PMID- 27470086
OWN - NLM
STAT- MEDLINE
DCOM- 20170313
LR  - 20181113
IS  - 1434-9949 (Electronic)
IS  - 0770-3198 (Print)
IS  - 0770-3198 (Linking)
VI  - 36
IP  - 3
DP  - 2017 Mar
TI  - Use of a risk characterisation approach to contextualise the safety profile of 
      new rheumatoid arthritis treatments: a case study using tofacitinib.
PG  - 683-688
LID - 10.1007/s10067-016-3359-x [doi]
AB  - 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 1.2x/1.5x/2.0x 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 (>/=1.2x), malignancies (excluding 
      non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events 
      (MACE) and lymphoma (each >/=1.5x), as well as opportunistic infections and 
      gastrointestinal perforations (>/=2x), 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.
FAU - Curtis, Jeffrey R
AU  - Curtis JR
AD  - The University of Alabama at Birmingham, 1720 2nd Ave S, Birmingham, AL, 35233, 
      USA.
FAU - Zhang, Richard
AU  - Zhang R
AD  - Pfizer Inc, 235 East 42nd Street, New York, NY, 10017, USA.
FAU - Krishnaswami, Sriram
AU  - Krishnaswami S
AD  - Pfizer Inc, Eastern Point Road, Groton, CT, 06340, USA.
FAU - Anisfeld, Andrew
AU  - Anisfeld A
AD  - Pfizer Inc, 235 East 42nd Street, New York, NY, 10017, USA.
FAU - Chen, Yan
AU  - Chen Y
AD  - Pfizer Inc, 500 Arcola Rd, Collegeville, PA, 19426, USA.
FAU - Strengholt, Sander
AU  - Strengholt S
AD  - Pfizer Inc, Rivium Westlaan 142, 2909 LD, Capelle a/d IJssel, The Netherlands.
FAU - Chen, Connie
AU  - Chen C
AD  - Pfizer Inc, 235 East 42nd Street, New York, NY, 10017, USA.
FAU - Geier, Jamie
AU  - Geier J
AD  - Pfizer Inc, 235 East 42nd Street, New York, NY, 10017, USA. 
      Jamie.Geier@pfizer.com.
LA  - eng
PT  - Journal Article
DEP - 20160728
PL  - Germany
TA  - Clin Rheumatol
JT  - Clinical rheumatology
JID - 8211469
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Piperidines)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrroles)
RN  - 87LA6FU830 (tofacitinib)
SB  - IM
MH  - Antirheumatic Agents/*adverse effects/therapeutic use
MH  - Arthritis, Rheumatoid/*drug therapy
MH  - Humans
MH  - Neoplasms/*etiology
MH  - Opportunistic Infections/*etiology
MH  - Piperidines/*adverse effects/therapeutic use
MH  - Pyrimidines/*adverse effects/therapeutic use
MH  - Pyrroles/*adverse effects/therapeutic use
MH  - Risk Assessment
PMC - PMC5323490
OTO - NOTNLM
OT  - Exposure
OT  - Rheumatoid arthritis
OT  - Safety
OT  - Tofacitinib
OT  - Tumour necrosis factor inhibitors
COIS- All tofacitinib studies were approved by the Institutional Review Boards (IRBs) 
      and/or Independent Ethics Committees of each investigational centre or a central 
      IRB. The studies were conducted in compliance with the Declaration of Helsinki 
      and the International Conference on Harmonisation Good Clinical Practice 
      Guidelines. All patients provided written informed consent. FUNDING: This 
      analysis was supported by Pfizer Inc. CONFLICT OF INTEREST: JC has received grant 
      or research support from Pfizer Inc for unrelated work. AA was a shareholder and 
      employee of Pfizer Inc at the time the analyses were performed. YC, SK, RZ, SS, 
      CC and JG are shareholders and employees of Pfizer Inc.
EDAT- 2016/07/30 06:00
MHDA- 2017/03/14 06:00
PMCR- 2016/07/28
CRDT- 2016/07/30 06:00
PHST- 2016/05/20 00:00 [received]
PHST- 2016/07/15 00:00 [accepted]
PHST- 2016/07/14 00:00 [revised]
PHST- 2016/07/30 06:00 [pubmed]
PHST- 2017/03/14 06:00 [medline]
PHST- 2016/07/30 06:00 [entrez]
PHST- 2016/07/28 00:00 [pmc-release]
AID - 10.1007/s10067-016-3359-x [pii]
AID - 3359 [pii]
AID - 10.1007/s10067-016-3359-x [doi]
PST - ppublish
SO  - Clin Rheumatol. 2017 Mar;36(3):683-688. doi: 10.1007/s10067-016-3359-x. Epub 2016 
      Jul 28.