US Food and Drug Administration-Mandated Trials of Long-Acting b -Agonists Safety in Asthma. Samy Suissa, PhD ; and Amnon Ariel, MD, FCCP

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1 CHEST Commentry US Food nd Drug Administrtion-Mndted Trils of Long-Acting b -Agonists Sfety in Asthm Will We Know the Answer? Smy Suiss, PhD ; nd Amnon Ariel, MD, FCCP For 2 decdes, long-cting b -gonists (LABAs) hve been ssocited with incresed sthm-relted deth risks in severl rndomized trils, even when dded to inhled corticosteroids (ICSs). In rection, the US Food nd Drug Administrtion (FDA) recently mndted tht the mnufcturers of LABAs conduct five lrge, noninferiority, rndomized trils of the LABA 1 ICS combintion in 53,000 ptients with sthm. Three methodologic issues in these trils could led to msking of or flsely detecting elevted risks. First, the effect of LABA discontinution mong the mny ptients lredy using these drugs t enrollment cn result in n underestimtion of the reltive risk by fctor of round 20%. This effect will bis downwrd the upper bound of the resulting CI wy from the preset noninferiority mrgin of 2.0 for the reltive risk, rtificilly mking it more difficult to detect risk increse. Second, the composite sthm outcome will be dominted by sthm hospitliztion, possibly dwrfing n incresed risk of sthm-relted deth, with differences s wide s seven deths under the LABA 1 ICS combintion vs one deth under ICS lone remining sttisticlly uncertin. Finlly, becuse of the multiple identicl trils being requested from the different mnufcturers of LABAs, even if ech tril is powered t 90%, there is 41% likelihood tht t lest one of the trils will not rule out risk increse when, in truth, there is no risk increse. In view of these impediments, the FDA should preempt such complexities by estblishing decision rules regrding the interprettion of the results from these momentous sfety trils before their completion, expected in CHEST 2013; 143(5): Abbrevtions: FDA 5 US Food nd Drug Administrtion; ICS 5 inhled corticosteroid; LABA 5 long-cting b-gonist; RR 5 rte rtio Recently updted, interntionl sthm guidelines stte tht the ddition of long-cting b -gonists (LABA) to dily regimen of inhled corticosteroids (ICS) improves severl sthm end points nd chieves clinicl control of sthm. 1 Prdoxiclly, despite its Mnuscript received November 28, 2012; revision ccepted Jnury 28, Affilitions: From the Center for Clinicl Epidemiology (Dr Suiss), Ldy Dvis Institute Jewish Generl Hospitl, nd the Deprtments of Epidemiology nd Biosttistics nd Medicine, McGill University, Montrel, QC, Cnd; nd Lung Unit (Dr Ariel), Emek Medicl Center, Aful, Isrel. Correspondence to: Prof Smy Suiss, Centre for Clinicl Epidemiology, Jewish Generl Hospitl, 3755 Cote Ste-Ctherine, Montrel, QC, H3T 1E2, Cnd; e-mil: smy.suiss@mcgill.c 2013 Americn College of Chest Physicins. Reproduction of this rticle is prohibited without written permission from the Americn College of Chest Physicins. See online for more detils. DOI: /chest therpeutic efficcy, chronic LABA use hs been implicted in sthm mortlity for the lst 20 yers, with lrge, rndomized controlled trils generting importnt signls of incresed incidence of sthm deth. 2,3 While the evidence is now convincing regrding this elevted risk in the bsence of concurrent ICSs, the question of possible risk when LABAs re dded to regulr ICS therpy remins controversil. The US Food nd Drug Administrtion (FDA) performed met-nlysis of rndomized trils involving. 36,000 ptients with sthm tking ICS nd compring LABA use with no-laba use on the risk of the composite outcome of sthm-relted deth, intubtion, or hospitliztion. 4,5 The incidence of the sthm composite outcome ws significntly incresed (rte difference: 6.1 events per 1,000 ptient-yers; 95% CI, ) with LABA use when the concurrent Commentry

2 ICS ws not prt of the rndomized tretment, but in the trils where ICS use ws mndtory t the sme dose, the incidence of the sthm composite outcome ws not incresed with LABA use (rte difference: 0.4 events per 1,000 ptient-yers; 95% CI, ). 5 Nevertheless, sthm mortlity remins concern. A pooled nlysis of rndomized trils of formoterol involving close to 60,000 ptients with sthm tking ICS reported seven sthm-relted deths mong 46,000 ptients tking formoterol nd one in 14,000 ptients not rndomized to formoterol (rte rtio [RR], 2.3; 95% CI, ). 6 A met-nlysis of 57 trils involving bout 35,000 ptients with sthm using ICS found three sthm-relted deths mong those tking LABA nd none in ptients not rndomized to LABA (RR, 3.0; 95% CI, ). 7 These two met-nlyses were limited by the unknown extent of the concurrent ICS being mndted or not s prt of the trils nd whether the ICS dose ws different between the LABA users nd nonusers. While the risk increses were not sttisticlly significnt, the consistency nd trend of the effect mke this issue continuing concern for ptients, clinicins, nd regultors. 8 In response, the FDA recently mndted tht the mnufcturers of LABAs conduct five lrge, rndomized trils in ptients with sthm. 9 These trils, which will ssess the effect of dding LABA to ICS on mjor sthm outcomes, begn in 2011, with the results expected in While the FDA believes tht these clinicl trils will clrify the sfety risk ssocited with LABAs when used concurrently with inhled corticosteroids, 9 recent pper questioned their relevnce. 10 In this rticle, we show tht three importnt methodologic spects inherent to the study design of these trils will ffect their results nd interprettion. We describe these issues nd quntify their effects on the expected results. The Trils Four of the rndomized trils, identiclly designed, ech involve 11,700 dult nd dolescent ptients with sthm per study, for totl of 46,800 ptients, while smller tril involves 6,200 children. 9 Ech tril compres the combintion of LABA with n ICS (LABA 1 ICS) vs monotherpy with the sme ICS t the sme dose. The primry end point is composite of serious sthm outcomes, including sthm-relted deth, intubtion, or hospitliztion, observed over 6-month follow-up. These trils re designed s noninferiority trils, which test whether the ptients in the LABA 1 ICS group re no worse thn those in the ICS-only group with respect to the risk of the serious sthm outcomes. 11,12 For the four dult/dolescent trils, no worse is defined in terms of the reltive risk for serious sthm outcomes compring LABA 1 ICS vs ICS being 2, which, in prcticl terms to ccount for rndom vribility, implies tht the upper bound of the 95% CI for the reltive risk must be, 2 to conclude tht LABA 1 ICS is no worse thn ICS lone. The smple size of 11,700 ptients per tril ws computed by fixing the power t 90%. Tht is, the tril is designed to rule out reltive risk of 2 for the composite outcome with probbility of 90% when, in fct, there is no increse in the risk. Under the hypothesized rte of 15 serious sthm events per 1,000 ptients per yer, the upper limit of 2 for the CI corresponds to point estimte of 1.32 for the reltive risk, so tht only if the estimted reltive risk is, 1.32 cn LABA 1 ICS be estblished s noninferior to ICS. The fifth tril, involving 6,200 children, ws designed to hve 90% power to rule out reltive risk of 2.7, tht is, for the upper bound of the 95% CI for the reltive risk to be, 2.7. Effect of LABA Discontinution t Rndomiztion The first methodologic issue reltes to the ptients lredy treted with LABA 1 ICS combintion nd who re eligible to enter these trils. Upon rndomiztion, these ptients re llocted to either continuing LABA 1 ICS tretment, lbeit possibly with nother gent, depending on the study they hve been recruited to, or discontinuing their LABA 1ICS tretment nd replcing it by tretment of n ICS only, which cn impct the outcome. A met-nlysis of five rndomized controlled trils provides evidence tht discontinution of the LABA component of LABA 1 ICS combintion is not inconsequentil on sthm outcomes, though it hd insufficient numbers of ptients to provide dt on sthm deths or hospitliztions. 13 It reported tht such LABA discontinution is ssocited with n increse in ED or unscheduled visits for sthm (RR, 2.2; 95% CI, ), in the use of systemic steroids (RR, 1.7; 95% CI, ) nd in the incidence of withdrwl due to lck of efficcy or loss of sthm control (RR, 3.3; 95% CI, ). It is conceivble tht these consistent effects cn trnslte to t lest 50% increse (RR 5 1.5) in the rte of the composite outcome under study in the FDA-mndted trils, prticulrly sthm hospitliztion. Such effects of tretment discontinution t rndomiztion hve been noted with ICSs in trils of ptients with COPD. 14 In view of the current sthm-tretment trends, we nticipte tht t lest hlf of the ptients enrolled in the FDA-mndted trils will lredy be treted with journl.publictions.chestnet.org CHEST / 143 / 5 / MAY

3 LABA 1 ICS. Consequently, we cn compute the expected effect of such LABA discontinution in these trils. Tble 1 shows tht with the plnned smple size nd 6-month follow-up for ny given tril, the projected composite outcome rte of 15 events per 1,000 ptients per yer in the ICS-only group nd the mximl reltive risk of 1.32 led to n expected 58 nd 44 events for the LABA nd no-laba groups, respectively, if we ssume no effects of LABA discontinution (RR, 1.32; 95% CI, ). Among the ptients who hd no LABA 1 ICS use prior to rndomiztion, the RR remins t 1.32, with 29 nd 22 events expected in the two tretment groups, respectively. If we incorporte the effect of discontinution mong the ptients who used LABA 1 ICS prior to rndomiztion, the group llocted to continue the LABA 1 ICS will not be ffected nd thus is expected to lso hve 29 events. However, the group llocted to ICS only, who thus hd to discontinue the LABA component t study enrollment, should hve 50% more events thn expected (ie, 33 events). As result, when the dt re pooled, the expected, overll RR of the composite outcome compring LABA 1 ICS with ICS only becomes 1.05 (95% CI, ). Thus, unknowingly, the mximl RR of 1.32 determined to estblish sfety could possibly be underestimted to Under the null hypothesis of no excess risk, the expected RR of 1.0 is reduced to 0.8 (e-tble 1). Tble 2 displys the results of sensitivity nlyses tht vried the degree of LABA discontinution t rndomiztion; nmely, ssuming tht 30%, 50%, nd 70% of the recruited ptients were on LABA t rndomiztion. It shows tht with incresing discontinution rtes, the upper bound of the CI rtificilly decreses further from the trgeted nd desired vlue of 2 for the reltive risk. Effect of the Primry Outcome Definition The second methodologic issue rises from the primry outcome definition in these trils, nmely, composite end point tht includes sthm-relted deth, intubtion, or hospitliztion occurring during the 6-month follow-up period. While the FDA recognizes tht the results will be dominted by the hospitliztion component of the outcome, it is useful to nticipte the effect of this dominnce. 9 We used dt from pooled nlysis of formoterol trils nd metnlysis tht provided dt on person-yers of exposure nd the corresponding incidences of sthm deths. 6,7 There were seven nd three sthm deths under LABA 1 ICS nd one nd no deths under ICS only, respectively, for the two nlyses, corresponding to pooled incidences of 0.33 sthm deths per 1,000 persons per yer under LABA 1 ICS nd 0.07 under ICS only. Applying these sthm-deth rtes, we cn expect to observe totl of five sthm deths mong the 46,800 subjects cross the four trils: four under LABA 1 ICS nd one under ICS only (RR, 4.0; 95% CI, ). Even sevenfold increse in the incidence of sthm deth (seven vs one sthm deths) with LABA 1 ICS will not led to sttisticlly significnt effect (RR, 7.0; 95% CI, ). Tble 3 provides expected results under three plusible scenrios of 1.13, 1.00, nd 0.75 for the RR of sthm hospitliztion or intubtion estimted from met-nlyses tht compred LABA 1 ICS with ICS. 15 With ll three scenrios, Tble 3 illustrtes the dominnce of sthm Tble 1 Expected Rtes Rtios of Composite Asthm Outcome in Any One of the Four Adult/Adolescent Trils Resulting From the Effect of LABA Discontinution t Rndomiztion, Assuming Tht 50% of Ptients Will Alredy Be on LABA t the Time of Rndomiztion Strtifiction by LABA Discontinution ICS 1 LABA ICS Only Rte Rtio (95% CI) No LABA discontinution effect: ll subjects Subjects 5,850 5,850 Person-y 2,925 2,925 Expected number of events ( ) LABA discontinution effect: no prior LABA use (50%) Subjects 2,925 2,925 Person-y 1,462 1,462 Expected number of events Discontinued LABA use (50%) Subjects 2,925 2,925 Person-y 1,462 1,462 Expected number of events All subjects Subjects 5,850 5,850 Person-y 2,925 2,925 Expected number of events ( ) Dt given s No., unless otherwise indicted. ICS 5 inhled corticosteroid; LABA 5 long-cting b-gonist Commentry

4 Tble 2 Expected Rte Rtios of Composite Asthm Outcome in Any One of the Four Adult/Adolescent Trils Resulting From the Effect of LABA Discontinution t Rndomiztion in 30%, 50%, nd 70% of Ptients LABA Discontinution Scenrios ICS 1 LABA ICS Only Rte Rtio (95% CI) Subjects 5,850 5,850 Person-y 2,925 2,925 Expected No. of events under LABA discontinution in: None of the subjects ( ) 30% of the subjects ( ) 50% of the subjects ( ) 70% of the subjects ( ) Dt given s No., unless otherwise indicted. See Tble 1 legend for expnsion of bbrevitions. hospitliztion on the composite outcome nd the negligible effect of fourfold increse in the rte of sthm deth. Effect of Multiple Trils The third issue rises from the inference involving four trils of the sme question. The 90%-power clcultion to rule out reltive risk of 2.0 for the composite outcome when, in truth, there is no increse in the risk, rrived t smple size of 11,700 ptients with sthm per study. Thus, for ech study, the 90% power implies tht there is only 10% probbility tht the study will produce flse result with the upper bound of the CI lrger thn 2.0 (which will deem the drug s unsfe ), when in truth there is no increse in the risk. While this clcultion pplies ppropritely to ech single study, it remins tht ll four studies will be ssessed together by the FDA, so tht the study-specific, 90%-power clcultion will not pply to ll studies s group. From this perspective, there is, in fct, probbility of 34% [ (0.90) 4 ] tht simply by chnce, t lest one study will not show noninferior outcome with the upper bound of the CI Including the fifth tril in children, this probbility increses to 41%. Consequently, becuse of this simultneous repliction of identicl studies, it becomes quite likely tht simply by chnce, one of the study drugs will be deemed unsfe, when, in truth, there is no increse in the risk. Figure 1 illustrtes simultion of the four identicl, 6-month trils of this smple size nd event rtes, showing tht under the null hypothesis, the upper bound of the CI for Tril 3 crosses the sfety limit of 2.0 purely by chnce; its corresponding LABA would, thus, be flsely judged s unsfe. Conclusion We discussed three methodologic issues tht will inherently ffect the risk estimtes produced by the Tble 3 Expected Rtes Rtios of Composite Asthm Outcome nd Components, Combining All Four Trils, for Three Different Scenrios of the Effect of LABA 1 ICS on Asthm Hospitliztion or Intubtion Bsed on Dt From Met-Anlyses of Rndomized Trils 15 Scenrios of Effect of Asthm Admission ICS 1 LABA ICS Only Rte Rtio (95% CI) Subjects 23,400 23,400 Person-y 11,700 11,700 Scenrio 1 Expected number of events of: Asthm deths ( ) Asthm hospitliztion/intubtion ( ) Composite outcome ( ) Scenrio 2 Expected number of events of: Asthm deths ( ) Asthm hospitliztion/intubtion ( ) Composite outcome ( ) Scenrio 3 Expected number of events of: Asthm deths ( ) Asthm hospitliztion/intubtion ( ) Composite outcome ( ) Dt given s No., unless otherwise indicted. See Tble 1 legend for expnsion of bbrevitions. Rte rtios of sthm hospitliztion or intubtion estimted from met-nlyses re 1.13, 1.00, nd 0.75 for scenrios 1, 2, nd 3, respectively. 15 journl.publictions.chestnet.org CHEST / 143 / 5 / MAY

5 Figure 1. A single simultion of the expected dt for the four dult/dolescent trils under the null hypothesis of no effect (rte rtio 5 1) with corresponding estimted rte rtios nd 95% CIs for the composite sthm outcome. The CIs for trils 1, 2, nd 4 do not cross the threshold vlue of 2, so tht the corresponding long-cting b -gonists (LABAs) would be judged s noninferior, but the CI for tril 3 does cross the threshold vlue of 2, so the corresponding LABA could not be judged s noninferior. FDA-mndted trils nd their interprettion. First nd foremost, in view of the effect of LABA discontinution from ptients lredy using these drugs t enrollment nd existing dt from met-nlyses, the reltive risk for ech study could be underestimted by fctor of t lest 20%. While 20% does not, t first glnce, pper to be mjor reduction, it is noteworthy tht the highest vlue of 1.32 for the estimted reltive risk to deem LABAs s sfe, corresponding to the upper limit of the CI just below the threshold vlue of 2, will be underestimted to 1.05 with the discontinution effect. This underestimtion will rtificilly mke it more difficult to detect rel risk. Second, in view of the nture of the composite sthm outcome dominted by sthm hospitliztion nd the existing dt on hundreds of rndomized trils involving tens of thousnds of ptients, the studies will likely show no incresed risk of the composite outcome. However, sthm deths, dwrfed in the composite outcome, my show n incresed risk with the LABA 1 ICS combintion, but only result of nine deths to one will result in sttisticlly significnt increse in sthm deths; even numericlly worrisome spred of seven deths to one will be interpreted s sttisticlly uncertin. Finlly, in view of the four identicl trils currently being conducted in dults nd dolescents, the role of chnce rising from such repliction hs not been considered in the decision process. Indeed, ech tril is designed with 10% probbility tht the study LABA is found unsfe when, in truth, it is sfe. However, this becomes 34% probbility tht one of the four trils will suggest tht the study LABA is unsfe when, in truth, it is sfe; this probbility rises to over 40% if we include the fifth tril in children. If one of the trils psses the predetermined threshold risk limit, it will be impossible to conclude whether this represents rel effect of the specific LABA studied in the tril or simply bd luck. In ll, inherent fetures of the study design of the FDA-mndted trils to ssess the sfety of LABA dded to ICS therpy cn led to inccurte results, possibly conceling genuine risk of increse in sthmrelted deths. The identicl replicted design is lso thret to one or more individul LABAs, which could be incriminted simply s result of ill luck. Thus, it is quite likely tht the clinicl trils will not, in the end, clrify the sfety risk ssocited with LABAs, 9 but rther bring more uncertinty. These multiple, identicl, FDA-mndted trils represent, for the regultory gencies, new prdigm tht clls for new decision tools. In view of the potentil impediments of this pproch, the FDA my wish to preempt such complexities by convening group of scientists, including experts in the design nd nl ysis of rndomized trils, tht could rrive t preset decision rules regrding the interprettion of the dt resulting from these criticl sfety trils. Acknowledgments Finncil/nonfinncil disclosures: The uthors hve reported to CHEST the following conflicts of interest: Dr Suiss hs prticipted in dvisory bords nd s speker for ll mnufcturers of the long cting b -gonists under study, nmely, AstrZenec plc, GlxoSmithKline plc, Merck & Co Inc, nd Novrtis AG; nd is on the dt monitoring committee of one of the trils on the sfety of formoterol fumrte (Novrtis AG). Dr Ariel hs prticipted in clinicl trils, dvisory bords, nd s speker for ll mnufcturers of the long cting b -gonists under study, nmely AstrZenec plc; GlxoSmithKline plc; Merck & Co, Inc; nd Novrtis AG. Other contributions: This pper is the outcome of session t the conference of the Isreli Society of Pulmonology, held in December 2011 in Eilt, Isrel. Additionl informtion: The e-tble cn be found in the Supplementl Mterils re of the online rticle Commentry

6 References 1. Globl strtegy for sthm mngement nd prevention. Globl Inititive for Asthm website. uplods/users/files/gina_report_2012.pdf. Updted Accessed Februry 21, Cstle W, Fuller R, Hll J, Plmer J. Serevent ntionwide surveillnce study: comprison of slmeterol with slbutmol in sthmtic ptients who require regulr bronchodiltor tretment. BMJ ;306 (6884 ): Nelson HS, Weiss ST, Bleecker ER, Yncey SW, Dorinsky PM ; SMART Study Group. The Slmeterol Multicenter Asthm Reserch Tril: comprison of usul phrmcotherpy for sthm or usul phrmcotherpy plus slmeterol. Chest ;129 (1 ): Levenson M. Long-cting bet-gonists nd dverse sthm events met-nlysis. Sttisticl briefing pckge for joint meeting of the Pulmonry-Allergy Drugs Advisory Committee. Accessed Mrch 8, McMhon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age nd risks of FDA-pproved long-cting b 2 -drenergic receptor gonists. Peditrics ; 128 ( 5 ): e1147-e Sers MR, Ottosson A, Rdner F, Suiss S. Long-cting betgonists: review of formoterol sfety dt from sthm clinicl trils. Eur Respir J ;33 (1 ): Rodrigo GJ, Morl VP, Mrcos LG, Cstro-Rodriguez JA. Sfety of regulr use of long-cting bet gonists s monotherpy or dded to inhled corticosteroids in sthm: systemtic review. Pulm Phrmcol Ther ;22 (1 ): Chowdhury BA, Dl Pn G. The FDA nd sfe use of longcting bet-gonists in the tretment of sthm. N Engl J Med ;362 (13 ): Chowdhury BA, Seymour SM, Levenson MS. Assessing the sfety of dding LABAs to inhled corticosteroids for treting sthm. N Engl J Med ;364 (26 ): Sers MR. The FDA-mndted tril of sfety of long-cting bet-gonists in sthm: finlity or futility? Thorx ; 68 (2 ): Schumi J, Wittes JT. Through the looking glss: understnding non-inferiority. Trils ;12 : Fleming TR. Current issues in non-inferiority trils. Stt Med ;27 (3 ): Brozek JL, Krft M, Krishnn JA, et l. Long-cting b2-gonist step-off in ptients with controlled sthm: systemtic review with met-nlysis. Arch Intern Med ;172 (18 ): Suiss S, Ernst P, Vndemheen KL, Aron SD. Methodologicl issues in therpeutic trils of COPD. Eur Respir J ; 31 (5 ): Rodrigo GJ, Cstro-Rodríguez JA. Sfety of long-cting b gonists for the tretment of sthm: clering the ir. Thorx ;67 (4 ): journl.publictions.chestnet.org CHEST / 143 / 5 / MAY