SOWTOX.pdf

ATTACHEMENT #2

STATEMENT OF WORK

Preclinical Toxicology of Drugs Developed for Cancer and Other Diseases

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 required to perform the Statement of Work below:

1. CONDUCT TOXICOLOGY AND PHARMACOLOGY STUDIES IN

ACCORDANCE WITH THE COMPLETE PROTOCOL REQUIREMENTS

DEVELOPED FOR EACH AGENT BY THE NCI PROJECT OFFICER.

It would be scientifically inappropriate to set rigid protocol guidelines that would be adequate for each compound that will be assessed, therefore, the guidelines below will be modified to account for data on the agent's in vitro cytotoxicity, biochemistry and schedule dependence as well as in vivo activity, if available.

The types of studies that the Contractor will be required to perform includes, but is not limited to the following:

a. Analytical Phase: Drug identity analysis (e.g., IR, NMR, MP, MS, or other emergent assay methodology designated by Contracting Officer’s Technical R), validation of the procedures supplied by the NCI for dose concentration analyses and validation of the requisite methodology for assay of drug in biological fluids shall be initiated immediately upon receipt of drug.

b. Pharmacokinetic Phase: Plasma elimination kinetics shall be determined in one or more of the following species: dogs, rodents and non-human primates after single intravenous doses of drug. 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. The ability of a drug to cross the blood-brain barrier shall be assessed in dogs or non-human primates.

c. Screening and Preliminary Phase: For each drug, establish a maximum tolerated dose (MTD) and dose limiting toxicities (DLT) in both beagle dogs and rodents. The use of non-human primates as an alternative species may be required for certain agents under evaluation.

The types of studies required in this phase shall be decided by the P.O.

and may include the following:

i. Short-term toxicity studies in rodents

ii. Single or multiple dose range-finding studies in rodents, beagle dogs, or non-human primates.

d. IND-Directed Toxicology Assesment Phase: For each drug, establish toxicity and safety in relation to drug plasma concentrations or area-under-the-curve in both beagle dogs and rodents. The use of non-human primates as an alternative species will be required for certain agents under evaluation. The types of studies required in this phase shall be decided by the COTR and may include the following:

i. Single or multiple daily dose schedules such as Dx1, q3hr x 3, q8hr x 15, 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, neurotoxicity, immunotoxicity may be requested as part of an existing study or in a separate study.

Note: Representative protocols of these various studies are included in Appendix A. (Does contracts have this appendix?)

2. GENERAL AREAS OF WORK

The work assignments issued under this contract will have the following objectives. The Contractor shall:

a. Validate the analytical methodology to quantitate drug levels in dosing solutions, biological fluids, and tissues as required. Measure drug plasma 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 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, neruotoxicity, immunotoxicity in rodents, beagle dogs and/or non-human primates as specified by the P.O.

3. WORK ASSIGNMENTS

Multiple contracts will be awarded and each will be administered on a work assignment managed basis. Work assignments will be issued under the "funded cost-reimbursement level-of-effort" contracts that result from this solicitation. (Change to multi-year?) Each work assignment will be issued after a cost estimate, labor and level of effort estimate has been received, found acceptable and agreement reached between the Government and the Contractor. The level of effort and cost of such a task shall not exceed that of the incremental-funded period.

4. GOVERNMENT FURNISHED PROPERTY/SUPPLIES

a. Animals, especially mice and rats, will be supplied by the Government when possible. Dogs, rabbits, non-human primates and specialty animals such as cathetered rats will be purchased by the contractor under this contract as specified by the P.O.

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

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 Government.

5. PERIOD OF PERFORMANCE

The period of performance shall be five (5) years after the date of the award of the contract.

6. AAALAC ACCREDITATION

Accreditation by the American Association for Accreditation of Laboratory Animal Care (AAALAC) is highly desirable. Documentation of a lack of findings from one or more ALLAC inspections may also provided.

7. 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.

8. 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.

9. ACCESS TO DATA

The Government requires that all data accumulated under the projected contracts be immediately available for its review and that provisions be made to maintain confidentiality of all data. Authority to release data may be granted only by the Contracting Officer together with the Project Officer and must be in writing.

All individual animal data should be provided to the PO in a format that allows integration into DTP databases. Excel or other tab delimited file formats for are acceptable. Other formats will be considered but compatibility shall be confirmed.

10. CONFIDENTIALITY OF INFORMATION

Certain data provided to the Contractor under this contract must be treated confidentially. The data to be treated confidentially is associated with certain Adiscreet@ compounds which are not available to the public.

When compounds are assigned to the Contractor, these discreet compounds will be identified by the letter AD@ as a prefix to the compound NSC number. 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 Project Officer.

11. REPORTING REQUIREMENTS

a. STUDY REPORTS

The final report on each study will be due between 15 and 60 working days following completion of the in-life phase of the study. The due dates for reports on each segment of the study will be mutually agreed to at the time of study initiation. Each report must be acceptable to the Project Officer for filing as Attachment 6a of an Investigational New Drug Application with the Food and Drug Administration.

This report will accurately and completely describe the study design, procedures and findings, present an analysis and summary of the data followed by the conclusions derived from the analyses. Protocol modifications and/or deviations will be presented and discussed as well.

The report will also include: (a) a cover page which will include the title, contract number, authors, laboratory name and address, dates of initiation and completion, and sponsor; (b) the NTIS Report Documentation Page, to be placed at the beginning of the final report; (c) a comprehensive summary to be placed after the NTIS page; (d) the dated signature of the Study Director and any others deemed necessary; (e) a table of contents;

and (f) a statement prepared and signed by the Quality Assurance Unit which will refer to all phases of the study and where the raw data records, reports and samples are stored. In addition, the following items must be included in each report. Additional items may be required per Principal Investigator/Project Officer discussions.

1. Compound information

a. Identity data

b. Lot number

c. History (dates received, on test and study completed)

d. Stability

2. All data requested

3. Animal history (source, sex, age, weight, immunization, procedure used for unique identification, etc.)

4. Baseline data (pre-test)

5. Control animals

6. Vehicle controls (if requested)

7. Dose formulation information

8. Route of administration

9. Rate of injection

10. Urinalysis data, if specifically requested

11. Methodologies of all test procedures

12. Days of sacrifice

13. Time period from death to necropsy

14. Gross and microscopic pathology

15. Rationale and documentation of all deviations from protocol

16. Statistical methods for analyzing data

17. Corrections or additions to reports are to be submitted in form of amendment clearly identifying that part of report being added to or corrected, reasons for addition or correction and dated signature of person responsible

18. All portions of the studies and reports must be in compliance with the GLP Regulations as published in the Friday, December 22, 1978 Federal Register, Vol. 43, No. 247, pp.59986-60025.

Examples of report content can be found in Appendix B.

b. RAW DATA

Data will be collected using the laboratory's in-house data management system. Final tabular data and raw data will be transmitted to the NCI for archival purposes. In addition, data can be transmitted electronically as part of the monthly report.

c. MONTHLY REPORTS

For each drug on test the contractor shall submit a monthly Status Report to both the Project Officer and the Contracting Officer between the 10th and 15th of each month. The report shall detail the status of the testing as of the reporting date, any problems encountered and the proposed means of resolution. Each monthly report shall NOT exceed 2 - 4 double spaced typewritten pages and may include charts and figures. The report shall include a listing of hours expended during the reporting period, cumulative work hours expended and work hours remaining for completion for each work assignment as well as the total contract. Notwithstanding the requirement for monthly progress reports, the Contractor shall notify the Project Officer whenever the time allocated to a work assignment is expected to exceed the originally allocated time, a personnel change is necessary or the cost of the work assignment is expected to exceed the originally estimated cost. Revision of the time allowed, and of the cost allocated for deliverables can only be made by mutual agreement of the Contracting Officer and the Contractor.

d. ANNUAL REPORTS

The Contractor shall submit an annual progress report. This report shall include a cover page which shows the contractor's name, contract number, contract title, Project Officer and period being reported, a brief description of work performed during period reported, including the significant findings, any problems experienced, and the anticipated work plan for the following period. Each report shall contain as the first section a brief summary (not to exceed 200 words) of the salient results to date.

The last portion of the annual report will contain a report on personnel and health and safety. This section should provide evidence that employees are properly instructed in the use of hazardous substances and have received appropriate medical history and physical examinations.

e. SPECIAL BUSINESS REPORT

On an annual basis the subject contract will have a merit technical review to evaluate the performance. Approximately 90 days prior to the expiration of each funded period, the Contractor shall submit to the Contracting Officer a status of funds, to included a breakdown of estimated costs and fixed fee for current year and a projection of expeditures (will change to expenditures) needed for the next funding period. This report shall follow the same itemized format as the basic business proposal submitted hereunder and will serve as the basis for the allocation for funds under this contract, pursuant to the General Provisions thereof, entitled ALimitation of Funds@. The original and two (2) copies shall be submitted.

f. FINAL REPORT The contractor shall submit a final report that documents and summarizes the results of the entire contract period of performance. This report shall be in sufficient detail to explain comprehensively the results achieved and shall contain a summary (not to exceed 200 words) of the salient results achieved during the performance of the contract. REPORTS ARE

REQUIRED AS FOLLOWS:

Reports

Period Covered Due Date

(By 15th of each Month)

CO 1

PO 2

Monthly

To Be Stated To Be Stated

1 Copy

Study Report (Draft)

NA 35 working days from the end of the live phase

None

Electronic

Copies

Study Report (Final)

NA 65 working days from the end of the live phase

None

Electronic signed Copies

1st Annual

2 Copies

2nd Annual

3rd Annual

4th Annual

5th Final

Business

Deliver To:

1 National Cancer Institute 2 National Cancer Institute

TSB/OA/OD/NCI T&PB/DTP/DCTDC/NCI

244 Miller Drive, P.O. B Executive Plaza North, Rm. 843 Ft. Detrick 9000 Rockville Pike (6130 Ex B) Frederick, MD 21702 Bethesda, MD 20892-7456 ATTN: Contracting Officer ATTN: Project Officer

12. LEVEL OF EFFORT

It is anticipated that five (5) or six (6) funded contracts will be awarded.

Only one award will be made to an institution.

Offerors are required to propose at both levels of effort, A and B as indicated above. (Where are the levels described?) The numbers for the two levels are restrictive for proposal purposes. A "staff year" has been defined as 1880 hours per year exclusive of fringe benefits.

For proposal purposes, offerors are also requested to submit cost proposals on each of the nine (9) protocols and the administrative work assignment contained in Appendix A (Do contracts have this appendix?)

in addition to a yearly summary cost proposal. This set of protocols would theoretically be the basis for the complete evaluation of one anticancer and one anti-HIV drug per year based on current scientific rationale.

In actual practice, the complete evaluation of a promising therapeutic agent may require more or less effort than estimated above depending upon the number and complexity of the final protocols utilized. 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 a number of drugs prior to completely evaluating one drug for the purpose of filing an IND.

13. TRAVEL REQUIREMENTS

1. The Contractor should expect that the Principal Investigator and/or a senior scientist on the contract will attend one national scientific meeting a year. Plan on payment of registration fee, one day per diem and one-half of the air fare for this meeting. This travel must be approved in advance by the Contracting Officer.