D1 SOW.pdf

STATEMENT OF WORK (SOW)

GENERAL INFORMATION

Title of Project:

A real-time cellular thermal shift assay (RT-CETSA) instrument that can perform luminescent reads to monitor target engagement at high temperatures. This is a COVID-19 action.

Statement of Need and Purpose:

The National Center for Advancing Translational Sciences (NCATS) Research Service Core seeks to obtain the professional services to design and build a RT-CETSA instrument to monitor target engagement.

Background Information and Objective:

The National Institutes of Health (NIH) is the nation’s leading medical research agency and the primary Federal agency whose mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability, conducting, supporting and making medical discoveries that improve people’s health and save lives.

NCATS is one of 27 Institutes and Centers at the NIH and its mission is to catalyze the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions.

NCATS has become a key partner in the Antiviral Program for Pandemics (APP), a multi-agency initiative that includes National Institute of Allergy and Infectious Diseases (NIAID) and

Biomedical Advanced Research and Development Authority (BARDA), to accelerate antiviral development through early discovery and preclinical development of safe and effective oral antivirals. The initial priority for the APP is to develop treatments for SARS-CoV-2 and other coronaviruses, with the program expanding to address other virus families with pandemic potential. NCATS will apply its proficiency in drug discovery and development and its cutting-edge technologies to fill critical needs of the APP, such as (i) target validation, (ii) high-throughput screening (HTS) for drug starting points, (iii) medicinal chemistry for lead optimization, and (iv) preclinical, investigational new drug (IND)-enabling development.

As per the preprint “A real-time cellular thermal shift assay (RT-CETSA) to monitor target engagement” published by NCATS, determining a molecule’s mechanism of action is paramount during chemical probe development and drug discovery. The cellular thermal shift assay (CETSA) is a valuable tool to confirm target engagement in cells for a small molecule that demonstrates a pharmacological effect. CETSA directly detects biophysical interactions between ligands and protein targets, which can alter a protein’s unfolding and aggregation properties in response to thermal challenge. In traditional CETSA experiments, each temperature requires an individual sample, which restricts throughput and requires substantial optimization.

Utilizing well-characterized inhibitors of lactate dehydrogenase alpha, RT-CETSA showed significant correlation with enzymatic, biophysical, and other cell-based assays. A data analysis pipeline was developed to enhance the sensitivity of RT-CETSA to detect on-target binding. The

RT-CETSA technology advances capabilities of the CETSA method and facilitates the identification of ligand-target engagement in cells, a critical step in assessing the mechanism of action of a small molecule. (abstract,1)

Thus, this Statement of Work seeks to obtain the professional services to design and build a real-time cellular thermal shift assay (RT-CETSA) instrument that can perform luminescent reads and withstand high temperatures to monitor target engagement to support NCATS and

APP.

Period of Performance:

The anticipated period of performance is September 26, 2022 through September 25, 2023 (12-months) or 12-months from date of award.

SCOPE OF WORK

General Requirements:

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

Specific Requirements:

This project will be broken down into three distinct phases as outlined below; Design, Build, and

Acceptance:

DESIGN PHASE:

1. Mechanical design – Risk assessment, design and detailing of mechanical system components. Includes structure, frame, guarding, motors, actuators, fixturing for substations, tooling.

2. Electrical design – Design of electrical and controls system.

3. Prototype/testing – Any areas needing early testing to provide feedback for the final design

4. Software Design – System software to control the motions and operation of the machine.

Note – not including data analysis software to evaluate test results.

1 Tino W. Sanchez, Michael H. Ronzetti, Ashley E. Owens, Maria Antony, Ty Voss, Eric Wallgren, Daniel

Talley, Krishna Balakrishnan, Ganesha Rai, Juan J. Marugan, Sam Michael, Bolormaa Baljinnyam, Noel

Southall, Anton Simeonov, Mark J. Henderson bioRxiv 2022.01.24.477382; doi:

https://doi.org/10.1101/2022.01.24.477382 https://doi.org/10.1101/2022.01.24.477382

The government estimates, at minimum, the commercially available major hardware modules needed for the instrument, as listed below:

1. Frame and mechanical structure

a. Mounting of all system components and outer frame

2. Camera Module

a. Camera (Hamamatsu C15440-20UP – Brand-name or equal)

b. Interface kit (Firebird CoaXpress board and cables – Brand-name or equal).

c. Water cooler

3. Emission filter

a. Filters to narrow down emission light wavelength

4. Detector lens

a. Telecentric lens for sample image detection

5. Heater block module

a. Heating block

b. Controller

c. Slot module

6. Microwell plate loading area

a. Station for loading plates, accessible for robotic loading or manual

7. Plate gantry

a. Transfer plates from external loading to imaging station

8. Controls Panel

9. Guarding

10. Utilities

a. Wiring

b. Pneumatics

c. Cooling water

11. Instrument PC

a. Dell 5820 (specified for camera performance) – Brand-name or equal

12. Peripherals

a. Barcode scanning capability

b. Process light stacks

c. E-stops/push buttons

The salient characteristics desired by the Government for the real-time cellular thermal shift assay (RT-CETSA) instrument that can perform luminescent reads and withstand high temperatures include:

• Heating Block Specifications:

o The heating block must be capable of rapid, precise, and uniform temperature adjustment for fully skirted 96 and 384-well PCR plates. The thermal cycler should also have a heated lid that sandwiches on top of the plate during the run, adjustable temperature range (30 to 100 °C) that allows luminescent signal to pass through from below. An assembly that uses a transparent, thermally conductive material, like glass

(e.g. top plate cover in the Roche 1536 Lightcycler), is preferable to allow for multiple plate formats without swapping out the lid. Metal lids with pinholes that allow signal to pass through (e.g. Roche Lightcycler 480 II, Fig 1 below) are acceptable if a mechanism to swap lids to accommodate both 96 and 384-well plate formats is included.

• Heating block Summary o Density 96 and 384-well PCR plates o Plate Style Fully skirted plates for compatibility with automation Temperature Range

(Lid) 30 - 100 °C o Temperature Range (Sample) 4 - 99 °C Heating Rate 0.1 - 5.0 °C/s o Cooling Rate (Max) 2.2 °C/s Temperature Uniformity± 0.2 C @ 55 °C

• Camera Specifications o The luminescence capture system should have the ability to image an entire 96, 384, or

1536 well PCR plate. The low-light optimized camera should be as sensitive as possible and retain ultra-low noise with measurements over >6 log orders of dynamic range using

ATP and firefly luciferase assays. The camera also needs to be compatible with the top heating assembly of the microplate and retain sensitivity over the course of a thermal ramp.

• Camera Summary o Style Back-illuminated, cooled scientific CMOS camera Sensor (Megapixel) >4 o Pixel Size 6.5 - 11 microns o Physical Sensor Chip Size 14.5 - 22 mm Quantum Efficiency (95%) @550 nm Ultra-low

Camera Read Noise 1 e- rms

• Software Specifications o Software development kit to allow for researchers to develop software to interface with the camera and the thermal plate controller. NCATS should retain the ability to control the heat block (ramp rate, start temperature, end temperature, intervening holds), control exposure time, gain settings, and image capture intervals, and extract luminescence intensity on per-well basis for images (both 96 and 384-well formats).

o Note: Not included in the scope of work is the software development to analyze and quantify results from the RT-CETSA instrument.

BUILD PHASE:

1. Component procurement and fabrication

2. Assembly – In house machine assembly.

3. Debug/Testing – Power up, I/O verification, sub system testing.

4. Software development – finalize system software.

ACCEPTANCE PHASE:

1. Factory Acceptance Testing (FAT) – Testing completed on contractor’s site to demonstrate machine functionality. At the FAT, contractor shall demonstrate compliance with the minimum salient characterists of the instrument.

2. Shipping and Installation – Shipping, handling and installation to NCATS, FOB

Destination, to the following address:

National Center for Advancing Translational Sciences (NCATS)

9800 Medical Center Drive

[Building and Room for to be provided at award.]

Rockville, MD 20850

3. Site Acceptance Testing (SAT) – Testing completed at NCATS to demonstrate machine has been installed correctly.

4. User training. Contractor shall provide training for up to 3 users in the operation, maintenance, and service of the device.

LEVEL OF EFFORT:

The Government anticipates award of Time & Material (T&M) contract type, whereas the estimated following mix of Labor Categories (LCAT) and Level of Effort (LOE) is suggested:

Description Hours

TOTAL LABOR 2050

PROJECT MANAGEMENT 150

MECHANICAL ENGINEERING 940

CONTROLS ENGINEERING 960

MACHINE ASSEMBLY 460

Offerors shall propose the LCAT and estimated LOE based on their suggested technical approach to achieving the objectives of this SOW.

For planning purposes, offerors should assume a materials budget of $170,500.00, for fabrication, purchase of commercially available parts, and other direct costs.

A description of all corresponding commercial job titles, experience, functional responsibility and education for those types of employees who will perform services shall be provided.

GOVERNMENT RESPONSIBILITIES

Designated point of contact to manage the project through commissioning.

Provide all requested information needed to complete the project on schedule.

Provide FAT Protocol no later than 10 weeks after design acceptance.

Provide correctly sized and controlled utilities and services to the proper location on the machine, at NCATS facility

Supply all information for state or local codes that NCATS are required to meet.

DELIVERY OR DELIVERABLES

All written deliverable reports shall be submitted in electronic draft format for the COR’s review and comment. Final copies shall be delivered to the COR and the Contracting Officer within five

(5) working days after receipt of the Government’s comments.

The delivery schedule is outlined in a delivery schedule table below:

Deliverable Deliverable Due Date

Design report addressing all elements identified in the DESIGN PHASE section of this SOW, as well as the plan to achieve the minimum salient characterists of the instrument and any additional findings or recommendations.

Three (3) months after award to the COR and CO

Build Phase reports with updates on the progress of the build phase section of this SOW.

Monthly to the

COR

Factory Acceptance Testing (FAT) report, based on the FAT protocol provided by NCATS – Report on the testing completed on contractor’s site to demonstrate machine functionality. At the FAT, contractor shall demonstrate compliance with the minimum salient characterists of the instrument, and the followings:

• All motions needed to move samples to and from imaging area

• All functions of the heating block (motion if necessary, heating and cooling)

• Camera functionality needed for data acquisition

• Machine safety (interlocks, e-stops, guarding) working as designed

Note: Not included in the scope of work is the software development to analyze and quantify results from the RT-CETSA instrument.

Proposed by the Contractor, approved by the

COR

Site Acceptance Testing (SAT) – Testing completed at NCATS to demonstrate machine has been installed correctly and the functionalities performed at FAT remains unchanged.

Twelve (12) months after award to the COR and CO

Complete System Documentation with the following:

• Operation manual

• Instrument bill of materials (BOM)

• CAD files (Mechanical and Electrical)

Twelve (12) months after the award to COR and CO

• Electrical Schematics

• Software documentation

REPORTING REQUIREMENTS

The Contractor shall provide monthly updates on the progress of the project, or more often as appropriate. Updates shall be provided electronically to the COR.

OTHER CONSIDERATIONS

Travel:

Travel is not required in the performance of this Statement of Work

Key Personnel:

Key personnel proposed must include at a minimum a Project Manager. For each proposed key person, a resume is required. All staff for which resumes are submitted will be considered key staff and dedicated to this project if a contract is awarded.

Data Rights:

FAR Clause 52.227-14, Rights in Data-General (May 2014) is included in the solicitation and resultant award. Under 52.227-14(c)(1), the contractor must obtain approval from the contracting officer to assert copyright in any data first produced in performance of this contract and published in academic, technical or professional journals, symposia proceedings, or similar works. Under 52.227-14(d)(2), the contractor must obtain approval from the contracting officer to use, release to others, reproduce, distribute, or publish any data first produced or specifically used by the contractor in the performance of this contract.

Non-Personal Services and Inherently Governmental Functions:

Pursuant to FAR 37.1, no personal services will be performed under this task order. All work requirements will flow only from the COR to the contractor's project manager. No contractor employee will be directly supervised by the government. All individual employee assignments, and daily work direction, will be given by the applicable employee supervisor. If the contractor believes any government action or communication has been given that would create a personal services relationship between the government and any contractor employee, the contractor shall promptly notify the contracting officer of this communication or action.

Pursuant to FAR 7.5, the contractor shall not perform any inherently governmental actions under this task order. No contractor employee will hold him or herself out to be a government employee, agent or representative. No contractor employee will state orally or in writing at any time that he or she is acting on behalf of the government. In all communications with third parties in connection with this contract, contractor employees will identify themselves as contractor employees and specify the name of the company for which they work. In all communications with other government contractors in connection with this task order, the contractor employee will state that they have no authority to in any way change the task order and that if the other contractor believes this communication to be a direction to change their contract, they should notify the contracting officer for that contract and not carry out the direction until a clarification has been issued by the contracting officer.

The contractor will ensure that all of its employees working on this task order are informed of the substance of this article. Nothing in this article will limit the government's rights in any way under the other provisions of the task order, including those related to the government's right to inspect and accept the services to be performed under this task order. The substance of this article will be included in all subcontracts at any tier.