Real-World Evidence to Contextualize Clinical Trial Results and Inform Regulatory Decisions: Tofacitinib Modified-Release Once-Daily vs Immediate-Release Twice-Daily for Rheumatoid Arthritis
Stanley B Cohen, Jeffrey D Greenberg, James Harnett, Ann Madsen, Timothy W Smith, David Gruben, Richard Zhang, Tatjana Lukic, John Woolcott, Kimberly J Dandreo, Heather J Litman, Taylor Blachley, Anne Lenihan, Connie Chen, Jose L Rivas, Maxime Dougados, Stanley B Cohen, Jeffrey D Greenberg, James Harnett, Ann Madsen, Timothy W Smith, David Gruben, Richard Zhang, Tatjana Lukic, John Woolcott, Kimberly J Dandreo, Heather J Litman, Taylor Blachley, Anne Lenihan, Connie Chen, Jose L Rivas, Maxime Dougados
Abstract
Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To provide additional clinical evidence in regulatory submissions for a modified-release (MR) once-daily (QD) tofacitinib formulation, we compared real-world adherence and effectiveness between patients initiating the MR QD formulation and patients initiating an immediate-release (IR) twice-daily (BID) formulation.
Methods: Two noninterventional cohort studies were conducted. First, adherence and two effectiveness proxies were compared between patients with RA who newly initiated tofacitinib MR 11 mg QD or IR 5 mg BID in the IBM® MarketScan® Commercial and Medicare Supplemental US insurance claims databases (March 2016-October 2018). Second, using data collected in the Corrona US RA Registry (February 2016-August 2019), two Clinical Disease Activity Index (CDAI)-based measures of effectiveness were compared between tofacitinib MR 11 mg QD and IR 5 mg BID, and against noninferiority criteria derived from placebo-controlled clinical trials of the tofacitinib IR formulation. Multiple sensitivity analyses of the registry data were conducted to reassure regulators of consistent results across different assumptions.
Results: In each study, approximately two-thirds of patients initiated the MR formulation. In the claims database study, improved adherence and at least comparable effectiveness were observed with tofacitinib MR vs IR over 12 months, particularly in patients without prior advanced therapy. In the registry study, the noninferiority of tofacitinib MR vs IR was demonstrated for both CDAI outcomes at ~6 months; this finding was robust across multiple sensitivity analyses.
Conclusion: These results demonstrate the value of real-world evidence from complementary data sources in understanding the impact of medication adherence with a QD formulation in clinical practice. These analyses were suitable for regulatory consideration as an important component of evidence for the comparability of tofacitinib MR 11 mg QD vs IR 5 mg BID in patients with RA.
Trial registration: Claims database study: ClinicalTrials.gov identifier NCT04018001, retrospectively registered July 12, 2019. Corrona US RA Registry study: ClinicalTrials.gov identifier NCT04267380, retrospectively registered February 12, 2020.
Keywords: Claims analysis; Clinical effectiveness; Drug approval process; Registry; Rheumatoid arthritis; Rheumatology; Tofacitinib.
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References
- Silverman B. A baker’s dozen of US FDA efficacy approvals using real world evidence. 2018. . Accessed 27 Feb 2020.
- Dreyer NA. Advancing a framework for regulatory use of real-world evidence: when real is reliable. Ther Innov Regul Sci. 2018;52:362–368. doi: 10.1177/2168479018763591.
- European Medicines Agency. Adaptive pathways. 2016. . Accessed 5 Feb 2020.
- European Medicines Agency. HMA–EMA Joint Big Data Taskforce—summary report. 2019. . Accessed 5 Feb 2020.
- Health Canada. Optimizing the use of real world evidence to inform regulatory decision-making. 2019. . Accessed 5 Feb 2020.
- Center for Drug Evaluation. Key considerations in using real-world evidence to support drug development (draft for public review). 2019. . Accessed 5 Feb 2020.
- Uyama Y. Proceedings: DIA 2018 global annual meeting. Utilizing real world data: a PMDA perspective. 2018. . Accessed 27 Mar 2020.
- US Food and Drug Administration. 21st Century Cures Act. 2016. . Accessed 17 Mar 2020.
- US Food and Drug Administration. Prescription Drug User Fee Act Reauthorization (PDUFA VI), Medical Device User Fee Act Reauthorization (MDUFA IV), Generic Drug User Fee Act Reauthorization (GDUFA II), and Biosimilar User Fee Act Reauthorization (BsUFA II). 2017. . Accessed 17 Mar 2020.
- US Food and Drug Administration. Use of real-world evidence to support regulatory decision-making for medical devices. 2018. . Accessed 17 Mar 2020.
- Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388:2023–2038. doi: 10.1016/S0140-6736(16)30173-8.
- Marengo MF, Suarez-Almazor ME. Improving treatment adherence in patients with rheumatoid arthritis: what are the options? Int J Clin Rheumtol. 2015;10:345–356. doi: 10.2217/ijr.15.39.
- European Medicines Agency. Tofacitinib (Xeljanz): summary of product characteristics. 2019. . Accessed 28 Feb 2020.
- US Food and Drug Administration. XELJANZ® (tofacitinib): highlights of prescribing information. 2019. . Accessed 8 Apr 2020.
- Taylor PC, Betteridge N, Brown TM, et al. Treatment mode preferences in rheumatoid arthritis: moving toward shared decision-making. Patient Prefer Adher. 2020;14:119–131. doi: 10.2147/PPA.S220714.
- Saini SD, Schoenfeld P, Kaulback K, Dubinsky MC. Effect of medication dosing frequency on adherence in chronic diseases. Am J Manag Care. 2009;15:e22–e33.
- van Heuckelum M, Mathijssen EG, Vervloet M, et al. Preferences of patients with rheumatoid arthritis regarding disease-modifying antirheumatic drugs: a discrete choice experiment. Patient Prefer Adher. 2019;13:1199–1211. doi: 10.2147/PPA.S204111.
- Cohen SB, Pope J, Haraoui B, et al. Methotrexate withdrawal in patients with rheumatoid arthritis who achieve low disease activity with tofacitinib modified-release 11 mg once daily plus methotrexate (ORAL Shift): a randomised, phase 3b/4, non-inferiority trial. Lancet Rheumatol. 2019;1:E23–E34. doi: 10.1016/S2665-9913(19)30005-0.
- Tanaka Y, Sugiyama N, Toyoizumi S, et al. Modified- versus immediate-release tofacitinib in Japanese rheumatoid arthritis patients: a randomized, phase III, non-inferiority study. Rheumatology (Oxford) 2019;58:70–79. doi: 10.1093/rheumatology/key250.
- Coleman CI, Limone B, Sobieraj DM, et al. Dosing frequency and medication adherence in chronic disease. J Manag Care Pharm. 2012;18:527–539. doi: 10.18553/jmcp.2012.18.7.527.
- Kremer JM. The Corrona US registry of rheumatic and autoimmune diseases. Clin Exp Rheumatol. 2016;34:S96–S99.
- Curtis JR, Baddley JW, Yang S, et al. Derivation and preliminary validation of an administrative claims-based algorithm for the effectiveness of medications for rheumatoid arthritis. Arthritis Res Ther. 2011;13:R155. doi: 10.1186/ar3471.
- Wolfe F. The epidemiology of drug treatment failure in rheumatoid arthritis. Baillieres Clin Rheumatol. 1995;9:619–632. doi: 10.1016/S0950-3579(05)80305-X.
- Harrell FE., Jr . Regression modeling strategies: with applications to linear models, logistic regression, and survival analysis. Springer Series in Statistics. New York: Springer Science + Business Media; 2001.
- Curtis JR, Yang S, Chen L, et al. Determining the minimally important difference in the clinical disease activity index for improvement and worsening in early rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 2015;67:1345–1353. doi: 10.1002/acr.22606.
- Kavanaugh A, Keystone E, Greenberg JD, et al. Benefit of biologics initiation in moderate versus severe rheumatoid arthritis: evidence from a United States registry. Rheumatology (Oxford) 2017;56:1095–1101. doi: 10.1093/rheumatology/kex042.
- Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45:613–619. doi: 10.1016/0895-4356(92)90133-8.
- Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43:1130–1139. doi: 10.1097/01.mlr.0000182534.19832.83.
- Ting G, Schneeweiss S, Scranton R, et al. Development of a health care utilisation data-based index for rheumatoid arthritis severity: a preliminary study. Arthritis Res Ther. 2008;10:R95. doi: 10.1186/ar2482.
- Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79:685–699.
- Murage MJ, Tongbram V, Feldman SR, et al. Medication adherence and persistence in patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis: a systematic literature review. Patient Prefer Adher. 2018;12:1483–1503. doi: 10.2147/PPA.S167508.
- Bonafede MMK, Curtis JR, McMorrow D, Mahajan P, Chen C-I. Treatment effectiveness and treatment patterns among rheumatoid arthritis patients after switching from a tumor necrosis factor inhibitor to another medication. Clinicoecon Outcomes Res. 2016;8:707–715. doi: 10.2147/CEOR.S115706.
- Sharma M, Nazareth I, Petersen I. Observational studies of treatment effectiveness: worthwhile or worthless? Clin Epidemiol. 2019;11:35–42. doi: 10.2147/CLEP.S178723.
- Bird P, Bensen W, El-Zorkany B, et al. Tofacitinib 5 mg twice daily in patients with rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs: a comprehensive review of phase 3 efficacy and safety. J Clin Rheumatol. 2019;25:115–126. doi: 10.1097/RHU.0000000000000786.
- Curtis JR, Schulze-Koops H, Takiya L, et al. Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis. Clin Exp Rheumatol. 2017;35:390–400.
- Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 2004;59:255–263. doi: 10.1093/gerona/59.3.M255.
- Widdifield J, Bernatsky S, Paterson JM, et al. Serious infections in a population-based cohort of 86,039 seniors with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2013;65:353–361. doi: 10.1002/acr.21812.
- Bathon JM, Fleischmann RM, van der Heijde D, et al. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. J Rheumatol. 2006;33:234–243.
- CORRONA. Corrona® RA Registry. 2019. . Accessed 12 Mar 2020.
- Curtis JR, Chen L, Bharat A, et al. Linkage of a de-identified United States rheumatoid arthritis registry with administrative data to facilitate comparative effectiveness research. Arthritis Care Res (Hoboken) 2014;66:1790–1798. doi: 10.1002/acr.22377.
- Curtis JR, Chen L, Greenberg JD, et al. The clinical status and economic savings associated with remission among patients with rheumatoid arthritis: leveraging linked registry and claims data for synergistic insights. Pharmacoepidemiol Drug Saf. 2017;26:310–319. doi: 10.1002/pds.4126.
Source: PubMed