Development of Clinical Imaging Drugs and Enhancers (DCIDE)
Version 003: Modified 8/02

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• Contact Information
• Description
• The Opportunity
• The Program
• The Scope
• The Process
• Requests for Support
• Evaluation Criteria
• Intellectual Property
• Industrial Intervention
• Assessment and Oversight
• Metrics for Judging Success
• Other Details
• Other sources of information and web sites
• The DCIDE Process Diagram
• Preclinical Development and Testing Diagram
• Information about Projects which have received approval for support through the DCIDE Review Committee

Contact Information

Barbara Y. Croft, Ph.D.
Program Director, DCIDE Program
Cancer Imaging Program, NCI
6130 Executive Blvd., Suite 6000
Rockville, MD 20892

Description: A competitive program to expedite and facilitate the development of promising investigational imaging enhancers (contrast agents) or molecular probes from the laboratory to IND status.

The Opportunity: A significant number of promising diagnostic imaging agents are not available for use in clinical trials. Many of these agents could enhance clinical medicine, either by providing a measure of response to chemopreventive interventions or therapy or by serving as surrogate endpoints to preventive measures or therapy. Multiple barriers inhibit successful development, but two of the most important are (1) uncertain economic potential that prohibits access to necessary resources and (2) lack of knowledge of clinical and regulatory requirements. These barriers have become more obvious as interdisciplinary boundaries have expanded to include technical researchers such as combinatorial chemists and bioengineers. Although researchers in an academic medical environment may have access to necessary resources for product development, others may have little or no access to such resources. Even among those with academic medical affiliation, competing needs for increasingly limited resources may prohibit development of a promising new agent. At the same time, advances in genomics and molecular biology have changed the nature of new diagnostic enhancers and molecular imaging probes. The emphasis on highly specific molecular targets and processes has led to products with increased complexity and higher costs of development but smaller market potential. This trend has effectively created a large class of "orphan-like" agents, which investors consider too risky for further development yet may have the potential to impact diagnosis and treatment significantly. This particular barrier applies not only to academia and small business but also to large businesses, where there may be significant numbers of potential diagnostic agents that do undergo further development for the commercial market.

The DCIDE program is intended to supply or enable missing steps so that promising discoveries may be translated to the clinical research environment despite the absence of development capacity, clinical connections, or industry interest. The DCIDE program will focus on promising diagnostic agents that are not otherwise likely to undergo adequate pre-clinical testing to warrant an IND application. The DCIDE program is not intended to provide full-scale clinical development but will facilitate the performance of pre-clinical evaluation to establish proof of principle of a compelling hypothesis. Once this is accomplished for specific products, it is anticipated that clinical development will continue along established mechanisms under the sponsorship of either private companies or the National Cancer Institute. The DCIDE program is not intended as competition for private industry; investigators intending to license discoveries to companies should not be deterred from doing so by the existence of a successful DCIDE program. Also it does not seem likely that companies interested in licensing an academic discovery will wish to risk loss of the opportunity by allowing the compound to go through the DCIDE program process first. It does, however, seem likely that the DCIDE program will add value to discoveries that are initially regarded by companies as problematic and will make these discoveries more attractive licensing candidates for industries.

To optimize the return from resources devoted to the program, developed probes will be maintained in a Translational Probe Library. This library will facilitate accessibility of housed probes for clinical trials groups or investigators as well as for pre-clinical researchers interested in in vivo imaging studies, including proof-of-principle animal model studies.

The Program: Through the DCIDE program, the developer of a promising diagnostic agent or probe will be given access to the pre-clinical development resources of the National Cancer Institute in a manner that is intended to remove the most common barriers between laboratory discoveries and IND status. Through a competitive selection process, the DCIDE program may supply assistance in any or all of the following activities:

1. Steps in pre-clinical development that are necessary to convert a potential new agent into a diagnostic drug candidate suitable for early clinical testing (IND status) and that are generally not otherwise available to the investigators. These steps may include pharmacokinetics, dosimetry, imaging feasibility, IND-directed toxicology, etc.
2. Regulatory affairs, so that requirements of the Food and Drug Administration may be satisfied by any investigator who seeks Investigational New Drug status.
3. Access to probes for approved pre-clinical protocols (including animal models).

The DCIDE program process will consist of two stages of evaluation. Stage 1 will be a competitive evaluation performed by a specially constituted DCIDE Evaluation Panel, consisting of non-NCI experts from academia and industry. This evaluation panel will provide individual opinions on the requests for resources.

This evaluation panel will include imagers with molecular imaging expertise, molecular biologists, combinatorial chemists, radiochemists, pharmacists, and oncologists. Criteria for the initial evaluation are stated below. Requests for resources with sufficiently high merit scores will then move to Stage II, where a committee of NCI staff members will evaluate the scored requests for resources. NCI staff will select the requests for resources that are most consistent with resources available for expedited development.

Agents that undergo successful development and testing will be maintained in a probe library. The DCIDE library will be a source of probes that researchers may find beneficial in basic research, including in vivo animal model imaging studies. This resource may expand the clinical applications of the probes by providing better understanding of mechanisms and imaging criteria. Requests for probes for this purpose will undergo internal review at NCI to ensure study design appropriate to the proposed objectives. The DCIDE program will either provide agents directly or facilitate their availability. Radiotracer-labeled probes represent a special case that will require direct source / investigator affiliation, with NCI fulfilling mainly an informational role.

The Scope: The DCIDE program will consider the full range of diagnostic imaging agents, including contrast agents, biologic and molecular probes, and radiolabeled compounds as well as agents that may be an integral part of image-targeted therapy. The program will also include agents relevant to detection or preventive interventions of pre-cancerous lesions. For example, a similar program, NCI's Early Detection Research Network (EDRN) supports research on biomarker development and testing for early detection and risk assessment. The DCIDE program is expected to yield new biomarkers that target specific receptors in pre-neoplastic and early invasive lesions, which can serve as imaging probes.

Although probes with high clinical potential are likely to be the most successful candidates, the DCIDE probe library will also provide agents for pre-clinical and basic research targeted at in vivo imaging, as noted above. The DCIDE program will provide or facilitate the acquisition of probes for these specific purposes but will not directly fund the basic research study. Funds for the research must come from other sources such as existing NCI grant programs.

The Process: Initially, the NCI announced a call for requests for resources two times a year. The frequency of the call for requests for resources was re-evaluated after the first year of experience; requests for resources may now be made on the first of every month, after consultation with program staff. Scientists are invited to submit innovative and compelling discoveries that have no existing avenue for pre-clinical development aimed toward application for an IND. Requests for resources will be competitively reviewed as described above (i.e., by a evaluation panel composed of outside experts).

The number of projects to be supported in any cycle will depend on both the level of merit and the availability of funds. Approved projects will receive the type of assistance requested to ensure the filing of an IND application at the earliest feasible date.

The decision to develop a new diagnostic agent for clinical use is not an unconditional commitment. Development will proceed sequentially, in logical order, through the routing suggested by the NCI staff. The start of one segment of the process (e.g., toxicology or dosimetry) will depend on satisfactory completion of the preceding segments (e.g., formulation). Insurmountable difficulties in any one segment may force abandonment of individual projects, as is true in any development program.

Format of requests for support

Please use PHS 398 to request support. Send an original and 4 copies to the contact person. Please observe the type size and line spacing requirements. In a document not to exceed 25 single-spaced pages, requestors are to supply the following information:

1. Face Page, AA: Complete relevant information. This is not a request for funding. No human subjects or vertebrate animals will be used.
2. Form Page 2, BB: Abstract: a summary of the project to fit into the box provided.
3. Form Page 3, CC: Table of Contents: Adapt to the information being supplied. Please number pages consecutively.
4. Form Page 6, FF: Biographical Sketch for the requestor.
5. Form Page 7, GG: Other Support: Use this format, with any expansion necessary, to describe all current and anticipated sources of support for the project. This includes a summary of the status of past, planned, or ongoing negotiations with companies relating to licensing or future development of the product, as well as reasons that negotiations to license have not been successful to date.
6. Research Plan Section: The following should be included in the Research Plan, substituting for the usual PHS 398 information:
   1. Background: a summary of the field from which the discovery has emerged that will allow evaluators to appreciate the scientific and medical importance of the imaging agent.
   2. Hypothesis: a clear statement of the hypothesis (-ses) that will be tested and the model and/or methodology required for biochemical validation or certification of the probe/agent.
   3. Request: a clear statement of specifically what is needed (and therefore requested from the National Cancer Institute) to bring the compound to IND status. Also, a clear statement about the anticipated role of the requestor or requestor institution in the development of the project once NCI becomes involved.
   4. Justification: an explanation of why the imaging agent represents a particularly innovative or promising approach to the prevention, detection, diagnosis, or treatment of cancer.
   5. Uniqueness: a discussion of related or similar molecules already under development by NCI or industrial (or other) sponsors and why this particular imaging agent should be given priority by the NCI in light of possible competition.
   6. F. Contact with relevant FDA staff: a disclosure of the current stage of discussions with the relevant FDA staff about IND filings for the imaging agent.
7. Checklist, II: Complete the relevant information.
8. Appendix (not included in page limitation): background preprints and reprints.
9. Intellectual Property: Each DCIDE applicant must include a letter with his or her application from the appropriate authorized staff person overseeing intellectual property and/or technology transfer for his or her affiliated institution or company verifying that she/he has reviewed the DCIDE request and that application is or is not eligible for consideration by the DCIDE program. The letter should include a statement by the applicant disclosing any patents, issued or pending, and/or licenses, granted and/or pending, with respect to the product of the application as well as any known patents that block the development of the products of the application. In the event that an application requires the use of a non-commercially available technology/material which is patented by a third party, applicant must provide documentation that the third party patent holder does not object to the applicant's use. If a technology/material is found not to be eligible for use in the DCIDE application and is central to the investigator's proposal, application to the DCIDE program is not encouraged.

Evaluation Criteria

Stage I: Scientific Merit (non-NCI reviewers):

1. Strength of scientific evidence and hypothesis
2. Certification (biochemical or physiological validation)
3. Potential clinical impact
4. Feasibility
5. Novelty

Stage II: Operational Feasibility (NCI staff):

1. Resource availability
2. Potential impact on current or proposed clinical trials by NCI
3. Magnitude of required pre-clinical studies to address scientific/regulatory issues
4. Resource intensity, i.e., costs and benefits

Intellectual Property: It is expected that originating parties will have acquired intellectual property protection prior to involvement of NCI. Normally, NCI will not acquire intellectual property rights to inventions made by its employees with Research Materials under DCIDE unless the originating investigator and NCI mutually agree that to do so would be in the best interest of the project. It the NCI does file a patent application, the originating investigator will be given the opportunity to negotiate for an exclusive license under procedures set forth in 37 CFR Part 404. Many DCIDE tasks will be accomplished by the use of NCI's development contracts. Normally, an NCI contractor may elect to retain rights under the Bayh-Dole Act for any contributions it makes that rise to the level of invention. NCI contractors have, as a term of their funding, agreed to offer a first option to the originating investigator for license negotiations. Certain other contractors or subcontractors may be subject to a Determination of Exceptional Circumstances through which their rights in subject inventions made using Research Materials may be assigned to the originating investigator. Should an invention occur, the originating academic party will thereby have acquired a valuable potential ally in commercializing the subject of the research and may have acquired additional intellectual property if the invention was derived from collaborative research. DCIDE Material Transfer Agreements will form the basis for sharing Research Material and confidential information with NCI.

Industrial Intervention: If a company decides to license a compound while it is in active development in the DCIDE program, NCI expects the company to assume a fair share of the costs required to complete the pre-clinical development and to meet all regulatory requirements for clinical trials.

Assessment and Oversight: The DCIDE program will be subject to oversight by a group of outside experts acting under the aegis of NCI's Board of Scientific Advisors. The group will serve the following functions:

1. Project Review. Oversight review of all activity conducted in the DCIDE program at an interval to be determined by BSA.
2. General Advice. Consultation with NCI staff on broad aspects of the program, such as modifications relating to content of applications, adjustment of evaluation criteria as a function of further experience, etc.

Metrics for Judging Success: The objective of the DCIDE program is to ensure that promising discoveries that would otherwise languish in developmental limbo are rapidly brought to Phase 1 clinical trial. Judging the success of the program will not be straightforward, since there is no obvious comparison group of discoveries in other programs that is equivalent in all relevant particulars to those approved by the DCIDE program. The following measures seem appropriate, in light of the total cumulative expenditures on the program over the initial three years of evaluation:

1. Number of novel imaging agents that achieve IND status, are brought to the clinic or are on their way to clinical use. It is assumed that these agents would not have received a clinical test, at least within a reasonable timeframe, without the DCIDE program. Although DCIDE program candidates by definition lack current industrial interest and therefore are not on a fast-track to the clinic, there is no way to validate the assumption, as some of them might have found their way to clinical trial by routes independent of NCI.
2. Demand by researchers for probes from the Probe Library.
3. Number of agents that are eventually licensed to companies as a result of data made possible by support from the DCIDE Program.
4. Knowledge gained on the relevance of the pre-clinical hypothesis to the behavior of the new agent in the clinic, measured by peer-reviewed publications in medical literature.
5. Total cost of the program over the period of evaluation.

Other details

• No more than two requests for support from the same principal investigator may be received on any given receipt date. An individual agent has three chances to be approved by DCIDE. After three unsuccessful attempts, subsequent requests focusing on the same agent will be returned without review.
• In the event that a DCIDE project is overrunning its projected budget in a way that will not readily lead to a desired data endpoint or clinical trials candidate, a status review group will be impaneled to consider the likelihood that further work in the project area will be fruitful. The investigator and NCI staff will present progress to date in a face-to-face forum to between three and five extramural scientists knowledgeable in the area and bound by conflict of interest guidelines. Following the presentation, the group may recommend continuance with new milestones or cessation of the project.
• DCIDE is not open to funded Federal laboratories.
• Please read the current Process and Procedures before submitting a DCIDE request. CHANGES OCCUR FREQUENTLY.

Other sources of information and web sites

• Choose the Clinical/Medical (Draft) link on the sidebar of http://www.fda.gov/cder/guidance/index.htm to find "8. Developing Medical Imaging Drugs and Biologics [HTML] or [PDF] (Issued 7/2000, Posted 7/28/2000)"
  http://www.fda.gov/cder/guidance/3646dft.pdf is the PDF version.
• Choose IND on the sidebar of http://www.fda.gov/cder/guidance/index.htm to find "1. Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs."
  The PDF version is at http://www.fda.gov/cder/guidance/phase1.pdf
• To find a number of useful documents, look at http://www.fda.gov/cder/regulatory/default.htm
• The International Council on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use are found at http://www.ifpma.org/ich1.html

Figure 1. The DCIDE Process

Figure 2. Pre-clinical Development and Testing

CIP DCIDE Projects by Round

Round 1

Mark D. Bednarski, Ph.D., Targasome, Inc., phone: 650-842-1823, fax: 650-842-1828

Project Name: PreClinical and Correlative Imaging of Tumor Angiogenesis

Summary: The agent is a recently developed molecular imaging technology using a paramagnetic particle targeted toward a cell surface receptor upregulated during the process of tumor angiogenesis. The method uses the human monoclonal antibody, Vitaxin 2, conjugated to polymerized vesicles (V2-PV) lableled with gadolinium ions that bind to the endothelial marker avß3 (V2-PV-Gd).

Timothy R. DeGrado, Ph.D., Duke University, phone: 919-684-7727, fax: 919-684-7130

Project Name: Pre-Clinical Testing of F-18 Fluorocholine

Summary: The aim of the project is to develop [18F]fluorocholine (FCH) for detection and localization of cancer using positron emission tomography (PET). The approach is motivated by the findings of elevated choline and choline kinase activity in a variety of cancer types, and recent reports of the utility of [11C]choline in PET studies in prostate carcinoma, brain tumors, and esophageal carcinoma.

Round 4

Mark M. Goodman, Ph.D., Emory University, phone: 404-727-9366, fax: 404-727-4366

Project Name: [F-18]FACBC A Novel Agent for Tumor Imaging by PET

Summary: The objective of this project is to develop a novel fluorine-18 labeled positron emitting alicyclic amino acid, [18F]FACBC, into a clinical project for the diagnostic imaging of human tumors. The movement of amino acids across tumor capillaries is up-regulated in comparison to most normal tissues by carrier-mediated facilitated transport involving both the “L” and “A” amino acid transport systems.

Gregory M. Lanza, M.D., Ph.D., Washington University, phone: 314-454-8635, fax: 314-454-5265

Project Name: MRI Detection of Angiogensis with avß3 –Nanoparticles

Summary: The subject of this research is the preclinical development of a novel, paramagnetic, targeted contrast agent for magnetic resonance imaging of the avß3 –integrin expressed by neovascular vessels associated with solid tumors.

Jason S. Lewis, Ph.D., Washington University, phone: 314-362-4696, fax: 314-362-9940

Project Name: Cu-ATSM: Preclinical Development via the DCIDE Program

Summary: Cu-ATSM, labeled with a radioisotope of copper, Cu-64, will have a significant clinical impact for both the imaging of hypoxia and the radiotherapy of cancer. The supporting evidence demonstrates that this compound has rapid uptake for hypoxic tissue for use as an imaging agent and is also effective in treating tumor burdens as a therapeutic agent.

Wolfgang A. Weber, M.D., Technische Universitat Munchen, phone: +49-89-4140-2961, fax: +49-89-4140-4950

Project Name:Pharmacology and Toxicology of F-19-Galacto-RGD

Summary: The integrin avß3 plays an important role in several diseases such as tumor cell metastasis, angiogenesis and inflammation. Galacto-RGD is a recently developed glycosylated cyclic pentapeptide (c(Arg-Gly-Asp-D-Phe-Lys(SAA)) with selective, high-affinity binding to avß3. Radiolabeled F-18-Galacto-RGD and positron emission tomography (PET) have been successfully used in animal models to image avß3 expression in xenotransplanted tumors as well as in chronic inflammatory processes.

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