E. Melissa Kaime, M.D., FACP; Captain, Medical Corps, USN, Director, CDMRP:

It's my pleasure today to talk to you about the Congressionally Directed Medical Research Programs and give you an overview of our program. The CDMRP has a unique research agenda that focuses on specific diseases and explicitly states a vision of eradicating these diseases. So it is very focused on patient needs. From its inception the CDMRP has included disease survivors and advocates in the funding decision processes. These individuals are the consumers of CDMRP. Their firsthand experiences with the disease adds perspective, passion, and a sense of urgency, ensuring that the human dimensions of disease are incorporated in program policy, investment strategy, and research focus. Serving as a consumer member on a review panel doesn't require an advanced scientific or medical degree. As we tell each of these consumers they may be intimidated by sitting shoulder to shoulder with Ph.D.s and M.D.s, but they've earned their own degree-they have their own set of credentials coming to the table. So this perspective helps the scientists understand the human side of how the research will impact the community and allows for funding recommendations that will reflect the concerns and needs of patients, the clinicians who treat them, their survivors, and their families. These consumers are very serious about increasing their own scientific knowledge and sharing what they learned during the review process with their community. This results in an increased awareness by patients and laypeople of the role of research in disease treatment. An informed public has a better understanding of the process by which lab research is translated into clinical trials and new treatments, and what to expect about the pace of this translation. By full participation in the peer review processes, these consumers are witness to the hard work and the integrity of the scientists submitting proposals-the hard work and decisions of the peer review panels resulting in funding the best research. As a corollary, scientists who can put a face on the disease frequently report that they are energized in the research approach. It is a CDMRP tradition to begin each of our meetings with a reminder of why we exist-to think about the people our funded research serves and our sincere wish that we could put ourselves out of business by eliminating diseases that we study. In that spirit, I want to start this session with a moment of silence to focus on friends, colleagues, and family members who have been taken from us far too soon by cancer as well as those living with the disease.

So let me just tell you a little bit more about who we are as the Congressionally Directed Medical Research Program. We live within the Department of Defense, as you can see by the uniform I'm wearing. Furthermore, we live within the Department of the Army; just by a set of circumstances my parent command lives within the U.S. Army Medical Research and Materiel Command. That's located at Fort Detrick, which is about 50 miles northwest of here. It's a large biomedical research command that has been focused on the needs of the warfighter for many, many decades. And so it was appropriate when Congress appropriated funds for the DoD to do biomedical research that it live within the medical research and materiel command of the U.S. Army and that's where we are for CDMRP.

So what do we do? We are the second largest funder for these various cancers-breast cancer, prostate cancer and ovarian cancer. Those are some of our largest cancer programs but we also have funding for these other cancer programs. So you can see those listed on the screen, I won't read them for you. Some of these belong in cancer programs or research programs that have a whole list of different topics within that program. And those topics may change from year to year. So it's important if you're looking for funding opportunities to check each of these programs each year because again the topic areas change. Let me just mention it's not we that decide the topic areas, its Congress that decides the topic areas. So many of you who have visited our booth here today say, "Well why don't you do cancer research in this particular kind of cancer?" We would be happy to; as an oncologist myself, I would love to do more research in all the various cancer that we face. But it's up to Congress to make those decisions. Unfortunately, I in uniform cannot tell Congress what they ought to do-but you as a public citizen can do that. So I urge you if you have a concern that more needs to be done in a particular area, use your voice as a citizen to influence Congress to do that.

So the history of the CDMRP is very important because it reiterates our focus of the consumer as being our true north, our foundation. It began in the early 90s when women with breast cancer marched on Congress and asked for more money for breast cancer research. Furthermore, they said we're not interested in the next logical step, the next step in science is important, but there's a large funding organization that already does that. We want to take that leapfrog advance. We want to take a chance, we want to take a risk and fund investigators that say, "I think this would work, I just don't have the preliminary data." Well that's exactly who we want to fund, we're willing to take a risk to hopefully propel the field forward. And so that's what forms the basis of how we approach science, we're willing to take that high-risk research. You can see that over the years we've added several other cancer programs over the years as you can see as I've listed there. And here it is just in graphical form for you since the early nineties when we began with breast cancer, there in kind of a fuchsia color ... that began in the early 90s with $210M. That's been our largest program each year and next behind that is prostate cancer that began in 1997. So these are all of our cancer research programs. CDMRP, in general, for all the programs we administer, cancer and non-cancer, it's about $500M a year.

Some of the hallmarks of CDMRP that make us a little different than other funding agencies are listed here. We fund diseases by specific disease category, so there's the breast cancer program, there's the prostate cancer program. We won't fund across lines, and this makes us different from say the NIH and NCI. They fund disease mechanisms, and that's fine, that's perfectly appropriate. But it would be hard for the NCI to answer what specifically did you spend on breast cancer when the disease mechanism crosses many different cancers. So just by the way our funds are appropriated, we can tell exactly how much we've spent on each of our diseases by disease.

Because Congress appropriates funds to us each and every year, we never know if we're going to get funding in the next year. And that increases a sense of urgency that we spend our money the very best way we can, not knowing if we'll have another opportunity to influence research. So knowing that we adapt our vision yearly, we bring together our Integration Panel, which is a team of senior scientists, clinicians, and consumer advocates to help us craft our vision for each year. What is the research gap, what is the need, what do we need to focus on this year? So it keeps us very flexible, very adaptable.

We follow a two-tier level of review recommended by the Institute of Medicine way back in the 1990s. Everybody takes that for granted now that you have a two-tier level of review, but that was actually a brand new concept back then and we adhere to that very carefully. As you can see we involve consumers in all of our processes at both levels, the scientific peer review as well as the second level, the programmatic review. And then we fund highly innovative research. That's our watchword.

Here's our program cycle just to tell you a little bit of how our process works. It's about a 2-year process. These funds are alive for 2 years. They have to be obligated within a 2-year timeframe. It takes about that long to really do this process right. We need time to get our panel together, to define that vision, and from that vision then we craft our program announcement-that's our solitation for proposals to tell the research committee exactly what we are looking for. Our program announcement is our covenant for the research world. It tells you what we want from you and what we expect from you and what you can expect from us as a funding agency. And so we will hear from several of our panelists here today, it's very important you read the program announcement-no two are alike and they may change from year to year. So you may be applying again for the same award mechanism-go back and read each line carefully. We really do mean what we say in each program announcement. Those are released-we have to get each investigator time to write that program announcement to get a good proposal. We receive those proposals. Many of our programs now review pre-proposals-so that's a very short maybe 3-page pre-proposal to tell us the essence of your research project. And then our Integration Panel or another panel then sorts through those and decides which ones to invite, and so we do that for several different reasons. If your research project isn't quite fitting in with the vision of that research program, we want to tell you earlier rather than later. It frees your time up to go seek funding in other places and also whittles down the number of very good proposals that we can take through the rest of the process. We invite those then that meet the intent of the award mechanism to submit a full proposal. That goes through a full scientific peer review. We need to give those peer reviewers time to read the proposals and to do a very robust summary statement-that's a document that gives you your strengths and weaknesses of each research proposal. That comes back to you so that if you can utilize that to strengthen your proposal next year if you didn't get funded. That scientific peer review is done in a very unique way different from other funding agencies. We don't have standing review panels. Who is on that panel is a confidential panel. We don't allow contact between applicants and the peer reviewers. We insist on a level playing field, and we rotate those panels by about 30% each year. Like I said, we don't want standing panels. If your whole watch word is innovation, you need to be willing to incorporate new ideas, fresh ideas, fresh eyes into the process. We want to avoid the group think that comes sometimes with standing review panels. We have to challenge ourselves each and every year to ask ourselves, is this innovative, is it new, is it meeting the mark? Likewise, then these summary statements provide detail on the strengths and weaknesses and then scores on the review criteria. The criteria that were published in the program announcement so you as an applicant will know how you are going to be scored and which particular area you are going to be graded on individually, and an overall score. We take all of that to the programmatic review. The programmatic review is our Integration Panel coming back now, completing the full circle. So the vision that they set out in the beginning of the year, now they come back and decide from proposal to proposal which one best meets the vision that they set forth in the beginning of the year. So that's a very comparative process. They don't have the full proposal, they have the statements from the scientific peer review so they have the essence of that full proposal there in those statements. And it's not just a pay line. If we were going to just do the pay line then we would choose the top-scoring proposals and we wouldn't need a second level of review. We ask for a second level of review because they are going to review not just the scores, not just because it is a great science project, but how well it filled the gaps. So they are going to look to do portfolio balance and so sometimes your high-scoring proposals will be in one concentrated area of the field. You want to spread across your investment strategy to all the gaps within that field, so that's their job. So just because you scored high doesn't mean you're necessarily going to get funded, unfortunately. We warn you of that in the program announcements, but that's still a hard thing to get when you get a high score and don't get funded, and it's for those reasons. So we don't have a funding pay line, so you understand that. The other thing you need to understand, is that different from other agencies, we obligate all our funds upfront, and so whatever your budget is you are guaranteed you will have that budget for whatever years of performance you have. Whether you are a 1-year period of performance or a 5-year period of performance, you're going to get your full budget amount. We will never come to you in your later years and say you know we're a little short of funds this year, you're not going to get your full funding-we will never say that. As long as you are successful and follow your statement of work and perform as you have set out to do, you will get your full funding. On the other side though, you don't get continuation funding no matter how successful you are in your research project, that you did everything you did and you did it superlatively and we have brand new research that's valuable to the field, it doesn't guarantee you continuation funding. You have to come back at the end of your period of performance and compete again. The large pool of scientists are in the same boat as you. You are successful now use that success but you have to come back and compete. We don't do continuation funding just because you have been successful.

Another thing that makes us different is we fund internationally. We fund research in 25 different countries, 442 awards. The philosophy there is that we are interested in the research, we are interested in finding a cure, we don't care what country it comes from. So we fund as far and away as, a couple of countries are Botswana and Guyana and everything in-between so all around the world you can see on our map. We like to be very transparent. We understand we are stewards of the citizen's money and so we try to be as transparent as possible. On our website you can see every single research proposal we have ever funded. You'll see the public abstract and technical abstract. You'll see any publications that are linked to that research on our web site. We've been doing that for years and years and years so it will tell you the award amount, who it's going to, etc. We also have sponsored conferences-these are investigative conferences for our large programs. So the Era of Hope for our breast cancer program, our Military Health Research Forum for all of our military relevant research programs, and the IMPaCT for the prostate cancer research program. So this is a meeting where investigators are required to come back and report out on their progress. Whether it was successful or not successful, they still need to report on what they did. Now we understand if we're funding high-risk research, by its very nature that there's a risk involved and that researcher may not be successful in getting where they wanted to get to and we understand that. And that's the whole point behind high-risk research and that's fine. We accept that, that research may not get where you want to get, but we still want to hear what did not work. Other investigators need to know that that didn't work, and we need to readjust and focus in another area, but that is still important information for the scientific community.

So each of our programs addresses critical issues in the research and the patient communities through different funding opportunities. That's why I say when you read your program announcement, realize it is different each and every year. Don't take it for granted that this award is the same old award. We try to refocus each and every year. We try to fill those gaps. I'm going to give you some examples on how we do that. In the breast cancer research program, in particular, our legacy kind-of program, our focus is on innovation so novel, outside-the-box ideas. That's the gap. So how do you get those really wild ideas that are going to propel the field forward. And so the solution is to fund opportunities that foster innovation. How do we do that? One way we do it is an award called the innovator award and we have had that for many, many years, and I'm going to tell you about one awardee and that's Dr. Stephen Johnston. Now the innovator award is a 5-year, 5 million dollar award it supports visionary individuals who have demonstrated creativity, innovative work, and leadership in the field. Now it may not be in the field of breast cancer research. In fact, we invite investigators from other fields to come network in the field of breast cancer. Stephen Johnston introduces himself as an innovator rather than by a particular field of research. His graduate training was in biogenetics and he saw a tool for genetic manipulation of plants and worked with an engineer to develop a gene gun that made it easy to transform animal and plant cells. So throughout his career, he has considered molecular interactions with fresh eyes-what he calls unfettered thinking, challenging paradigms, and transcription regulation pathogenesis and immunogenesis. For his innovator award, he proposes to develop a prophylactic breast cancer vaccine. He plans a concentrated effort to find all the breast tumor translocations and gene fusions that result in peptides. These neoantigens that collectively contain candidate antigens to cover about 90% of all known breast tumors, and then establish which neoantigens are neoreactive and then develop a vaccine. That's not easy. It's going to be a challenge, but I think he has a track record to overcome that challenge. So he is one of our innovative awards.

Another award that we put forth that we've had for many years in the breast cancer program as well as many of our other programs is the idea award. It's designed to promote new ideas that are still in the early stages of development and have the potential to yield highly impactful data and new avenues of investigation. An important aspect of this award is it does not require preliminary data. So there's not many other funding agencies where you can put forth an award for a fairly large sum of money that does not require any preliminary data. It needs solid scientific rationale, but if it makes sense it can be awarded.

So let me tell you about this investigator, Dr. Zohar has applying his knowledge of fluid mechanics and micro-mechanical systems to solve a problem in breast cancer research, and so we have for years and years devices that capture circulating tumor cells. But his approach is a little bit different in that it is the transformation of a distinguishing biochemical characteristic of the target cells, such as in this case, regulated cadherin phenol-type into a mechanical, electrical, or magnetic property that makes it possible to selectively manipulate the cells on a micro scale. So here you can see, this is his device, his micro device, and we see a mixture of 1 to 1 cells, cancer cells with and without overexpression of cadherin-11, and you can see that the green cells that overexpress cadherin-11 are being caught in the wafer and the other cells are not. Those are the reds cells floating on by.

So another area in which we address the impediments to progress is in the ovarian cancer research program, and the barrier here is that there is a very small research community within ovarian cancer. So how do you take this small research community that's spread all over the country and generate energy and synergy? And the way they did this was to facilitate researcher communication through an award called the ovarian cancer research program academy. This award takes a combination of paired scientists of junior faculty and their senior mentors from all different institutions around the country, and those pairs also team up with other pairs around the country under an academy dean. You can see the dean there in the middle and through many different collaborations-on-site collaborations, virtual collaborations-we're going to move the field forward. And they're going to focus on three important areas in ovarian cancer: the initiation of precursor lesion in ovarian cancer; molecular understanding of disease heterogeneity; and finally validating the biomarkers for diagnosis, molecular imaging, and therapeutic response. I don't think there is another award quite like this out there.

In the prostate field, many of you in the field understand the gaps here. And the gaps here are the fact that there are no cures for advanced disease, and I posted a slide there for you. So the 5-year survival rate since 1998 really has not changed much for those men diagnosed with stage 4 prostate cancer that are M1 distant bone-in disease. That green line there is pretty flat lined since 1998. So we need to improve our care for those patients diagnosed with advance disease. The other gap is a lack of informed decision-making for primary disease treatment. As we all understand, PSA screening is very common post, what do you do when you have an elevated PSA and your doctor does a biopsy and says don't worry you have indolent disease? How well can that patient appreciate that that truly is indolent disease and you don't need to do anything more? You don't need to take the step of surgery or radiation therapy that may have an effect on your quality of life. And so we need better tools to confirm the expected progression of disease. And so how do we do that? For FY10 all of our programs announcements have two focus areas, two overarching challenges: (1) develop effective treatments for advanced prostate cancer and (2) how to better distinguish lethal from indolent disease. So the whole entire program focuses on these two overarching questions.

So I think I have shown you that we, everybody can fund great research, and we take pride in doing that, but how do you change the face of research, the way researchers conduct themselves to change the face of research? I think the CDMRP has done that very well with our program announcements, and I'll end with that consumer statement on that slide for you. Thank you very much.