title: Use of a risk characterisation approach to contextualise the safety profile of new rheumatoid arthritis treatments: a case study using tofacitinib.
abstract: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient-years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs' accrual within pooled phase (P)1, P2 and P3, as well as long-term extension, studies of tofacitinib in RA (March 2015 data-cut) and published AE incidence rates for bDMARDs. Sample size calculations were based on a Poisson distribution to estimate pt-yrs' exposure required for 90 % probability that the lower bound of the 95 % confidence interval for tofacitinib/bDMARD would be >1, assuming that tofacitinib rates were 1.2×/1.5×/2.0× greater than comparator rates. AE rates for bDMARDs were derived from sources intended to optimise similarity with the tofacitinib database in terms of baseline characteristics, study duration and follow-up. Based on the tofacitinib exposure accrued (19,406 pt-yrs), data were sufficient (90 % probability) to detect potential differences over external bDMARD comparator rates in serious infections (≥1.2×), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and lymphoma (each ≥1.5×), as well as opportunistic infections and gastrointestinal perforations (≥2×), should they exist. This risk characterisation approach can support the comparative safety of new RA medications. To date, tofacitinib safety appears similar to approved published data from bDMARDs with respect to serious infections, malignancies (excluding NMSC), NMSC, MACE, lymphoma, opportunistic infections and gastrointestinal perforations.
authors.affiliation: The University of Alabama at Birmingham, 1720 2nd Ave S, Birmingham, AL, 35233, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Curtis
authors.affiliation: Pfizer Inc, 235 East 42nd Street, New York, NY, 10017, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Pfizer Inc, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
authors.affiliation: Pfizer Inc, 235 East 42nd Street, New York, NY, 10017, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Anisfeld
authors.affiliation: Pfizer Inc, 500 Arcola Rd, Collegeville, PA, 19426, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Pfizer Inc, Rivium Westlaan 142, 2909 LD, Capelle a/d IJssel, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Strengholt
authors.affiliation: Pfizer Inc, 235 East 42nd Street, New York, NY, 10017, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Chen
authors.affiliation: Pfizer Inc, 235 East 42nd Street, New York, NY, 10017, USA. Jamie.Geier@pfizer.com.
authors.forename: Jamie
authors.initials: J
authors.lastname: Geier
mesh_terms: D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D006801:Humans; D009369:Neoplasms / Q000209:etiology*; D009894:Opportunistic Infections / Q000209:etiology*; D010880:Piperidines / Q000009:adverse effects* / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects* / Q000627:therapeutic use; D018570:Risk Assessment
chemical_list: D018501:Antirheumatic Agents; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib
keywords: Exposure; Rheumatoid arthritis; Safety; Tofacitinib; Tumour necrosis factor inhibitors