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Orthopaedic and Osteoarthritis Clinical Trials Roundtable Summary
Monday, December 14, 2009
NIH Campus, Building 31, Room 6C10
Stephen I. Katz, M.D., Ph.D., NIAMS
Robert H. Carter, M.D., NIAMS
Joan McGowan, Ph.D., NIAMS
This roundtable was convened as part of a larger NIAMS effort to assess its support of clinical trials across the Institute’s mission areas. Goals include defining needs and opportunities, as well as identifying key steps for evaluating trials and the significance of individual studies in the broader context of future clinical needs. There were prior discussions on the subject at the 2009 NIAMS Scientific Retreat and with the NIAMS Advisory Council. A Council subcommittee is being created for further developments. Roundtable attendees canvassed their relevant communities in advance, to bring more than their own opinions to the meeting.
Although osteoarthritis (OA) is one of the most prevalent musculoskeletal conditions, and threatens to affect more individuals as the population ages, many mechanistic aspects of disease etiology are not understood. Clinicians do not have disease-modifying treatments to offer their patients. Moreover, they do not understand why some injuries lead to post-traumatic OA. Current research aimed at identifying OA biomarkers is likely to help researchers and healthcare providers determine who might develop post-traumatic or degenerative OA. The ability to identify and target people who are at high-risk of OA would lay a foundation for primary prevention efforts to reduce the burden OA places on the public’s health.
Research needs related to secondary and tertiary prevention strategies include understanding how OA progresses and the role of inflammation in OA, and testing non-pharmacologic interventions to reduce pain and disability (such as exercise, behavioral, or mind-body strategies). Knowledge of how the addition of lean body mass reduces OA risk, for example, could lead to the discovery of drugs to halt OA progression.
Because most total joint replacement procedures for end-stage OA are elective surgeries, orthopaedics is particularly well-suited for studies that examine factors influencing patient preference. Emergency surgery for severe trauma also provides a laboratory for studies to improve patients’ capacity to adjust to disabilities. Although researchers have documented variation in how surgeons interact with patients from different ethnic groups, discussants noted that more could be learned about how communication influences decision making and, ultimately, health outcomes.
Pediatric orthopaedic surgeons face many clinical situations for which the research base is weak. Some participants suggested trials that would help them treat children who have spinal deformities, rheumatoid arthritis, or avascular necrosis. The need for research into various childhood injury prevention strategies also was mentioned. Surgeons treating children who have diaphyseal fractures (fractures to the long bones in the arms or legs) would like evidence that could help identify which children should have surgery and determine what type of procedure is most appropriate.
Most people who have musculoskeletal back pain receive treatment from their primary care physicians. Therefore, discussants emphasized the importance of including these healthcare providers when designing and conducting studies. Research questions that community practices and academic medical centers could collaborate on include:
- What predicts the transition from acute to chronic back pain?
- At what point does a degenerating disc require treatment?
- Are advanced imaging procedures (e.g., MRI) necessary to inform treatment decisions?
- Which patients benefit from injections/physical therapy/opiates/cognitive behavioral therapy?
- Who needs surgery?
Participants raised similar questions in the context of pain associated with carpal tunnel and ulnar nerve entrapments, and knee, shoulder, and elbow tendinopathies. At present, clinicians do not have a way of reversing age-associated joint and tendon degeneration. Discussants noted that, although rotator cuff tears become increasingly prevalent as people age, they were not aware of any research evaluating combinations of aggressive operative and non-operative regimens for partial rotator cuff tears.
Baby boomers need to maintain their bone health and prevent osteoporotic fractures. Potential studies to address this public health challenge include interdisciplinary research that incorporates strategies to promote wellness, activities to improve or maintain balance and proprioception, and aerobic and anaerobic exercises. Likewise, the health concerns of older Americans and their desire to maintain an active lifestyle provide orthopaedic researchers with the opportunity to partner with other disciplines as they design fitness and pain management studies.
Throughout the day, participants noted the importance of incorporating biopsychosocial research questions into clinical trials. They discussed the value of international partnerships, and expressed a need for infrastructure that would help with the logistics of establishing international study sites. Results from research into orthopaedic trauma care in developing nations are likely to have implications for U.S. military personnel in remote areas abroad, and for accident victims in sparsely populated regions of the United States.
Future needs: obtaining input for important questions
The NIAMS is developing a strategy to collect important research questions, and identify the most qualified groups of scientists who can answer them, while continuing to encourage investigator-initiated proposals. Participants offered several suggestions regarding how the NIAMS could formalize such a process. Options include engaging a professional survey company or partnering with professional societies that can poll their members on behalf of the NIAMS. The professional societies and specialty groups routinely identify dozens of research needs as they prepare evidence-based guidelines and technology overviews. Reports from the Agency for Healthcare Research and Quality (AHRQ), the Institute of Medicine (IOM), and other entities also list questions and opportunities that NIAMS-funded investigators could explore.
Participants noted that academic researchers need more encouragement to move preclinical findings into clinical settings. While some supported the general concept of bringing scientists together to brainstorm about potential new clinical research areas—either as a standing committee or through other, ad hoc, efforts—they urged the NIAMS to remain open to investigator-initiated proposals for small, relatively inexpensive studies that address clinical issues.
In addition to the strategies noted for collecting input regarding “future needs,” the NIAMS and interested investigators could examine data from registries, case-control studies, and natural history cohorts for research questions that are ready for clinical trials. Scientists also should use information available from such resources when they formulate their research proposals. They might, for example, combine observational study data and sophisticated computer algorithms to determine how many people should be enrolled, and what characteristics these participants should have, as they design their study. They also could look at completed clinical trials for subpopulations that have different responses to an intervention.
The NIAMS must consider a study’s timeliness when assessing whether its results are likely to influence clinical practice. The best opportunity for a clinical trial might be when an intervention is relatively new, or is beginning to be used “off-label.” One discussant noted that research studies, although expensive, cost considerably less than the adoption of unproven practices.
Once a clinical need is identified, its corresponding research opportunity may be a study other than a randomized clinical trial. Participants urged the NIAMS to consider alternative study designs. They discussed the advantages and appropriateness of Bayesian and other adaptive statistical techniques, cluster randomization, and recruitment strategies that rely on self-enrollment of patients and the public through Web-based social networks. Despite limitations, studies that recruit participants through social networks and collect outcomes through insurance claims are likely to become increasingly popular with participants and healthcare providers.
The ability to enroll and retain patients is essential to the success of any clinical trial. When trials take longer than expected, or ultimately fail to answer the major questions, the problems often stem from difficulty in recruiting subjects. Investigators with history of running successful clinical trials were thought to have an advantage over less experienced researchers; however, the Institute’s new policy of requiring planning grants before funding a full clinical trial should allow all applicants to demonstrate their abilities to design and manage clinical trials before launching a full-scale project. Some discussants viewed the initial award as a low-risk investment during which a researcher could develop a procedure handbook, submit an investigational new drug (IND) application, select a data coordinating center, or establish a research team. Planning grants might not be needed in all situations, particularly for experienced groups of clinical investigators. The smooth transition between the planning grant and the full study must be addressed.
Clinical researchers are challenged to write exciting applications that engage the enthusiasm of peer reviewers. Participants discussed whether every clinical trial should include a mechanistic component, noting that the community perceives reviewers to be most interested in fundamental research questions. They noted the value of leveraging investments in clinical trials by funding ancillary studies that address disease or treatment mechanisms.
Investigators, professional societies, and advocacy organizations can work together to form research teams that are qualified to select and address high-priority topics. Although some discussants wanted the NIAMS to focus on prevalent, costly conditions (such as those recently identified by the IOM as priorities for comparative effectiveness research), the NIAMS will not neglect the rare diseases within its mission.
Many factors other than scientific evidence influence whether healthcare providers, patients, or the public change their behaviors. Discussants emphasized the importance of expanding efficacy studies to address questions of effectiveness in community practices. They reasoned that opening studies to local physician groups would allow more clinicians to participate in a study and, because they contributed, accept its results. Professional and specialty societies also can reach community physicians through practice improvement efforts. Some suggested that specialized journals, such as the Journal of Bone and Joint Surgery, may be more effective than higher-profile, more general, journals at reaching clinicians in a certain practice niche.
Many clinical trials continue to produce practice-changing results after they have finished following the patients. Participants cited examples of proven interventions (e.g., secondary prevention activities such as prescribing blood pressure medication to people who have had a heart attack; primary prevention efforts such as smoking cessation) that were known for decades before they were adopted. Periodically, the NIAMS could do post-hoc analyses of its research portfolio to determine whether well-designed trials changed clinical practice, and what factors influenced whether people accepted the findings.
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BHANDARI, Mohit, M.D.
Canada Research Chair in Musculoskeletal Trauma and Surgical Outcomes
Department of Surgery
BRODERICK, Joan E., Ph.D.
Associate Professor of Research Psychiatry
Department of Psychiatry and Behavioral Sciences
State University of New York at Stony Brook
BUCH, Barbara D., M.D.
Deputy Director, Division of Surgical, Orthopedic, and Restorative Devices
U.S. Food and Drug Administration
BUCKWALTER, Joseph, M.D., M.S.
Professor, Head and Steindler Chair
Department of Orthopaedics and Rehabilitation
University of Iowa
IBRAHIM, Said A., M.D., M.P.H.
Chief, Section of Health Care Disparities and International Health
Department of Medicine
VA Pittsburgh Healthcare System
KATZ, Jeffrey N., M.D., M.S.
Associate Professor of Medicine and Orthopedic Surgery
Brigham and Women’s Hospital
LESTER, Gayle, Ph.D.
Director, Osteoarthritis Initiative and Diagnostic Imaging Program
Division of Musculoskeletal Diseases
MCALINDON, Timothy, M.D., M.P.H.
Chief, Rheumatology Department of Medicine
Tufts Medical Center
MESSIER, Stephen P., Ph.D.
Director, J.B. Snow Biomechanics Laboratory
Department of Health and Exercise Science
Wake Forest University
MIRZA, Sohail, M.D., Ph.D.
Vice Chair, Department of Orthopaedics
Dartmouth-Hitchcock Medical Center
MOEN, Laura, Ph.D.
Director, Division of Extramural Research Activities
O’KEEFE, Regis J., M.D., Ph.D.
Chair, Department of Orthopaedics and Rehabilitation
Director, Center for Musculoskeletal Research
University of Rochester Medical Center
OUELLETTE, Elizabeth Anne, M.D., M.B.A.
Director, Miami International Hand Surgical Services
Jackson Memorial Hospital
PANAGIS, James S., M.D., M.P.H.
Director, Orthopaedics Program
Division of Musculoskeletal Diseases
SERRATE-SZTEIN, Susana, M.D.
Director, Division of Skin and Rheumatic Diseases
SPINDLER, Kurt, M.D.
Professor, Department of Orthopaedics and Rehabilitation
Director, Vanderbilt Sports Medicine Center
Vanderbilt University Medical Center
TYREE, Bernadette, Ph.D.
Director, Cartilage and Connective Tissue Program
Division of Musculoskeletal Diseases
WANG, Fei, Ph.D.
Director, Musculoskeletal Development, Tissue Engineering, and Regenerative Medicine Program
Division of Musculoskeletal Diseases
WEBER, Kristy L., M.D.
Professor, Departments of Orthopaedic Surgery and Oncology
Chief, Division of Orthopaedic Oncology
Johns Hopkins School of Medicine
WRIGHT, James G., M.D., M.P.H.
Surgeon-in-Chief and Chief of Peri-Operative Services
The Hospital for Sick Children