Reflections from the OARSI 2022 clinical trials symposium: The pain of OA-Deconstruction of pain and patient-reported outcome measures for the benefit of patients and clinical trial design

Abstract

Objective: Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field.

Method: The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development.

Results: Signs or symptoms indicative of nociceptive pain occur in 50-70% of OA patients, neuropathic-like pain in 15-30% of patients, and nociplastic pain in 15-50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions.

Conclusions: The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials.

Keywords: Biomarkers; Clinical trial design; EMA; FDA.

Figure 1:

Variability of pain in individuals with different degrees of structural severity. The two figures illustrate identical datasets of baseline WOMAC pain as a mean +standard error of the mean (SEM) (Figure A), and the same data as a point scatter plot (Figure B). Based on data on file from the OA oral Calcitonin studies, N=2,206, NBCD A/S and Nordic Bioscience A/S)(5)

Figure 2:

Venn diagram of three types of pain and their overlap in OA. Nociceptive pain: Injury and inflammation. Neuropathic pain: Nerve lesion. Nociplastic pain: Central sensitization. These different pain types may show similar effect size on WOMAC but represent different pathologies that may need different treatments.

Figure 3:

hypothetical example of 4 potential study participants being considered for enrollment into a trial. The numerical values in the bars reflect the hypothetical relative proportion of mechanisms contributing to the individual’s pain experience

Figure 4:

Schematic illustration of disease activity versus disease status. A: Total disease activity may be independent of disease status. B: Targeting of intervention may need to consider periods of mechanism-based disease activity assessments that influence overall disease status rather than solely targeting based upon disease status without consideration of disease activity. Additionally, the treatment target should be matched to the specific mechanism contributing to the disease activity. Reproduced with permission from (1)

Figure 5:

Descriptive nomenclature Venn diagram. We illustrate how AT(N) biomarker grouping and cognitive status interact for classification of research participants in this Venn diagram. For simplicity, MCI and dementia are combined into a single (cognitively impaired) category and the A−T−(N)− groups are not shown. Also “Alzheimer’s and concomitant non-Alzheimer’s pathologic change” [A+T−(N)+] in cognitively impaired is not shown in this figure. Abbreviation: MCI, mild cognitive impairment. Reprinted with permission from (46).