`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203214Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`
`
`Cross-Discipline Team Leader Review
`
`
`Date
`July 20, 2012
`From
`Sarah Yim, M.D.
`m_ Cross-Disci line Team Leader Review
`NDA/BLA #
`NDA 203214
`
`Su n lement#
`
`
`
`Date of Submission
`
`PDUFA Goal Date
`
`October 21, 2011
`
`Au st 21, 2012
`
`Proprietary Name /
`Established S names
`
`Xeljanz/Tofacitinib
`
`Dosa_e forms / Stren_ h
`
`5 and 10 mo immediate-release tablets
`
`Proposed Indication(s)
`
`Recommended:
`
`. Treatment of Adult Patients with Moderately to
`Severely Active Rheumatoid Arthritis (RA) and
`Inadequate Response to One or More Disease-
`Modifying—Anti—Rheumatic Drugs ODMARDs)
`A roval, with Revisions to Pralosed Label
`
`1. Introduction
`
`New Drug Application (NDA) 203214 from Pfizer for the new molecular entity (NME)
`tofacitinib (also known as CP-690,550), an oral small molecule inhibitor of the Janus
`associated kinases (JAK) being proposed for the treatment of adult patients with moderately to
`severely active rheumatoid arthritis who have had inadequate response to one or more disease-
`modifying anti-rheumatic drugs (DMARDs). The product is being proposed as immediate-
`release tablets for oral administration in 5 and 10 mg dosage strengths. Pfizer proposes the
`recommended starting dose as 5 mg twice a day, with an added qualifier that some patients
`may benefit from an increase to 10 mg twice a day based on clinical response.
`
`In kinase assays, tofacitinib inhibits JAKl, JAK2, JAK3 and, to a lesser extent, TyK2. In the
`immune system, JAKl, JAK2, and TyK2 are ubiquitously expressed, whereas JAK3
`expression is restricted to hematopoietic cells. JAKl knockout mice display perinatal lethality
`(thought to be related to neuroapoptosis due to lack of gpl30 signaling), and JAKl inhibition
`would be expected to enhance susceptibility to infections by viruses and bacteria related to
`defective signaling by class II cytokine receptors and receptors that use the gp130 subunit.
`JAK2 has a pivotal role in the signal transduction required in definitive erythropoiesis and
`JAK2 knockout mice are embryonically lethal due to a lack of erythropoesis. TyK2 knockout
`mice are viable with no overt abnormalities, but do show reduced CD4+ cell diflerentiation to
`Th1 cells. JAK3 knockout mice display T and B cell lymphopenia without effects on myeloid
`lineage cells. Autosomal recessive JAK3 deficiency in hmnans results in a form of severe
`
`Reference ID: 31 62509
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`Page 1 of 53
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` NDA 203214: Tofacitinib for RA
`Pfizer, Inc.
`
`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`combined immunodeficiency disease (SCID) that is characterized by lack of circulating T cells
`and NK cells, but a normal number of B-cells.1
`
`If approved, tofacitinib would be the first JAK inhibitor for rheumatoid arthritis (RA), and the
`first orally administered agent approved since leflunomide’s approval in 1998. However, one
`other JAK inhibitor, ruxolitinib, has been approved since November 2011 for myelofibrosis
`indications. The NDA for tofacitinib posed a number of review issues which will be the focus
`of this memorandum. These issues include:
`• Whether the submitted data are adequate to conclude that tofacitinib is a disease-modifying
`agent for RA and if the conclusion applies to both proposed doses (5 and 10 mg BID)
`• What the most pressing safety concerns are for tofacitinib, and whether there is a dose or
`exposure related increase in risk for these concerns.
`
`
`These issues, and the overall benefit-risk profile of tofacitinib, were discussed at a meeting of
`the Arthritis Advisory Committee on May 9, 2012. Highlights of this discussion are
`summarized in Section 9, below.
`
`
`2. Background
`
`
`Rheumatoid Arthritis (RA) has been the prototypical autoimmune disease for drug
`development; especially since the late 1990s with the success of the targeted biologic
`therapies. It is a chronic, inflammatory polyarthritis affecting approximately 1% of adults
`worldwide, approximately 75% of whom are women. The majority of patients would have
`persistent, progressive disease which would result in increasing disability, if untreated.2
`Fortunately, many effective treatments have been developed and approved for RA, as
`summarized in Table 1 below.
`
`
`
`1 L Vijayakrishnan, R Venkataramanan, and P Gulati, “Treating inflammation with the Janus Kinase inhibitor CP-
`690,550.” Trends Pharmacol Sci 2011 Jan; 32(1):25-34.
`2 SL Scott and S Steer, “The course of established rheumatoid arthritis,” Best Practice & Research Clinical
`Rheumatology 2007, 21(5):943-967
`
`Reference ID: 3162509
`
`Page 2 of 53
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`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`Table 1 FDA Approved Drugs and Biologics for RA
`
`
`
`
` NDA 203214: Tofacitinib for RA
`Pfizer, Inc.
`
`
`
`
`Since the late 1990’s, clinical development programs evaluating the efficacy of proposed
`products for RA have primarily utilized American College of Rheumatology (ACR) response
`criteria to assess treatment effect on signs and symptoms, the Health Assessment
`Questionnaire-Disability Index (HAQ-DI) to assess treatment effect on physical functioning,
`and a standardized radiographic scoring system, such as the Sharp Score or modifications
`thereof, to assess treatment effect on structural damage progression. These outcome measures
`will be described in greater detail later in this memorandum.
`
`One conundrum associated with the assessment of efficacy in RA is the possible dissociation
`between clinical and radiographic outcomes. Radiographic progression may occur in people
`who have very low apparent disease activity and patients with clinical disease activity may
`have no evidence of radiographic progression.3 Thus, documentation of a benefit of treatment
`on structural damage progression has been an important goal of clinical development programs
`for new products proposed for RA, particularly if the product has a novel target. This has
`become an increasingly important aspect of the risk-benefit assessment for new RA treatments
`in light of the many approved treatments that have documented beneficial effects in inhibiting
`structural damage progression.
`
`Relevant Regulatory History for Tofacitinib in RA
`
`At the time the investigational new drug application (IND) for tofacitinib was submitted,
`Phase 1 clinical data were already available. Dose-ranging study A3921019 was the initial
`protocol submitted to the IND, which proposed monotherapy with tofacitinib at doses of 5, 15,
`and 30 mg BID for a duration of 6 weeks. Lack of nonclinical coverage for the proposed
`doses was noted at that time. However, because there were pre-existing human data in
`approximately 180 patients at doses up to 50 mg BID for 14 days, the Agency at that time
`made an internal decision that the clinical data were adequate to support the safety of
`
`
`3 EC Keystone, “Clinical implications of understanding radiographic findings in relation to clinical outcomes in
`rheumatoid arthritis.” J Rheumatol 2009; 36 Supple 82:11-16
`
`Reference ID: 3162509
`
`Page 3 of 53
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`
`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE H/DPARP
`
`NDA 203214: Tofacitinib for RA
`Pfizer. Inc.
`
`proceeding with the study, despite the lack of nonclinical support for all of the proposed doses,
`which would typically be required.
`
`In January 2007, the Agency provided written feedback regarding the proposed design of
`Study A3921025 and an extension study. Study A3921025 included proposed doses of l_, 3, 5,
`10, 15 mg BID and 20 mg QD, to be given with stable background methotrexate (MTX) for a
`duration of 6 months. The design of the study was considered generally acceptable, although
`it was noted that the nonclinical data appeared to only support chronic dosing in patients 11p to
`5 mg BID. The review team at that time determined that previous clinical experience appeared
`to support the ability to proceed with the proposed study.
`
`0
`
`In December 2008, an End of Phase 2 (EOP2) meeting took place to discuss the tofacitinib
`development program. The Agency generally agreed with the proposed Phase 3 program
`elements and endpoints. Discussions included:
`0 Pure placebo control should be limited to 3 months, even if patients had apparent
`symptomatic improvement (i.e., ACR20).
`5 mg BID and 10 mg BID doses appear reasonable; 3 mg BID should be considered. QD
`regimens may warrant further study.
`0 The safety database proposal appeared to be adequate (1500 patients on the to—be—marketed
`dose for a year or more).
`0 Concern regarding effects on lipids and the implications for cardiovascular safety, and the
`need for this to be comprehensively evaluated for NDA.
`
`At the Pre-NDA meeting for this application in February 2011, general agreement was reached
`on the proposed format and content of NDA, and the adequacy (to support review of the
`application) of the nonclinical program and clinical safety database.
`
`M0
`
`3. CMC/Device
`
`CMC Reviewers: Craig Bertha, Ph.D.,' Donghao Lu, Ph.D., Ying Wang, PII.D., Bogdan
`Kurtyka, Ph.D.,' Supervisory: Eric Dufijz, PILD.
`
`0 General product quality considerations
`
`The drug substance tofacitinib citrate (CP—690,550-10) is a white to off-white
`that is
`
`"'""
`
`M0
`
`Tofacitinib citrate is highly soluble as per
`the Biophannaceutics Classification System and the applicant indicates that it has low
`permeability (BCS class 3). The structure of tofacitinib citrate includes an arylamine flmction,
`which is a structural alert for mutagenicity. The drug substance is not photosensitive and the
`
`Reference ID: 31 62509
`
`Page 4 of 53
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`
`
`Cross Discipline Team Leader Review
`Sarah Yim. M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`NDA 203214: Tofacitinib for RA
`Pfizer. Inc.
`
`(me, as well as the
`stability data provided supports both the proposed retest period of
`post-approval stability protocol proposed. The drug substance is manufactured at Pfizer
`Ireland Pharmaceuticals, Ringaskiddy, Ireland. It is packaged in
`(hm
`
`(IN)
`
`supported.
`
`and retest period of
`
`(I!) (4) l
`
`s
`
`The drug product immediate release tofacitinib tablets are formulated as fihn—coated round
`tablet. Two strengths, 5 mg and 10 mg, are proposed for commercialization. The strengths of
`the drug products are based on the equivalent amount of tofacitinib. The 5 mg tablets are white
`to off-white, fihn—coated, round tablets debossed with “Pfizer” on one side and “JKIS” on the
`other side.
`M0
`mm
`
`The tablets are manufactured with a
`
`(b) (4)
`
`The drug product
`is packed in high-density polyethylene (HDPE) bottles with desiccant and closures with
`induction seal liners. The drug product is manufactured and packaged in Frieburg, Germany
`and is also being packaged in Puerto Rico. The submitted drug product stability data include
`12 months at long term storage condition of 25°C/60%RH and 6 month accelerated storage
`condition of 40°C/75%RH for 3 batches of each strength. The stability data supports the
`proposed 24 month shelf life for the drug product when stored at the proposed 20°C to 25°C
`(68°F to 77°F),
`W"
`
`0 Facilities review/inspection
`
`At the time of this review, the Establishment Evaluation Request (EER) is still pending.
`
`0 Other notable issues (resolved or outstanding)
`
`From a Chemistry, Manufacturing, and Controls (CMC) perspective, the application is
`recommended for approval pending an acceptable recommendation from the Office of
`Compliance regarding the facilities’ inspections. No CMC Phase 4 commitments are
`recommended.
`
`4. Nonclinical Pharmacology/Toxicology
`
`Pharm-Tox Reviewer: Lawrence S. Leshin, D. VM, Ph.D.,' Supervisor: Molly Shea, PhD.
`
`0 General nonclinical pharmacology/toxicology considerations
`
`Pivotal nonclinical toxicology studies were conducted in rats (6-month, doses of 0, l, 10, 100
`mg/kg/day) and cynomolgus monkeys (9-month, doses of 0, 0.5, 2, 10 mg/kg/day, 4 monkeys
`per sex per group). No-Observed-Adverse—Effect-Levels (NOAELs) could not be determined
`as adverse effects were noted in each of the lowest doses tested. Toxicities were associated
`
`Reference ID: 31 62509
`
`Page 5 of 53
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` NDA 203214: Tofacitinib for RA
`Pfizer, Inc.
`
`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`with suppression of the immune and hematopoietic systems, to include suppression of myeloid
`and erythroid bone marrow production, reductions in circulating red and white blood cells,
`increased bacterial infections, and reduced or atrophied lymphoid organs. Reversibility of
`these findings was not evaluated in the chronic toxicity studies. However shorter duration
`repeat-dose toxicity studies in rats and monkeys demonstrated that these findings were at least
`partially reversible.
`
`In the nonclinical program, including shorter (i.e. 1 to 1.5 month) studies, adverse effects
`resulting in mortality included:
`•
`in rats, bacterial infections of the kidney, lung alveolar histiocytosis and interstitial
`inflammation
`in monkeys, lymphomas, and bacterial and viral infections
`
`•
`
`In the 9-month (39-week) chronic toxicology study in cynomolgus monkeys, three monkeys in
`the high dose group (10 mg/kg/day) developed lymphomas. Pfizer concluded that these
`lymphomas were consistent with gamma herpes-virus induced lymphoproliferative disorder
`associated with immunosuppression. Additional details are discussed in the context of the
`human lymphoma findings in the RA and renal transplant settings in the safety section of this
`memorandum.
`
`
`• Carcinogenicity
`
`
`Tofacitinib was not mutagenic or genotoxic based on in vitro and in vivo tests for gene
`mutations, chromosomal damage, and DNA damage. Carcinogenicity was assessed in a 6-
`month mouse study and a 2-year rat study. The mouse study did not suggest oncogenic
`potential related to tofacitinib. The rat study neoplastic findings included interstitial cell
`adenomas of the testes, and benign thymomas and malignant hibernomas in females.
`
`
`• Reproductive toxicology
`
`
`In reproductive toxicology studies, tofacitinib did not appear to affect the fertility of male rats,
`but decreased pregnancy rate, numbers of corpora lutea, implantation sites, and viable fetuses
`in female rats, with an increase in early resorptions, pre-implantation loss and post-
`implantation loss. Tofacitinib was teratogenic (visceral and skeletal abnormalities) in rats and
`rabbits.
`
`
`• Other notable issues (resolved or outstanding)
`
`
`The Pharmacology/Toxicology team believes the information in this application is adequate to
`support approval. However they also recommend that the male fertility study and the juvenile
`rat study be performed again using a revised design:
`1. In the male fertility study, males were administered tofacitinib for at least 63 days,
`but matings occurred after 1 month of treatment, an insufficient duration of drug
`exposure for a complete spermatogenic cycle. Therefore, at least the study in adult
`males should be repeated and conducted in accordance with ICH5(R2).
`
`Reference ID: 3162509
`
`Page 6 of 53
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`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`
`
`
`
` NDA 203214: Tofacitinib for RA
`Pfizer, Inc.
`
`2. In the juvenile rat study, both males and females were administered CP-690550
`from weaning on day 21 until near or at puberty in the female, and in the male
`through expected puberty for an appropriate duration of exposures in both sexes.
`However, they were not mated until a few weeks after drug dosing stopped,
`allowing for recovery of any potentially adverse effects on fertility. The study in
`juvenile animals was not required, but if done correctly, could be incorporated into
`labeling to provide safety for treatment of pediatric patients with regards to
`reproductive maturation and fertility. These differ from classic segment 3 postnatal
`studies in that in the segment 3 studies the juvenile animals are not dosed with
`drug, only the dams are dosed, and the juvenile are followed to see if there are
`generational effects of the drug. The study in juvenile rats incorporates drug
`administration directly to the juvenile animals. This is an optional study, but if
`conducted, should also be designed and evaluated as recommended in ICH5(R2).
`
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`Clinical pharmacology reviewer: Lokesh Jain, Ph.D.; Supervisor: Suresh Doddapaneni, Ph.D.
`Pharmacometrics reviewer: Lokesh Jain, Ph.D. and Atul Bhattaram, Ph.D.; Supervisor: Atul
`Bhattaram, Ph.D.
`Pharmacogenomics reviewer: Jeffrey Kraft, Ph.D.; Supervisor: Michael Paconowski,
`Pharm.D., M.P.H.
`
`
`• General clinical pharmacology/biopharmaceutics considerations, including
`absorption, metabolism, half-life, food effects, bioavailability, etc.
`
`
`The absolute bioavailability of tofacitinib at the 10 mg dose was 74%. The systemic exposure
`(AUC0-∞) and peak plasma concentration (Cmax) increased in proportion to dose in the dose
`range of 1 to 100 mg. Tmax was reached by approximately 0.5-1 hours following oral
`administration. Coadministration with food had no significant effect on the extent of
`absorption (AUC0-∞) but rate of absorption (Cmax) was reduced by 32%. Upon multiple
`dosing, steady-state was reached by 24-48 hours with negligible accumulation. Tofacitinib is a
`substrate of P-gp transporter.
`
`Tofacitinib has a total plasma protein binding of approximately 39%. Tofacitinib binds
`moderately to albumin and does not bind to alpha-1 acid glycoprotein. Steady-state volume of
`distribution (Vdss) for tofacitinib following intravenous infusion administration was 87 L,
`suggesting distribution into tissues.
`
`Tofacitinib was extensively metabolized by the liver; primarily by CYP3A4 enzyme with
`minor contribution from CYP2C19. All metabolites comprise less than <8% of total drug
`exposure and their potency was reported to be <10% of the potency of tofacitinib for JAK1/3
`inhibition. Based on in vitro studies, tofacitinib is not a substrate of BCRP transporter. Based
`on in vitro studies, at therapeutic concentrations, tofacitinib has low potential for induction or
`
`Reference ID: 3162509
`
`Page 7 of 53
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` NDA 203214: Tofacitinib for RA
`Pfizer, Inc.
`
`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 metabolic enzymes and low potential
`of inhibition for P-gp, OCT2, OATP1B1, OATP1B3.
`
`Of the 94% drug recovered following oral administration in a mass balance study,
`approximately 29% and 51% was recovered in urine as parent drug and metabolites,
`respectively. In feces, proportion of parent and metabolites recovered was approximately 1%
`and 13%. The terminal elimination half-life of tofacitinib was approximately 3 hours after
`single- or multiple-dose administration.
`
`
`• Drug-drug interactions
`
`
`Tofacitinib coadministration with a strong CYP3A inhibitor, ketoconazole, increased the mean
`tofacitinib AUC (90%CI) by 103% (91%, 116%) and Cmax by 16% (5%, 29%).
`When coadministration with a strong CYP3A4 inhibitor is necessary, the clinical
`pharmacology team recommends a dose reduction as follows:
`•
`If 10 mg BID is an approved dose, then the dose with concomitant administration should
`not exceed 5 mg BID.
`If 5 mg BID is the limit, then a reduced dose of 5 mg QD is recommended.
`
`•
`
`Coadministration with a moderate CYP3A4 and strong CYP2C19 inhibitor, fluconazole,
`increased mean tofacitinib AUC (90%CI) by 79% (64%, 96%) and Cmax by 27% (12%, 44%).
`Thus the same dose reduction recommendation applies for moderate CYP3A4 and strong
`CYP2C19 inhibitors.
`
`Tofacitinib coadministration with a strong CYP3A inducer, rifampin, resulted in substantial
`decreases in mean tofacitinib AUC (90%CI) by -84% (-86%, -82%) and in Cmax by -74% (-
`77%, -69%). Coadministration with rifampin is not recommended because that may result in
`ineffective concentrations of tofacitinib.
`
`Coadministration with tacrolimus, a CYP3A substrate with narrow therapeutic index,
`increased mean (90%CI) tofacitinib AUC (90%CI) by 21% (13%, 30%) and decreased Cmax
`by -9% (-17%, -1%). Coadministration with cyclosporine, a CYP3A substrate with narrow
`therapeutic index and also an inhibitor of P-gp increased mean (90%CI) tofacitinib AUC
`(90%CI) by 73% (62%, 85%) and decreased Cmax by -17% (-29%, -3%). The clinical
`pharmacology team raised concerns regarding a possible pharmacodynamic interaction with
`the tofacitinib and either tacrolimus or cyclosporine and recommended the two drugs not be
`coadministered. However, immunosuppressive drugs are not uncommonly combined based on
`the clinical judgment of the healthcare professional for the particular clinical scenario, and I
`would not recommend labeling specifically prohibiting coadministration on the basis of a
`concern for pharmacodynamic interaction alone.
`
`Coadministration with methotrexate, had no significant effect on tofacitinib exposure and no
`dose adjustment is needed for tofacitinib when coadministered with methotrexate. Tofacitinib
`had no substantial effects on the plasma levels of oral contraceptives (ethinylestradiol and
`levonorgestrel), midazolam (CYP3A substrates), or methotrexate, thus no dose adjustment is
`needed for these drugs when coadministered with tofacitinib.
`
`Reference ID: 3162509
`
`Page 8 of 53
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`
`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`
`
`
`
`
` NDA 203214: Tofacitinib for RA
`Pfizer, Inc.
`
`• Intrinsic factors potentially affecting elimination: age, gender, hepatic
`insufficiency and renal impairment
`
`
`There was no substantial impact of age, weight, and gender on PK parameters, after
`accounting for differences in renal function (i.e., creatinine clearance).
`
`For subjects with mild, moderate and severe renal impairment, mean percentage change in
`AUC (90%CI), compared to subjects with normal renal function were respectively: 41% (-5%,
`109%), 71% (14%, 157%), and 156% (69%, 287%). Mean percentage changes in Cmax (90%
`CI) for these cases were respectively: 1% (-31%, 49%), 2% (-31%, 52%), and 21% (-19%,
`81%). Based on these data, the clinical pharmacology team recommends dose reduction (as
`described above) of tofacitinib in patients with moderate and severe renal impairment.
`
`For subjects with mild and moderate hepatic impairment, mean percentage change in AUC
`(90%CI), compared to subjects with normal hepatic function were respectively: 3% (-22%,
`36%) and 65% (25%, 117%). Mean percentage change in Cmax (90% CI) for these cases
`were respectively: -1% (-25%, 32%) and 49% (12%, 97%). Based on these data, the clinical
`pharmacology team recommends dose reduction of tofacitinib for these patients. Tofacitinib
`was not evaluated in patients with severe hepatic impairment, but as tofacitinib is extensively
`hepatically metabolized, there is reason to believe that increased exposure, and risk, would
`occur in this population, and therefore use of tofacitinib in this population is not
`recommended.
`
`
`• Demographic interactions/special populations
`
`Based on available data are no major differences were seen in tofacitinib AUC and Cmax
`between White, Black and Asian patients, after accounting for differences in renal function
`(i.e., creatinine clearance). However, population PK analysis in RA patients showed 43%
`lower apparent clearance in RA patients relative to a healthy adult.
`
`
`• Thorough QT study
`
`
`QT effect was evaluated in a randomized, blinded, crossover, single-dose study, in which
`60 healthy subjects received a supra-therapeutic tofacitinib dose of 100 mg, placebo, and
`moxifloxacin 400 mg. The washout duration between treatment periods was 7 days. No
`significant QT prolongation effect was detected at the tested 100 mg tofacitinib dose. The
`largest upper bounds of the 2-sided 90% CI for the mean difference between CP-690,550
`100 mg and placebo were below 10 ms, the threshold for regulatory concern as described in
`the ICH E14 guideline.
`
`
`• Other notable issues (resolved or outstanding)
`
`
`
`Reference ID: 3162509
`
`Page 9 of 53
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`
`
`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`NDA 203214: Tofacitinib for RA
`Pfizer. Inc.
`
`The Office of Clinical Pharmacology has determined the information in NDA 203214
`acceptable. No outstanding issues have been identified or Phase 4 commitments
`recommended.
`
`6. Clinical Microbiology—MIA
`
`7. Clinical/Statistical- Efficacy
`
`Clinical Primary Reviewer: Niko/av Nikolov, MD.
`Statistical Reviewer: Yongman Kim, Ph.D., Statistical Team Leader: Joan Buenconsejo, PILD.
`
`Overview ofthe clinicalprogram
`
`Five randomized placebo-controlled trials have been submitted as the primary evidence of
`efficacy and safety of tofacitinib, as summarized in Table 2 below. As study numbers all
`begin with “A32,” they will at times be abbreviated by the last four digits of the study number.
`A single trial (1044) evaluated radiographic outcomes, a single trial (1064) included a control
`arm with the TNF inhibitor adalimumab, and a single trial (1045) evaluated tofacitinib
`monotherapy.
`
`Patients completing the Phase 3 trials had the option to enroll in open-label long-term
`extension @TE) studies. Study 1041 is an LTE for patients completing clinical development
`studies in Japan (Phase 2 studies 1039 and 1049, and Japanese participants in global Study
`1044). Study 1024 is the LTE for all other patients in the clinical development program.
`These studies allowed for 5 or 10 mg BID doses, to be adjusted as needed for either efficacy or
`safety reasons. Prior to amendment 3 (January 2009), all patients were initiated on 5 mg BID
`upon entry in the LTE. Subsequent to this, all patients (with exceptions in certain countries)
`have been initiated on 10 mg BID.
`
`(5) (4)
`
`Reference ID: 31 62509
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`Page 10 of 53
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`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`Table 2: Summary of the Phase 3 Studies in RA Submitted for the NDA
`
`
`
`
` NDA 203214: Tofacitinib for RA
`Pfizer, Inc.
`
`
`
`Brief Description of Efficacy Endpoints
`
` •
`
`
`
` ACR Response Rates
`
`
`In 1995, the American College of Rheumatology (ACR) published a definition of
`improvement for clinical trials in rheumatoid arthritis, which have since been used in drug
`development trials to demonstrate evidence of efficacy for signs and symptoms of RA.4 The
`ACR20 response is calculated as a >20% improvement in:
`•
`tender joint count (of 68 joints) and
`• swollen joint count (of 66 joints) and
`• 3 of the 5 remaining ACR core set measures
`o Patient Global Assessment of Arthritis on a visual analog scale (VAS)
`o Physician Global Assessment of Arthritis on a VAS
`o Patient Assessment of Pain on a VAS
`o Patient Assessment of Physical Function (e.g. Health Assessment
`Questionnaire)
`o Acute Phase Reactant (Erythrocyte Sedimentation Rate or C-reactive
`protein)
`Fifty percent and 70 percent improvement (ACR50 and ACR70) are similarly calculated using
`these higher levels of improvement.
`
`
`4 DT Felson, et al., Arthritis & Rheum, 1995 June, 38(6):727-735
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`Reference ID: 3162509
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` NDA 203214: Tofacitinib for RA
`Pfizer, Inc.
`
`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`• Health Assessment Questionnaire-Disability Index (HAQ-DI)
`
`The Agency has historically recognized a distinct claim in RA for “improvement in physical
`function” based on outcome measures such as the HAQ-DI.5 This instrument assesses a
`patient’s level of functional ability and includes questions pertaining to fine movements of the
`upper extremity, locomotor activities of the lower extremities, and activities that involve both
`upper and lower extremities. There are 20 questions in 8 categories of functioning which
`represent a comprehensive set of functional activities: dressing, rising, eating, walking,
`hygiene, reach, grip, and usual activities. Patients respond on a four-level difficulty scale
`ranging from zero (no difficulty) to three (unable to do). The 8 category scores are averaged
`into an overall HAQ-DI score on a scale from zero (no disability) to 3 (completely disabled).
`The most widely accepted figure on the minimal clinically important difference in the HAQ-
`DI score is an improvement (decrease) of at least 0.22 units.
`
` •
`
` Disease Activity Score (DAS)-28
`
`
`The DAS28 is a composite index of RA disease activity which incorporates the number of
`tender and swollen joints (out of 28 possible), a patient global assessment of disease activity
`(0-100 mm visual analog scale), and erythrocyte sedimentation rate (ESR) results.6 An
`alternative equation is available for use with c-reactive protein (CRP) results. These variables
`are summed and weighted mathematically into a single numerical value ranging from 0 to 10.
`Comparing the DAS28 and the ACR response criteria, beyond the differences in number of
`maximum tender or swollen joints counted (e.g. DAS28 does not include the joints of the feet),
`additional variables of physician global assessment, patient pain, and HAQ score are
`incorporated into the ACR response criteria. The DAS28 has additional utility in measuring
`the level of disease activity at a given timepoint, whereas the ACR response criteria are
`calculated as improvement in the variables over a set period of time. A DAS28 score >5.1 is
`indicative of high disease activity, and <3.2 of low disease activity. A score of <2.6 has been
`used to describe an even lower threshold of disease activity.
`
` •
`
` Radiographic Outcome: Van der Heijde modified Sharp Score
`
`
`The Van der Heijde-modified Sharp radiographic scoring method grades the presence of
`erosions in the joints of the hands and feet, and the presence of joint space narrowing (JSN) in
`the hands, wrists, and feet.7 The scores for each feature for the individual joints are summed.
`Erosions are assessed at 16 locations in each hand and wrists and 12 locations in each foot,
`using a 6-point scale from 0 to 5. Scores are derived based on the number and size of discrete
`erosions in each location, but are summed to a maximum of 5. Thus the maximum erosion
`score for the hands/wrists is 160, and the maximum erosion score for the feet is 120, for a
`maximum total erosion score of 280. JSN scores are based on 15 locations in each hand and
`
`5 B Bruce and JF Fries, “The Health Assessment Questionnaire (HAQ).” Clin Exp Rheumatol 2005; 23 (Suppl
`39):S14-S18
`6 J Fransen and PLCM van Riel, “The Disease Activity Score and the EULAR Response Criteria.” Clin Exp
`Rheumatol 2005; 23 (Suppl 39): S93-S99
`7 S Boini and F Guillemin, “Radiographic scoring methods as outcome measures in rheumatoid arthritis:
`properties and advantages.” Ann Rheum Dis 2001; 60:817-827
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`Reference ID: 3162509
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` NDA 203214: Tofacitinib for RA
`Pfizer, Inc.
`
`Cross Discipline Team Leader Review
`Sarah Yim, M.D.
`DHHS/FDA/CDER/ODE II/DPARP
`
`wrist and 6 locations in each foot, scored using a 5-point scale from 0 to 4: 0 = normal; 1 =
`focal or minimal and generalized narrowing; 2 = generalized narrowing <50%; 3 = generalized
`narrowing >50% or subluxation; and 4 = ankylosis or complete dislocation. The maximum
`total JSN for the hands/wrists is 120, and the maximum total JSN for the feet is 48, for a
`maximum total JSN score of 168. Therefore the theoretical maximum modified total Sharp
`Score (mTSS) is 448, although the actual clinical range in RA drug development trials is
`typically much lower because a given individual typically only has a fraction of his or her
`joints affected by radiographically evident damage.
`
`Dose selection
`
`The proposed recommended starting dose is 5 mg twice a day, with an added qualifier that
`some patients may benefit from an increase to 10 mg twice a day based on clinical response.
`Pfizer selected 5 and 10 mg BID doses of tofacitinib based on dose-response modeling of
`safety and efficacy data from Study 1025, with supportive data from Study 1019 and Study
`1035. The key design features of these studies and efficacy results for the American College
`of Rheumatology (ACR) Responses are summarized in Table 3 and Figure 1 below. On
`background methotrexate (MTX) in Study 1025, the dose response was very flat across the
`range of doses from 3 mg BID to 20 mg QD. There was some suggestion in Study 1035 (a
`monotherapy evaluation) that 10 mg BI