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Bone Diseases Clinical Trials Roundtable Summary
Wednesday, December 2, 2009
NIH Campus, Building 50, Room 1227/1233
Stephen I. Katz, M.D., Ph.D., NIAMS
Robert 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 identifying needs and opportunities, as well as finding 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.
Much of the discussion about current research needs focused on the question "Whom to treat, with what medication, and for how long?" The three issues are relevant to all diseases and conditions addressed by the NIAMS mission, and require a combination of basic, translational, and clinical studies. Better identification of people who lose bone rapidly will enable treatment to start earlier. However, researchers lack data proving that early interventions with existing therapies will help this patient population. Understanding whom to treat also requires better measures of fracture risk, as bone mineral density (BMD) is only one aspect of bone quality and fails to incorporate other risk factors such as falls.
Clinicians need data regarding how best to treat people who have conditions that may complicate their bone health and response to osteoporosis treatments. Subpopulations that could provide useful information include people with conditions affecting bone, such as those who
- Are obese.
- Have diabetes.
- Have chronic renal failure or low glomerular filtration rates.
- Have had bariatric surgery.
- Have celiac disease or other conditions that affect absorption of nutrients or medications.
- Are addicted to opiates.
- Are infected with HIV.
Healthcare providers need evidence regarding the clinical utility of bone turnover markers and imaging. They often decide to stop prescribing osteoporosis medications when markers show that a drug has suppressed bone turnover below a certain level; this "drug holiday" allows patients’ bone building and bone breakdown processes to recover, at which point, therapy is resumed. However, the community lacks definitive evidence that long-term repression of bone turnover is harmful, and that these breaks from treatment are beneficial. Clinicians also need to know how often they should have their patients get follow-up bone density scans and measure bone turnover markers after beginning an intervention.
Children who are at high fracture risk usually have low bone turnover, which makes bisphosphonates therapy undesirable. Bone-building medications, however, usually are not appropriate for children. Therefore, participants felt that the development and testing of drugs for pediatric patients were pressing clinical needs.
Discussants also addressed research on non-pharmacologic interventions. Development and implementation of cost-effective strategies to promote healthy bone formation during infancy and childhood are important. Exercise and nutrition also may prevent falls in the elderly, thereby playing a role in fracture prevention that extends beyond bone strength. In addition to resolving what levels of calcium and vitamin D are appropriate for bone health at different life stages, discussants were interested in understanding the optimal levels of other minerals and vitamins (e.g., B12 and vitamin C), and amino acids.
Future needs: obtaining input for important questions
As the NIAMS seeks input as to questions that will influence future patient care, it will continue to rely on critical peer review by a cross-section of the scientific community. The Institute will use all of its standard processes for soliciting and funding applications. However, it is looking to adopt a systematic strategy to scan the landscape for clinical questions that its researchers could address.
Participants discussed whether the bone research community would benefit from a NIAMS committee designated to discuss clinical trial opportunities, and provide input and advice to the NIAMS staff on the value and significance of both the concepts for trials, as well as specific proposed trials. The NIAMS will consider a variety of resources developed by professional societies and advocacy groups in regularly assessing the research needs and opportunities. Other options that participants discussed included
- Sessions at professional society meetings.
- Consensus conferences.
- Roundtable discussions with clinical investigators, clinicians, professional groups, and advocacy groups.
Existing datasets (e.g., registries, administrative databases, observational epidemiologic studies, and natural history studies) provide information that can guide researchers as they identify opportunities for high-impact clinical trials. However, researchers need to understand the limitations of publically available databases, such as the vitamin D measurements collected through the National Health and Nutrition Examination Survey (NHANES). Not all datasets are equal, and researchers should be cautious when combining them. Participants discussed the value of identifying subgroups of participants who influence the outcomes of trials, and the importance of mining data from placebo groups to identify untreated subsets of people who are at risk of fracture. They also addressed the value of conducting comparative effectiveness research through data analysis, either in conjunction with a prospective clinical study or by mining databases.
Observational study data can provide insights into medications’ unexpected benefits and risks. Researchers also can mine the data to
- Identify risk factors.
- Predict bone loss or target specific populations to make a trial more effective.
- Generate hypotheses regarding what keeps people healthy and how they differ from those who become frail and sick.
Some researchers suggested that observational studies would be more useful if they had better data about medications and dosages, including what the study participants were taking between visits.
The NIAMS needs a balanced clinical research portfolio of translational (i.e., first-in-human) studies, database analyses, observational studies, and randomized clinical trials. It is committed to ensuring that it funds high-quality clinical trials. Underpowered trials, and those that cannot recruit enough patients to answer meaningful research questions, must be avoided.
Participants suggested that the NIAMS adapt some of the strategies noted above to the priority-setting processes. The NIAMS could consider the potential to leverage its resources through collaborations with other Federal agencies (e.g., AHRQ, other NIH components) when determining which studies to fund. The Institute also should be aware of studies that pharmaceutical and biotechnology companies are supporting, as it should invest in answering questions that industry will not pursue.
The NIAMS will need to reflect on multiple outcomes as it evaluates the impact of clinical trials. Questions include:
- Does a study have the potential to change clinical practice, or patient behavior?
- Did the study achieve the stated goals, which peer-reviewers deemed meaningful? Some studies will not change clinical practice, because they were designed to set up next-level questions for subsequent studies or validate methodologies that move the research field.
- Have the media or professional societies broadcast the findings? Is there any evidence that the results changed behavior?
BARON, Roland, D.D.S., Ph.D.
Professor and Chair, Department of Oral Medicine, Infection and Immunity
Harvard School of Dental Medicine
BOUXSEIN, Mary, Ph.D.
Assistant Professor of Orthopedic Surgery, Harvard Medical School
Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center
CHEN, Faye, Ph.D.
Health Science Administrator, Division of Musculoskeletal Diseases
CURTIS, Jeffrey, M.D., M.P.H.
Director, University of Alabama at Birmingham Arthritis Clinical Intervention Program
University of Alabama at Birmingham
HANEY, Elizabeth, M.D.
Assistant Professor, Division of General Internal Medicine and Geriatrics
Oregon Health and Science University
KEHOE, Theresa, M.D.
Medical Officer, Center for Drug Evaluation and Research
Food and Drug Administration
KHOSLA, Sundeep, M.D.
Dr. Francis Chucker and Nathan Landow Research Professor, Departments of Medicine and Physiology
Mayo Clinic College of Medicine
KRONENBERG, Henry M., M.D.
Chief, Endocrine Unit, Massachusetts General Hospital
Professor of Medicine, Harvard Medical School
MOEN, Laura, Ph.D.
Director, Division of Extramural Research Activities
ROODMAN, G. David, M.D., Ph.D.
Professor of Medicine and Vice Chair for Research, University of Pittsburgh School of Medicine
Director, Center for Bone Biology, UPMC Health System
ROSEN, Clifford, M.D.
Director, Center of Clinical and Translational Research
Maine Medical Center
SELLMEYER, Deborah, M.D.
Medical Director, Metabolic Bone Center
Associate Professor of Endocrinology, Johns Hopkins Bayview Medical Center
SHANE, Elizabeth, M.D.
Professor of Medicine
SOLOMON, Daniel H., M.D., M.P.H.
Associate Professor of Medicine, Division of Rheumatology, Immunology and Allergy
Brigham and Women’s Hospital