Global Health Nexus, Winter 2003

Clinical Research: The Time Is Now

by Dominick P. DePaola, D.D.S., Ph.D., President and CEO, The Forsyth Institute.

The spectacular scientific and technological advances of the past two decades offer dental medicine an unprecedented opportunity to transform clinical practice and revolutionize our profession. The challenge is to transfer these new research findings to the public domain through new diagnostics, new modes of prevention, novel therapeutics, and a generation of over-the-counter products that I predict will dramatically impact public health and well-being.

Whereas most of us are familiar with the concept of the clinical trial in which a new therapy is tested, the broader term “clinical research” also encompasses studies that occur earlier in the chain of drug/product development and that are a necessary prelude to actual human testing. For example, studies that draw correlations between the presence of a certain mediator in a human disease and its progression, e.g., elevated levels of prostaglandins (PG) in gingival crevicular fluid in periodontitis, set the groundwork for testing PG synthetase inhibitors to slow the progress of the disease. This is translational research; it goes hand in hand with clinical correlation and often involves “proof of principle” studies in an animal model of a human disease. Therapies that pass these tests move on to Phase I FDA studies, in which the safety of the drug/product is verified in a small population. Phase II studies involve a determination of efficacy, again in small populations. Phase III is the full-scale clinical trial, in which both safety and efficacy are again assessed in a much larger study group.

Why now? Many of us can recall a similar emphasis on translational and clinical research in the early 1970s. It was presumed that the basic knowledge to bring about dramatic cures, in cancer, stroke, heart disease, and even oral diseases, had already been developed, and that the missing link was translation into clinical practice. In retrospect, of course, this presumption was naive. The basic knowledge of genes, molecules, and molecular mechanisms and the sophisticated technologies of modern biology were still decades away from realization.

The difference today is that, with the completion of the Human Genome Project, we now have at hand all of the essential information about the human organism. Certainly there is much work still to be done in terms of deciphering and integrating all of the genomic and proteomic data, and in determining how it all fits together. However, correlations with other animal genome projects, particularly the mouse, will allow scientists to efficiently test the role of individual genes in determining normal and abnormal development, healing and tissue repair, susceptibility to disease, and even longevity.

Why the urgency? Consider that the 2000 Surgeon General’s Report on Oral Health was a clarion call to address the silent epidemic of oral disease. Consider that dental diseases remain the nation’s number one unmet health need, that too many children go to bed with pain from oral conditions, that they miss school and experience low self-esteem as a consequence of oral disease, that one person dies every hour from oral cancer and that control of oral infections has the potential to reduce the risk of systemic diseases such as cardiovascular disease, stroke, pulmonary disease, low birth weight, premature birth, diabetes, and a host of others. Consider that disfiguring clefts of the lip and palate are among the most prevalent human birth defects.

It is estimated that it takes approximately 20 years for a finding to proceed from the bench to the bedside, or for a new technology to go from concept to market. Dentistry, like medicine, is a conservative profession, predicated on the Hippocratic admonition to “do no harm.” Yet the landscape has changed and the vast benefits of aggressively translating science into practice now outweigh traditional caution. Over the past decade, the American public has strongly supported basic science research, most recently through a doubling of the budget of the National Institutes of Health. Payback time is now.

Translating science into applications that benefit society will require forging unique partnerships among the private sector, federal government, health professions schools, scientists, clinicians, and the consumer. It will also require the acquisition and investment of sufficient resources to enable the conduct of multiple clinical research studies and trials in a manner consistent with today’s needs and tomorrow’s challenges. Unfortunately, there has been only modest emphasis on clinical research for decades, largely based on the assumption that translation into practice was premature. However, if we continue to approach clinical research non-aggressively and without appropriate partnerships and resources, we will not only be missing great opportunities, but indeed will be negligent in our collective responsibility to alleviate human suffering. As Einstein said: Concern for man himself . . . must always form the chief interest of all technical endeavors.

The opportunities are truly unbelievable. Let me provide some examples for your consideration. One that hits home is that the scientific community is close to developing a vaccine for dental caries! Think about this for a second, a 
vaccine that can largely prevent the most prevalent infectious disease of mankind. Consider the effects of this vaccine on underserved populations in the United States and on children in third world countries who never see a dentist! Reducing dental caries worldwide is within the realm of possibility using the oldest public health strategy known, and now only awaits confirmation of efficacy in large-scale clinical trials.

As it stands now, the dental practitioner is still treating caries and periodontal disease using a “surgical approach” rather than with pharmacotherapeutics. Existing antibiotics have shown great promise in reducing infections with oral pathogens in many studies, yet use in routine practice is still lagging. The pharmaceutical and biotechnology industries are poised to work with the scientific and practitioner communities to develop new-generation antibiotics and novel therapeutics targeted toward oral pathogens. Moreover, new targets for therapeutics have been identified from the sequencing and annotation of the genomes of oral pathogens, like Porphyromonas gingivalis, a major causative agent of periodontal disease. We need clinical studies to confirm the efficiency and safety of non-surgical treatments for caries and periodontal diseases. How will these types of therapy affect access to care issues, the public health, and the practice of dentistry?

With the discovery of relationships between periodontal infections and systemic diseases, we need multiple, clinical intervention studies to confirm these relationships and to establish whether they are causal or not. But just consider the ramifications to the health of the public and to the integration of dental medicine into the medical community if we confirm that preventing or treating a periodontal infection will reduce the risk of cardiac disease. Of stroke. Of giving birth prematurely. These data will position dentists as crucial players in overall health care delivery—as true primary care health professionals.

We are also moving closer to the time when diseased teeth and bones will not be replaced by artificial means such as implants, but can be regenerated using the principles of stem cell research and bioengineering. The impact on clinical practice of regenerating teeth and bones would be truly revolutionary. Moreover, scientists are working on the engineering platform(s) that will allow multiple salivary analytes to be measured precisely and simultaneously, like today’s standardized blood test, enabling saliva to be used like blood and other body fluids—only better because of the non-invasive nature of collecting it. Salivary antibodies can be measured to detect oral bacterial infections, diagnose viral hepatitis, monitor the progression of Sjogren’s Syndrome and drug and alcohol abuse, determine response to therapy in breast cancer, and even assess the progression of Alzheimer’s disease. With full appreciation of what this will mean to the public’s health, Dr. Larry Taback and many other insightful scientists are encouraging clinical research in this area.

Interestingly, both the caries vaccine and the tooth regeneration studies conducted at Forsyth, as well as at other institutions, have been widely reported in the print and broadcast media, and have captured the imagination and attention of the scientific community, the lay public, the private sector, and political decision makers worldwide. Accordingly, all signs point to the timeliness, the need, and the feasibility of forging a true National Agenda for Dental, Oral and Craniofacial Clinical Research. The goal would be to identify those clinical research questions that have the most promise for success, secure sources of funding for those projects, reevaluate the educational requirements for dental and health care professionals to practice in this new environment, and build the necessary coalitions to advance the Agenda and create the political and consumer momentum necessary to transfer the science today . . . not later, but now!