in-house capacity, facilities, equipment, qualified and experienced personnel, capabilities, and Quality Systems to conduct the required number and types of studies.

viii. If any work will be subcontracted, demonstrate the Offeror’s capability to effectively identify, contract, and oversee one or multiple subcontractors to support the required studies per year for the NIH biologics development programs.

ix. Contractor should specify how many manufacturing studies they can accommodate in any 12-month performance period using in-house capabilities and/or subcontractor support.

x. While the sample task orders are focus on ASO and AAV manufacturing activities, the NIH expects to require manufacturing services for other modalities as well. The

Attachment #8 offeror should provide in-house or subcontractor capabilities for other manufacturing modalities.

xi. At minimum, the offeror’s proposal must describe its team for each of the following manufacturing modalities, and if activities are to be executed by subcontractor(s), the Offeror should provide letters of intent for each of the following manufacturing modalities:

a. AAV manufacturing

b. ASO manufacturing

c. Peptide manufacturing

d. Antibody manufacturing

Offeror must address its capability to perform the above manufacturing activities in its technical proposal and provide a cost estimate using the appropriate tabs in the Business Proposal Template:

a. AAV Manufacturing Small Scale

b. AAV Manufacturing Clinical Scale

c. ASO Manufacturing Small Scale

d. ASO Manufacturing Clinical Scale

Offeror should use Sample Task Orders 2 and 3 as a reference point in developing these estimates. Task Order 2 – AAV9 Manufacturing Support includes both general and specific requirements for small scale AAV manufacturing (base task) and clinical scale AAV manufacturing (optional task). Task Order 3 – ASO Manufacturing Support includes both general and specific requirements for small scale ASO manufacturing (base task) and clinical scale ASO manufacturing (optional task).

For both the base task and the optional task in Sample Task Orders 2 and 3, Offeror must address: (1) how long of a lead time (i.e. number of weeks) is anticipated from issuance of the Task Order (or exercise of the option) to study initiation, and (2) how many weeks is anticipated from study initiation to final study report.

For cost assumptions for Sample Task Orders 2 and 3, Offeror should assume each study falls within the following contract year:

Task Study Type Period Est. Dates

Base Task Delivery of GLP Lots Contract Year 1 7/1/22 - 6/30/23

Optional Task Delivery of cGMP lot Contract Year 2 7/1/23 - 6/30/24

Task Area 2 - Nonclinical Studies

Offeror must demonstrate (either through in-house capacity and/or subcontracts) that it has the technical staff and expertise, laboratory, animal and surgical facilities, equipment, and Quality Systems to handle capacity for concurrent testing requirements to perform the following types of studies within a performance period of 12 months:

i. Develop and/or qualify at least 5 bioassays per year, including but not limited to

ELISAs, neutralization assays, relative potency assays to support release testing of manufactured biologics, assays that measure the biological activity of a bioactive molecule, human or animal tissue bioassays, etc.

ii. Conduct at least 5 animal efficacy studies evaluating biologics in small and/or large animal models. Efficacy studies may include but are not limited to the following types of studies:

a. Evaluation of biologics in patient-derived iPSCs

b. Evaluation of biologics in small animal models of neurologic disease (e.g., mice, rats)

c. Evaluation of biologics in large animal models of neurologic disease (e.g., minipigs, dogs)

d. Evaluation of biologics in NHP models of neurologic disease (e.g., cynomolgus macaques, rhesus macaques)

iii. Conduct at least 5 non-GLP and/or GLP PK/PD-ADME studies per year. For each investigational agent, pharmacokinetics studies are aimed to determine brain and plasma exposure at one or multiple doses including oral and other routes of administration.

iv. Conduct at least 5 dose ranging and/or maximum tolerable dose (MTD) studies to define the highest dose of a biologic therapeutic that does not cause unacceptable side effects or toxicity.

v. Conduct at least 5 non-GLP and/or GLP toxicology studies in small animal models per year

vi. Conduct at least 3 non-GLP and/or GLP toxicology studies in NHPs

vii. If any work will be subcontracted, demonstrate that the subcontractor(s) has the appropriate in-house capacity, facilities, equipment, qualified and experienced personnel, capabilities, and Quality Systems to conduct the required number and types of studies

viii. If any work will be subcontracted, demonstrate the Offeror’s capability to effectively identify, contract, and oversee one or multiple subcontractors to support the required studies per year for the NIH biologics development programs.

Offeror must address its capability to perform the above nonclinical studies in its technical proposal and provide a cost estimate using the appropriate tabs in the Business Proposal Template:

Study 1: GLP Rat Single Dose Pharmacokinetics Study 2: GLP Mouse Single Dose Pharmacokinetics Study 3: GLP Rat Multi-Dose Pharmacokinetics Study 4: GLP Mouse Multi-Dose Pharmacokinetics Study 5: GLP Pharmacodynamics (Tissue Distribution in Mice)

Study 6: Assay Development, and/or Qualification, and/or Validation, and/or Plasma and Tissue Sample Analysis Study 7: GLP Dog Single-Dose Pharmacokinetics Study 8: GLP NHP Single-Dose Pharmacokinetics Study 9: GLP Dog Multi-Dose Pharmacokinetics Study 10: GLP NHP Multi-Dose Pharmacokinetics Study 11: GLP Rat Single-Dose Toxicology Study 12: GLP NHP Single-Dose Toxicology

Offeror should use Sample Task Order 4 – Pharmacokinetics and Toxicology Studies as a reference point in developing these estimates. This Sample Task Order includes both general and specific requirements for the above types of studies.

For each study (1-12), Offeror must address: (1) how long of a lead time (i.e. number of weeks) is anticipated from issuance of the Task Order to study initiation, and (2) how many weeks is anticipated from study initiation to final study report.

For cost proposal assumptions for Sample Task Order 4, Offeror should assume each study falls within the following contract year:

Study No. Study Type Period

Est.

Dates

1 GLP Rat Single Dose PK Contract Year 1 7/1/22 - 6/30/23

2 GLP Mouse Single Dose PK Contract Year 1 7/1/22 - 6/30/23

3 GLP Rat Multi-Dose PK Contract Year 1 7/1/22 - 6/30/23

4 GLP Mouse Multi-Dose PK Contract Year 1 7/1/22 - 6/30/23

5 GLP PD (Tissue Distribution in Mice) Contract Year 1 7/1/22 - 6/30/23

Assay Development, and/or Qualification, and/or Validation, and/or Plasma and Tissue Sample Analysis

Contract Years 1-2

7/1/22 - 6/30/24

7 GLP Dog Single-Dose PK Contract Year 2 7/1/23 - 6/30/24

8 GLP NHP Single-Dose PK Contract Year 2 7/1/23 - 6/30/24

9 GLP Dog Multi-Dose PK Contract Year 2 7/1/23 - 6/30/24

10 GLP NHP Multi-Dose PK Contract Year 2 7/1/23 - 6/30/24

11 GLP Rat Single-Dose Toxicology Contract Year 3 7/1/24 - 6/30/25

12 GLP NHP Single-Dose Toxicology Contract Year 3 7/1/24 - 6/30/25

Offerors should address how much study costs are affected by whether a study is conducted under GLP verses non-GLP.

Contract Management

Offeror must address its capability to manage the total number of manufacturing activities and nonclinical studies outlined above (either in-house and/or through subcontracting) in its technical proposal.

Offeror should use Sample Task Order 1 – Kickoff and Project Management Plan as a reference point in developing its estimate for the applicable tabs of the Business Proposal Template. This Sample Task Order includes the contract Project Management Plan and Kick-Off Meeting.