RFP Mod 1 Nov 22 2010.doc

RFP#NIH-NIMH-2010-023

Modification #1 November 22, 2010

1. Please provide guidance as to the anticipated number of compounds entering each segment of the work scope. Working backwards, in the 5 years of the program, a total of 6 Phase 2 projects (each project equivalent to 1 compound) will be conducted, chosen from 20 Phase 1 projects. Based on the description of the initial PK studies in Phase 1, it appears that a project is not equivalent to 1 compound but rather to 3 compounds (for a total of 60 compounds to test in the rat PK study and 40 of these 60 to test in the dog PK study in Phase 1 over 2 years). Is it the case that the In Vitro ADMET panel is not part of Phase 1, but rather guides the selection of the 60 Phase 1compounds? If so, how many compounds per project are anticipated to enter the In Vitro ADMET panel to provide 60 Phase 1 compounds (3 compounds/project)?

It is not possible to definitively determine the number of each type of study that will be conducted under this contract. For purposes of proposal development, the major study types have been combined into Phase 1 and Phase 2, and estimates of the yearly workload have been provided. Based on the anticipated workload, over the 5 years of the program, 60 compounds will be evaluated in rodent PK in Phase 1, 40 of those will be tested in dog PK. Those results will be used to inform medicinal chemistry and support candidate selection to identify the 6 compounds that will be tested in Phase 2.

The in vitro ADMET assays will primarily be conducted through the Blueprint Neurotherapeutics medicinal chemistry contract. The PTNP contractor shall have the capability and capacity to perform all in vitro ADMET assays listed in the Statement of Work, however that capability will be used primarily to provide additional capacity, in the event additional resources are needed beyond those available through the medicinal chemistry component of the Blueprint Neurotherapeutics network.

2. Does the government anticipate use of radiolabeled compounds in any in vitro or in vivo studies?

The use of radiolabeled compounds is not anticipated to be standard; however, it may be required to support a subset of projects under the contract.

3. Attachment 9 (Additional Business proposal instructions), page 1, Anticipated workload, Phase 1. The Description of the initial PK study in rat states “including assessment of blood to plasma ratio.” However, the chart on page 2 of this same section states “including brain to plasma ratio” for this study. Please clarify if blood to plasma ratio is required or if only brain to plasma ratio is required for the Phase 1 rat PK study.

The statement should read, ‘including assessment of brain to plasma ratio’. This will be required in the Phase 1 PK study to provide an assessment of brain penetrance, which is likely to be required for potential therapeutics for nervous system disorders.

4. Attachment 9 (Additional Business proposal instructions), page 1, Anticipated workload, Phase 1. Please clarify if brain to plasma ratio is required for all time points or if it is acceptable to use cannulated rats such that brain would be collected only from the final time point.

Specific protocols for each study will be developed in coordination with the Lead Development Team for each project, and different approaches may be required for different studies. For the purpose of proposal development, Offerors should propose the study outline that best meets the goal of the PTNP program, which is to support medicinal chemistry optimization, candidate selection, and IND-directed development of therapeutics for nervous system disorders.

5. Attachment 9 (Additional Business proposal instructions), page 1, Anticipated workload, Phase 1. Please clarify if use of one gender (males only) is acceptable for the initial rat and dog PK studies.

Specific protocols for each study will be developed in coordination with the Lead Development Team for each project, and different approaches may be required for different studies. For the purposes of proposal development, Offerors may assume that a single gender is sufficient for Phase 1 PK studies.

6. Attachment 9 (Additional Business proposal instructions), page 1, Anticipated workload, Phase 1. Please clarify if the Phase 1 initial PK studies in rat and dog are to include a dose response or if only a single dose is to be assessed.

Specific protocols for each study will be developed in coordination with the Lead Development Team for each project, and different approaches may be required for different studies. For purposes of proposal development, Offerors may assume that a single dose will be assessed in Phase 1 PK studies.

7. Attachment 9 (Additional Business proposal instructions), page 2, Chart. Please clarify what is meant by “batch size”. Does this refer to amount of compound, number of tests, number of compounds, other? Given the information in the “cost” column, it is unclear what batch size represents.

Batch size refers to the number of compounds.

8. Attachment 9 (Additional Business proposal instructions), page 1, Anticipated workload, Phase 2. Please clarify if the single-dose dose range finding (DRF) study in rats and dogs is to include full TK or if it is acceptable to perform full TK analysis on Days 1 and 7 of the 7-day repeat-dose DRF study in rats and dogs to obtain single dose TK data.

Specific protocols for each study will be developed in coordination with the Lead Development Team for each project, and different approaches may be required for different studies. For the purposes of proposal development, Offerors may assume that single dose TK data is sufficient for the DRF study.

9. Attachment 9 (Additional Business proposal instructions), page 1, Anticipated workload, Phase 2. Please clarify if it is acceptable for the full PK assessments and the DRF studies in rat and dog to be conducted as non-GLP compliant studies (which is typical) and that only the genotoxicity, rat and dog 28-day toxicity and safety pharmacology (CV and pulmonary) studies must be GLP-compliant.

It is acceptable that Phase 2 PK studies be conducted as non-GLP.

10. Attachment 9 (Additional Business proposal instructions), page 2. Please clarify if the hERG requested in the chart as part of the in vitro ADMET panel is intended to be a non-GLP screening assay. In addition, does the NIMH anticipate requesting GLP-compliant hERG inhibition studies under this contract since such studies are required to support an IND?

The hERG screening included in the in vitro ADMET panel is intended as a screening assay. GLP-compliant hERG may be required under this contract.

11. Can the Government confirm that Phase 1 involves the in vitro ADMET initial PK in rats and the initial PK in dogs and that Phase 2 entails non-GLP full PK in rats, non-GLP full PK in dogs, non-GLP rat DRF, non-GLP dog DRF, GLP genotox, GLP rat 28-day tox, GLP dog 28-day tox, cardiovascular and pulmonary safety pharmacology, and toxicokinetcs?

It is not possible to determine in advance the exact number and types of studies that will be required for each compound in the Blueprint Neurotherapeutics Network. This will be determined on a case by case basis, by the Lead Development Team for each project.

For proposal development purposes, the NIMH has divided the type of work to be conducted into two phases and provided an estimate of the number of compounds to be tested in each in each phase. Phase 1, as described in the Statement of Work, does not include in vitro ADMET assays. While the contractor must be capable of conducting all in vitro assays listed in the Statement of Work, the majority of these studies will be conducted by another component of the Blueprint Neurotherapeutics Network. The PTNP will provide additional capacity for these assays, so they were not included in anticipated workload. Phase 1 consists of initial PK in rat and dog. Phase 2 entails non-GLP full PK in rats, non-GLP full PK in dogs, non-GLP rat DRF, non-GLP dog DRF, GLP genotox, GLP rat 28-day tox (including CNS safety pharmacology and micronucleus), GLP dog 28-day tox, cardiovascular and pulmonary safety pharmacology, and toxicokinetics.