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The Challenge of Translational Research at the NIDCR: Remarks by Lawrence A. Tabak, D.D.S., Ph.D.

The Challenge of Translational Research at the NIDCR: Environmental scan, NIDCR Challenges, The Translational "Highway" - Roadblocks and Solutions...

Well, good morning. It's really a great pleasure to start this conference off. What I propose to do this morning is to review with you an environmental scan, some of the challenges faced by NIDCR, and then talk about the metaphorical translational highway—not dwelling on the roadblocks, but perhaps suggesting some solutions.

So, in terms of the environmental scan, I think you all appreciate the landscape that we all face together

Evolving Public Health Challenges: Acute to Chronic Conditions, Aging Population, Health Disparities, Emerging Diseases, Biodefense

—one where the disease burden that we now face has shifted from acute diseases and conditions to those of chronicity. The "boomers" are turning 60—that's a very scary thought—I'll just leave it at that. Clearly, despite all of the extraordinary advances made in biomedical science, there still remain real health disparities. You cannot get through the day without hearing about something about some new, or emerging, or re-emerging disease. Particularly when it comes to this area of the country, issues of biodefense certainly weigh heavily. So, taken collectively, we need to put into context anything that we need to accomplish within these overarching challenges.

Need To Transform Medicine in the 21st Century

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Now, I think you will all agree that 20th century medicine was predicated on treating the disease when symptoms appeared or when normal function was lost, and in part this related to the fact that we did not understand the molecular and cellular events that underlie many diseases and conditions. The net result, of course, is tremendous expense both in terms of treatment and disability. If the system is not to collapse on itself in the 21st century, we need to intervene well before the symptoms even appear, thereby preserving normal function for as long as possible. And to do this, clearly we need to understand the preclinical molecular events, and detect patients at risk. Presumably that will provide a much more effective, fiscal solution for us.

Multi- and interdisciplinary research teams, will be required to solve the “puzzle” of complex diseases and conditions: Genes, Behavior, Diet/Nutrition, Infectious agents, Environment, Society

Eleni has already alluded to multi- and interdisciplinary research, and many of us feel that it is multi- and interdisciplinary research teams that will be required to solve what has been termed the puzzle of complex diseases and conditions. And by complex diseases, of course, we mean those diseases and conditions that result from an interplay between and among things such as genes and behavior, diet and nutrition, infectious agents, environment and society, and who knows what else. So, this is very, very complicated. Often when I use this slide, no one will ever ask it in the public session, but somebody will come up afterwards and say, "But what does this have to do with Dentistry?" Indeed, what I would argue is that virtually every disease that we deal with in dental, oral, and craniofacial health falls under this rubric.

Multi- and interdisciplinary research teams, will be required to solve the “puzzle” of complex diseases and conditions. Cartoon: One scientist tells another, 'I'm on the verge of a major breakthrough. But I'm also at the point where chemistry leaves off an dphysics begins, so I'll have to drop the whole thing.'

For those of you in the back who cannot read the caption, the cartoon reads: "I'm on the verge of a major breakthrough. But I'm also at the point where chemistry leaves off and physics begins. So, I'll have to drop the whole thing." At least this is the way I was brought up in science, too many years ago. We have to prevent that from ever happening again, and that's what this emphasis on multidisciplinary research teams is all about.

Research Teams of the Future: Interdisciplinary Research Teams made up of Physicians, Mathematicians, Psychologists, Physicists, Nurses, Economists, Engineers, Dentists, Sociologists

So, if you look at research teams of the future that will be required to do these types of interdisciplinary research, no doubt they will be composed of sociologists, engineers, physicists, mathematicians, economists, nurses, and dentists as well. It's going to be our collective challenge to figure out how to get all these folks to interact. The initial major barrier, of course, is that if you put all of these folks in a room together, it would be like a Tower of Babel. There would be a lot of talking, but no one would understand one other. So, a great deal of what we need to emphasize early on is some common platform, some common lexicon whereby these folks from these different fields are able to communicate effectively with one another.

Now let me shift a little bit more provincially to some specific NIDCR challenges. The first one is that we need to convince physicians and lay people that without oral health you are not healthy.

NIDCR Challenges: Convincing physicians and laypersons that without oral health you are not healthy

Somewhere along the way, this became dismembered from the rest of the body. "Oh, it's just a tooth" or "It's just a little ulcer in the mouth", or… you can fill in the detail. Clearly, this is part of the body, yet we have a hard time convincing both physicians and lay persons of that point.

NIDCR Challenges: Convincing physicians and laypersons that without oral health you are not healthy. Changing oral health care from a prevention/surgical model to one of prevention/biotherapeutics.

Secondly, we need to change oral health care from the prevention-surgical model that is captured in this horrible cartoon, to one of prevention via therapeutics. So, we've got the prevention part right, and indeed, in many ways, are ahead of where our colleagues are in medicine. But, this transformation needs to begin. We surely have the opportunity, and it is conferences like this that can help catalyze this to a reality.

Some of you know I am trained as an endodontist, so I can put this up. This comes from Newsweek. We need to keep strong in order to keep Dentistry part of Medicine, and away from Cosmetology. Again, conferences like this will help that. Because a great deal of what the public demands, in terms of tooth brightening and breath freshening and all sorts of other "stuff," relates more to Cosmetology than it does to Medicine.

NIDCR Challenges: (A quote from Oral Health in America: A Report of the Surgeon General) "…Oral health is essential to the general health and well-being of all Americans and can be achieved. However, not all Americans are able to take that message to heart."

Our biggest challenge was articulated in the Surgeon General's Report on the Oral Health of America in 2000. It was acknowledged that oral health is essential to general health and well being, and that this can be achieved. But the message that is often forgotten from this report is that not all Americans are able to take that message to heart.

Here's the problem… when you look at this beautiful child, first of all, you cannot help smiling back at her. That's your first instinct. The second thing is… this is who you know. This is your neighbor, this is your child, this is your niece. Because your concept of oral health is the perfect smile, the beautiful child. But sadly, that is not the case for many Americans. Indeed, for many Americans

The Impact of Oral Diseases: Oral, dental and craniofacial diseases aren’t just dental problems: they affect our ability to eat, communicate and thrive in society.

this is the reality. I show this picture, just to drive home the point, to those who perhaps are on the fringe of our field. This is not just about teeth, and indeed, all dental and craniofacial diseases aren't just dental problems. They affect our ability to eat, communicate, and indeed thrive in society. How well do you think this child is going to do in school this morning? She was up all night in pain. She will be tired and cranky. She is not going to be responsive to the teacher. She will be embarrassed to be in school. She's going to be shunned by her classmates. There is much more at stake here than tooth brightening and fresh breath.

The “Research Highway” (Photo of a highway)

So, now I want to turn to the "research highway"—this metaphor that we all use when we discuss translational opportunity. It is always depicted as this straight road, where everything is just great, you can drive at the speed limit with no problems. But we all know in this room, that there are a number of challenges.

Navigating the Translational Highway: Central Challenges

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Indeed, Sung and colleagues, in JAMA a few years ago articulated a number of central challenges: cost, fragmented infrastructure, the need for public participation, a variety of regulatory requirements, workforce training, and the need for dissemination and transfer of knowledge to practice. I would just like to go through these quickly to give you sense of some of these issues.

Let's begin with cost because that drives so very much of what we are speaking about.

Dental Services as a Percentage of Total U.S. Health Care Expenditures, 2004: 30% Hospital Care, 21% Physician Services, 11% Prescription Drugs, 6% Nursing Home Care, 4% Dental Services, 28% Other

So in '04, dental services constituted about 4 percent of health care expenditures in the US. I guess you could look at this as being a half-full or a half-empty glass. From my viewpoint, since that translates to 78 billion dollars, that is a significant sum of money, which is only going up each year. So that was in Fiscal Year '04.

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Now let's look at the public investment in research. If I accomplish only one thing this morning, if I can get you all to acknowledge that the resources spent for NIH are an investment, and not a cost, then I will have succeeded. If you look at the public investment per person in the United States, the large institutes such as the NCI or NIAID are investing between $15 and $16 dollars per person in the US. At the smaller institutes (such as NIDCR) the investment is about $1.10. So, all totaled (if you do the math) this translates into less than $100 per American per year. That's what the public investment is in your health. And the latest figures suggest that industry is spending about twice that, bringing us to about $300 per person when you put it all together. That's what we have to work with. So, knowing that, we need to be as absolutely efficient as possible in translating things as they become available, so that they become tangibles that impact people's health and people's lives.

So how do we maximize the return on this investment? Horig and colleagues redefined goals and guidelines from product development and they outlined the following:

Redefining goals and guidelines for product development

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First, that the goal of translational research is productive testing and validation of new therapeutic modalities or diagnostic and prognostic markers. Earlier I pointed out to you that most of the diseases and conditions that we now deal with have become chronic in nature and so the standard clinical endpoints for chronic diseases such as survival, or disease-free survival, or symptom-free intervals can take decades to assess. And so this underscores, when you take them together, the need to identify surrogate biomarkers that can predict outcomes of new therapies.

So let's talk a little bit about surrogate biomarkers.

The need to identify surrogate biomarkers to predict the outcome of new interventions. A picture of a pipe and mass spec numeric data are displayed with the caption: This is not a biomarker A number of years ago, Goldstein and Brown presented this cartoon which has stuck in my mind for many years. On the top is a painting in 1929 entitled, "This is not a pipe." Of course it's not a pipe--it's a picture of a pipe. And just beneath it is some DNA sequence. And the caption below reads, "This is not a drug," to underscore that just because you've decoded the human genome doesn't mean that by definition you'll now have all these new interventions to take advantage of. Well, to update this a little bit, many of you may not be familiar with this, but this is what a mass spec looks like. This is the raw data that comes out of a mass spec. And this is not a biomarker. There's a lot more to a biomarker than just identifying some protein by de novo sequencing using LCMSMS.

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And so adapted from Zolg and Langen are the phases that one needs to traverse in order to identify, develop, and then ultimately verify biomarkers as commercial products. So while the initial phases are ones that we take a lot of time and care to work through, we spend less time on validating the marker, and then of course, commercializing it. It is these interfaces that we will pay particular attention to during this conference.

Of course, the infrastructure is fragmented--you all know this.

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This horrible traffic signal--which is real, that's not made up--underscores the fragmented infrastructure. In part it relates to things like incompatible databases, it relates to non-availability of GMP facilities--there's a whole litany of things that one could point to.

Standard Model: (An arrow starts and ends in this sequence) - Laboratory Research, Translational Research, Clinical Research, Population Research, and Public Health

This is the standard model that everybody uses. Laboratory research is translated into clinical research which becomes population research which becomes public health research. And it really is intellectually pleasing to see this flow.

Standard Model - Reconsidered: Laboratory Research and Translational Research (are along the horizontal line and then the line disseminates from) Clinical Research (to) Population Research (and to) Public Health But, of course, you all appreciate that it looks more like this. The concept I borrowed from my colleague, Claude Lenfant, who published a very interesting essay back in 2003 where he made the point that the proximal part of this standard model is incredibly fragmented and incredibly challenging and indeed, as you try and go from clinical research to population research, and from population research to disseminate to get practitioners to engage in the new practice, that‘s really where the major challenge is.

Now ultimately you would like it to work like this.

The Way it Should Work: Laboratory Research, Patient-oriented Clinical Research, Population-based Clinical Research, and Clinical Trials

Eleni commented that for the past few years we've been emphasizing Phase III trials. A number of my basic science colleagues, privately and not so privately, have wondered have I lost my mind. I may have--but not related to inciting people to do Phase III clinical trials, because it's a push - pull. The way it should work is laboratory research begets all of this. But a trial that provides insight into some novel therapeutic will feed back into and give many opportunities for laboratory research.

Engaging the Public in Clinical Research: Engaging the public is not an option; it is a priority
Public participation: So we want to do all this clinical research, but it clearly has to be a priority. It's not an option. We have to get people involved. While this is a fairly diverse audience, we have to make sure that the participants look more like society as a whole. There is already some suggestion of differences in interventions that are appropriate for one group of individuals versus another group. We need to have all of society participate.

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Regulatory Requirements: I can bring you all to tears if I say things like "HIPAA" and things of this nature. I also acknowledge that there are some conflicting practices amongst governmental agencies, although the agencies involved are hard at work in trying to reconcile those differences.

Workforce Training: This is something that is particularly acute to our field. For years if you had a professional degree--if you had a dental degree--you were acknowledged to be qualified to do state-of-the art clinical research. "After all, I'm a dentist. I know how to do clinical research. Those are my patients we're going to be doing the research on. Who knows better than I do?" Those days are done. Clinical research has become a discipline unto itself. It has become a sophisticated scientific pursuit. It is not for the fainthearted. Convincing our traditional community of that fact has consumed the energies of a lot of people in this room. But I'm very pleased to say that the community is now beginning to engage in that and is beginning to work towards this.

So let's just say a few things about translational research training and clinical research training. How do we best do this? So this cartoon, which is from many, many years ago, says, "Herr Professor pointing out all of his independent co-workers." And if you think about the way universities operate, and in large part still operate, this is still true. In order for us to break out of this model we have to figure out ways to incite all team members so that they are co-equals as opposed to this sort of extreme view.

We appreciate that clinical research training has been haphazard, but we acknowledge that this new academic discipline is emerging.

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Very recently the Director of NIH, Dr. Zerhouni, published in the New England Journal of Medicine, the Sounding Board on "Translational and Clinical Science--Time for a New Vision," where he describes the so-called CTSA program, which I know you will be hearing more about during this conference. One of the features of this is that it will advance the assemblage of institutional academic homes where you have the properly integrated resource set that one needs to perform clinical research.

NIDCR Initiatives: Institutional NRSA's to support clinical research training, Career development awards (K08, 24, 25) in clinical research, Curriculum development awards,and Loan repayment

It's through strategies such as this--and there are many, many others, and I won't belabor and list them all--but it is through these types of approaches that NIH is trying to do its part in working through these roadblocks.

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The last one here that I've listed--and this is particularly crucial for our field--is that we have to consider the entire career pathway to reduce the barriers, but most importantly, enhance retention of researchers. Just last week I had occasion to speak with folks from ADEA, AADR and ADA, and we all agreed that at no time in history has the brain drain been more acute. Faculty members at schools of dentistry are leaving to go into private practice. Private practice in dentistry now is so lucrative that faculty members are just saying, "I have to do what's best for me and my family," and so forth. This has never happened before. It's very rare in history. Yet we need to take that into account. And so at the distal end we're trying to encourage young oral clinicians to get involved in the academic/research pipeline. When they see their faculty members leaving academia to go into private practice this is a real dilemma and one that we have to come to grips with. So there are all sorts of initiatives that we are using. We now have Institutional National Research Service Awards to support clinical research training specifically. In the past we lumped these together and the concern was that by lumping them together in a complete menu of opportunity, that the clinical research was given short shrift. So now we have these separate programs. We have a series of career development awards (and I won't go through this alphabet soup; just grab some of our staff and they can tell you what it all means), curriculum development awards where additional adjunctive novel approaches can be worked through, and then the Loan Repayment Program which is NIH-wide, and of course, NIDCR participates.

Dissemination and transfer of knowledge to practice. The four stages are: (1) adoption of advance by providers, patients and the public; (2) reimbursement to enable adoption; (3) data collection to support outcomes research; and (4) intervention refinement as needed

The last point is dissemination--the transfer of knowledge to practice. This is crucially important and the steps in this need to be considered. First, you have to adopt the advance. Providers, patients and the public have to be willing to adopt the advance. You have to figure out ways of reimbursement so that you can execute the adoption. Then you have to collect data to support the outcomes research that helps you then refine the intervention as required.

"To us knowledge, how good and lovely soever it be for its own sake, must always be a by-end, a step merely towards the still better and lovelier goal of good-will towards men" - Thomas King Chambers, 1850

So I'll conclude with a quote from Thomas King Chambers which actually was in the article by Claude Lenfant that I alluded to earlier. "To us, knowledge, how good and lovely soever it be for its own sake, must always be a by-end, a step merely towards the still better and lovelier goal of 'good-will towards men'." In other words, everything that everybody in this room is doing has ultimately got to be for the good will of everybody - men and women. And so, absent that, we are just creating some more tooth whiteners, we are just creating some more breath fresheners, but we're really not getting to the real problem.

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