Application 1168 Injection Ofbotox (Botulinumtoxin Type A)For Prophylaxis Ofheadaches

Public Summary Document

Application 1168– Injection ofBOTOX®(botulinumtoxin type A)for prophylaxis ofheadaches inadultswith chronicmigraine

Sponsor/Applicant/s:AllerganAustralia PtyLtd

Dateof MSAC consideration:29–30November 2012

1.Purpose of application

InFebruary2011,an application to theMedical Services AdvisoryCommittee (MSAC)was received from AllerganAustraliaPtyLtd forinjection ofbotulinum toxin(BOTOX®) forthe prevention (prophylaxis)of chronicmigraine. TheMSACapplication is co-dependent on an application to thePharmaceutical Benefits AdvisoryCommittee (PBAC)forthedrug component oftheservice(i.e. extension ofthe current Botulinum Toxin Program(Section 100 arrangements)so thedrugis listed forprophylaxis ofheadaches in adults with chronicmigrainewho meet certain criteria).

PBAChas madetwo separaterecommendations on BOTOX®for chronicmigraine, thelatest beingin July2012. PBACrejected both applications, but theJuly2012 submission meets criteria forindependent review.

This application was lodged duringtransitional arrangements formanaging co-dependent PBAC/MSACapplications, so was not assessed duringajoint sittingofthose committees (which is now the approved process). Although PBACrejected thedrugcomponent ofthis application (furtherdetailprovided underSection 2), it is seekinginformation from MSACon theMBSfee fordeliveringthedrug, consultation feerequired to assessand re-assess each patient, patient out-of-pocket costs and ExtendedMedicareSafetyNet (EMSN) risk.

Injection ofbotulinum toxin typeA purified neurotoxin complex(BOTOX®), lyophilised powder100 units, forprophylaxis ofheadaches inadults with chronicmigraine. The recommended doseis 155 units to 195 units, withinjections divided acrossseven specific head and neck areas,andincludingfixed-site, fixed-doseinjections at 31 sites, totaling 155 units and up to an additional 40 units to eight ‘follow thepain’sites. Thedrugis administered using a30-gauge, 0.5 inch needle as0.1 mL(5 units)injections persite.

Prophylaxis ofheadachesin adults with chronicmigraine (defined as headaches on at least

15 days permonth, with at least 8 days with migraine). Chronicmigraineis asub-typeof chronicdailyheadache.

2.Background

This is the first timeMSAChas considered thismedical service. However, PBAChas considered fundingofthedrugforchronicmigraineon two separateoccasions, both ofwhichhavebeen unsuccessful.Most recently(July2012), PBACrejected there-submission ofBOTOX®formigraineon thebasis of:

•Uncertaincost-effectiveness, dueto uncertaintyassociated with theMBSfeeto administerthedrug;

•The assumption that all patients experiencinglessthan a50%reduction in headache dayswould discontinuetreatment; and

•Extrapolation ofthetrial datato a5-yeartimehorizon with asustained treatment effect forresponders.

TheTherapeuticGoodsAdministration (TGA)has approved andregistered BOTOX®for chronicmigraine,whichwas the first chronicmigraineprophylaxis agent to bespecifically evaluated bytheTGA.

3.Prerequisites to implementation of any funding advice

TGA approved BOTOX®fortheprophylaxis ofheadaches in adults with chronicmigraine(headaches onat least 15days permonth, ofwhich at least 8 days arewithmigraine)on

15 March 2011.

4.Proposal for public funding

Services would berestricted to patients with headaches on at least 15 days permonth, with at least 8 ofthosedays withmigraine.Therecommended re-treatment scheduleis every

12 weeks, but patients should not receivemorethan 3 cycles oftreatment priorto an assessment oftheneed for furthertreatment.

MSACESCconsidered it appropriateto restrict theserviceto patients with chronicmigraine, but agreed thediagnosis of chronicmigraine (CM) as distinct from episodicmigraine (EM)is not straightforward dueto theinherentlysubjectivenatureofheadache andsymptom assessment.Ifapatient has asymptom scorejust underthe8 daythreshold, this could be easilymodified to meet the arbitrarycriteria forreceiving BOTOX®therapy,even though by definition, thepatient mayhaveEM, not CM.

Patients must have failedat least threemigraineprophylacticmedications.This is more restrictivethan theTGAapproval, but is consistent with theproposed PBSlisting.

As patients arerequired to have failedat least threemigraineprophylacticmedications, MSACESCclarified that BOTOX®should onlybe considered as afourth-linetreatment option, not athird-linetreatment as specified in the Final Decision AnalyticProtocol (DAP).

TGA product information recommends patients should be evaluated byaneurologist orpain management specialist priorto receivingtreatment(dueto difficulties involved in diagnosing chronicmigraine).

TheSBA report indicated that the FacultyofPainMedicinehas chosen not to applyfor accreditation fordeliveringtheserviceat this time, meaningadministration ofthedrugwould belimited to neurologists (mainlyin out-patient orconsultingroom settings). TheDAP indicated otherpractitioners (includingplasticsurgeonsandgeneral practitioners) currently administerBOTOX®forchronicmigraine. Workforceissues maynecessitatethatneurologists perform theinitial diagnosis and prescription, but otherspecialists mayperform subsequent injections. Thesespecialists would need to seek approval and registration under theBotulinum Toxin Program in orderto deliveraMedicare-funded BOTOX®service. MSACESCagreed that thediagnosis and deliveryofinjections should beperformed by appropriatelytrained neurologists, who arespecificallyapprovedand registered underthe Botulinum ToxinProgram (Section 100 Arrangements).

5.Consumer Impact Statement

TheSBA report stated that listing BOTOX®on thePBSand MBSformigraines would allow refractory(non-responsive)patients (who havenoalternativetreatment option) access to a safe andefficacious prophylactictreatment. TheSBA report stated that prophylaxis of headaches in patients with chronicmigraineusing BOTOX®has beenfound to reducethe frequencyand severityofheadachedaysand episodes, and reducetheduration ofheadaches, ultimatelyleadingto improved qualityoflife forpatients.

Theservicewill beprovided byspecialists (in this case, neurologist)whoarespecifically approved andregisteredundertheBotulinum Toxin Program. This necessaryrequirement will limitthenumberof approved specialists, with possible access issues for rural patients. However, beingan out-of-hospital service,ruralaccess maybebetterthaniftheservicewas provided in hospital, as well as benefittingpatients without privatehealth insurance.

No comments were received from the applicant orprofessional bodies on theConsultation DAP. One responsewasreceived from aconsumergroup, makingthe followingcomments in support ofthe clinical need and publichealth significanceoftheproposedservice:

•chronicmigraineis acommon typeofpersistent pain;

•manypatients havetriedavarietyofmedicationsand non-medical strategies to tryto reducemigraineincidenceorintensity. It is rarefor all thepain to be alleviated by current treatments; and

•botulinum toxin should bemade available at thesecondaryand tertiaryhealth levels to treat intractable chronicmigraine. It should not beviewedas a first linetherapy.

6.Proposed intervention’s place inclinicalmanagement

Thereis no current alternativetreatment on theMBS. This would be an additional intervention on theMBS.Best supportivecareisavailablewhereothertreatments have failed (i.e. wherepatients havenot responded to migraine-prophylacticmedications).

[source: Page49 ofSBAreport]

7.Other options for MSACconsideration

MSAC PASCdid not present anyotheroptions forMSACto consider, otherthan aligning theMSACrecommendation to thePBACrecommendation (including applyingthesame patient restrictions to theMBSservicethat would be applied to prescription ofthedrug– i.e. patients must have failedat least threemigraineprophylacticmedications).

MSACESCconsidered the risk ofleakageoftheserviceto otherindications to below, as the proposed listingrequirespatients to have failedat least threemigraineprophylactic medications and havetheserviceperformed byaneurologist.

8.Comparator to the proposed intervention

This serviceis currentlynot publiclyfunded, so thereis no MBScomparator. TheSBAreport nominated ‘best supportive care’as the appropriatemain comparator. Thisconsisted ofno furtherprophylaxis, but continuation of acuteheadachepain medicines as required. Themain arguments provided in support ofthis comparatorwerethat patients identified within the proposed restrictions have failed to respond to, orareunableto tolerate, treatment with the availablemigraineprophylaxis options. BOTOX®would not beasubstitute forother prophylaxis therapy.

The Final DAPnominated “best current practice, i.e. 1st and 2nd lineprophylactic pharmaceuticals” as thecomparator forpatients who fail or experienceinadequate improvement with 1st and 2nd line agents.It accepted that “failure” and“inadequate improvement”with theseagents would bedefined byMSAC PASCduring its determination. Given the revisedcircumstances in which thedrug is beingre-assessed byPBAC(asan option followingthe failureofthreeprophylacticmedications), theCritiqueoftheSBA considered that thenew comparatoris moreappropriate.

TheCritiqueoftheSBAreport considered that, although best supportivecare as a comparatoris more relevant to thepotential pharmacological benefits ofthedrug, it is also appropriatein terms oftheMSACpotential listingofaserviceto inject thedrug. Thesafety and effectiveness ofinjectingthedrugis comparedagainst ascenario ofno injection, togetherwith the financial implications to theMBSofanew listing.

In its July2012 assessment ofthe re-submission BOTOX®for chronicmigraine, PBACnoted that the current re-submission requested listingforpatients with chronicmigrainewho have inadequateresponse, intoleranceor contraindication to at least threemigraineprophylaxis medications, comparedwith at least two in theinitial submissionto PBAC(November2011). PBAC agreed that thenominated comparatorofbest supportive care(BSC)was the appropriatecomparatorforthepopulation meetingtherequestedrestriction.

MSACESCagreedBOTOX®therapywould be an alternativetoBSC(in patients who have inadequateresponse, intoleranceor contraindication to at least threemigraineprophylaxis medications).

This will mainlybe an MBSout-of-hospital procedure, performed in doctors’private rooms. It maybeprovided onanin-hospital basis, but expected rates aredifficult to predict, and will likelybelow.

Even though somepractitioners maycurrentlybebillingMBSconsultation items to provide this service, this billingbehavioris impossibleto identify, as the activityis masked bythe vast rangeofotherservices provided under consultation items that arenot recorded by Medicare (Department ofHuman Services).

9.Comparative safety

Themajorityof evidenceon comparativesafetyofthetreatment wasfocused on thedrug component which is subject to assessment byPBAC. MSACESCdetermined that the injection method to deliverBOTOX®formigraineappears no moreorlesssafethan the injection method to deliverBOTOX®under existingMBS-listed items to administer BOTOX®forhemifacialspasm (items 18350 and 18351) and blepharospasm(items 18372 and 18373). No furthermatters wereidentified forMSACconsideration,such as whetherthe safetyofthedrugvariesbythecompetencyoftheperson injectingit.

10.Comparative effectiveness

Themajorityofthe evidenceon comparativeeffectiveness ofthetreatment related to thedrug component is subject to assessment byPBAC. MSACESCdetermined that theinjection method to deliverBOTOX®formigraine appearsno moreorless effectivethan theinjection method to deliverBOTOX®under existingMBS-listed items to administerBOTOX®for hemifacial spasm (items18350 and 18351) and blepharospasm(items 18372 and 18373).

MSACESCalso noted that the clinical significanceofareduction of even2 headachedays permonth should not be excluded. This reduction maybesignificant forpatients who have severe, long-lastingmigraines.

No furthermatters wereidentified forMSACconsideration, such as whetherthe clinical effectiveness ofthedrug varies bythe competencyoftheperson injectingit.

11.Economicevaluation

TheSBA report did not present aneconomic evaluation ofthe cost-effectiveness ofBOTOX® treatment forchronicmigraine, as this issuewas to be considered byPBAC. However, financial implications fortheMBSas aresult ofapositivelistingwere examined.

Section D oftheSBAreport was mainlyconfinedto providingan analysis ofthetimethat a specialist would taketo provideaservice, togetherwith estimation ofthe cost ofthis time.In theSBA report, the applicant concurredwith MSAC PASC’s determination that 20 minutes is an appropriateamount oftimespent with apatient to delivertheinjection service. However, the applicant proposed ahigher fee fortheservicethan that determined byMSAC PASC, based on an hourlyrate foraspecialist servicederivedfrom theWorkers Compensation RegulatoryAuthority(in theabsenceofotherdata)adjusteddownwards to align with anexistingMBSitem fee ($122.50). TheSBA report stated this feewas more appropriatethan that proposed byMSAC PASC($74.10, based on existingMBSitem 116), givingas its reason that thelowertheMBSfeeis, thelargerthepatients’out-of-pocketcostswill be. MSACmaywishto consult morewidelyon appropriateness oftheDecision Analytic Protocol-proposed fee ($74.10)versus thehigherapplicant-proposedfeein theSBA. Both the lowerMSAC PASC-determined fee($74.10) andahigherfeeof$160.70weretested in the sensitivityanalysis.

TheSBA report stated (and expert clinical opinion confirmed)thatasmall numberof specialists currentlyinject BOTOX®formigraineprevention in somepatients. Thepatient is required to payforthedrugand professional service fee. Somepractitioners maybebilling MBSprofessional attendanceitems fortheservice(for example, MBSconsultant physician follow-up attendanceitem 116, with an MBSfeeof$74.10), but theseprofessionalattendanceitems aregenericMBSitems forawide rangeofpractitioners and services, meaningdatadoes not exist on individual practices undertheseitems. The SBA report noted that, in someinstances, self-payarrangements result in atotal doseno greaterthan 100 units (onevial)beingadministered in orderto minimise cost.It is stated that thistotal doseis less than that been used in PhaseIIItrials and less thantheTGA-approved dose.

MSAC PASChad determined that the appropriate feefortheinjection ofthedrugshould be modelled on a consultantphysician MBSitem 116, as a20 minuteservice.The fee forthis item is $74.10 ofwhich $55.60 is payable fora75% rebate and $63.00 payable for85%.

TheMBSfeenominatedin theproposed item descriptor (in theSBA report)is higherat$122.50. Although not explicitlystated, it is assumed that the equivalent rebates would be$91.90 (75%in-patient rebate)and $104.15 (85%out-patient rebate). The SBA report statedthat the feeof$74.10 is “too low to coverthe costoftheserviceto theneurologist for administering BOTOX®for chronicmigraineprophylaxis.Listing BOTOX®forchronic migraineon theMBSata feethat is considered too low mayresult in largeco-payments to thepatients.”Justifications, usingcosting-analyses and set out below, wereprovided for statingthat the appropriate feeshould bein therangeof$133.30–$186.70,although the proposed feeis adjusteddownwards from this and set at $122.50.

It was considered that thedetermination of anappropriate fee forthis itemwould beakey consideration forMSACand fortheDepartment ofHealth and Ageing, andthat the final fee will haveasignificant impact on MSACs consideration ofthe financial impact ofthe proposed new service.

MSACESCagreeda feeof$122.50 was appropriate, notingit would beconsistent with the fee forotherMBSitems for administeringbotulinum toxin into areas ofthe face (i.e. injection ofBOTOX®forhemifacial spasm -items18350 and 18351 and blepharospasm - items 18372 and 18373).

PBAC noted that the economic model presented in the re-submission had been updated to reflect the changed continuation criteria, a reduced price for botulinum toxin and reduced costs of botulinum toxin administration. The structure of the model was otherwise unchanged from the previous submission. The updated base model did not include any changes to parameters identified by PBAC as being of concern in the previous submission; namely the transition probabilities, utilities, cost of migraine health states and exclusion of disutility for adverse events. However, PBAC noted that these were addressed in sensitivity analyses. The base-case incremental cost per extra quality adjusted life year gained was(redacted information) (redacted information)between $15,000 and $45,000. ICERs were less favourable when different utilities and costs of migraine health states and different adverse effect disutilities were used. Concerns about the transition probabilities were partlyaddressed by presentation of an additional model of three health states, and when shorter time horizons were used.

PBAC noted that the model extrapolated the 24-week trial data to 5 years, assumed a sustained treatment effect in responders without attenuation beyond the trial duration, and assumed that patients in whom treatment is less than its definition of response would discontinue. However, PBAC considered that the evidence presented to support the assumption of a sustained treatment effect in responders over 5 years was limited. Furthermore, while PBAC accepted that it was reasonable to assume that patients would not continue to undergo treatment if they did not achieve any response due to the unpleasant nature of the administration protocol, PBAC had significant concerns regarding the likelihood that patients who experience a partial response would continue treatment. PBAC noted that application of the continuation rule was important in driving the modelled ICER because it reduced the trial-based incremental cost per extra quality adjusted life year gained at 24weeks from(redacted information)between $105,00 - $200,000 to between $15,00 - $45,000, and considered that these factors contributed significant uncertainty.

In the SBA report, the applicant proposed a higher MBS fee for the service than that determined by MSAC PASC (presented in the Decision Analytic Protocol). The applicant’s proposed fee was based (in the absence of other data) on an hourly rate for a specialist service derived from the Workers’ Compensation Regulatory Authority, adjusted downwards to align with an existing MBS item fee ($122.50). In the SBA report, the applicant stated this fee is more appropriate than the fee proposed by MSAC PASC ($74.10, based on existing MBSitem 116 for a 20 minute consultant physician service), giving as its reason that the lower the

MBS fee is, the larger the patients’ out-of-pocket costs will be.

PBACconsideredthattherewasahighdegreeofuncertaintyregardingtheproposedMBSfeeof$74.10(comparedwiththeapplicant'sproposedfee)foreachadministrationofBOTOX®usedintheeconomicmodel, whichalsocontributedtouncertaintyoftheICER(incrementalcost-effectivenessratio).Therefore,PBACsoughtadvice fromMSAC regarding thefeeforadministeringBOTOX®inthetreatmentofchronicmigraine,inadditiontothelongconsultationfeethatislikelytoberequired toassessandre-assesseachpatientand implicationsforout-of-pocketpaymentsandExtendedMedicareSafety NetriskwhenmedicalpractitionerswillbechargingpatientsmorethantheMBSfee.

PBACconsideredthatthere-submissionestimatesofthelikelynumberofpatients treated andfinancialcoststothePBSwereuncertainbecause ofunderestimatesintheprevalence anddiagnosisofchronicmigrainerefractorytootherprophylactics,andduetothepotential forusebeyond theintendedpopulationinpartialresponders. PBACnotedthattherewasan increaseintheutilization estimates, despite the tighter requested restriction, (redacted information) (redacted information) (redacted information) (redacted information). PBAC therefore rejected there-submissionon the basis of certain cost-effectiveness, due to uncertainty in the economic analysis associated with the fee to administer BOTOX®, the assumption that all patients experiencinglessthana50%reductioninheadachedays would discontinuetreatment,andextrapolationoftrialdatatoa5-yeartimehorizonwithasustained treatmenteffectforresponders.

Expertclinicalopinion wasthatitisdifficulttoknowwhatpractitionersarebillingpatients fortheservice,giventhelownumbersofpractitionerswhoaredoingso.Aswellas neurologists,expertclinicalopinionwasthatplasticsurgeons,de1matologistsandgeneral practitionersincosmeticclinics(i.e.cosmeticsurgeons)wouldbeprovidingthemajorityof services.IfneurologistsarebillingtheservicetotheMBS,theywouldbebillinga subsequentconsultantphysicianitem116,with anMBSfeeof$74.10.

MSAC ESC considered that anecdotal evidence suggests that patient out-of-pocket costs for the se1vice would be about $400, but this would include the cost of the drug. Average fees charged under existing consultation items would be useful to inform MSAC of any additional costs incurred (these may be billed prior and following the proposed se1vice for patient assessment and re-assessment). MSAC ESC also noted that the MBS listing of the se1vice may result in an initial spike in referral rates.

However, MSAC ESC agreed that the proposed inte1vention should be prevented from being billed on the same occasion (same day) as a professional attendance item (e.g. MBS consultation items 110 and 116).

In theabsence of information on current billing of the service, it is difficult to determine the need for capped benefits under the Extended Medicare Safety Net (EMSN).

MSAC ESC agreed that consideration should be given to placing an EMSN benefit cap onthe proposed MBS item, and requested additional information on out-of-pocket costs patients are currently incurring under existing similar MBS items (for injection ofBOTOX® into head, neck and facial areas; i.e. MBS hemifacial spasm items 18350 and 18351; and MBS blepharospasm items 18372 and 18373). MBS data on other items currently being claimed with these items would also assist MSAC in establishing any additional costs that may be incurred.

12. Financial/budgetary impacts

There is no MBS comparator for the service. Expert clinical opinion was that there are few Australian neurologists (perhaps two per capital city) who currently treat migraine with Botox. Expert clinical opinion is that more neurologists will perform the service if it is MBSandPBSlisted,withanestimateofone-thirdtoone-halfofallneurologistsmovinginto migraine preventionwithBOTOX®.The(mostrecent)2009AustralianInstituteofHealth andWelfare(AIHW)MedicalLabourForceinformationshowed 374neurologiststobe practisinginAustralia,whichcalculatestoanestimateof125to187neurologistswhomay provideprivate(MBS-billed)BOTOX®servicesformigraineprevention inthefuture.

Aftertheinitialinjection,repeatinjectionsareprovidedperpatientat12weekintervals.If, aftertwoinjections,apatientfailstorespondtotreatment, injectionsarediscontinued.

Intheabsence ofcomparative MBSdata,expertclinicalopinionwasthataneurologist wouldseearound10patientsperweekforchronicmigraine, butonly3wouldbecandidatesfor BOTOX®treatment,withrepeatinjectionsat12weekintervals.

TheCritiquestatedthatthetotalnumberofpatientslikelytousethedrugisdependentonan assumed initiationrate,togetherwithapplicationofassumedcontinuationfromtheprevious year,takingintoaccountpatientswhofailedto respondtoaninitial treatment, whothenre-trialit during the following calendar year (redacted information) (redacted information).

Thelikelynumberofpatientsperyearwasestimatedinthesubmissiontobelessthan10,000inYear5.

ThetotalnetcosttotheMBSwasestimatedbythesubmissiontobebetween

$5-$10millionoverthefirst5 years.