Lung cancer is the second-most common form of cancer

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1 At Glnce Originl Reserch Prcticl Implictions p SP7 Author Informtion p SP15 Full text nd PDF Web exclusive eappendix Lung Cncer: Copyments nd Behvior Following Erlotinib Formulry Tier Chnge Nicole M. Engel-Nitz, PhD; Sch Strm-Hong, PhD; Feng Co, PhD; nd Crolin M. Reyes, PhD ABSTRACT Objectives: To exmine how moving erlotinib from formulry tier 3 to tier 2 ffected lung cncer ptients copyments nd tretment behvior. Methods: The phrmcy benefi t chnge occurred on September 1, Medicl nd phrmcy clims from lrge US helthcre dtbse were retrospectively nlyzed; ptients ged >18 yers with evidence of lung cncer (My 1, 2004, to April 30, 2009) were seprted into 3 cohorts bsed on erlotinib initition/ termintion. The study period consisted of the index dte (fi rst fi lled erlotinib prescription), the bseline period (6 months before index dte), nd vrible follow-up period (from index dte until 1 yer post-index, helth pln disenrollment, or Mrch 30, 2009, whichever occurred erlier). Ptients hd no evidence of erlotinib use t bseline nd >2 qulifying lung cncer medicl clims (primry position) on seprte service dtes. Results: Although men copyments decresed following tier chnge, medin copyments, which hd risen signifi cntly in the 4 yers before tier chnge, dropped only to the level of 3 to 4 yers before tier chnge. Following the formulry chnge, signifi - cntly more erlotinib prescriptions were fi lled. Erlotinib dherence differences were not signifi cntly ssocited with formulry position (tier 3 vs tier 2). However, bsolute copyment level ws ssocited with dherence; ptients with <$30 copyments were more likely to dhere to erlotinib therpy thn ptients with $45 to $60 copyments. Furthermore, ptients were 21% less likely to discontinue tretment fter the tier chnge compred with before. Conclusions: Erlotinib formulry chnge resulted in lung cncer ptients hving lower copyments with evidence of higher tretment persistence. (Am J Phrm Benefi ts. 2012;4(Specil Issue):SP6-SP16) Lung cncer is the second-most common form of cncer in both men nd women 1 nd is the leding cuse of cncer-relted mortlity in the United Sttes. 2 It ws estimted tht more thn 219,440 new cses of lung disese were dignosed in 2009, with 159,690 deths. 1 Of the lung cncers, pproximtely 80% re non smll cell lung cncer (NSCLC) types. 3 For ptients with dvnced NSCLC (stges IIIb nd IV) for whom rdition nd/or surgicl resection re no longer vible option, first-line tretment involves intrvenous chemotherpy gents nd my be combined with rdiotherpy nd/or other trgeted biologic gents. 4 However, pproximtely 30% to 40% of ptients with dvnced NSCLC fil to respond dequtely to first-line chemotherpy nd re cndidtes for second-line therpy. 5 For ptients who hve loclly dvnced or metsttic NSCLC nd hve hd filure of t lest 1 prior chemotherpy regimen, erlotinib (Trcev; Genentech, Inc, nd OSI Phrmceuticls, Inc) ws pproved in November 2004 s monotherpy. 6 Erlotinib is n orl epiderml growth fctor receptor tyrosine-kinse inhibitor (TKI), nd in clinicl trils, resulted in 2-month increse in survivl for lung cncer ptients. 7 With the use of self-dministered orl chemotherpy drugs, concern hs been rised regrding ptient dherence nd persistence. 8 In prticulr, underdosing due to either nondherence or dose reductions/delys my result in lower plsm drug levels nd subsequently incresed risk of cncer relpse nd progression. 9,10 Furthermore, nondherence hs been ssocited with higher medicl service utiliztion. 11 Fctors tht hve been found to modify mediction dherence include ptient chrcteristics (femle sex 12 nd younger ge ) nd comorbid conditions (incresed depression symptoms 13 or higher Chrlson Comorbidity Index score 15 ), mediction dosing 12 nd type, 14 clinicin drug choice nd ptient eduction, 14 nd finncil spects of the helthcre system 12,14,16 including higher out-of-pocket expenses 13,15 nd copyment. 17 However, it is uncler whether these fctors SP6 The Americn Journl of Phrmcy Benefi ts Specilty Phrmcy 2012

2 Impct of Erlotinib Formulry Tier Chnge ffect ptients dherence to tretment for diseses such s lung cncer with high nd rpid mortlity s much s they influence mediction use for the tretment of chronic diseses. Most orl chemotherpy dherence reserch hs been conducted on either brest cncer ptients 15,16 or chronic myeloid leukemi ptients ,18 In one study of NSCLC ptients, Greer nd collegues 19 identified smoking behvior nd nxiety s predictors of infusion-bsed chemotherpy regime dose delys/reductions; for the 14% of their ptients who were lso receiving n orl epiderml growth fctor receptor TKI, dherence dt were not presented. Furthermore, Rmsey nd collegues 20 noted in their evlution of lung cncer chemotherpy use within lrge US insurnce clims dtbse tht erlotinib prescriptions were incresingly filled nd tht erlotinib ws the second most commonly used second- nd third-line tretment for refrctory lung cncer. These reserchers lso evluted cost utiliztion nd grouped orl erlotinib mediction costs with other outptient phrmcy costs. Erlotinib therpy resulted in phrmcy costs of $3888 nd $1290 per-ptient-per-month for second- nd third-line outptient therpy, respectively. During the November 2004 December 2006 time frme of the study by Rmsey nd collegues, 20 erlotinib ws clssified s tier 3 drug on the prescription drug list for helthcre pln insurnce reimbursement. However, this helthcre pln moved erlotinib to tier 2 strting on September 1, This nturl experiment provided the opportunity to exmine whether the high copyments nd other spects of finncil burden tht hve been ssocited with dherence in other mediction studies lso ffect dherence with erlotinib for ptients with NSLC. The purpose of this retrospective study ws to exmine the impct of the erlotinib tier chnge on ptient copyments nd its impct on tretment behvior mong ptients with lung cncer. PAT IENTS AND METHODS Study Design nd Eligibility Criteri This retrospective nlysis used medicl nd phrmcy clims to identify ptients from lrge US helthcre clims dtbse ffilited with OptumInsight who hd evidence of lung cncer nd hd filled prescriptions for erlotinib. Medicl nd phrmcy clims, s well s enrollment informtion from My 1, 2004, to Mrch 30, 2009, were used. A vrible follow-up period (until the erliest of 1 yer following index dte, disenrollment, deth, or Mrch 30, 2009) ws used to ssess copyments, discontinution, nd dherence with erlotinib. The phrmcy PRACTICAL IMPLICATIONS After erlotinib ws moved from tier 3 to tier 2 on helth pln s phrmcy benefi ts formulry, the impct on lung cncer ptients copyments nd tretment behviors ws evluted. Men copyments decresed; however, medin copyments, which hd risen signifi cntly in the 4 yers before the chnge, dropped only to the level of 3 to 4 yers before the chnge. Erlotinib dherence differences were not signifi cntly ssocited with formulry position; however, bsolute copyment level ws ssocited with dherence. Erlotinib formulry chnge resulted in lung cncer ptients hving lower copyments with evidence of higher tretment persistence. benefit chnge tht moved erlotinib from tier 3 to tier 2 occurred on September 1, A 6-month bseline period (bseline period) before the first filled prescription dte (index dte) ws used to identify ptient chrcteristics. The follow-up period ws from the index dte until either disenrollment from the helth pln or Mrch 30, 2009, whichever occurred erlier, nd ws used to ssess erlotinib use nd outcomes (Figure 1). Eligibility Criteri Eligible ptients hd erlotinib prescriptions filled from November 1, 2004, through December 31, Ptients were lso required to hve continuous eligibility in commercil helthcre pln with both medicl nd phrmcy benefits during the bseline period through the follow-up period. Ptients were 18 yers or older with no evidence of erlotinib use during the bseline period. Dignostic evidence of lung cncer in the medicl clims ws bsed on Interntionl Clssifiction of Diseses, Ninth Revision, Clinicl Modifiction codes occurring t ny time during the study period. Ptients were further required to hve either t lest 2 qulifying medicl clims for lung cncer with codes of (mlignnt neoplsm of bronchus nd lung) or 163.x (mlignnt neoplsm of pleur) in the primry position on seprte service dtes within the study period, or t lest 1 qulifying medicl clim for lung cncer with codes of or 163.x in the primry position plus t lest 1 qulifying medicl clim for lung cncer with codes (crcinom in situ of bronchus nd lung other specified site, including pleur or unspecified site) in the primry position. All qulifying clims were required to occur on seprte service dtes within the study period. Ptients were required to hve evidence of chemotherpy use during the bseline period bsed on pproprite Helthcre Common Procedure Vol. 4, Specil Issue The Americn Journl of Phrmcy Benefi ts SP7

3 Engel-Nitz Strm-Hong Co Reyes Figure 1. Study Design to Evlute the Impct of Erlotinib Formulry Tier Chnge Prescription Drug List Tier Chnge My 1999 My 2004 Nov 2004 Sep 2007 Jun 2008 Dec 2008 Mr 2009 Rnge of Ptient Identifiction Period Ptient identifiction period index dte = dte of first filled prescription for erlotinib Rnge of 6-Month Bseline Period Bseline period = continuous enrollment with medicl nd phrmcy benefits for 6 months prior to index dte Rnge of Vrible 1-Yer Follow-up Period Follow-up period = vrible follow-up period from the index dte up until 1 yer post-index, disenrollment from the helth pln or Mrch 30, 2009 Pre-Tier Subjects Initited nd ended erlotinib use prior to September 1, 2007 Post-Tier Subjects Initited erlotinib use fter September 1, 2007 Crossover Subjects Initited erlotinib use prior to September 1, 2007, with follow-up beyond September 1, 2007 Code System chemotherpy codes (eappendix, vilble t ). Lbortory clims either t lbortory sites or for lbortory services were excluded. Tretment Cohorts Ptients were ctegorized into 3 nlytic cohorts bsed on the period of time when they initited nd ended erlotinib use. Ptients who strted (index dte) nd ended use of erlotinib before September 1, 2007, were designted s pre-tier ptients. Ptients with index dtes occurring fter September 1, 2007, were designted s post-tier ptients. Ptients strting use of erlotinib before September 1, 2007, nd continuing erlotinib use beyond this sme dte were designted s crossover ptients. Outcomes Mesures Ptient demogrphics including ge, sex, geogrphic loction, nd enrollment dtes were used. Clinicl chrcteristics were evluted nd included the following: Chrlson Comorbidity Index score; dignosis of dditionl disese nd tumor types t bseline nd follow-up; use of rdition, surgery, or other chemotherpy t bseline nd follow-up; nd mortlity. Erlotinib copyment ws defined s the men monthly prescription copyment cost (per 30 dys) nd ws clculted s the totl out-of-pocket cost divided by totl number of 30-dy prescriptions (ccounting for mil order). For prescription counts, totl number of prescriptions ws counted, with prescriptions filled by mil order credited s multiple prescriptions bsed on dys of supply. Erlotinib dherence ws defined s the totl dys of supply of ll prescription fills between the first nd lst fill divided by the number of dys between the first nd lst fill; dherence vlues of >80% were used s cutoff vlue (commonly used in the literture 21,22 ). This definition excluded ptients with just 1 prescription fill. Erlotinib persistence (or discontinution) ws defined s 60-dy gp in therpy between the run-out dte of the mediction fill nd the subsequent refill. Sttisticl Anlysis Descriptive sttistics were generted for bseline ptient chrcteristics strtified by tier-chnge cohort. Comprisons of bseline chrcteristics mong tier-chnge cohorts were ssessed using the t test for continuous vribles nd the χ 2 test for ctegoricl vribles. Erlotinib men copyments nd men dherence rtes in the pre-tier nd post-tier cohorts were compred by using t tests; Wilcoxon rnk-sum tests were used to compre medin copyments. Pired t tests were used to compre men copyments, nd Wilcoxon signed-rnk tests were SP8 The Americn Journl of Phrmcy Benefi ts Specilty Phrmcy 2012

4 Impct of Erlotinib Formulry Tier Chnge used to compre medin copyments for the crossover cohort before nd fter the tier chnge. Rtes of tretment discontinution were compred by using χ 2 tests. Due to smll smple size nd difficulty in determining intke of orl doses before nd fter tier chnge, the differences within the crossover cohort for erlotinib use were not determined. The dichotomous mesure of dherence (>80%) to tretment ws ssessed using multivrite logistic regression; persistence ws ssessed using Cox proportionl hzrds modeling. Both compred pretier nd post-tier cohorts on risk of tretment use (either dherence or discontinution) nd were djusted for ge, sex, Chrlson Comorbidity Index score, nd prior surgery or rdition. For the primry nlysis, the primry independent vribles of interest were the cohort (pre-tier nd post-tier) nd ptient copyment for erlotinib. Sensitivity Anlysis For sensitivity nlysis, the smple ws restricted to ptients with similr follow-up times nd included ptients with 1 or more prescriptions. Prescription use (n lterntive dherence mesure) ws defined s totl supply divided by length of follow-up with dherence vlues of >80% used s cutoff. Multivrite logistic regression ws used to ssess prescription use, nd tretment discontinution ws ssessed using Cox proportionl hzrds modeling. Both models compred cohorts on risk of tretment utiliztion (use or discontinution) nd were djusted for ge, sex, Chrlson Comorbidity Index score, nd prior surgery or rdition. For the sensitivity nlysis, the independent vrible of interest ws the cohort (pre-tier nd post-tier). RESULTS Popultion Demogrphics We identified 1460 ptients with lung cncer who hd filled t lest 1 erlotinib prescription from November 1, 2004, through December 31, Of these, 949 ptients received erlotinib before the tier chnge (pre-tier cohort), 410 received erlotinib fter the tier chnge (post-tier cohort), nd 101 ptients received erlotinib both before nd fter the tier chnge (crossover cohort). As shown in Tble 1, ptients in the post-tier cohort were slightly older compred with the pre-tier cohort ptients (60.91 yers vs yers; P =.0212), lthough the difference in distribution of ge groups ws not significnt. Sex distribution ws similr between the pre-tier nd post-tier cohorts. Ptients in the post-tier cohort hd significntly fewer other tumor types identified; cross ll cohorts, the most common type of other tumor ws connective tissue/brest cncer (13.6%). By design, there were significnt differences between the cohorts for index dte. The post-tier group hd significntly fewer clims-bsed deths compred with pre-tier cohort; however, this my be due to the longer follow-up period in the pre-tier cohort. During the bseline period, ptients in the post-tier cohort hd significntly fewer other chemotherpies nd rdition nd more surgeries compred with the pre-tier cohort ptients. Although post-tier ptients hd significntly lower men Chrlson Comorbidity Index score (7.29 vs 7.58; P =.0008), the difference of 0.29 ws considered cliniclly insignificnt. Copyments Erlotinib men (Figure 2A) nd medin (Figure 2B) copyment levels were compred cross yers of erlotinib initition. The overll difference between the men copyment of post-tier ptients nd the men copyment of pre-tier ptients ws not sttisticlly significnt, lthough the overll medin copyment ws significntly lower for post-tier ptients thn for pre-tier ptients. For post-tier ptients who initited erlotinib in 2007, both men nd medin copyments were significntly lower compred with those for pre-tier ptients. Medin, but not men, copyment differed for post- nd pre-tier ptients inititing erlotinib in 2004, 2005, or For ptients in the crossover cohort, men (P <.05) nd medin (P <.001) copyments were significntly lower fter the tier chnge compred with before the tier chnge. Prescription Counts Erlotinib men (Figure 3A) nd medin (Figure 3B) prescription counts were compred cross yers nd by yer of erlotinib initition. The verge number of erlotinib prescriptions ppered to vry cross the pretier nd post-tier cohorts when strtified by the yer of erlotinib initition, lthough differences were not sttisticlly significnt when ll yers were combined. The men number of prescriptions ws 3.37 for the pre-tier cohort nd 3.41 for the post-tier cohort (medin of 2 prescriptions for both the pre-tier nd post-tier cohorts) when ll yers were combined. Among post-tier cohort ptients who initited erlotinib therpy in 2007, significntly more prescriptions were filled (3.41 prescriptions) compred with those for pre-tier cohort ptients who initited erlotinib in 2007 (2.39 prescriptions; P =.0416). Primry Adherence nd Persistence Anlysis Pre-tier nd post-tier ptients hd similr rtes of dherence to erlotinib (84.45% nd 83.75%, respectively; P = Vol. 4, Specil Issue The Americn Journl of Phrmcy Benefi ts SP9

5 Engel-Nitz Strm-Hong Co Reyes Tble 1. Ptient Demogrphics nd Disese/Tretment Chrcteristics Chrcteristic Pre-Tier (n = 949) Post-Tier (n = 410) Crossover (n = 101) Pre-Tier vs Post-Tier P Age, men (SD), y (10.44) (10.30) (9.68).0212 Age group, n (%), y (0.74) 3 (0.73) 2 (1.98) (6.95) 15 (3.66) 3 (2.97) (24.13) 89 (21.71) 28 (27.72) (39.73) 174 (42.44) 43 (42.57) (18.76) 83 (20.24) 16 (15.84) >75 92 (9.69) 46 (11.22) 9 (8.91) Sex, n (%).7719 Mle 478 (50.37) 203 (49.51) 38 (37.62) Femle 471 (49.63) 207 (50.49) 63 (62.38) Other tumor types, n (%) 445 (47.95) 171 (41.71) 46 (45.54).0342 Connective/brest, n (%) 138 (14.54) 45 (10.98) 16 (15.84).0771 Index yer, n (%) < (3.90) 0 (0.00) 0 (0.00) (46.26) 0 (0.00) 10 (9.90) (34.04) 0 (0.00) 28 (7.72) (15.81) 118 (28.78) 63 (62.38) (0.00) 292 (71.22) 0 (0.00) Other chemotherpy, n (%) Bseline period 783 (82.51) 314 (76.59) 85 (84.16).0111 Follow-up period 456 (48.05) 186 (45.37) 59 (58.42).3629 Rdition therpy, n (%) Bseline period 413 (43.52) 156 (38.05) 44 (43.56).0606 Follow-up period 311 (32.77) 126 (30.73) 41 (40.59).4600 Surgery, n (%) Bseline period 39 (4.11) 31 (7.56) 9 (8.91).0082 Follow-up period 20 (2.11) 7 (1.71) 3 (2.97).6275 Disese in bseline period, n (%) Metsttic disese 745 (78.50) 315 (76.83) 61 (60.40).4940 Brin/other CNS 111 (11.70) 29 (7.07) 5 (4.95).0101 Disese in follow-up period, n (%) Metsttic disese 684 (72.08) 303 (73.90) 58 (57.43).4882 Brin/other CNS 72 (7.59) 22 (5.37) 5 (4.95).1386 Deth (clims-bsed) in follow-up period, n (%) 492 (51.84) 172 (41.95) 32 (31.68).0008 Chrlson Comorbidity Index score, men (SD) 7.58 (1.94) 7.29 (2.04) 7.32 (2.48).0211 CNS indictes centrl nervous system; SD, stndrd devition..7917; Tble 2). After multivrite djustments (Tble 3), compred with ptients with copyments of <$30, ptients with copyments of $45 to <$65 hd significntly decresed odds of dherence (odds rtio [OR] 0.54, 95% confidence intervl [CI] ). Differences between the lowest-copyment group nd ptients with copyments of $30 to $45 (OR 0.67, 95% CI ) or >$65 (OR 0.52, 95% CI ) were not sttisticlly significnt. For erlotinib persistence (representing drug discontinution), pre-tier ptients were more likely thn post-tier ptients to discontinue erlotinib (44.78% vs 37.07%; P =.008) (Tble 3). In multivrite nlysis, post-tier ptients SP10 The Americn Journl of Phrmcy Benefi ts Specilty Phrmcy 2012

6 Impct of Erlotinib Formulry Tier Chnge Figure 2. Erlotinib Copyment Levels: Men (Pnel A) nd Medin (Pnel B) Costs A Men Ptient Copyment per 30-Dy Prescription, $ $121 $77 $68 $68 Pre-Tier Versus Post-Tier Cohort $92 $52 $90 Within Crossover Cohort $75 $44 Pre-Tier Cohort (n = 949) Post-Tier Cohort (n = 410) P <.05 0 All Yers All Yers Yer Erlotinib Initited B Medin Ptient Copyment per 30-Dy Prescription, $ $40 $30 Pre-Tier Versus Post-Tier Cohort $43 $30 $42 $40 $50 Within Crossover Cohort All Yers All Yers Yer Erlotinib Initited $40 $25 were 21% less likely to discontinue tretment thn pretier ptients (hzrd rdio 0.79, 95% CI ). Sensitivity Anlysis Sensitivity nlysis of ptients prescription use found tht 41.94% of the pre-tier cohort nd 47.56% of the post-tier cohort were dherent using this lterntive definition (Tble 4), with no sttisticlly significnt difference in dherence between pre-tier nd post-tier cohorts (P =. 0551). After multivrite djustment, the logistic regression model showed no sttisticlly significnt difference in dherence between pre-tier nd post-tier cohorts (P =.0815; Tble 5). Erlotinib copyments nd ptient totl outof-pocket expenses hd significnt effect on prescription use nd persistence (both P <.001; Tble 5). In the sensitivity nlysis of erlotinib use, 44.76% of the pre-tier cohort nd 37.07% of the post-tier cohort discontinued tretment (Tble 4) when the smple ws restricted to ptients with similr follow-up times nd 1 or more prescriptions. After multivrite nlysis, the effect of tretment cohort ws no longer sttisticlly significnt (P =.059; Tble 5). DISCUSSION Our results show tht for 2007, when erlotinib therpy ws initited both men nd medin copyments were significntly lower for ptients who strted erlotinib fter the chnge from tier 3 to tier 2; this finding is further supported in the crossover cohort. Although medin copyments hd incresed from 2005 to 2007, these rtes were lower compred with erlotinib copyments in Following the insurnce formulry chnge from tier 3 to tier 2, significntly more prescriptions were filled for erlotinib on verge. Although the formulry chnge ws not ssocited with significnt differences in dherence, ptients with copyments of <$30 were more likely to be dherent to erlotinib compred with ptients with copyments of $45 to $60. Furthermore, post-tier ptients were 21% less likely to discontinue tretment thn pre-tier ptients. Of note, we used the sme lrge Vol. 4, Specil Issue The Americn Journl of Phrmcy Benefi ts SP11

7 Engel-Nitz Strm-Hong Co Reyes Figure 3. Erlotinib Prescriptions: Men (Pnel A) nd Medin (Pnel B) Counts A 7 Pre-Tier Versus Post-Tier Cohort Within Crossover Cohort Men Prescription Counts per Yer Pre-Tier Cohort (n = 949) Post-Tier Cohort (n = 410) P <.05 B Medin Prescription Counts per Yer All Yers All Yers Yer Erlotinib Initited Pre-Tier Versus Post-Tier Cohort Within Crossover Cohort All Yers All Yers Yer Erlotinib Initited US insurnce clims dtbse used by Rmsey nd collegues. 20 This ws the first study of erlotinib to evlute the effect of copyments on tretment behviors. Previous studies of erlotinib did not seprte copyments from either other phrmcy clim expenses 20 or other orl nticncer tretments. 23 Our dt show tht copyments were significntly lower in 2007 (men $48 vs $121; medin $25 vs $43) following the formulry chnge. Notbly, our dherence rtes were higher (83%-85%) when ptients with only 1 prescription fill were removed nd dherence ws defined by the proportion of dys covered between the first nd lst erlotinib fill. Comprisons with other erlotinib studies re limited s these re either currently ongoing 24 or did not seprte TKI tretments nd only looked t infusion chemotherpy dosing dherence. 19 Our dherence rtes were higher thn those reported for rel-world dherence to orl brest cncer drugs (50%-80% of ptients when the definition included ptients with t lest 1 prescription or microelectronic monitoring system ws used). 25 However, the definition of dherence vries cross studies. Other reserchers hve used lterntive dherence definitions, 26 including number of ptient prescriptions filled divided by number of physicin prescriptions written 10 nd dys of supply divided by the length of the study period. 11,12 In our sensitivity nlysis, erlotinib prescription use rtes vried from 41% to 48% when defined by >80% dherence nd including ptients with 1 or more prescriptions. Our lower prescription use rtes my be due to prescribing over multiple yers, since dherence rtes tend to drop over longer durtion of prescribing. 27,28 Furthermore, the inclusion of ptients who hd only 1 prescription filled my hve resulted in lower dherence rtes. Our study found tht 37% to 45% of ptients discontinued erlotinib therpy nd the difference between the pre-tier SP12 The Americn Journl of Phrmcy Benefi ts Specilty Phrmcy 2012

8 Impct of Erlotinib Formulry Tier Chnge Tble 2. Primry Adherence nd Persistence Anlysis Cohort Ptients Eligible for Anlysis With 2 Erlotinib Prescriptions Filled, No. (%) No. (%) Undjusted Sttistics Pre-Tier vs Post-Tier P Adjusted Model Sttistics Hzrd Rtio 95% CI Erlotinib dherence b Pre-tier 611 (64.38) 516 (84.45) Post-tier 277 (67.56) 232 (83.75) Crossover 101 (100.00) 70 (69.31) NA NA NA Erlotinib persistence c Pre-tier 425 (44.76) Post-tier 152 (37.07) Crossover 56 (55.45) NA NA NA CI indictes confi dence intervl; NA, not pplicble. Logistic regression nd Cox proportionl hzrds models were djusted for ge, sex, verge erlotinib copyment, Chrlson Comorbidity Index score, nd prior surgery or rdition. b Percent with dherence >80%, bsed on the proportion of dys covered between the fi rst nd lst fi ll for erlotinib. Excluded ptients with 1 fi ll. c Defi ned s discontinution, bsed on time to discontinution of erlotinib, llowing for 60-dy gp in therpy between the run-out dte of the mediction nd the subsequent fi ll. Tble 3. Primry Multivrite Models for Adherence nd Persistence Logistic Regression Model for Adherence (n = 807) Cox Proportionl Hzrds Model for Persistence (n = 1359) Vrible Odds Rtio SE 95% CI P Hzrd Rtio SE 95% CI P Tretment cohort (reference: pre-tier) Averge erlotinib copyment $30 to <$45 (reference: $0 to <$30) $45 to <$ >$ Age, y > Mle Bseline rdition therpy Bseline surgery Chrlson Comorbidity Index score Dys in follow-up CI indictes confi dence intervl; SE, stndrd error. nd post-tier cohorts ws significnt. Those rtes re higher thn the 12.8% discontinution rte reported by Streeter nd collegues. 23 In ddition, our discontinution rtes re higher thn the 15% to 32% rte reported cross 3 studies evluting tmoxifen discontinution in brest cncer ptients In generl, Streeter nd collegues 23 reported incresed bndonment of orl nticncer drugs with incresing cost shring, incresing multiple prescription needs, nd decresing income. With tmoxifen therpy, women with nonpositive belief in tretment, in the youngest or oldest ge groups, previous use of ntidepressnt drugs, nd side effects (depression, nuse, visul problems, vginl bleeding) were more likely to discontinue therpy In our study, formulry chnge ws not ssocited with significnt differences in dherence, wheres Mdden nd collegues 32 identified cost-relted nondherence when evluting the impct of implementtion of Medicre Prt D. In study by St. Chrles nd ssocites, 17 higher Vol. 4, Specil Issue The Americn Journl of Phrmcy Benefi ts SP13

9 Engel-Nitz Strm-Hong Co Reyes Tble 4. Sensitivity Anlysis of Prescription Use nd Tretment Discontinution Ptients Eligible for Undjusted Sttistics Adjusted Model Sttistics Anlysis With 1 Erlotinib Pre-Tier vs Hzrd Pre-Tier vs Cohort Prescriptions Filled, No. No. (%) Post-Tier P Rtio 95% CI Post-Tier P Erlotinib Prescription Use Pre-tier (41.94) Post-tier (47.56) Crossover (42.57) NA NA NA NA Erlotinib Tretment Discontinution Pre-tier 425 (44.76) Post-tier 152 (37.07) Crossover 56 (55.45) NA NA NA NA CI indictes confi dence intervl; NA, not pplicble. Logistic regression nd Cox proportionl hzrds models were djusted for ge, sex, verge erlotinib copyment, Chrlson Comorbidity Index score, nd prior surgery or rdition. Tble 5. Sensitivity Anlysis: Multivrite Anlysis Models for Erlotinib Adherence nd Persistence Logistic Regression Model for Adherence Cox Proportionl Hzrds Model for Persistence Vrible Odds Rtio 95% CI P Hzrd Rtio SE 95% CI P Tretment cohort (reference: pre-tier cohort) Erlotinib copyment < Ptient totl out-of-pocket costs <.0001 Age group, y > Mle Bseline rdition therpy Bseline surgery Chrlson Comorbidity Index Score CI indictes confi dence intervl; SE, stndrd error. copyments were ssocited with lower dherence, similr to our findings. Nondherence nd nonpersistence with orl chemotherpy mediction my result in sfety nd efficcy concerns. 33 Furthermore, use of the gent s second- or third-line chemotherpy my hve influenced the numbers. With pprovl of erlotinib s first-line mintennce tretment, 34 dditionl chnges in use nd ssocited costs my occur in the future. Limittions Clims dt re collected for reimbursement purposes rther thn for reserch; therefore, clims my not include ll relevnt clinicl informtion needed. For exmple, differences in the underlying severity of illness of ptients using erlotinib in the pre-tier nd post-tier cohorts my hve chnged over time nd my not hve been dequtely cptured in clims dt. We were limited in how long we could follow the post-tier cohort; thus, potentil length of follow-up vried significntly between pre-tier nd post-tier cohorts. We did not investigte the reltive burden of ptients out-of-pocket expenditures in reltion to overll income or welth, which my be more significnt driver of ptients dherence thn the ctul mount SP14 The Americn Journl of Phrmcy Benefi ts Specilty Phrmcy 2012

10 Impct of Erlotinib Formulry Tier Chnge of the expenditures. The proportion of ptients in this study receiving ssistnce with copyments from ptient ssistnce progrms ws unknown. This is n importnt limittion becuse it is unknown whether such ssistnce resulted in unobserved use of erlotinib (ie, ptients who ppered to hve discontinued erlotinib were ctully receiving erlotinib through the ptient ssistnce progrm). The verge chnge in copyment ws not very lrge; it is possible tht for condition with high risk of ftlity, lrger copyment/ptient out-of-pocket burden would be required to ffect ptient dherence. Also, the use of erlotinib s second-line versus third-line therpy my influence phrmcy-relted costs. 20 The dt used for this study come from commercil mnged cre popultion; therefore, results of this study my not be pplicble to ptients who were uninsured or receiving Medicre or Medicid. CONCLUSIONS Although moving erlotinib from tier 3 to tier 2 resulted in decrese in men copyments, medin copyments hd lso risen significntly in the 4 yers preceding the tier chnge; thus, the medin copyment following the tier chnge dropped only to the level tht it hd been 3 to 4 yers before the tier chnge. The reltive position of erlotinib on the formulry (tier 3 vs tier 2) ws not ssocited with sttisticlly significnt differences in dherence; however, bsolute copyment level ws ssocited with dherence. Following the formulry chnge from tier 3 to tier 2 for erlotinib, ptients with lung cncer hd lower copyments with evidence of higher tretment persistence. Acknowledgments The reserch, s well s editoril nd medicl writing ssistnce, ws performed t OptumInsight. Erlotinib is mrketed in the United Sttes under the registered trde nme Trcev through n greement between Genentech, Inc ( member of the Roche Group, 1 DNA Wy, South Sn Frncisco, CA) nd Astells Phrm US, Inc (n ffilite of OSI Phrmceuticls, LLC, Frmingdle, NY). Trcev is trdemrk of OSI Phrmceuticls. The uthors thnk the following OptumInsight employees for their contributions: Lur Oberthur Johnson, PhD, medicl writer, for her contribution in prepring the first drft nd finl revision of this pper; Victori Porter, BS, medicl writer, for providing ssistnce with study mterils; nd Shiqing Li, MS, for progrmming the nlytic dt set. Author Affilitions: From OptumInsight (formerly Innovus; Eden Pririe, MN) (NME-N, FC), Eden Pririe, MN; Q.D. Reserch, Inc (SS-H), Grnite By, CA; Genentech, Inc (CMR), South Sn Frncisco, CA. Funding Source: Genentech, Inc, provided externl funding to OptumInsight for the study. Author Disclosures: Dr Strm-Hong reports receiving pid consultncies from Genentech, Inc. Drs Engel-Nitz nd Co re employees of OptumInsight. Dr Reyes reports employment with Genentech, Inc, nd owns stock in the compny. Authorship Informtion: Concept nd design (NME-N, SS-H, CMR); cquisition of dt (FC, CMR); nlysis nd interprettion of dt (NME-N, SS-H, FC, CMR); drfting of the mnuscript (NME-N, SS-H); criticl revision of the mnuscript for importnt intellectul content (NME-N, SS-H, CMR); sttisticl nlysis (NME-N, SS-H, FC); obtining funding (CMR); dministrtive, technicl, or logistic support (SS-H); nd supervision (NME-N). Address correspondence to: Nicole M. Engel-Nitz, PhD, OptumInsight, Technology Dr, Eden Pririe, MN E-mil: Nicole.Engel-Nitz@optum.com. REFERENCES 1. Americn Cncer Society. Wht is non-smll cell lung cncer. Published Accessed Dec 21, Brown ML, Riley GF, Schussler N, Etzioni R. Estimting helth cre costs relted to cncer tretment from SEER-Medicre dt. Med Cre. 2002;40(8) (suppl):iv Pge N, Red W, Tierney R, et l. The epidemiology of smll cell lung crcinom [bstrct 1216]. Proc Am Soc Clin Oncol. 2002;21: Rmlingm S, Sndler AB. Slvge therpy for dvnced non-smll cell lung cncer: fctors infl uencing tretment selection. Oncologist. 2006;11(6): Govindn R, Grfi eld DH. Tretment pproches in ptients with dvnced nonsmll cell lung cncer nd poor performnce sttus. Semin Oncol. 2004;31(6) (suppl 11): Curtiss FR. Phrmcy benefi t spending on orl chemotherpy drugs. J Mng Cre Phrm. 2006;12(7): Shepherd FA, Rodrigues Pereir J, Ciulenu T, et l; Ntionl Cncer Institute of Cnd Clinicl Trils Group. Erlotinib in previously treted non-smll-cell lung cncer. N Engl J Med. 2005;353(2): Hede K. Increse in orl cncer drugs rises thorny issues for oncology prctices. J Ntl Cncer Inst. 2009;101(22): Webb T. Under-dosing study rises questions bout wys to improve regimen dherence. J Ntl Cncer Inst. 2004;96(16): Tsng J, Rudychev I, Pesctore S. Prescription complince nd persistency in chronic myelogenous leukemi (CML) nd gstrointestinl stroml tumor (GIST) ptients (Pts) on imtinib (IM): 2006 ASCP Annul Meeting Proceedings, prt I. J Clin Oncol. 2006;24(18S)(suppl): Wu EQ, Guerin A, Yu AP, Bollu VK, Guo A, Griffi n JD. Retrospective rel-world comprison of medicl visits, costs, nd dherence between nilotinib nd dstinib in chronic myeloid leukemi. Curr Med Res Opin. 2010;26(12): Drkow T, Henk HJ, Thoms SK, et l. Tretment interruptions nd nondherence with imtinib nd ssocited helthcre costs: retrospective nlysis mong mnged cre ptients with chronic myelogenous leukemi. Phrmcoeconomics. 2007;25(6): Zivin K, Rtliff S, Heisler MM, Lng KM, Piette JD. Fctors infl uencing cost-relted nondherence to mediction in older dults: conceptully bsed pproch. Vlue Helth. 2010;13(4): Piette JD, Heisler M, Horne R, Cleb Alexnder G. A conceptully bsed pproch to understnding chroniclly ill ptients responses to mediction cost pressures. Soc Sci Med. 2006;62(4): Sedjo RL, Devine S. Predictors of non-dherence to romtse inhibitors mong commercilly insured women with brest cncer. Brest Cncer Res Tret. 2011;125(1): Moore S. Nondherence in ptients with brest cncer receiving orl therpies. Clin J Oncol Nurs. 2010;14(1): St. Chrles M, Bollu VK, Hornyk E, Coombs J, Blnchette CM, DeAngelo D. Predictors of tretment non-dherence in ptients treted with imtinib mesylte for chronic myeloid leukemi. ASH Annul Meeting Abstrcts : Wu EQ, Johnson S, Beulieu N, et l. Helthcre resource utiliztion nd costs ssocited with non-dherence to imtinib tretment in chronic myeloid leukemi ptients. Curr Med Res Opin. 2010;26(1): Greer JA, Pirl WF, Prk ER, Lynch TJ, Temel JS. Behviorl nd psychologicl predictors of chemotherpy dherence in ptients with dvnced non-smll cell lung cncer. J Psychosom Res. 2008;65(6): Rmsey SD, Mrtins RG, Blough DK, Tock LS, Lubeck D, Reyes CM. Secondline nd third-line chemotherpy for lung cncer: use nd cost. Am J Mng Cre. 2008;14(5): Vol. 4, Specil Issue The Americn Journl of Phrmcy Benefi ts SP15

11 Engel-Nitz Strm-Hong Co Reyes 21. Sikk R, Xi F, Aubert RE. Estimting mediction persistency using dministrtive clims dt. Am J Mng Cre. 2005;11(7): Andrde SE, Khler KH, Frech F, Chn KA. Methods for evlution of mediction dherence nd persistence using utomted dtbses. Phrmcoepidemiol Drug Sf. 2006;15(8): Streeter SB, Schwrtzberg L, Husin N, Johnsrud M. Ptient nd pln chrcteristics ffecting bndonment of orl oncolytic prescriptions. J Oncol Prct. 2011;7(3)(suppl):46s-51s. 24. Timmers L, Boons CC, Mngnus D, et l. The use of erlotinib in dily prctice: study on dherence nd ptients experiences. BMC Cncer. 2011;11: Hohneker J, Shh-Meht S, Brndt PS. Perspectives on dherence nd persistence with orl medictions for cncer tretment. J Oncol Prct. 2011;7(1): Foulon V, Schöffski P, Wolter P. Ptient dherence to orl nticncer drugs: n emerging issue in modern oncology. Act Clin Belg. 2011;66(2): Prtridge AH, LFountin A, Myer E, Tylor BS, Winer E, Asnis-Alibozek A. Adherence to initil djuvnt nstrozole therpy mong women with erly-stge brest cncer. J Clin Oncol. 2008;26(4): Prtridge AH, Wng PS, Winer EP, Avorn J. Nondherence to djuvnt tmoxifen therpy in women with primry brest cncer. J Clin Oncol. 2003;21(4): Brron TI, Connolly R, Bennett K, Feely J, Kennedy MJ. Erly discontinution of tmoxifen: lesson for oncologists. Cncer. 2007;109(5): Demissie S, Sillimn RA, Lsh TL. Adjuvnt tmoxifen: predictors of use, side effects, nd discontinution in older women. J Clin Oncol. 2001;19(2): Fink AK, Gurwitz J, Rkowski W, Gudgnoli E, Sillimn RA. Ptient beliefs nd tmoxifen discontinunce in older women with estrogen receptor positive brest cncer. J Clin Oncol. 2004;109(5): Mdden JM, Grves AJ, Ross-Degnn D, Briescher BA, Soumeri SB. Cost-relted mediction nondherence fter implementtion of Medicre Prt D, JAMA. 2009;302(16): Weingrt SN, Spencer J, Bul D, et l. Mediction sfety of fi ve orl chemotherpies: proctive risk ssessment. J Oncol Prct. 2011;7(1): Cohen MH, Johnson JR, Chttopdhyt S, et l. Approvl summry: erlotinib mintennce therpy of dvnced/metsttic non-smll cell lung cncer (NSCLC). Oncologist. 2010;15(3): SP16 The Americn Journl of Phrmcy Benefi ts Specilty Phrmcy 2012

12 Impct of Erlotinib Formulry Tier Chnge eappendix. Chemotherpy Agents Type of Chemotherpy Non-pltinum lkylting gents Pltinum gents Antimetbolites Antimiotic gents Topoisomerse I inhibitors Topoisomerse II inhibitors (nthrcenedione) Podophyllotoxins Antineoplstic ntibiotic Biologiclly directed therpies Immune therpies Miscellneous gents Medictions Included Bendmustine, busulfn, crmustine, crmustine/polifeprosn, chlormbucil, cyclophosphmide, dcrbzine, estrmustine, ifosfmide, lomustine, mechlorethmine, melphln, procrbzine, temozolomide, thiotep, urcil mustrd Crbopltin, cispltin, oxlipltin Methotrexte, pemetrexed, cldribine, clofrbine, cytrbine, fl udrbine, mercptopurine, nelrbine, pentosttin, thiogunine, zcitidine, cpecitbine, fl oxuridine, fl uorourcil, gemcitbine, hydroxyure Docetxel, pclitxel, lbumin-bound pclitxel, vinblstine, vincristine, vinorelbine, ixbepilone Irinotecn, topotecn Mitoxntrone Etoposide, teniposide Bleomycin, dctinomycin, mitomycin C, plicmycin, streptozocin, dunorubicin, doxorubicin, pegylted liposoml doxorubicin, epirubicin, idrubicin, vlrubicin Alitretinoin, bexrotene, bortezomib, dstinib, erlotinib, gefi tinib, imtinib, lptinib, nilotinib, sorfenib, sunitinib, temsirolimus, tretinoin, lemtuzumb, bevcizumb, cetuximb, gemtuzumb, ibritumomb, pnitumumb, rituximb, tositumomb, trstuzumb Aldesleukin (IL-2), interferon lf-2, interferon lf-2b, lenlidomide, thlidomide Altretmine, rsenic trioxide, sprginse, BCG vccine, decitbine, denileukin, levmisole, mitotne, pegsprgse, porfi mer, strontium-89, zoledronic cid, vorinostt Vol. 4, Specil Issue The Americn Journl of Phrmcy Benefi ts SP17