Larger sample sizes, longer duration needed for osteoarthritis drug trials
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Clinical trials for drugs intended to treat the underlying disease process of osteoarthritis will require larger sample sizes and longer durations than previously seen, according to findings published in Arthritis Care & Research.
“Currently available approved drugs treat only short-term symptoms of OA, primarily pain and function, and do not target the underlying causes or long-term progression of the disease,” Yura Kim, PhD, of the FDA, and colleagues wrote. “Therefore, there is an unmet need for drugs to alter the underlying disease process. One approach to development of such drugs discussed in the literature is to utilize an assessment of structural changes in the joint based on imaging as a primary endpoint (e.g., X-ray and/or MRI measures of cartilage thickness/catabolism/anabolism, pathological remodeling of subchondral bone, or synovial inflammation).”
“However, as noted in the recent FDA draft guidance, ‘the ability of treatment effects on common measures of structural progression to reliably predict treatment effects on direct measures of how patients function and feel, has not been established,’” they added. “An alternative, and more clinically relevant, approach ... is to utilize a long-term clinical endpoint, i.e., a direct measure of how patients function, feel, or survive, as the primary endpoint. However, there have been concerns that using such endpoints would not be feasible in a clinical trial to support drug approval.”
To propose clinical endpoints that could provide direct clinical benefit aimed at OA’s underlying pathophysiology, and to examine the feasibility of such endpoints, Kim and colleagues analyzed data from the Osteoarthritis Initiative (OAI). According to the researchers, this multi-center, longitudinal, observational cohort includes 4,796 individuals aged 45 to 79 years. Participants in the OAI primarily demonstrated knee OA, with follow-up of up to 9 years and assessments covering joints, surgical interventions, performance outcomes, and patient‐reported outcomes.
For their own study, Kim and colleagues reviewed this database to identify existing outcome measures that were of direct clinical benefit. They then examined the feasibility of performing trials using these prospective endpoints, estimating incidence rates and estimating the required sample sizes and study durations in time‐to‐event analyses.
In all, the researchers considered seven prospective clinical points, each defined as time to a specific event. These were time to total knee replacement, time to total knee replacement or a WOMAC disability score of at least 51, time to total knee replacement or a WOMAC pain score of at least 15, time to total knee replacement or a WOMAC disability score of at least 51 in two consecutive visits, time to total knee replacement or a WOMAC pain score of at least 15 in two consecutive visits, time to total knee replacement or a WOMAC disability score of at least 51 or a pain score of at least 15, and time to total knee replacement or a WOMAC disability score of at least 43 and a pain score of at least 13.
According to the researchers, a study using time to total knee replacement as an endpoint, with an average follow‐up time of 3 years, would require approximately 3,000 to 18,000 participants, depending on effect size. Alternatively, a composite endpoint — such as time to total knee replacement or severe pain or severely impaired functioning — would require a sample size of approximately 2,000 to 11,000 for a 3‐year study.
“Our estimates suggest that clinical studies for products intended to treat the underlying disease process of OA will require larger sample size and longer duration than historical OA clinical trials,” Kim and colleagues wrote. “Importantly, such OA studies will provide the evidence needed to confirm a direct long-term patient benefit and to ensure that the magnitude of benefit outweighs any risks of new OA interventions.”
“Based on our analyses, we propose the concept of using a composite endpoint (e.g., time to TKR or surpassing a threshold on WOMAC pain, time to TKR or surpassing a threshold on WOMAC disability, or time to TKR or surpassing a threshold on WOMAC pain AND/OR surpassing a threshold on WOMAC disability) to improve feasibility and clinical relevance,” they added. “This approach utilizes an endpoint based on direct measures of how a patient functions, feels, or survives. In addition, the incorporation of thresholds for pain and function in the endpoint improves feasibility by increasing the background incidence rate.”
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