Rituximab utilization for approved and off‐label nononcology indications and patients’ experiences with the Patient Alert Card

Abstract This study used retrospective chart review and survey data to evaluate: (1) off‐label use of rituximab (MabThera®/Rituxan®) in autoimmune conditions and (2) patients’ receipt and knowledge of the Patient Alert Card (PAC), a risk minimization measure for progressive multifocal leukoencephalopathy (PML) and serious infections. Anonymized patient data were collected from infusion centers in Europe from December 2015 to July 2017. Adults receiving rituximab in the same centers were provided a self‐administered survey. Outcomes included patterns of off‐label rituximab use for nononcology indications, and evaluation of patients’ receipt and knowledge of the PAC and its impact. Of 1012 patients in the retrospective chart review, 70.2% received rituximab for rheumatoid arthritis or granulomatosis with polyangiitis/microscopic polyangiitis, and 29.8% received rituximab off label. Among 524 survey participants, 32.8% reported receiving the PAC, 59.3% reported not receiving the PAC and 7.9% did not know whether they received the PAC. A total of 72.4% of patients reported that they were unaware that some patients receiving rituximab experience PML. A higher proportion of PAC recipients identified PML as a potential risk of rituximab than nonrecipients (37.8% vs 19.9%); 58.3% of PAC recipients had poor awareness of PML. Most PAC recipients (90.0%) and nonrecipients (85.5%) correctly answered that they should seek medical attention for infection symptoms. In conclusion, approximately 30% of patients received off‐label rituximab. Most patients reported not receiving the PAC or having knowledge of PML but demonstrated understanding of the recommended action in the event of infection symptoms, regardless of PAC receipt.

Furthermore, the objective of the PAC is to ensure that patients seek medical attention early and that HCPs are aware of the need for timely and appropriate measures to diagnose PML. The rationale is that, with a timely diagnosis of PML or infection, treatment with rituximab could be discontinued and reductions or discontinuation of concomitant immunosuppressive therapy considered. Reconstitution of the immune system in immunocompromised patients with PML has resulted in stabilization or improved outcome. 10 Whether early detection of PML and suspension of rituximab therapy may lead to similar stabilization or improved outcome is unknown. 2,11 The aims of this study were: (1) to quantify and characterize off-label use of rituximab by evaluating the medical records of patients treated with rituximab for nononcology conditions, and (2) to use survey data to assess the extent to which patients receive and read the PAC, their knowledge of the PAC content, and whether distribution of the PAC might influence patient actions. The study index date, 19 June 2015, corresponded to the date the first invitation letter was sent to infusion centers. Medical records data F I G U R E 1 Study Design. † Data abstraction of medical records spanning June 2014 to June 2015 ("look-back period") from a period of 12 months prior to index date were retrospectively reviewed and abstracted ( Figure 1). This "look-back period" from June 2014 to June 2015 was used to ensure that data collected were fully reflective of the real-world administration of rituximab and not influenced by study awareness. The observation period corresponded to the interval between the first and last infusion dates of rituximab, if treatment was discontinued before the index date. If the patient was still receiving rituximab at the index date, then the observation period was the interval between the first infusion date and the index date.

| Medical record data collection to determine off-label use
This study was conducted in accordance with all applicable ethical and regulatory requirements, including the Declaration of Helsinki. Approval from each relevant ethics committee was obtained prior to the study start in each country and documented in a letter to the center specifying the date on which the ethics committee granted approval. All patients provided informed consent for participation in the medical records data collection and/or survey.

| Safety
Individual adverse event (AE) information captured during the survey was reported to Roche as the Marketing Authorization Holder (MAH).

| Statistical analysis
Analyses of both rituximab off-label use (for indications other than RA or GPA/MPA; the pemphigus vulgaris indication was not approved at the time of this study) and the evaluation of patient receipt and knowledge of the PAC were descriptive in nature and included summary statistics and the frequency distribution of item responses. No statistical testing was performed; however, 95% CIs of the proportions of patients receiving rituximab for approved and off-label uses were calculated to assess precision of the prevalence estimates. Missing data were not imputed, and the data were analyzed and presented as recorded. Sjögren's syndrome

| Medical records data for off-label use
Eosinophilic granulomatosis with polyangiitis

| Limitations
Findings of this study largely pertain to the infusion centers involved in routine rheumatological practice that predominantly (≈80%) participated in this study; therefore, certain off-label conditions not primarily treated in routine rheumatology practice (eg, some dermatologic or ophthalmologic conditions) were unlikely to be captured in this study.
As is the case with all voluntary surveys, invited patients self-se- Finally, all analyses were descriptive, with no correlations noted or statistical significance tests performed; therefore, it is not possible to confirm an association between PAC receipt and a greater understanding of the risks of PML and other infections.
Results of this study demonstrated that in nononcology condi- The patient survey showed that most patients reported that they did not receive the PAC, and the results indicate slightly better knowledge scores among patients who reported that they received the PAC compared to those who reported that they did not receive the PAC. Although PAC recipients did not show greater knowledge of the risk or symptoms of PML, overall, patients demonstrated an understanding of the recommended action to take in the event of infection symptoms, regardless of PAC receipt.

E TH I C S S TATEM ENT
This study was conducted in accordance with all applicable ethical and regulatory requirements, including the Declaration of Helsinki. Approval from each relevant ethics committee was obtained prior to the study start in each country and documented in a letter to the center specifying the date on which the ethics committee granted approval. All patients provided informed consent for participation in the medical records data collection and/ or survey.

ACK N OWLED G EM ENTS
Support for third-party writing assistance for this manuscript, furnished by Nicola Gillespie, DVM, of Health Interactions, Inc, was provided by F. Hoffmann-La Roche Ltd. This study was funded by F.

D I SCLOS U R E S
The study sponsor, F. Hoffmann-La Roche Ltd, was involved in the study design, collection, analysis, and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication. K. Sarsour is an employee of Genentech, Inc.

DATA AVA I L A B I L I T Y S TAT E M E N T
Access to individual patient level data from the datasets used and/ or analyzed during the current study may be requested by qualified researchers through the clinical study data request platform (www.