Signal Detection of Docetaxel in Canadian Spontaneous Adverse Event Reports

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1 Shrwn Singhl et l. / Journl of Phrmy Reserh 01,5(), Reserh Artile Avilble online through ISSN: Signl Detetion of Doetxel in Cndin Spontneous Adverse Event Reports Shrwn Singhl* nd Dr. Bhswt S. Chkrborty CRO-Cdil Phrmetils Ltd.,1389, Trsd Rod, Dholk ,Dist.: Ahmedbd, Gujrt, Indi Reeived on: ; Revised on: ; Aepted on: ABSTRACT Introdution: Cner is one of the most widespred nd fered diseses in the world tody -fered lrgely beuse it is known to be diffiult to ure. The min reson for this diffiulty is tht ner results from the unontrolled multiplition of subtly modified norml humn ells. One of the min methods of modern ner tretment is drug therpy (hemotherpy). Doetxel is linilly well estblished nti-mitoti hemotherpy medition (tht is, it interferes with ell division). It is used minly for the tretment of brest, ovrin nd non-smll ell lung ner. Doetxel hs n FDA pproved lim for tretment of ptients who hve lolly dvned or metstti brest or non smll-ell lung ner who hve undergone nthryline-bsed hemotherpy nd filed to stop ner progression or relpsed nd Europen pprovl for use in hormone-refrtory prostte ner. Doetxel binds to mirotubules reversibly with high ffinity nd hs mximum stoihiometry of 1 mole doetxel per mole tubulin in mirotubules. This binding stbilises mirotubules nd prevents depolymeristion from lium ions, deresed temperture nd dilution, preferentilly t the plus end of the mirotubule. Doetxel hs been found to umulte to higher onentrtion in ovrin denorinom ells thn kidney rinom ells, whih my ontribute to the more effetive tretment of ovrin ner by doetxel. It hs lso been found to led to the phosphoryltion of onoprotein bl-, whih is poptosis bloking in its onoprotein form. Most ommon dverse retions ross dotxel inditions re infetions, neutropeni, nemi, febrile neutropeni, hypersensitivity, thromboytopeni, neuropthy, dysgeusi, dyspne, onstiption, norexi, nil disorders, fluid retention, stheni, pin, nuse, dirrhe, vomiting, muositis, lopei, skin retions, mylgi but flushing is reported in very minor tegory of hypersentivity retion. Objetive: Mjor objetive of this study ws extrt to Cndin Adverse Retion Monitoring Progrm (CADRMP) dtbse for possible toxi signl detetion (SD) of doetxel, evlute the frequeny of the flushing ssoited with it in different strtified groups for puttive signl, nd generte wreness in helthre professionls regrding usefulness of SD. Mterils nd Methods: Approprite sttistil methods were used for Adverse drug retion (ADR) signl detetion suh s, proportionl reporting rtio (PRR); reporting odds rtio (ROR); the Chi-squre (X ) sttisti method; the 95% onfidene intervl (CI); the observed to expeted rtio (O/E); nd Du Mouhel method were used to lulte the possible signls. Signifine of X nd other lulted sttistis, e.g., PRR nd ROR, ws bsed on omposite riterion of regultory guidelines nd not on ny prtiulr sttistil level of signifine. Results: Clulted sttistis by different methods were ompred with regultory riteri of sttisti vlue 4.0 for X, nd 3.0 for the rest for SD to be delred signifint. The PRR sttisti ws found to be ; by the ROR method it ws ; the X sttisti ws , wheres the lower nd upper limits of 95% CI of PRR were found to be 1.133nd 1.647, respetively, by the O/E rtio ws found to be , nd PRR with the help of Du Mouhel ws found to be Thus, the flushing doetxel.signls lulted in this study were signifint. Conlusions: The therpeuti lss speifi signl of flushing ssoited with doetxel ws found potent enough to use flushing. Key words: Adverse drug retions, Cndin dverse drug retion monitoring progrm, Doetxel, signl detetion INTRODUCTION The WHO defines toxi signl s: Reported informtion on possible usl reltionship between n dverse event nd drug, the reltionship being unknown or inompletely doumented previously. [1] Usully, more thn single report is required to generte signl, depending upon the seriousness of the event nd qulity of the informtion. Adverse drug retions (ADRs) re thought to be the 4-6 lrgest use of deth in the USA nd re estimted to use 3-7% of ll hospitl dmissions.[] More thn hlf of these ADRs re not reognized by the physiins on dmission, nd ADRs my be responsible for deth of 15 of 1000 ptients dmitted.[3] There is need of lose link between the mrket uthoriztion holder (MAH) nd the phrmovigilne (PV) system, llowing produts to be uthorized erlier under strit nd lerly defined rules for post-uthoriztion sfety studies, thus offering hope to ptients with urrently unmet medil needs.[4] *Corresponding uthor. Shrwn Kumr Singhl CRO-Cdil Phrmetils Ltd. 1389, Trsd Rod, Dholk Dist.: Ahmedbd, Gujrt, Indi The role of SD nd PV do not end by estblishing drug ADR pir only, prompt regultory tions need to be tken to ppropritely restrit or bn the drug. In the reent pst, ritil opinions hve been ired bout the sle of mny drugs from some ountries tht hve been bnned in other ountries.[5] All over the world, nimesulide hs been withdrwn, but unfortuntely it still ontinues to be sold in most ountries.[6] Another drug tht hs been voluntrily withdrwn reently by the mnufturer (Merk) from the world mrket ws Vioxx whih ws ontining rofeoxib.[7] Cner is leding use of deth worldwide nd ounted for 7.6 million deths (round 13% of ll deths) in 008. Tobo use is mjor risk ftor for ner. Hrmful lohol use, poor diet nd physil intivity re other min risk ftors. Cner is leding use of deth worldwide nd ounted for 7.6 million deths (round 13% of ll deths) in 008. The min types of ner re: lung (1.4 million deths), stomh ( deths), liver ( deths), oloretl ( deths), brest ( deths). More thn 70% of ll ner deths ourred in lownd middle-inome ountries. Deths from ner worldwide re projeted to ontinue to rise to over 11 million in 030. [8] Doetxel exhibits ytotoxi tivity on brest, oloretl, lung, ovrin, gs-

2 Shrwn Singhl et l. / Journl of Phrmy Reserh 01,5(), tri, renl nd prostte ner ells.doetxel does not blok disssembly of interphse mirotubules nd so does not prevent entry into the mitoti yle, but does blok mitosis by inhibiting mitoti spindle ssembly. [9] Resistne to plitxel or nthryline doxorubiin does not neessrily indite resistne to doetxel. Mirotubules formed in the presene of doetxel re of lrger size thn those formed in the presene of plitxel, whih my result in improved ytotoxi effiy. [10] Abundnt formtion of mirotubules nd the prevention to replite used by the presene of doetxel leds to poptosis of tumour ells nd is the bsis of doetxel use s ner tretment. [10] reports were eliminted frequeny of prtiulr drug event pir. When the sttistis from different lultions, PRR, ROR, X, the 95% CI, the O/E rtio, nd Du-Mouhel method did exeed ertin vlue (for X to be 4.0 nd, for the rest to be 3.0) then the signl would be onsidered signifint.[1] The Proportionl Reporting Rtio: As shown in Tble 1, * ontingeny Tble ws prepred to pture the inidenes of flushing (trgeted event Y) nd ll other events for the trgeted drug X, i.e., Doetxel, nd ll other drugs in the dtbse to lulte PRR.[11] MATERIALS AND METHODS The three-fold methodology used in this study ws s follows: Dt extrtion from publi dtbse Extrtion of relevnt dt from CADRMP dtbse ws rried out s follows. First, the Helth Cnd website ( ws essed; then the following setions were serilly essed: Drug nd helth produts nd MedEffet Cnd Adverse Retions. Finlly, in the setion of Cnd Vigilne Progrm, the CADRMP online dtbse ws extrted Proedure followed for signl detetion in this study The CADRMP is the vigilne progrm dtbse of Helth Cnd. The Individul Cse Sfety Reports (ICSRs) in this dtbse were olleted by forwrding request to helth Cnd, nd the remining ICSRs were olleted from the offiil website of helth Cnd. The free text olleted from the CADRMP ws onverted into strutured formt, nd finlly sttistil methods were pplied to lulte n tul mesure of signls. Therpeuti lss-speifi SD lultions were then rried out s shown in Figure 1. Vrious methods, pproprite for nlyzing lrge number of reports, were used for SD lultions. These methods of lultions were seleted following systemti literture review. [11-1] An ttempt ws mde to mintin the originlity of dt olleted from CADRMP dtbse while omputing tul SD. Signl detetion lultions Disproportionlity: Disproportionlity or signls of disproportionte reporting re the frequeny or reltive Figure 1: Proedure followed for Signl Detetion by sttistil nd quntittive methods. The sub-dtbse reted here for omputing signl onsists of only Individul se sfety Reports reported for prtiulr therpeuti lss of nti ner drugs. While lulting n tul signl, duplite Colletion of ICSRs from CADRMP Conversion of free text to strutured informtion Dt lening nd duplite detetion The PRR ws lulted s follows: PRR ( ( b ) d ) The Reporting Odds Rtio: The proedure followed to lulte ROR ws similr to tht of the PRR method.[11] The sme ontingeny Tble [Tble 1], prepred for PRR, ws lso followed in the se of ROR lultions. The ROR ws lulted s follows: ROR b d (1) () The Chi-squre (X ) sttisti: The Chi-squre sttisti[1] ws pplied to test the independene of tegoril vribles. X ws used s n lterntive mesure of heterogeneity in the Tble 1 * Contingeny tble for the omputtion of proportionl reporting rtio Trgeted All other Totl event Y events Trgeted drug X A B AB All other drugs C D CD Totl AC BD ABCD In this Tble the elements ounted A, B, C, nd D were ICSRs vilble in the CADRMP dtbse. Thus, given ICSR my ontribute to only one of the ells of the Tble event, if the individul se refers to multiple mediinl produts or multiple dverse events ontingeny Tble built with the mediinl produt X nd the dverse event Y. Chi-squre Σ ( Observed Expeted Expeted ) (3) The 95% onfidene intervl of the PRR: The stndrd error of the nturl logrithm of the PRR ws estimted bsed on the following formul: (4) SE 1/ A 1/ C 1/( A B) 1/( C D) Applying quntittive or sttistil methods Computing n urte mesure for SD The 95% CI for ln (PRR) ws then estimted s ln (PRR) ± 1.96SE, nd its exponentil ws tken.[1] Lower nd upper limits of 95% CI for PRR [PRR/ exp(1.96se), ln(prr) ± 1.96 se] (5)

3 Shrwn Singhl et l. / Journl of Phrmy Reserh 01,5(), The observed-to-expeted (O/E) rtio: The ws O/E[11] lulted s follows: A ( A B ) OE ( A C ) ( A B C D ) (6) Du Mouhel Method: This method ws bsed on * ontingeny Tble vlues s well s the rtio of vlues of A nd expeted A ws tken into onsidertion for lultions. A ( A B) PRR (7) ( A C ) N ( A B)( A C) E () N PRR A E() (8) (9) The sttistil signifine of PRR, ROR, X, O/E rtio, nd Du-Mouhel sttistis ws bsed on regultory guidelines[1] s mentioned bove. RESULTS The detils of lulted sttistis re presented s follows: Cndin dverse drug retion monitoring progrm The Cndin Adverse Drug Retion Monitoring Progrm (CADRMP) is the Helth Cnd s post-mrket surveillne progrm whih ollets nd ssesses suspeted dverse retion reports for Cndin mrketed helth produts suh s phrmeutils, biologis (inluding frtionted blood produts, s well s therpeuti nd dignosti vines), nturl helth produts, nd rdiophrmeutils.[13] The following dt were extrted from CADRMP dtbse: % Totl ICSRs inluded in dtbse 1049 Flushing ssoited with Doetxel 99 Other ADR s ssoited with Doetxel 11 Flushing ssoited with other thn Doetxel 584 Other ADR s ssoited with other thn Doetxel These dt were orgnized into ontingeny tble [Tble ]. PRR ( ( b ) d ) 99 (99 11 ) 584 ( ) PRR The PRR lulted from Tble ws ROR ROR b d ROR The ROR lulted from Tble ws (1) () Chrteristis of system orgn lss The ourrene of ADRs in primry system orgn lss (SOC) ffeted using 5% metbolism nd nutrition disorders, % entrl nervous system disorders, 0.5% er disorders, 5% neutropeni, 3% rdi disorders, 8% Musulr system, 5% Chest pin, 10% respirtory system, 3% Anemi, % eye disorder, 7% flushing, 4% oedem, % pruritis, 15% gstrointestinl disorders, 30% generl disorders nd dministrtion site onditions nd 0.3% deth. Prtiulrly totl 99 ses of flushing re reported due doetxel in out 368 ptients reeived doetxel drug. The eighty four femles nd twenty five mles, respetively, reported flushing of ssoited with the doetxel out of ninety nine reports. Essentil dt for Signl detetion Tble 4. Frequently reported dverse events ssoited with doetxel to spontneous reporting system in Cndin dt bse: Adverse events s per system orgn lss Number (%) of AE % Flushing 99 7 % Metbolism nd nutrition disorder 67 5 % Centrl nervous system 5 % Er disorder % Neutropeni 69 5 % Crdi disorder 39 3 % Musulr system % Chest pin 67 5 % Respirtory system % Anemi 37 3 % Eye disorder 7 % Edem 53 4 % Pruritis 6 % GIT disorder % Generl disorder % Deth % ( Observed Expeted ) Chi-squre Σ (3) Expeted ( ) ( ) ( ) ( ) The X sttistis ws lulted from the dt orgnized in Tble 3 ws Tble. Dt obtined from ndin dverse drug retion monitoring progrm dtbse to lulte signl detetion Flushing Not Flushing Doetxel Not Doetxel Tble 3. Dt obtined from ndin dverse drug retion monitoring progrm dtbse to lulte signl detetion Flushing Not Flushing Totl Doetxel Not Doetxel Totl

4 Shrwn Singhl et l. / Journl of Phrmy Reserh 01,5(), 95%onfidene intervl for PRR: 1/ A 1/ C 1/( A B) 1/( C D) (4) 1/ 99 1/ 584 1/1311 1/ SE % Confidene Intervl for PRR ln(prr) ± 1.96 SE (5) ln(4.1330) ± 1.96 (0.1049) ± Therefore, the lower limit of 95% Confidene Intervl of PRR ws found to be nd Upper limit ws found to be OBSERVED TO EXPECTED RATIO: A ( A B) ( A C) ( A B C D) OE (6) 99 (99 11) (99 584) ( ) OE Hene, the Observed-to-expeted rtio for flushing-doetxel pir of PRR ws found to be DU MOUCHEL METHOD : PRR The E() ws lulted to be , wheres the PRR vlue by Du Mouhel ws found to be Dt by gender nd ge The dt reeived from CADRMP dtbse ws onverted into strutured formt nd then it ws strtified into two groups on the bsis of gender. The flushing ssoited with doetxel ws found to be more prominent in femle s high s 68% s ompred to 6% in mle nd 0.5% gender not speified. In nother method, dt were strtified into three different groups on the bsis of ge: Group A: 0-18 yers, Group B: yers, Group C: yers nd Group D: Age not speified showed 3.5%, 6%,4% nd 10% flushing, respetively, ssoited with doetxel. Tble: 4 AGE CASES Flushing % 0-18 Yers % Yers % Yers % As not reported 1, % Totl 10, PRR A ( A B) ( A C) N (7) 99 Flushing ssoited with Doetxel b 11 Other ADR s reported with Doetxel 584 Flushing ssoited with other thn Doetxel d Other ADR s ssoited with other thn Doetxel N 3359, totl sum of eh ell of tble. PRR PRR E () ( A B)( A C) N (8) Where E () expeted vlue of A i.e. Flushing ssoited with doetxel (1311)(683) E () 6.94 PRR A E() (9) Dt of flushing reported s yer speifi Tble: 5 Yer Cses Flushing Other ADRs Totl Cse of flushing

5 Shrwn Singhl et l. / Journl of Phrmy Reserh 01,5(), The dt reeived from CADRMP dtbse of ses of flushing were strtified into eight different groups on the bsis of 5 yers of intervl of reported ADRs: Group A: 1970 to 1975 yers, Group B: 1976 to 1980 yers, Group C: 1981 to 1985 yers, Group D: 1986 to 1990 yers, Group E: 1991 to 1995 yers, Group F: 1996 to 000 yers, Group G: 001 to 005 yers, nd Group H: 006 to 010 yers 0, 0,0, 0, 1,, 41 nd 35 flushing, respetively, ssoited with doetxel. Tble 6. Chrteristis of reports ssoited with Doetxel from Jnury 1970 to Mrh 010 Chrteristis Number of reports % The essentil dt (see Essentil Dt for SD in Results nd Dt Overview setion) were lened up nd duplite reports were eliminted. The dt, whih were onverted into strutured informtion formt, were inluded in Tble 1, to get the vlues of A, B, C, nd D. The onfirmtion bout orret vlues reeived ws lso heked by the sum totl of ll ells (N). The PRR nd other lultions involve omprisons of reporting reltionship for speifi mediinl produt X nd trgeted dverse event Y with ll other mediinl produts in dtbse. When we onsidered the therpeuti lss of nti-ner drugs s the bkground dt, it should be noted tht our results might differ slightly from the signl produed by the doetxel - flushing pir reported using whole dtbse. Gender Mle Femle Unknown Totl % Tble: 7.Deteted signl for doetxel by dt mining nd existene of informtion on drug lbel Adverse events No. of reports PRR ROR IC 95% LCI Drug lbel Flushing * * 1.133* Y Thyrdi Y Neutropeni Y Neuropthy Y Pruritis N Ototoxiity Y There ws more inidene of flushing in femles but 67% ses of femle out of totl reported ses of doetxel treted ptients however, the geritri ptient s ge yers of ge definitely showed higher inidenes of flushing. Tble: 8 Signl detetion prmeters Results PRR Signifint ROR Signifint Chi squre test Signifint 95% Confidene Intervl nd Signifint Observed to Expeted Rtio Signifint Du-Mouhel Method Signifint Signifine of lulted Signl detetion prmeters The PRR ws lulted by inorporting ll the vlues of CADRMP dtbse in Tble nd pplying Eqution 1. It should be noted tht if C 0 in Tble, then PRR nnot be lulted. The lulted PRR ws found to be whih ws >3.0, nd hene, the flushing inidenes ould be lled potentil toxi signl. The ROR (Eqution ) ws found to be Although this vlue is high (muh more then 3.0), it ould be lled signl by regultory riteri (>3.0). For signl, when PRR ws displyed with X sttistis, the PRR should be > nd the X should be >4 by the regultory riteri.[1] The individul number of ses should be more thn three. The X ws found to be ; therefore flushing inidenes ould be lled potentil toxi signl. Similrly, the results of 95% CI nd Du-Mouhel prmeters were signifint s signls. Summry results of ll sttistil nd quntittive lultions re provided in Tble 4. DISCUSSION The dt reeived from line listing request to CADRMP indite tht in 30 yers of time (01/01/ /03/010), thirty five ICSRs of flushing ssoited with the doetxel ws reported. For therpeuti lss-speifi SD of flushing ssoited with the doetxel the ICSRs were olleted from CADRMP online dtbse. Extrting ll the neessry informtion nd the bkground dtbse is very tedious job. All neessry dt for SD from eh individul ICSR were olleted nd pled in n pproprite formt. The strutured formt for SD inludes the Seril number, Report ID number, Dte reeived, Ptient informtion, ADR speified like flushing or other thn flushing, nd detils bout suspeted drugs. The initil deision on whether drug event pir should be further investigted ws bsed on omposite regultory stndrds[1] pplied to the estimtes of the PRR nd other sttistis. There ws pure signifine level pplied to ll lultions of SD. The vlue of the PRR nd onsequently the signl deteted with this method depend on the dt in the dtbse on whih the PRR ws omputed. Therefore, the PRR interprettion should tke the following elements into ount: The type of mediinl produts inluded in the dtbse. The mediinl terminologies tht hve been used in the reports populting the dtbse. The oding prties. The soures of ICSRs.The bsene of signl deteted in this dtbse does not neessrily exlude the possibility of n ssoition between the mediinl produt X (Doetxel) nd the dverse event Y (Flushing) nd therefore further investigtions re required in other dtbses. The PRR my be refined by using similr tehniques to other SD like ombining multiple mediinl produts nd or dverse events, strtifition by ge nd sex of the ptient. The novelty of this work inludes method tht enbles SD lultions in spite of the limittions of extrting whole dtbse. The new ide generted in this pper shows wy of lulting SD prmeters within therpeuti lss when lrge number of reports re vilble within tht lss. The sme ides n be implemented for SD in speifi popultions nd lso for strtified dt on the bsis of gender, ge, nd yer. The SD is vitl nd essentil prt of drug use nd surveillne informtion. With the help of SD, the uthorities nd prtitioners n esily minimize the number of unwnted drug withdrwls. The lss-speifi SD proedures desribed in this pper, owing to the nlysis of lrge number of reports, will eventully filitte the linil sfe use of the drug nd promote ptient re. REFERENCES 1. WHO (00) Sfety of Mediines: A Guide to Deteting nd Reporting Adverse Drug Retions: Why helth professionls need to tke tion. World Helth Orgniztion. [retrieved 005 on Mr]., Avilble

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