OA Drug Development Workshop Technical Highlights
Co-hosted by the FDA and the Arthritis Foundation on June 22, 2021
By Maria Vassileva, Senior Vice President, Scientific Strategy
Session 1: The Current State of Osteoarthritis (OA) Research: challenges, patient perspectives and best approach for advancing future clinical research and drug development
In Session 1, the historical context for studying OA over the last several decades was discussed to cover the fact that in the 20th century, OA was considered to be a cartilage degeneration disease, while in the 21st century, our understanding has evolved to the point where OA is now considered a whole-joint disorder. Since OA is now understood to result from joint failure, multiple tissues are involved in the long disease progression, and that makes studying it complex. Therefore, we need better ways to assess clinical benefit from a potential treatment, especially in a disease which progresses over decades.
Currently there are very limited options for patients with OA — none of them are disease-modifying and most of them are not sufficient to address patients’ pain, which in turn affects other functions such as their ability to work, sleep and move. The purpose of this session of the workshop was to focus on best approaches for assessing functional improvements important to the patient, given the multi-factorial nature of the OA disease and the complex nature of pain.
There was an interesting proposal to consider testing pain per unit of activity, given that patients accommodate to their pain over time and OA is a disease that gradually progresses. It was discussed that the pain instruments, such as the WOMAC, are designed to track pain over the course of 16- to 24-week trials. They are not as suitable for utilization in two- to five-year clinical studies. Additionally, presenters emphasized the different types of pain that occur in OA. Therefore, more sophisticated assessments of pain are currently necessary in the context of OA. When activity is combined with pain level, then it becomes a more sensitive outcome than either of these taken in isolation. There has been recent evidence of the inverted relationship between pain and structural progression in OA from several different studies, and that continues to be a big problem. A conclusion was reached that to assess functional status in terms of change over time, we need better performance-based outcome measures for use in OA patients to be tracked long-term.
The field needs a unified core measurement of OA clinical severity. This measurement does not exist because of our current lack of understanding of the disease process and of the link between structure changes and pain. It has recently become more obvious that we might need to consider aiming at two targets at the same time to get over that hurdle.
Another current need is for one or more biomarkers that can early predict with high sensitivity future, long-term changes, and for it or them to be used in the FDA biomarker qualification process. This could eventually assist with shortening extremely long and expensive clinical trials, and lead to the approval of new agents for the treatment of OA. It is important to consider what we need to measure in the long term. It is also critical to consider innovative trial designs, such as pragmatic trials, for the resolution of some of the challenges outlined above.
Session 2: OA Biomarkers
In this session, two academic researchers talked about imaging and biochemical biomarkers. First, data on imaging biomarkers for different kinds of outcomes, including cartilage loss, pain and knee replacement, were presented. This presentation demonstrated some promise for imaging biomarkers, especially when utilizing machine learning algorithms on various datasets.
As for the biochemical biomarkers, both systemic blood and urine biochemical biomarkers were examined for their relationship and correlation to imaging and clinical data with cross-sectional and longitudinal outcomes. That analysis showed variable results, suggesting promise for urine CTX-2 and other novel biomarkers. Additional research will be needed now that the FNIH OA Biomarker study and others are complete.
In the third talk, there was a comparison of the utility of X-ray and MRI for OA measurements, and it was determined that X-ray results in variability and heterogeneity, plus it does not accurately portray the structure of the joint. On the other hand, MRI presents morphologically more accurate information than X-ray and is therefore the preferred imaging measurement for OA.
At the moment, the available evidence for biomarkers is insufficient to understand the duration or the magnitude of the effect of a drug to the direct benefit an OA patient. In fact, current researchers do not believe we are even at the point of a predictive biomarker yet. We are still operating in the prognostic biomarker space where we are looking at the relationship of biomarkers at baseline with outcomes collected over time. For future biomarker qualification efforts, the context of use will be very important. The field would like to move toward qualifying a predictive biomarker, and eventually get to the holy grail of the surrogate endpoints. Endpoints allow us to determine benefit, and that is why they are so important.
Session 3: Assessment of OA Disease Progression and Long-Term Benefit
As we are re-thinking our concepts of OA, taking into consideration the whole joint and considering pain and function together with structure changes in a unified way becomes very important. During the workshop, two recent completed clinical trials were reviewed. The Phase 2 sprifermin trial in 2020 showed a decrease in progression of cartilage loss by MRI but did not demonstrate a correlation of that decrease with the pain improvement for the subjects long-term. The other trial discussed at the workshop was a large canakinumab (CANTOS) trial, which was designed to study cardiovascular outcomes. However, in the analysis, an interesting trend was observed: Patients with OA showed fewer total joint replacements in the canakinumab treatment arm than in the placebo arm. The results of this exploratory trial are both unexpected and exciting. The investigators used elevated hs-CRP level as an entry criterion, and since this requirement is not routine in osteoarthritis trials, it may have identified a subgroup of persons with osteoarthritis in whom inflammatory cytokines activate pathways that accelerate joint degeneration.
All the experts at the workshop were in agreement that performance-based pain assessments are needed. To pursue finding the right assessments for pain, and to work toward a unified approach toward the important factors for the OA disease, FDA performed several analyses on the NIH-funded Osteoarthritis Initiative (OAI) database in an attempt to develop a composite endpoint that appropriately captures long-term clinical benefit and decreases the potential sample size to encourage manufacturers to perform future clinical trials. They were looking at time to event, or a composite of need for knee replacement and progression to unbearable pain. While additional similar studies will be needed, this analytical work suggested that decrease in the sample size and trial duration might be possible for OA trials in the near future.
The Final Recap
While the FDA team is diligently working on refining their regulatory approach in the OA space for faster approval of future therapies for the disease, they are also engaging with patients and patient advocacy organizations like the Arthritis Foundation and listening to what is important to consider. The workshop that was held on June 22 made it clear that all the stakeholders are in agreement that the model of short trials with expectation to demonstrate symptomatic change is not going to work in the context of OA. Currently the approach is to look for a delay in disease progression and ability to improve cartilage regeneration while at the same time using a composite endpoint for assessing the treatment effect of new drugs. To decide on the right endpoints, criteria such as the effect size (both anticipated and observed for the product that is investigated), the product characteristics and its mechanism of action are going to be important and will be closely examined. At the same time, the academic and pharmaceutical communities are exploring new measurements to incorporate in future trials, such as functional unit of pain, activity-induced pain, actigraphy, hand-held ergonomics, brain MRI for the evaluation of pain, use of mobile devices for short-term and long-term clinically meaningful data collection that evaluates OA-affected joints.
The critical gap of knowledge and OA disease understanding is where target modifications will have to occur on tissue, cellular and molecular levels to switch the balance of cartilage degeneration and regeneration. That knowledge can lead academic researchers and drug developers to engineer products that eventually have a meaningful and lasting treatment effect for patients. Only then we will be able to decrease disability numbers caused by OA and ameliorate the medical and economic burden of this complex and pervasive disease. The Arthritis Foundation and FDA continue to encourage stakeholders from all sectors to keep having open discussion and collaborate to address these challenges for the benefit of OA patients. Having patients be involved in all these discussions remains more critical than ever. In addition, individual company development pipelines would hopefully begin to support long-term outcome studies for their own drugs and incorporate novel endpoints in them.
See the full workshop here.
FDA Workshop Summary
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