Attach_3-SOW-Small_Tox_IDIQ_Base.pdf

Attachment 3, Dated 07/15/2022 75N91021R00003

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.

TASKS

Task Orders will be awarded to perform one or more of the following tasks as specified in the individual task order. Toxicology and Pharmacology work conducted under this small molecule contract will include, but not be limited to, the following types of tasks:

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.

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 Task Order(s) issued for each test article 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 individual Task Order.

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.

Task Orders issued may include one or more of the following types of studies:

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. Specialized studies such as cardiotoxicity, reproductive, neurotoxicity, and immunotoxicity. Alternatively, these endpoints may be included in a general toxicology 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

Unless otherwise specified in the individual Task Order, 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. Travel may be required to disseminate technical and scientific information and/or present results at a national meeting and/or conference.

c. The Contractor shall develop, monitor, and modify the timelines, tasks, budgets, objectives and milestones as discussed with and/or prioritized by the COR before and during the performance of activities under the respective Task Order. If changes need to be made to the technical protocol at any time, the Contractor shall notify the COR by phone or email as soon as possible, but within 24 hours, and also document the change in the monthly progress reports for each Task Order. When practical, the COR must provide concurrence and approval, whether written or verbal, prior to the Contractor implementing any proposed change(s). However, in those instances where the Contractor cannot gain concurrence from the COR in a timely manner, the attending veterinarian or Study Director at the Contractor facility shall make the necessary decisions to minimize any pain or distress to the animals. This may include, but is not limited to, withholding treatment of the test article, treating clinical signs, or euthanizing the animals, as appropriate. The Contractor shall also follow-up with a detailed summary of the incident and changes via an email to the CO and COR. When appropriate, i.e., for GLP-compliant studies, the Contractor shall also document the change as a protocol deviation in the study report. These updates shall include changes made and the reason(s) for the change.

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 needed to perform the tasks listed above.

b. The Government will furnish the test articles and some of the control articles used in these studies as specified in the individual Task Order.

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.) shall be 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 as specified in the Task Order.

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 contract and Task Orders 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. The Contractor shall also prepare study reports with study data generated in the electronic Common Technical Document (eCTD) format.