HHS-NIH-NCI-SBSS-TSB-00305-55- SOW.pdf

STATEMENT OF WORK

PRECLINICAL TOXICOLOGY OF SMALL MOLECULE DRUGS

DEVELOPED FOR CANCER AND OTHER INDICATIONS

1. CONDUCT TOXICOLOGY AND PHARMACOLOGY STUDIES ACCORDING TO

THE REQUIREMENTS OF THE PROTOCOL(S) DEVELOPED FOR EACH TEST

ARTICLE BY THE CONTRACTING OFFICER’S REPRESENTATIVE (COR).

Since each protocol will be written based upon the unique scientific characteristics of each drug being studied, the guidelines below will be modified depending upon the available scientific data (in vitro activity, schedule dependence, chemistry, etc.) for each small molecule drug. The types of studies that the Contractor may be directed to perform 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. This work shall be initiated 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 shall be decided by the COR and may include exploratory toxicity studies and single or multiple dose range-finding studies.

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 will be conducted under Good Laboratory Practice regulations.

The types of studies required in this phase shall be decided by the COR and may include the following:

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.

In actual practice, the complete evaluation of a promising therapeutic agent may require study designs that differ in complexity from the protocols provided. There may also be instances when studies on a drug will be terminated after the initial protocol. Conceivably, the laboratory may be required to perform a preliminary evaluation (one or two protocols) on several drug candidates prior to completely evaluating one drug for the purpose of filing an IND.

2. GENERAL AREAS OF WORK

The projects issued under this small molecule contract will have the following objectives. The Contractor shall:

a. Validate the analytical methodology to quantify drug levels in dosing solutions, biological fluids, and tissues as required. Measure drug plasma and tissue levels in rodents, beagle dogs and/or non-human primates treated with the agent under study. Calculate and report all important pharmacokinetic parameters from the derived data.

b. Determine bioavailability of drug after oral and/or intraperitoneal, subcutaneous or intramuscular administration. Calculate and report all relevant pharmacokinetic parameters from the derived data.

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

3. GOVERNMENT FURNISHED PROPERTY/SUPPLIES

a. Dogs, rats, rabbits, mini-pigs, non-human primates and specialty animals such as cathetered rats will be purchased by the contractor under this contract as specified by the

COR.

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.) will be furnished by the contractor.

4. HUMAN SUBJECTS

It is hereby understood and agreed that research involving human subjects shall not be carried out under this contract, and that no material developed, modified or delivered by or to the Government under this contract, or any subsequent modification of such material will be used by the Contractor or made available by the Contractor for use by anyone other than the Government for experimental or therapeutic use involving humans without the prior written approval of the Contracting Officer. However, refuse human materials such as blood, serum, plasma, bone marrow, liver, kidney, other tissues, etc.

may be necessary for use on this contract.

5. HUMAN MATERIALS

Human samples will be coded and anonymized such that the donors cannot be identified. The Contractor is 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.

Additionally, ship samples generated in-house or received externally to other laboratories at the request of the COR.

The acquisition and supply of all human specimen material used under this contract shall be obtained by the Contractor in full compliance with applicable State and Local laws and the provisions of the Uniform Anatomical Gift Act in the United States, and no undue inducements, monetary or otherwise, will be offered to any person to influence their donation of human material.

The Contractor shall receive written documentation that all human materials obtained as a result of research carried out by collaborating sites were obtained with prior approval by the Office for Human Research Protections (OHRP) of an Assurance to comply with the requirements of 45 CFR 46 to protect human research subjects. This restriction applies to all collaborating sites without OHRP-approved Assurances, whether domestic or foreign, and compliance must be ensured by the Contractor.

Provision by the Contractor to the Contracting Officer of a properly completed "Protection of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption", Form OMB No. 0990-0263(formerly Optional Form 310), certifying IRB review and approval of the protocol from which the human materials were obtained constitutes the written documentation required. The human subject certification can be met by submission of a self-designated form, provided that it contains the information required by the "Protection of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption", Form OMB No. 0990- 0263(formerly Optional Form 310).

6. HEALTH AND SAFETY PLAN

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.

7. 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 should 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 will be supplied in SEND-compliant format for those studies specified by the COR.

8. CONFIDENTIALITY OF INFORMATION

Data provided to the Contractor under this contract must be treated confidentially.

Under no circumstances are chemicals or drugs or any information associated with these chemicals or drugs to be released or divulged without prior written approval of the

NCI COR.