A review of real-world studies assessing patient-reported outcome measures of patients with rheumatoid arthritis (RA) found that although clinical outcomes were similar, patients taking a biosimilar were found to have higher discontinuation rates, possibly as a result of the nocebo effect.
A review of real-world studies assessing patient-reported outcome measures of patients with rheumatoid arthritis (RA) found that although clinical outcome were similar, patients taking a biosimilar were found to have higher discontinuation rates, possibly as a result of the nocebo effect.
Patients with RA are one of the largest patient populations receiving the widest spectrum of available biologics, according to authors of a recent review article. Tumor necrosis factor (TNF) alpha inhibitor biologics are a first-line therapy for RA, and increasing uptake of anti-TNF biosimilars could improve access to quality of care of RA by allowing a greater number of patients to be treated earlier in the disease course.
However, the reviewers said, patient and physician preferences impact biosimilar uptake. Patients may have negative perceptions of biosimilars, driven by factors such as reluctance to change medications they are satisfied with, fear of new side effects, or the perception that lower-cost medications are lower in quality. These perceptions can lead to the nocebo effect, a worsening of symptoms resulting from a patient’s negative expectations.
The authors noted that patient-reported outcome measures (PROMs) are frequently reported as secondary outcomes in most clinical trials and are recognized as measures of treatment efficacy by the US FDA and European Medicines Agency. The authors provided an overview of PROMs in studies of anti-TNF biosimilars to gain insight into how the patient perspective affects treatment of RA.
Their review of 31 publications that used PROM as a secondary outcome measure found that PROMs were similar between reference product and biosimilar groups in randomized controlled trials (RCTs). Open-label and real-world studies “revealed high discontinuation rates of therapy, mainly for subjective worsening of disease activity or non-specific adverse events.”
Frequently used PROMs in studies of biologics in RA include physical function, patient global assessment (PtGA), health-related quality of life (HRQoL), and occasionally fatigue. The authors commented that other important measures, such as sleep and psychological well-being, were not assessed.
Results from RCTs “uniformly showed that mean change in PROMs scores is comparable between biosimilar and reference biologic treatment groups,” the authors wrote. For example, the mean change in Health Assessment Questionnaire Disability Index (HAQ-DI), assessed in five RCTs, was comparable between biosimilar and reference product groups. The PtGA, which was reported in 3 trials, had a score range of 0 to 100, and is a factor in remission criteria in RA.
In RCTs, the mean changes in PtGA in biosimilar groups were comparable -30.3 to -35.1 in biosimilar groups and -26.6 to -39.4 in originator groups. SF-36 questionnaires, which assessed HRQoL in three RCTs “did not demonstrate any differences” between the biosimilar and reference product groups, suggesting biosimilars improved health-related quality of life in patients with RA, the authors said.
Furthermore, in RCTs of switching from an originator to a biosimilar, PROMs were comparable. For example, in NOR-SWITCH, which found that switching from the infliximab reference product to biosimilar CT-P13 (Celltrion) was not inferior to staying on the reference product, there were “no significant differences” between groups in PROMs.
In contrast to RCTs, the reviewers found many cases of subjective disease worsening or higher rates of discontinuation of therapy in real-world studies, in which patients were aware of taking a biosimilar rather than an originator.
For example, in analyses of the Danish DANBIO registry, 3 months after switching from infliximab originator to CT-P13, disease activity “was essentially unchanged in most patients” with RA. However, CT-P13 retention rates were “slightly lower” compared to the reference product after 54 weeks.
Similarly, in the BIO-SWITCH study, among those who discontinued CT-P13 because of a perceived lack of efficacy, PROM scores worsened, but objective measures (swollen joint count and C-reactive protein) remained stable.
In patients who switched from the etanercept originator to biosimilar SB4 (Samsung Bioepis) in the DANBIO registry, disease activity measures were “not clinically different” pre- and post-switch. Nonetheless, a subgroup of patients taking SB4 switched back to the reference product, and the main reason given was lack of effect. However, “changes in disease activity at the etanercept restart were mainly subjective (PtGA) rather than objective (C-reactive protein and swollen joint counts were close to zero).”
In contrast, 2 studies did not find any difference in PROMs between the etanercept reference product and biosimilar SB4.
The authors cited a previous systematic review that found a median biosimilar discontinuation rate (for any reason) of 14.3% in observational studies compared to 6.95% in RCTs. Given the data they reviewed from RCTs were “positive,” with respect to PROMs, but real-world studies showed high rates of discontinuation of therapy mainly for subjective reasons, the authors proposed that the nocebo effect is “probably the best explanation” for these high rates of biosimilar’s discontinuation.
The nocebo effect may be driven by a reluctance to switch away from a medication the patient is satisfied with, insufficient communication from providers regarding biosimilars, a provider’s lack of confidence in biosimilars, or a perception that the biosimilar is a lower-quality medication.
The authors suggested shared decision-making between patients with RA and their clinicians could increase biosimilar uptake and improve patients’ perceptions of the effectiveness of their treatment. Shared decision making has been “associated with good disease response, increased biosimilars’ acceptance, and reducing the nocebo effect.”
Horta-Baas G. Patient-reported outcomes in rheumatoid arthritis: A key consideration for evaluating biosimilar uptake? Patient Relat Outcome Meas. 2022;13:79-95. doi:10.2147/PROM.S256715