National Institutes of Health, Office of Procurement Management, 6011 Executive Blvd., Rockville, Maryland 20892-7260

B -- TOXICOLOGY AND CARCINOGENICITY STUDIES ON TWO NEW COMPOUNDS SOL 263-99-P(BN)-0055 DUE 083199 POC Foteni T. Tiffany, Contracting Officer, 301-402-3079 This is a combined synopsis/solicitation for commercial items prepared in accordance with the format in FAR 12.6, as supplemented with additional information included in this notice. This announcement constitutes the only solicitation; proposals are being requested and a written solicitation will not be used. The solicitation number is 263-99-P(BN)-0055 and is issued as a Request for Proposal (RFP). The solicitation/contract will include all applicable provisions and clauses in effect through FAC 97-12. The standard industrial code (SIC) is 8734 and the size standard is $5,000,000 in average annual receipts over the preceding three fiscal years. This is not a small business setaside. The National Institutes of Health, National Institute of Child Health and Human Development, has a requirement for toxicology and carcinogenicity studies of two recently developed compounds. This shall further efforts in developing materials to reduce HIV transmission rates. In the United States and Worldwide, heterosexual transmission of HIV has resulted in an increased rate of HIV-infection in women. Microbicides offer a female-controlled alternative for prevention of transmission of HIV. To date, all microbicide prevention trials have utilized currently available spermicidal compounds. These compounds contain either nonoxynol 9 or octoxynol as the active ingredient. The compounds have some degree of toxicity associated with their use. BufferGelTM and C31G gel are two non-nonoxynol microbicidal compounds that are likely to be available within the next year for phase II/III clinical trials. BufferGelTM has been shown to be safe in Phase I clinical trials both at sites in the United States and in developing countries. C31G gel will be completing Phase I safety trials in the United States this Fall. These compounds are further along in development than any other non-nonoxynol products. In order to proceed to Phase II/III clinical trials; FDA guidelines specify 6 and 12 month chronic toxicology in 2 animal models and Segment Iand II toxicity studies in rats and rabbits. Additionally, 2-year carcinogenicity studies in rats and mice are required during the late stages of drug development for submission of the NDA. The following toxicology and carcinogenicity studies will be needed to satisfy the FDA: 1. Intravaginal application of BufferGelTM for a) 6 month toxicology in the rat; b) 9 month toxicology in the dog; and c) 2 year carcinogenicity studies in rat and in mouse, and 2. Intravaginal application of C31G gel for a) Segment I toxicity study in rats and Segment II toxicity studies in rats and rabbits; b) 6 month toxicology in the rat; and c) 2 year carcinogenicity in the rat and mouse. These studies need to be performed in accordance with establish FDA guidelines (www.fda.gov/cder/guidance/ptcnonclinical.htm). To support the safety of the individual phases of clinical development, studies in at least two animal species (one being a non-rodent) should be used to assess acute, subchronic and chronic toxicity at the proposed site of exposure. Segment I and II studies should be performed in accordance with FDA protocols. All toxicology studies should use at least three dose levels of the drug and an appropriate control, with the high dose showing frank toxicity (it is understood that there may be limits to the ability to achieve a toxic dose), and the low dose showing little or no toxicity. With the exception of the varying concentrations of the active product, the drug to be applied should be in its final formulation and the study duration should be equal to, or longer than, the proposed duration of treatment in the clinical trial. All nonclinical studies carried out to assess safety of a drug should be performed according to Good Laboratory Practices as outlined in 21 CFR. 58. The respondent shall consult with the FDA reviewing pharmacologist concerning approaches and protocols regarding these issues. For carcinogenicity studies, the drug should be administered for two years and the doses used should be chosen according to the principles outlined in the document entitled, "Guideline for Industry, Dose Selection for Carcinogenicity Studies of Pharmaceuticals." Copies of the Guideline are available from the CDER Consumer Affairs Branch, HFD-210, Center for Drug Evaluation and Research, 5600 Fishers Lane, Rockville, MD 20857. Respondents will consult with the appropriate reviewing division within the FDA for the current position and strategic approaches to these issues. Respondents will have the protocols for the carcinogenicity studies reviewed by Executive Committee of the Carcinogenicity Assessment Committee of the Center for Drug Evaluation and Research prior to their initiation. The qualified respondent shall be able to demonstrate prior experience in intravaginal inoculation of non-nonoxynol 9 compounds into animals and toxicology and carcinogenicity testing in accordance with the guidelines outlined above for minimally five other compounds. The experience should include provision of reports acceptable to FDA for moving the productsinto Phase II/III trials and for NDA submission. The deliverables for this solicitation will include FDA-acceptable reports on the toxicology and carcinogenicity testing, and a complete database on CD rom. These deliverables will be due in two phases. The reports and database for the toxicology studies will be due 90 days after completion of the those studies, and the reports and database for the carcinogenicity studies will be due 90 days after completion of those studies. Drugs (BufferGelTM and C31G gel)for the studies will be provided by the government. II. STATEMENT OF WORK A. General Description of the Required Objectives and Desired Results. 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 undertake toxicity, toxicology and carcinogenicity studies for BufferGelTM and C31G B. Technical Requirements. Specifically, the Contractor shall: 1. Provide protocols and testing for the intra-vaginal testing of BufferGelTM for chronic toxicity for a 6-month study in the rat and a 9-month study in dogs. These studies shall be used to assess acute, sub-chronic and chronic toxicity at the proposed site of exposure. The toxicology studies will use at least three dose levels of the drug and an appropriate control, with the high dose showing frank toxicity (it is understood that there may be limits to the ability to achieve a toxic dose), and the low dose showing little or no toxicity. All studies will be performed according to Good Laboratory Practices as outlined in 21 CFR. 58. The Contractor shall consult with the FDA reviewing pharmacologist concerning approaches and protocols. 1a. Provide protocols and testing in accordance with FDA guidelines for the intravaginal testing of C31G gel for Segment I and II toxicology testing for fertility and ealy embryonic development in rats, and Segment II testing for embryo-fetal development in rabbits. 1b. Provide protocols and testing for the intra-vaginal testing of BufferGelTM and C31G gel for 2-year carcinogenicity studies in rat and in mouse. The doses used will be chosen according to the principles outlined in the document entitled, "Guideline for Industry, Dose Selection for Carcinogenicity Studies of Pharmaceuticals." Copies of the Guideline are available from the CDER Consumer Affairs Branch, HFD-210, Center for Drug Evaluation and Research, 5600 Fishers Lane, Rockville, MD 20857. The Contractor shall consult with the appropriate reviewing Division within the FDA for the current position and strategic approaches to these issues. The Contractor shall have the protocols for the carcinogenicity studies reviewed by the Executive Committee of the Carcinogenicity Assessment Committee of the Center for Drug Evaluation and Research prior to their initiation. Carcinogenicity testing should begin upon satisfactory completion of the Phase II clinical trial. 2. Obtain prior approval for all protocols, and any modifications of the protocols from the Project Officer. 3. Schedule all testing in an expeditious manner to ensure optimal efficiency. 4. Provide adequate and appropriate organizational support for all aspects of the testing program. 5. Establish and maintain laboratory procedures and controls toprovide for the safety of personnel and facilities. 6. Maintain separate animal facilities for housing rodents and rabbits in compliance with all existing Federal, State and NIH guidelines and with accreditation by AAALAC. 7. Provide for individual caging of all animals during experimental studies. Maintain animal rooms for a given species with separate controls for light, temperature and humidity. 8. Maintain a duly constituted animal care and use committee throughout the contract period for the review of the experimental protocols and animal health and welfare. 9. Provide space for the orderly storage of submitted compound at various temperatures i.e. room temperature, 4oC,. 10. Maintain an inventory of the test articles containing dates of receipt of material, quantity used in test procedures, storage conditions, and the amount on hand at any given time. 11. Administer test materials intra-vaginally or by other routes as specified by the Project Officer in consultation with FDA. 12. Observe and record changes in behavior and external organs, conduct necropsies for obtaining specified tissues and organs, record organ weights, preserve specified tissues for histological processing including the preparation of stained sections for microscopic examination and obtain photographs of animals, organs and tissues as part of the laboratory record. Contractor shall also undertake gross and microscopic pathology of tissues and organs using, where necessary, expert consultants (Board Certified) in the field. These studies may be undertaken in house or through consulting services in part or in total. 13. Undertake the assay of the clinical chemistries, urinalysis and hematology. These studies may be undertaken in house or throughconsulting services in part or in total. 14. Send frozen sera or other materials from test animals to other laboratories for analyses upon request of the Project Officer. 15. Analyze raw data using conventional methods appropriate for the study. Additional statistical analysis may be requested at the direction of the Project Officer after consultation with FDA. 16. Make available to the Government, at all times, the status of all tests including laboratory notebooks, data analysis, etc. Communicate frequently with the Government and/or the supplier of test material regarding the status of projects in progress. 17. Participate with the Project Officer, in the preparation of reports for FDA submission. A. Deliverables. The deliverables for this solicitation will include FDA-acceptable reports on the toxicology and carcinogenicity testing, and a complete database on CD-rom. These deliverables will be due in two phases. The reports and database for the toxicology studies will be due 90 days after completionof the those studies, and the reports and database for the carcinogenicity studies will be due 90 days after completion of those studies. B. Terms and Conditions. This shall be a fixed price contract for a period of 30-36 months from initiation. All materials submitted for testing shall remain the property of the Government or the supplier to the Government. Disposition of materials remaining after completion of testing shall be specified by the Project Officer. All data obtained under the contract shall remain the property of the Government and/or the supplier of test materials and may not be published or otherwise disseminated without specific permission from the Project Officer. III. Evaluation Criteria 1. Adequacy of the proposed plans to address the toxicology and carcinogenicity of BufferGel and C31G in animal species via intravaginal administration, including adequacy of personnel and facilities. 50 points 2. Documented past experience with intravaginal inoculation of non-oxynol-9 compounds inanimal species. 10 points 3. Documented past experience in toxicology and carcinogenicity testing in accordance with the guidelines outlined above for minimally five other compounds. The experience should include provision of reports acceptable to FDA for moving the products into Phase II/III trials and for NDA submission. 15 points 4. Provide the above services at maximum cost-benefit to the Government. 25 points Please provide a fixed price for each of the following: 4a. Segment I in Rats (C31G) 4b. Segment II in Rats (C31G) 4c. Segment II in Rabbits (C31G) 4d. 6 months Toxicity in Rats (C31G and BufferGel) 4e. 9 month toxicity in Dogs (BufferGel) 4f. 2 year carcinogenicity in Rats and Mice (C31G and BufferGel) Award will be made in whole or in part to that offeror whose proposal provides the combination of features that offers the best or greatest overall value to the Government. A technical proposal addressing the evaluation criteria, a cost proposal including costs for each of the areas in paragraph #4 above and a completed copy of the FAR provision 52.212-3, Offeror Representations and Certifications Commercial Items, are required as part of the offer. The clause 52.212-4 Contract Terms and Conditions-Commercial Items applies to this acquisition. The clause at 52.212-5, Contract Terms and Conditions Required to Implement Statutes or Executive Orders-Commercial Items applies to this acquisition. The Contractor will be paid as each study area is completed. Offers are due in the designated contracting office by 11:00 a.m. local time, August 31, 1999. Proposals must be in writing and addressed to the attention of Ms. Foteni Tiffany, Room 529W, at the above address. Posted 08/11/99 (W-SN366555). (0223)

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