What are the barriers between the research laboratory and the clinical setting, and how can we get past them?
An aging population in the United States is increasing the demand for new, innovative treatments for orthopaedic ailments that most significantly affect function and activity later in life. Although research into new treatment modalities is active and ongoing, communication gaps exist between the research and clinical settings, which frequently present real barriers to clinical implementation of the most successful research innovations. The challenge faced by both the scientific and clinical communities is identifying these gaps and suggesting mechanisms to bridge them successfully.
Translational research is broadly defined as research that has a clearly defined goal for a clinical application. Transational research builds on the information gained through basic research, and should result in practical solutions that address particular clinical problems or unmet needs.
The endpoint of transational research is often a product, with some protectable intellectual property that ultimately leads to commercialization. It brings together two disciplines with a common goal: to develop and promote the treatments that have the highest potential for application in the clinical setting.
Combining two research disciplines presents certain difficulties, that may include variables such as the following:
- The gap between actual clinical need and development of new research areas
- Insufficient interaction between scientists and clinicians
- Safety and regulatory approval hurdles
- Ethical and moral questions concerning industry involvement
- Limited availability of funding
Evaluating currently available clinical solutions
Translational research is needed because some of the most promising advances in benchtop research are not being actualized in the clinical setting.
For example, current end-stage clinical solutions for osteoarthritis (OA) of the knee or hip include total joint arthroplasty, hemiarthroplasty, and resurfacing. Cutting edge clinical treatments for the early stages of OA include mosaicplasty, or the Osteo-chondral Autograft Transplant System (OATS). This treatment has received high praise for its effectiveness, but is challenging to execute and can result in complications over time.
Another cutting-edge approach involves harvesting the patient’s own cartilage cells, expanding them in culture, and reimplanting them under a periosteal flap to minimize cellular loss at the repair site. This technique’s effectiveness is limited, due to a narrow viable patient population, a significant time delay between cell harvest and re-implantation, and the need for two surgical procedures, which increases the possible morbidity to the patient.
Because current treatment strategies have shortcomings, we must ask from where the next generation of solutions will come. Finding the answer should, from its inception, be based on current clinical need, the latest fundamental research, the latest available technology, and its suitability/appropriateness in the clinical environment. Accomplishing these goals can only occur if researchers and clinicians collaborate.
Integrating clinical need into research designs
Translational solutions should be evaluated with respect to patient need and urgency, which may be categorized as short-term, intermediate-term, or long-term (Table 1). In the OA example, short-term solutions would focus on patients who require joint replacement surgery, but will not have to undergo revision surgery in the future. First, any persistent shortcomings should be identified. The design and development of better implants can begin with improved materials to reduce wear particles, or with the enhancement of existing operative procedures, or with newer methodologies for achieving lasting fixation. Collaboration between the clinician and the materials scientist could result in the modification of current materials to satisfy these criteria, while maintaining other aspects—such as durability after implantation—upon which the surgeon relies.
In the intermediate stage, the focus may shift to curing early stages of osteoarthritis through a better understanding of the biologic and mechanic factors influencing the repair and progression of the disease. The interdisciplinary dialogue between cell biologist and biochemist would be crucial in achieving this goal.
Long-term solutions might focus on the regeneration of an entire joint through the development of artificial bone and cartilage with cell-biomaterial matrices based on cutting-edge research. These solutions might include biodegradable polymer systems, stem cells, and growth factors, and would certainly involve the materials scientist, the cell biologist, and the biomedical engineer.
Regardless of the time frame, collaboration between the clinician and the researcher is at the core of each step of progress. Unfortunately, the number of independent laboratories focused on small niche questions may actually be a barrier to finding successful clinical applications. The establishment of larger collaborative centers could eliminate some of the barriers to translational research.
Even after an idea becomes a practical solution, numerous barriers to its clinical implementation remain. The most significant hurdle is gaining regulatory approval for use of the product.
Although the Food and Drug Administration’s (FDA) 510(k) mechanism may significantly shorten the approval process, it is predicated on the manufacturer’s ability to establish substantial equivalency to a previously approved product. Another important consideration is whether the material will be categorized as a device, a biological, a drug-delivery system or—as with many new orthobiologics under development—a combination product.
For instance, as the usefulness and availability of growth factors increases, integrating them with currently available implant materials is likely. Determining whether to treat such combination products as devices or biologics may influence the design and fabrication of such products.
Finally, the route to pre-market approval should be selected carefully. Traditional, modular, streamlined, and product development routes are available, depending on the product’s development stage when the FDA approval process is initiated. Early and frequent communication with the FDA is critical to navigating regulatory pathways.
Bioethics of research and clinical application
Ethical considerations emerge at the level of the researcher, regulatory offices, the manufacturer, and physicians as end-users of products. Rather than make ethical judgements in this article, however, we hope to raise some considerations that currently exist, or may become relevant as translational collaborations prosper.
The burden on the researcher is one of accuracy and complete disclosure of results. Comprehensive evaluation and full disclosure of results is critical at this phase to support the continued evaluation of the solution at hand. Collaboration between pharmaceutical/implant companies and researchers are potentially symbiotic relationships, but both must be willing to publish negative results, and researchers must have the freedom to present work even if it is to the detriment of the corporate entity. If the project moves on to the regulatory phase, those involved in the regulatory phase must be heard, both in favor of and dissenting from, ideal outcomes.
Furthermore, the balance between foreign and U.S. data and experience should be considered with the patient’s best interest as the focal point. Manufacturers must report material/implant failures as soon as possible, as well as any modifications made to manufacturing processes. Physician users must make every effort to avoid being placed in a potentially compromising position, particularly as a consultant receiving royalties or research funding.
Patient care and research should supercede corporate relationships. Workable situations require an added element of self-scrutiny to ensure the purity of the research and the prominence of patient care. None of these factors will be an issue if there is no financial support for such researcher-clinician pursuits.
Mechanisms to encourage collaboration
One critical barrier to fostering research relationships between clinicians and scientists/engineers is funding. Funding for biomedical research has plateaued and even dropped in recent years, so a smaller percentage of grant proposals are being funded by the National Institutes of Health (NIH). The NIH, however, realizing the impact of an aging population and increasing healthcare costs, has begun a bold initiative to fund translational projects. In the shift toward treating chronic rather than acute conditions, the clinician-researcher relationship is the focal point.
The NIH Roadmap (September 2003) outlined three areas of concentration for the coming decade: New Pathways to Discovery, Research Teams of the Future, and Re-engineering the Clinical Research Enterprise. At the center of these initiatives is the Clinical and Translational Science Award (CTSA).
According to NIH Director Elias A. Zerhouni, MD, CTSAs will “provide integrated intellectual and physical resources for the conduct of original clinical and translational science.” These awards will promote applicant-designed research centers backed by a strong institutional commitment. CTSAs and related programs are designed to hasten the time from scientific discovery to relevant clinical application and to provide the funding for such collaborations to move from conception to inception.
Zerhouni EA. Translational and clinical science—time for a new vision. N Engl J Med. 2005 Oct 13;353(15):1621-3.
Yusuf Khan, PhD, is an assistant professor of orthopaedic surgery and biomedical engineering at the University of Virginia. William M. Mihalko, MD, PhD, is an associate professor of orthopaedic surgery and mechanical and aerospace engineering at the University of Virginia and a member of the Biomedical Engineering Committee. He may be reached at email@example.com. Faculty from the AAOS Symposium “Benchtop to Bedside: Examining the Barriers Between the Research Laboratory and the Clinical Setting” contributing to this article include Cato T. Laurencin, MD,PhD (moderator); Khaled J. Saleh, MD; Joshua J. Jacobs, MD; Xudong (Joshua) Li, MD, PhD; Gary Balian, PhD; and Robert Sah, MD, ScD.