Table of Contents - How to Access:

• In vitro anticancer assays
• In vivo screening
• Web-accessible data sets and data mining tools
• Individual research compound samples
• • Synthetics
  • Natural Product Extracts
  • Biologic Agents
• Compound library sets
• Cell lines, tumors, or research animals
• Early development resources (such as in vivo testing, PK/PD, early formulation research).
• Mid to Late Development resources (range-finding and IND-directed toxicology, clinical formulation)

The drug discovery and development resources of the DTP are widely available to the NIH intramural program. The following paragraphs describe these resources and the means by which NIH intramural investigators access them.

Discovery Resources

• In vitro assays. Materials can be evaluated in our primary anticancer (3 cell line assay, 60 cell line assay) and anti-HIV screens. To submit small molecules to these screens, utilize the DTP on-line submission form. Submit biologics (Antibody, Gene Therapy, Oligo, Peptide, Vaccine, Other) via a brief letter (e-mail or memo) describing the biologic and any special handling/testing requirements to (or for more information on these services):

  Dr. Ven L. Narayanan
  Drug Synthesis & Chemistry Branch, DTP
  Building EPN, Room 8024
  narayanv@exchange.nih.gov
  

  Once the small molecule or biologic is accepted for testing, instructions for shipment of the sample to the storage contractor will be supplied to the researcher.

• In vivo screening. Agents which are reviewed as "active" in the 60 cell line screen are automatically referred to the DTP's Biological Evaluation Committee (BEC) and considered for no cost in vivo testing (hollow fiber, limited xenografts). Intramural researchers may request such testing without 60 cell line data, if compelling data exist, by making an application to the BEC (see below under Early Development Resources)

• Web-accessible data sets and data mining tools from our in-house screening programs and extramural collaborations.

  • Bulk data for download including: Human tumor cell line assay, AIDS antiviral assay data, yeast assay data, chemical structures, characterizations of molecular targets in cell lines, data from the Botstein/Brown Stanford U. Microarray Project
  • Tools for searching and analyzing data including: Searches by chemical name, NSC number, substructure, COMPARE searches.

• Individual Research Compound Samples.

• • Synthetics: Small amounts of synthetic and pure natural product compounds are available to investigators for research purposes. Compounds are requested via the on-line sample request form. Samples are available at no charge. The investigator must sign an intramural Materials Transfer Agreement (MTA) in order to receive the sample.

  • Natural Product Extracts: extracts from the Natural Products Repository are available either in vials or in 96 well plates for distribution to researchers through the Open Repository Program and the Active Repository Program. Access to these programs will be subject to signing a Material Transfer Agreement protecting the rights of all parties.

  • Biologic agents: The Biological Resources Branch Preclinical Repository is an NCI-sponsored facility which contains bulk cytokines, monoclonal antibodies, and cytokine standards that are maintained under carefully controlled storage conditions. The purpose of this facility is to maintain a constant and uniform supply of high quality reagents for scientists. There is no charge for this service.

• Compound Libraries (Compounds supplied on microtiter plates).

  • Small "Discovery" Sets. The structural diversity (1990 compounds), mechanistic diversity (879 compounds all active in the 60 cell line assay), and challenge sets (57 compounds active in the 60 cell line assay with undetermined mechanism) are widely available to intramural researchers. An explanation of the background of these sets is available. The requestor must submit a brief proposal providing the background on the target of the screen, a description of the screen, and plans for follow-up on hits. Requests are reviewed by the DTP Office of the Associate Director (OAD) staff. Requests for multiple copies of any sets will be reviewed separately. These sets are available at no cost to intramural researchers. An intramural MTA must be signed.
  • The 140,000 Compounds plated set. Plates in 5,000 well increments, up to the entire 140,000 plated set, are available for molecular target-based assays relevant to cancer or AIDS. Requestors must submit to OAD a 3-5 page proposal for approval. The DTP Biological Evaluation Committee (BEC) will review all requests. An intramural MTA similar to that used for the small plated sets must be signed by the researcher. Access to the full plated repository must be preceded by the screening the diversity set, with good performance of the assay exhibited. Intramural researchers do not incur shipping charges. To reimburse the extramural contract dollars for the production of the plates, intramural researchers must submit a chargeback to DTP of $1,715 per 5,000 wells up to $48,000 for the entire set (approximately $0.34 per compound). Note - Two exceptions to chargeback:
    1. If the intramural investigator agrees to post the data from the screening of the open plated set will be posted to the DTP web site or an NCI web site on an agreed-upon timetable, there will be no charge for plated compounds, or
    2. If the intramural screening effort has been peer-reviewed in a competitive fashion which includes extramural researchers (e.g. Chemistry/Biology P01s, Molecular Target Drug Discovery grants, etc.)

• Cell Lines, Tumors, Animals. The Biological Testing Branch of DTP provides cell lines, tumors and animlas free of charge to the NIH intramural program. A complete description of this service is available.

Early Development Resources

To access resources including mechanistic studies, non-GMP resynthesis, early formulation, pharmacology and pre-range-finding toxicology studies for either biologic or small molecules with evidence of a targeted effect, researchers should present data to the Biological Evaluation Committee (BEC), which is comprised of DTP staff. This early development level of support is referred to as "Stage IB." Compounds must meet DTP criteria for interest (in general - novel structural type, affects a cancer-relevant target of current interest). 60 cell line screening results are helpful but are not a requirement for presentation to the BEC for Stage IB resources. These resources are available at no cost to intramural researchers. To request DTP development resources, researchers should submit an application which should be no more than five typed singled-spaced pages and include:

• Abstract: 300 words or less.
• Background: a summary of the field that clarifies the scientific and medical context from which the opportunity emerges.
• Hypothesis or Pressing Opportunity: a clear statement of the hypothesis or important public health related opportunity that development of the relevant molecule will allow.
• Specific Request: a clear statement of the tasks and support specifically being requested.
• Justification and Uniqueness: why the project under consideration represents a particularly innovative or promising approach to cancer treatment. Include a discussion of related or similar molecules already under development by NCI or known to be in development under industrial sponsorship, and why the NCI should undertake development in light of this.
• Additional Support: a clear statement by the applicant of all current or anticipated support for the development of the agent. This includes, where relevant, a summary of the status of past, planned, or ongoing negotiations with companies related to licensure or future development of the product.
• Intellectual Property: information regarding any patents issued or pending with respect to the product.
• Anticipated Costs: Optional. These should be broken out by task
• Appendix: background preprints or reprints (maximum of five; not included in the page limitation).

Applications are accepted on an ongoing basis. Please contact us for specific meeting dates.

To submit an application or to request additional information contact: ddg@dtpax2.ncifcrf.gov

Mid-to-Late Development Resources

Potential therapeutic agents arising from the intramural program can enter clinical trials in both the intramural program and at extramural sites. DTP resources for bulk synthesis, clinical formulations, pharmacology, range-finding and IND-directed toxicology studies can be accessed in two ways. When the clinical trial will involve only the intramural clinical center, an internal CCR committee reviews the request and funds the approved tasks. The Cancer Therapy Evaluation Program (CTEP) must approve and file the IND. If, in addition to the clinical center, the clinical trial will be placed at extramural sites, the intramural researcher may apply to the Drug Development Group (DDG), a DCTD committee, for these resources. Approval of an agent by the DDG means that no costs are incurred by the CCR. Two non-voting extramural experts review each application. Further information.

Presentation to the DDG may be facilitated by an identified CTEP or DTP staff member to act as liaison, who coordinates with the originator the preparation of the DDG application. Note: the DDG application uses the same format as given above for the BEC. The depth of the information supplied should be commensurate with the level of development resources being requested. Agents are presented as either Stage IIA, IIB or III development candidates. Typical activities at each stage are given below:

Stage IIA - Range-finding toxicology, GMP synthesis, formulation

Stage *IIB - IND-directed toxicology, clinical lot manufacture.

Stage *III - Clinical trials. Phase I with progress to Phase II

Presentation at the IIA level occurs without external review but with the presence of the originating party. Presentation at the IIB or III level will have two expert external reviewers selected from the NCI reviewer pool of peer reviewed grant awardees. The usual conflict of interest recusals will be in effect, and a specific statement that there is no conflict of interest with the particular matter will be obtained, with a signed confidentiality agreement. Reviewers are ad hoc and are not permanent members of the DDG.

Applications are accepted approximately six weeks prior to each scheduled DDG meeting to allow review of the application for completeness. Please contact us for specific meeting dates.

To submit an application or to request additional information contact: ddg@dtpax2.ncifcrf.gov