For many years the NCI has conducted a vigorous program in the discovery and development of new drugs for the treatment of cancer. We have in place a variety of award and support mechanisms to increase the rate of discovery of new molecular entities and approaches relevant to cancer and to expedite the flow of these new discoveries to the clinic.
This summary explains how we decide which discoveries offer particular promise for cancer therapy and should, therefore, receive support for the various pre-clinical development steps toward clinical trial. Academic investigators interested in new cancer therapies and companies involved in cancer drug discovery may find this information helpful in understanding how NCI works and in deciding how best to interact with NCI.
PATHS FOR DEVELOPMENT SUPPORT - WHICH IS RIGHT FOR YOU?
NCI has two programs for developing therapeutic candidates. Which one of these applies to an individual drug candidate depends on who will be responsible for clinical testing and on the goal of the clinical testing itself.
Rapid Access to Intervention Development (RAID). This initiative focuses on assisting academic investigators with the development steps necessary for them to initiate clinical trials with their own discoveries. RAID assumes that the clinical agent will be studied under an Investigational New Drug (IND) application that is held either by the investigator or a close collaborator. The goal of RAID is to facilitate proof-of-principle clinical testing by, or in close association with, the investigator group from which the new discovery has emanated. For fully approved RAID projects, NCI commits to making sufficient compound only for the early stages of clinical testing. Review of RAID proposals is by an ad hoc committee of experts external to the NCI; this group prioritizes projects for NCI contract support. A detailed description of the RAID program is available at http://dtp.nci.nih.gov/docs/raid/raid_index.html.
Drug Development Group (DDG). For agents where NCI is anticipated to be the IND-holder and the sponsor of clinical testing, the DDG is the decision-making body. NCI creates the clinical development plan for each agent, often in collaboration with a pharmaceutical or biotechnology company; the goal of the clinical testing is, whenever feasible, a full-scale exploration of the new agent's potential against human cancer. This group consists of NCI staff, assisted by two external reviewers for each proposed project; the external reviewers serve on an ad hoc basis. For a complete description of how the DDG operates, see http://dtp.nci.nih.gov/docs/ddg/ddg_descript.html.
SPECIAL CONSIDERATIONS FOR BIOLOGIC AGENTS
Since 1994, the total capacity of the production resources available to NCI's Biological Resources Branch (BRB) has steadily increased, as has demand. Currently, the demand for support of peer-reviewed, approved, and funded projects exceeds production capacity; this circumstance demands careful oversight and prioritization of these valuable resources.
A summary of BRB capabilities is found at http://web.ncifcrf.gov/research/brb/bdp.asp
Review of biological projects includes distinct aspects. An initial review for scientific merit of the proposed project is performed by either the RAID review committee or the DDG. In order to make cost-effectiveness determinations, the initial review committee evaluates cost and time-line estimates generated by BRB and contractor staff (see below), and applicable cost estimates from other DTP components. Cost and time-line estimates generated by BRB and contractor technical staff allow assessment of feasibility, identification of remaining research and development steps, and a projection of impact on available BRB resources. Investigators are also encouraged but not required to seek comparative estimates from commercial vendors.
The Biological Resources Branch Oversight Committee (BRB-OC) provides second-level technical feasibility review and prioritization for RAID or DDG-approved prospects. This group consists of extramural and NCI scientists knowledgeable about the practical implementation of biological projects.
The BRB-OC may determine that a previously approved project suffers from technical feasibility flaws that might not have been apparent during initial scientific review. In that event, project details may have to be re-considered; the originator may have to address these technical concerns before NCI proceeds with production. The BRB-OC also evaluates significant technical problems that emerge in the course of production and may significantly increase cost or require major additional research and development. Examples include mutations first recognized on sequencing, undesirable contaminants that are difficult to separate from product, protein aggregation, instability, low yield, or problems in validating key assays. In such cases, the BRB-OC may decide to recommend interruption of an ongoing project pending resolution of the problems, or to make other changes in the approved production plan.
CURRENT MEMBERSHIP OF BRB-OC
- Dr. Estuardo Aguilar-Cordova, Advantagene, Inc.
- Dr. Christopher Benz, UCSF
- Dr. Esteban Celis, Mayo Clinic
- Dr. Stanton Gerson, Case Western Reserve University
- Dr. Thomas Kipps - Chair, UCSD Cancer Center
- Dr. Edmund Lattime, The Cancer Institute of New Jersey
- Dr. Andrew Raubitschek, City of Hope National Medical Center
- Dr. Paul Sondel, University of Wisconsin
- Dr. Walter Storkus, Hillmann Cancer Center
- Dr. Richard Whitley, University of Alabama
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DRUG DEVELOPMENT AND NCI'S INTRAMURAL RESEARCH PROGRAM (IRP)
The NCI IRP may be the source of products to be studied in both the IRP and at extramural sites.
Preclinical development of agents discovered in NCI's IRP and anticipated to receive initial clinical trials only in the IRP may receive DCTD resource support for pre-clinical development or IND filing without consideration by DDG, provided that the contract costs are fully reimbursed by intramural funds. This assumes that there is sufficient approved level of effort available on the contract for IRP use and that DCTD scientific staff are in agreement with the goals and interpretation of proposed studies.
Overall plans for the Clinical studies in the IRP of agents whose IND is held by DCTD will be reviewed by the DDG prior to IND filing but without extramural reviewers, as the IRP is already reviewed externally as part of its site-visit process. Individual proposals for such trials will be considered by the members of the DDG according to the criteria to be described below. This review is an important opportunity for DCTD clinician - scientists to comment formally on the suitability of the proposed agent for clinical study, and their comments will influence the priority given to NCI's filing an IND for the proposed agent.
For agents to be studied both in the IRP and at extramural sites, clinical trials proposals will also have extramural reviewers. Prioritization of IRP products for use of biologicals production contracts will remain with the BRB-OC.
If NCI is anticipated to be the IND-holder for the agent, DDG will be the decision making body. This group consists of NCI staff, assisted by two external reviewers for each proposed project; the external reviewers serve on an ad hoc basis.
Discovery Services Development Services Discovery Funding R·A·N·D RAID DDG Grants Is money provided directly to applicant? No No No Yes How often can I apply? 2 times / year 2 times / year On a continuing basis Varies by grant type How many times can I re-apply? Up to 2 times Up to 2 times Up to 2 times Varies by grant type Who holds IND? N/A Applicant NCI Applicant's Institution What is the extent of development that can be supported by this mechanism? Up to Lead Discovery Up to but not including clinical trials Into clinic Theoretically, all preclinical development, but usually only proposals covering early stage activities successful Who is eligible? Academic or Academic/SBIR Academic or Academic/SBIR All Varies by grant type