Putting the Risk Back Into Research

Written by Al Staropoli

$5.3 billion program expands the
boundaries of research innovation.

“At the time, we applied for other federal monies and most people didn’t believe we could do this work and weren’t very supportive,” said Slamon, who was played by Harry Connick Jr. in the made-for-TV movie “Living Proof,” which chronicles the development of Herceptin.

“The first peer-reviewed federal money came from the Congressionally Directed Medical Research Program (CDMRP),” added Slamon, who initially received funding in 1994. These monies were instrumental in allowing him and colleagues to develop a tumor tissue bank so that they could study gene alterations in depth. Over time, they clarified and consolidated their knowledge on the HER2 gene alteration, which eventually led them to the development of Herceptin.

BEGINNINGS

The Congressionally Directed Medical Research Program began in the early 1990s, when patients with breast cancer petitioned Congress to increase the amount of research funding for the disease. Advocates were eventually successful and persuaded Congress to appropriate $210 million toward the disease.

Since then, the CDMRP has grown to fund research for more than a dozen illnesses, including autism, breast cancer, chronic myelogenous leukemia, osteoporosis, prostate cancer and amyotrophic lateral sclerosis (ALS). To date, the program has provided $5.3 billion through 8,000 awards for more than 6,000 scientists.

From the get-go, the program was different. It involved consumers beyond traditional advocacy roles and incorporated them into the grant review process. “While you’re sitting at the table reviewing grants, knowledgeable patients who might have metastatic breast cancer are also sitting with you,” said Slamon. “And they may ask, ‘This is elegant science, but how will that impact patients soon?’ This reminds us that it isn’t just about satisfying our intellectual curiosity.”

“We are very patient-centric,” said CDMRP Director Captain Melissa Kaime, M.D. “What make us different from other agencies is that we focus on high-risk, high-reward research while involving advocates from the very start.”

At the end of every year, the program needs to be accountable to consumers and Congress because monies are appropriated on a year-by-year basis, partially based on advocate suggestions.

HOW IT WORKS

Early on, the CDMRP reached out to the National Academy of Sciences to determine the best way to invest the funds appropriated by Congress. One of the academy’s recommendations was to establish a two-tier peer review process, which still stands today.

A scientific peer review panel reviews grants for scientific merit while a second panel of policymakers, consumer advocates and clinicians reviews the grants to provide a vision to guide the investment strategies and recommend a broad-based portfolio. Nearly 50,000 proposals have been reviewed for grants ranging from $50,000 to $60 million and lasting from one to five years.

CONSUMERS

The CDMRP currently involves consumer advocates (individuals or family members affected by the disease) as well as advocacy organizations such as the National Breast Cancer Coalition, American Cancer Society, Us TOO International, Ovarian Cancer National Alliance, the Children’s Tumor Foundation, Autism Speaks and others. The program is essentially a partnership among four key players: government, the military, the scientific community and the American public.

Consumers are important because they can reinforce the need for tangible results and provide a sense of urgency. They can be nominated by an advocacy organization through a simple two-page application. Prior to grant review, they are guided through the review process by a mentor, such as an experienced consumer reviewer. Consumers also help define research areas on a yearly basis and attend multidisciplinary meetings held by the CDMRP, such as the Breast Cancer Research Program’s Era of Hope meetings.

SYNERGISM AND VISION-SETTING

The Era of Hope meeting gathers experts worldwide to exchange ideas and explore new research paths. The idea is to create a synergistic environment.

“Every few years, in many of our programs, we invite all the investigators we funded to come back and report on what they’ve done with the research funds we gave them,” said Kaime. “The forum includes not only researchers, but part of the general public to whom they have to defend their work.”

Vanderbilt University researcher Todd Giorgio, Ph.D., who is funded by the CDMRP, has attended the meeting. “It is very motivating because cancer survivors are always invited,” said Giorgio. “What better way to motivate your research activities than to meet and interact with individuals who have suffered the disease?”

Vision-setting also involves consumers. On a yearly basis, CDMRP staff, researchers and consumers convene to review research goals. “This is a find-a-cure program,” said Kaime. “So every year when we do visionsetting we ask ourselves, ‘Where are the greatest research needs to find a cure?’”

In a sense, developments over the previous year, along with new research priorities, guide the development of funding mechanisms. In other words, if significant progress in basic research has been made, new mechanisms are developed to fund studies in animal models and eventually clinical trials. If a significant gap exists in trained scientists in a particular area, training grants are developed. Mechanisms are therefore partially based on the research needs of the community studying a disease.

Research Areas Currently Funded

MANY WAYS

CDMRP grants are unique in the broad scope they cover. Various types of awards exist, which allows substantial flexibility to scientists and can support them in various ways.

One such award, called a Concept award, funds the exploration of untested, high-risk questions. Researchers need submit only a one-page proposal, and, unlike many other awards, they do not require any preliminary data. The awards range from $75,000 to $150,000 and can last up to 18 months. “Concept awards allow us to open a novel investigation, such as, ‘Does this new approach have any validity to it?’” said Giorgio. “This is the kind of critical support that is difficult to find in many other funding organizations.”

With a Concept award, Giorgio developed preliminary data needed to secure funding from other organizations. His research focuses on manipulating the surface of nanoparticles to allow them to stick better, and more specifically, to a particular target such as cancer cells.

Once released into the body, these fluorescent nanoparticles could then bind to small precursor tumor, allowing early treatment. Toxic drugs could also be latched onto these tiny particles and delivered to cancer cells.

The CDMRP funds various types of research, including the development of drugs, devices, clinical or public health interventions, biological resources and biological molecules. Funding falls into four broad categories:

• Innovative Research
• Clinical Research
• Training
• Resources

INNOVATIVE RESEARCH

These awards forge creative environments to stimulate the exploration of ideas that could ultimately lead to a scientific breakthrough or an innovative disease treatment, such as Herceptin.

Innovator, Idea and Concept awards are some of the funding mechanisms that fall into this category. Like the Concept award, the Idea award does not require preliminary data and can provide up to $450,000 in funding for up to three years.

Slamon, who has been funded for over a decade, is funded today through an Innovator award that allows for significant research leeway. “It’s not a traditional grant,” said Slamon. “They ask for a general idea of what you’ll be working on and let you use the money as you see fit to make those objectives happen. You’re given the flexibility to move the money from one category to another as the research leads you, which is what really needs to happen much more commonly.”

Through the Innovator award, Slamon is further investigating HER2. “Herceptin has led great results for a large number of women, but about half the women who have the alteration don’t respond. We also know that when people do respond, they can develop progressive disease even though they are on the drug.” Slamon is using CDMRP funding to better understand these quandaries. He hopes that answering these questions could eventually lead to better therapeutic interventions.

CLINICAL RESEARCH

Clinical awards have been provided to conduct small pilot studies as well as international trials. The Clinical Trial award supports clinical research leading to a major impact in treatment, management or cure of a disease. It can last from three to five years and range from $335,000 to $2.5 million. Clinical awards are also available to support the transition from the lab to clinical research, and to help institutions collaborate on studying a disease. Nearly 150 clinical research awards have been granted thus far.

TRAINING AND RECRUITMENT

Moving forward in discovery can only be done through the dedication and commitment of researchers. Training and recruitment awards include support for career development, pre- and postdoctoral training, and clinical and physician scientist training. More than 2,200 training and recruitment awards have been made to date.

The New Investigator award, which falls into this category, supports independent principal investigators in the early stages of their careers through awards of up to $225,000 for two to three years.

Medical or other doctoral graduates can obtain the necessary experience to develop an independent research career through Postdoctoral Fellowship awards, which can provide $250,000 to $300,000 for two to three years.

Support is also available for physicians. The Physician Research Training award helps train and prepare physicians to conduct research. Funding allows them to secure at least 40 percent of their time to research.

RESEARCH RESOURCES

Research resources such as the funding of multidisciplinary consortia, pilots, infrastructure, technology development and coordinating centers are all supported through this funding mechanism. Awards range from $150,000 to $60 million and can last for one to five years.

AWARDS IN ACTION

The Psychological Health and Traumatic Brain Injury program and the Peer Reviewed Medical Research program described below are only two of more than a dozen research areas funded by the CDMRP.

PSYCHOLOGICAL HEALTH AND TRAUMATIC BRAIN INJURY

Veterans are sometimes exposed to lifeand- death situations that can lead to post-traumatic stress disorder (PTSD). It is estimated that nearly 20 percent of military personnel returning from Iraq has suffered from PTSD.

Through funding from CDMRP, a multidisciplinary consortium of 85 investigators is trying to understand the prevention and treatment of PTSD. A training program is currently being developed to teach health providers how to deliver short-term, efficacious and evidence-based treatments to individuals with PTSD. Research is also being undertaken to better understand the relationship between PTSD and depression.

Exploding bombs and projectile impacts can cause traumatic brain injury (TBI), which has been called by some the “signature injury of the Iraq War.” TBI can be extremely disabling and have a long-term negative impact on the individual’s quality of life. It affects in estimated 20 percent of wounded personnel.

A consortium of 10 clinical sites, coordinated by the University of California, San Diego, brings together more than 100 psychologists, psychiatrists, neurologists, trauma surgeons and rehabilitation specialists to better understand how to provide effective care to those suffering from PTSD and TBI.

Nearly $300 million was allocated to study these conditions in 2007 alone. Some of the discoveries could be translated to be used in the thousands of civilians who arrive to the emergency rooms as a result of head trauma.

PEER-REVIEWED MEDICAL RESEARCH PROGRAM

This program requests proposals every year on a broad range of research areas specified by Congress, including lupus, epilepsy and multiple sclerosis. In 2008 and 2009, a total of $50 million was appropriated for the program.

Since 2001 the Peer Reviewed Medical Research program has supported the development of preventive vaccines and new drugs for malaria. The disease causes large casualties for personnel deployed to tropical areas. Discoveries in this area could also impact the nearly 500 million civilians with malaria worldwide.

On another front, investigators at the University of California, Los Angeles, are developing a vaccine for tularemia— an infectious disease that can be turned into a biological weapon and cause highly fatal pneumonia.

Given its potential for weaponization, the development of a vaccine for tularemia is essential. Results of research conducted in the area show that 100 percent of vaccinated mice have survived a lethal infection of the bacterium that causes tularemia.

MOVING FORWARD

Kaime foresees future growth for the CDMRP. The forthcoming research areas are difficult to ascertain, as they are determined by advocates and Congress on a yearly basis.

The CDMRP’s unique model of intensive consumer involvement will likely help propel future innovative research, which could impact thousands of individuals. It seems that the approach has paid off, at least judging by the development of Herceptin.

For more information on funding and applications, please visit http://cdmrp. army.mil/funding. Consumer involvement information can be found at http://cdmrp.army.mil/cwg. ♦

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