The path that any product takes from the birth of a concept to affirmation of its benefits can be a long, arduous — and often very expensive — road. Regulatory hurdles are just one of many speed bumps to market that can delay what may be a very beneficial product.
To help alleviate some of bottlenecks that slow the process of bringing promising contrast agents and molecular probes to clinical trials, the National Institutes of Health (NIH of Rockville, Md.) and the National Cancer Institute (NCI of Bethesda, Md.) have created a program called DCIDE — Development of Clinical Imaging Drugs and Enhancers.
DCIDE is designed as a bridge to help expedite and facilitate the development of medical imaging agents and probes and help transport them from the laboratory to a point where they are ready for an investigational new drug (IND) application.
The program is modeled after a recent NCI initiative known as RAID — Rapid Access to Intervention Development — which was created to help direct therapeutic drugs through the regulatory process.
The NCI saw the same delays — due in great part to a lack of knowledge about the regulatory process — surfacing with medical imaging contrast agents, where a significant number of promising products at various stages of development were not advancing into clinical trials.
“It became very clear to us that we needed somehow to assist, especially investigators, because academic investigators in particular are not terribly familiar with the drug development and approval process,” says DCIDE Director James L. Tatum, M.D. “They frequently don’t have the funding for some of the very sophisticated studies that are required by the FDA to get into a Phase One trial.”
For acceptance into the program, DCIDE will consider a range of medical imaging agents, including contrast agents, biologic and molecular probes, radiolabeled compounds and agents designed for image-targeted therapy. It is available to companies, as well as academic researchers. The program is managed by a group of non-NCI experts acting under the aegis of the NCI’s Board of Scientific Advisors.
Through DCIDE, imaging agent or probe developers can apply to the NCI for research assistance. The NCI, in turn, offers pre-clinical development resources to developers with concepts that the NIH and NCI believe have the most potential for market success and patient benefit.
According to the NCI, an emphasis on highly specific molecular targets and processes has produced agents and probes with increased complexity and higher costs of development. At the same time, the agents and probes have smaller market potential and individual investor companies consider some ventures too risky for commercial development, even if the products have the potential to influence diagnosis and treatment.
“If you talk to large drug companies about imaging agent development, one of the things they will tell you — along with the market being small — is if the market is less than $50 million, it probably isn’t worth doing at all,” Tatum says. “One-hundred million dollars may be more the cutoff point.”
Two-part process
Each year, the NCI has two rounds — six months each — of evaluation and assistance beginning in September and March.
The two-part process begins with a competitive evaluation by DCIDE’s panel of specialists — molecular biologists, chemists, radiochemists, pharmacists, and oncologists — from academia and industry and who are not associated with the NCI.
The first round of evaluation is based on five criteria: strength of scientific evidence and hypothesis; certification (biochemical or physiological validation); potential clinical impact; novelty; and feasibility.
The panel rates the imaging agents, probes and concepts, and those with the highest scores move to the second round of evaluation, where internal NCI staffers review requests for assistance.
The second round of review focuses on: resource availability; potential impact on current or proposed clinical trials by NCI; magnitude of pre-clinical studies required to address scientific/regulatory issues; and what the NCI calls “resource intensity,” such as costs and benefits. The NCI staff also aligns the applications with clinical trials, which may be compatible to the concept compound.
NCI also will contract for any missing steps — toxicity studies, for example — that may be required for submission of an IND application. The agency can arrange for pre-clinical developments tests to be conducted at private companies, academic laboratories, or government-owned, contractor-operated facilities.
The DCIDE program does not provide full-scale clinical development, but will help the performance of pre-clinical studies necessary to bring an imaging agent to IND status.
Property rights
The agent or probe developer has the right to patent any of his or her discoveries while participating in the DCIDE program. The NCI, however, adds that the originating laboratory collaborating scientifically with the NCI contractor also is entitled to be named co-inventor in any patent applications stemming from DCIDE-related activities.
The NIH or NCI retains no property rights to agents or probes developed through DCIDE. The NCI will hold an IND if it is helpful to the investigator and to help expedite clinical or research applications.
According to NCI, if a company licenses a compound while it is in active development in the DCIDE program, the company will assume what the agency describes as a “fair share of the costs required to complete the pre-clinical development and to meet all regulatory requirements for clinical trials.”
Agents or probes that have been developed with the assistance of the DCIDE program and subsequently included in the NCI Probe Library will be provided to outside investigators only after they agree to a non-exclusive license that would ensure the originator a co-inventorship position in any discoveries resulting from use of the agent/probe.
Agents that make it as far as successful development and testing will be maintained in the DCIDE library, which the program uses as a source that individuals may find beneficial for basic research, including in vivo animal model imaging studies.
Once a contrast agent receives IND status, its clinical development will continue along established mechanisms under the sponsorship of either private companies or NCI. Upon filing of the IND, agents will be included in a Translational Probe Library managed by NCI and available to other investigators by limited agreement.
The DCIDE library is one vehicle the NCI wants to use to provide information and validation on agents and probes that often are not easily available.
“There have been no good studies in many compounds to prove that what you are imaging — particularly in targeted cases — is what you think you are imaging and reporting back in quantitative fashion,” Tatum says.
While the DCIDE program does not sponsor clinical trials, the NIH provides funding in the form of research project grants, cooperative groups, and cooperative agreements for helping companies and researchers pay for funding clinical trials.
So far, so good
The NCI has finished two rounds of the DCIDE program so far and participation has been relatively small.
“We want more interest and more people coming forward,” Tatum says. “We don’t have a typical audience. Some people may be chemists working in a lab; there could be some imagers.
“The people we have talked to have an idea, but they don’t know where to go with it or don’t think it has an application,” he continues. “We want to receive a nice collection of potential compounds across a broad spectrum and we’d like to work on different ones at the same time.”
As for the six-month evaluation process, Tatum says it has been enough time to adequately determine the potential of images and probes that the agency has seen.
“One of the things we did in the first two rounds is try to encourage that products that are brought forward are a little more developed,” Tatum says. “As we move into this venture, people will bring things that are in the conceptual stages. That will be more difficult and the process will be longer. As long as our experts can say ‘This is pretty good data, this is feasible, it can be done in large production,’ here are the elements that need to be done and we can see that.”
Tatum says DCIDE currently is working on three compounds, which, he adds, are “very different.” The program is involved with toxicity studies with one compound, drug validation experiments on another and basic pharmacology work on a third potential product.
“We also are in the initial stages of a funded NCI Phase One and Phase Two trials for drugs that have come through the program or other drugs that have INDs,” he adds. “We will fund small Phase One studies and larger Phase Two studies to try to move these [drugs] further along past the IND process. The other option is that there are other existing trials in NCI that are looking for a specific agent that can be incorporated into a trial.”
Phase One and Phase Two will have a contract mechanism, which will allow clinical sites to submit requests for proposals (RFPs) and be engaged in these clinical trials.
Some of the more intriguing concepts to come before DCIDE, Tatum says, are in nano-, or micro-, engineered probes. From a regulatory perspective, the question becomes whether the nanoprobes are a device or a drug.
“I am sure both groups would say it is theirs,” he adds, “but that could be very interesting in the approval process.”
Ultrasound contrast imaging is one area that is getting attention from DCIDE applicants. Tatum opines that the modality has a fair amount of potential when combined with a contrast agent, but lacks healthcare provider support.
“I think we have undersold ultrasound for too long. It is a non-radiation producing and its power when you put it together with these nanodevices is quite interesting,” Tatum opines.
DCIDE’s next round begins in September and the NCI currently is taking applications for the next review. Applications and more information is available at http://www.nci.nih.gov/dip. 
