75N91021R00003- Draft SOW.docx.pdf

Attachment 1- Draft SOW 10/30/2020

STATEMENT OF WORK

PRECLINICAL TOXICOLOGY OF SMALL MOLECULE DRUGS

DEVELOPED FOR CANCER AND OTHER INDICATIONS

1. SCOPE

Independently and not as an agent of the Government, the Contractor shall furnish all necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government, as needed to support the Developmental Therapeutics Program

(DTP) with conducting toxicology and pharmacology studies related to small molecule drugs. The timeline or schedule for support activities will be specified by the NCI

Contracting Officer’s Representative (COR) based on the study. Projects could be stopped, restarted, and/or reprioritized at any given time at the discretion of the Government based on need and immediate findings. Written instructions will be provided by the Government if a project needs to be changed.

TASKS

Toxicology and Pharmacology work conducted under this small molecule contract will involve the following types of tasks. For each task across any and all studies, the

Contractor shall expend hours in planning, ordering, initiating work and documenting findings including, but not limited to:

a. Validating the analytical methodology to quantify drug levels in dosing solutions, biological fluids, and tissues as required. Measuring drug plasma and tissue levels in rodents, beagle dogs and/or non-human primates treated with the agent under study.

Calculating and reporting all important pharmacokinetic parameters from the derived data.

b. Determining bioavailability of drug after oral and/or intraperitoneal, subcutaneous or intramuscular administration. Calculating and reporting all relevant pharmacokinetic parameters from the derived data.

c. Determining acute toxicity, (including, but not limited to, clinical observations, body weights, clinical pathology, histopathology) and plasma and tissue drug levels in rodents, beagle dogs and/or non-human primates over specified time periods.

d. Assessing subacute toxicity (including, but not limited to, clinical pathology, hematology, histopathologic evaluation of tissues, clinical observations) in rodents, beagle dogs and/or non-human primates.

e. Assessing cardiotoxicity, neurotoxicity, and immunotoxicity in rodents, beagle dogs and/or non-human primates as specified by the COR.

f. Assessing mutagenicity in vitro and in vivo (e.g., Bacterial Reversal Mutation Assay, Mouse Lymphoma Assay, Chromosomal Aberration Assessment).

g. Assessing the metabolic profiles of drugs using hepatocytes in vitro.

2. TYPES OF TOXICOLOGY AND PHARMACOLOGY STUDIES

The types of studies that the Contractor shall perform according to the requirements of the protocol(s) developed for each test article by the Contracting Officer’s Representative (COR) include, but are not limited to, the following:

a. Analytical: Drug identity analysis (e.g., using IR, NMR, MS, or other assay methodology specified by the COR), validation of dose concentration analysis procedures that are supplied by the NCI, and/or validation of the requisite methodology for the assay of drug in biological fluids. The Contractor shall initiate work immediately upon drug receipt.

b. Pharmacokinetic: Plasma elimination kinetics shall be determined after single intravenous doses of drug in one or more of the following species: rodents, dogs, and non-human primates. Other routes of administration such as oral, intraperitoneal, subcutaneous and intramuscular may be necessary to evaluate as well. Bioavailability of non-parenteral routes and plasma clearance rates shall be determined in order to establish the dose required to produce effective drug concentrations in plasma for future toxicity studies.

c. Exploratory or Dose Range-Finding Toxicology: For each drug, establish a maximum tolerated dose (MTD) and dose limiting toxicities (DLT) in rodents and/or beagle dogs. The use of an alternative species such as non-human primates, rabbits, or mini-pigs may be required for certain agents under evaluation. The types of studies required in this phase may include exploratory toxicity studies and single or multiple dose range-finding studies, as specified in the protocols.

d. IND-Directed Toxicology: For each drug, establish the MTD, DLTs, and reversibility of toxicity in rodents and/or dogs. The use of an alternative species such as non-human primates, rabbits, and mini-pigs may be required for certain agents under evaluation.

The types of studies required in this phase may include single or multiple-dose studies. Studies shall be conducted under Good Laboratory Practice regulations.

Protocols for the following types of studies may be issued:

i. Single or multiple daily dose schedules such as Dx1, q3hr x 3, Dx5, Dx28, etc.

ii. Continuous administration to mice via Alzet osmotic pumps and to beagle dogs, rats and non-human primates via infusion pumps for periods of from one hour up to 30 days.

iii. Twenty-eight days or more of repeated administration of drug to rodents, beagle dogs and/or non-human primates.

iv. Special studies such as cardiotoxicity, reproductive, neurotoxicity, and immunotoxicity may be requested as part of an existing study or in a separate study.

e. In vitro and in vivo mutagenicity assays/assessments, such as the Bacterial Reversal

Mutation Assay, the Mouse Lymphoma Assay, and the Chromosomal Aberration

Assessment).

f. In vitro metabolic profile analyses of drugs using hepatocytes.

3. GENERAL REQUIREMENTS

The Contractor shall engage in the following project management tasks:

a. Participate in planning and progress review meetings:

i. The Contractor shall plan for and participate in meetings to review requirements and timelines, discuss technical plans and approaches, and identify any anticipated problems/obstacles to completing the requirements. Meetings shall be attended by Contractor key personnel (including subcontractor personnel as appropriate), the COR, and other representatives at the discretion of the COR

(e.g., CO, Subject Matter Experts, investigator representatives).

ii. Key personnel or other senior staff coordinator(s) shall be available for ad hoc meetings/teleconferences with the COR immediately upon a meeting request.

b. As needed and upon permission of the CO and COR, travel may be required to disseminate technical and scientific information and/or present results at a national meeting and/or conference.

4. GOVERNMENT FURNISHED PROPERTY/SUPPLIES

a. Dogs, rats, rabbits, mini-pigs, non-human primates and specialty animals such as cathetered rats shall be purchased by the contractor under this contract as s needed to performed the projects listed above.

b. The Government will furnish the test articles and some of the control articles used in these studies.

c. Available analytical chemistry information including chemical identity data and methodology for dose concentration analysis, plasma drug analysis procedures, formulation information, available literature, etc. will be supplied by the Government.

d. Specialized equipment for infusion studies (pumps, jackets, collars, etc.) shallbe furnished by the contractor.

5. HUMAN MATERIALS

Human refuse materials such as blood, serum, plasma, bone marrow, liver, kidney, other tissues, etc. may be necessary for use on this contract. If necessary, samples will be coded and anonymized such that the donors cannot be identified. The Contractor shall be responsible for any local IRB approvals required for work with human samples as described herein and for implementation of, and adherence to, all federal, local, and institutional policies regarding the occupational health and safety of personnel working with animal and/or human plasma, urine, or other tissues.

6. SHIPPING

The Contractor shall be responsible for shipping samples generated in-house or received externally to other laboratories at the request of the COR.

7. HEALTH AND SAFETY

Each agent will be considered potentially hazardous. Therefore, all necessary precautions must be taken to protect personnel and the environment against possible exposure to the agents being tested. The Contractor shall perform all work associated with this contract in accordance with all applicable Federal, State and local regulations including transportation and disposal of hazardous waste.

8. ACCESS TO DATA

The Government requires that all data accumulated under the projected 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

Contracting Officer together with the COR and must be in writing.

All individual animal data shall be provided to the COR in a format that allows integration into DTP databases. Excel or other tab delimited file formats are acceptable.

Other formats will be considered but compatibility shall be confirmed. In addition, data shall be supplied in SEND-compliant format for those studies specified by the COR.