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more useful for the greater implementation of pharmacogenomics and personalized medicine, a
substantiveinvestmentincomputationalandclinicallaboratoryinfrastructurehastobemadeatanational
level.
BiobanksandhandlingofDNAsamplespresentbothscientificopportunitiesandpolicychallengesfor
regulatory agencies worldwide. Efforts to establish best practices and address the regulation of
processing,storage,andusesofsamplesarebeingundertakenbyanumberofnationalandinternational
regulatoryagencies,includingtheU.S.FDA,theEuropeanMedicinesAgency,Japan’sPharmaceuticals
andMedicalDevicesAgency,andHealthCanada.Onepromisingopportunityisthattheseagenciesare
workingtoward global harmonization of standards for theuse ofpharmacogenomic tests and targeted
therapeutics.
Another area that is broadly presenting policy challenges involves ethical, legal, and social issues
(ELSIs),suchas patient privacyandprotectionofdata andgeneticsamples, returnofresults obtained
withinthecontextofresearchstudiestopatients,decisionsrelatedtotheuseofgenomicinformationand
insurance coverage, and more recently the open science movement (Granados Moreno et al., 2019).
Aimed at protecting Americans from future genetic discrimination, the Genetic Information
NondiscriminationAct(GINA)waspassedin2008(GINA,2008).However,anumberofELSIsrelated
toprivacyandprotectionofgeneticdataremaintobeaddressedbylegislatorsandpolicymakers(Jolyet
al., 2020). Issues surrounding the education of health care providers and other stakeholders are also
increasingly presenting barriers and challenges to the full implementation of pharmacogenomics. A
number of studies have concluded that there remains a serious lack of knowledge of genetics and
genomicsonthepartofcliniciansSquassinaetal.(2010).Stepsareincreasinglybeingtakentoaddress
the educational needs of current and future health care providers. Pharmacogenomics is being
incorporatedinthecurriculaofmedicalandpharmacyschools.
KeepingUpwithClinicalPharmacogenomicsScience
Thisdiscussionoftheeducationalneedsoffutureclinicians,includingnursepractitionersandphysician
assistants, brings ustoa discussionofhownurse practitioneror physicianassistant(PA) studentscan
keepupwiththestateofscienceandclinicalpractice inpharmacogenomics.Althoughthisisarapidly
evolving and fast-moving field, there are some resources that students (Rackover et al., 2007) and
cliniciansshouldbe awareofandconsultonaregularbasis.Currently,thereareover260U.S.FDA–
approved drugs that incorporate pharmacogenomic information in the label
(https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-
labeling).InadditiontotheFDAWebsiteandtheFDA’sTableofPharmacogenomicBiomarkersinDrug
Labeling, there are other useful Web sites. For example, the DailyMed project
(http://dailymed.nlm.nih.gov/dailymed/), administered by the U.S.National Libraryof Medicine of the
National Institutes of Health (NIH), provides detailed information about package inserts of many
prescriptiondrugs,includingpharmacogenomicinformation.TheDailyMedWebsiteisuser-friendlyand
hasapowerfulsearchengine,makingiteasytonavigate.
There are also several organizations with online resources related to pharmacogenomics and its
implementationinclinicalpractice, suchastheClinicalPharmacogenomicsImplementationConsortium
(Relling & Klein, 2011) and the Dutch Pharmacogenomics Working Group (Swen et al., 2011). In
particular, these organizations provide guidelines and recommendations for the clinical use of
pharmacogenomics. As they continually update their resources, their Web sites are worth checking
routinely(Box7.3).
TheCDC’sOfficeofPublicHealthGenomicstracksandprovidesevidencerelatedtovariousgenomic
testsfromresearchtoclinicalandpublichealthapplication.TheNIHalsomaintainstheclinicaltrials.gov
Web site, which is a mandatory listing of all clinical trials being conducted; this Web site includes
information on the purpose of the clinical trial, the study’s eligibility requirements, sites where the
clinicalstudyisbeingconducted,thestatusofpatientrecruitmentandenrollment,andcontactinformation
fortheinvestigators.Althoughclinicaltrials.govis notrestrictedtopharmacogenomicsandincludesall
ongoing trials, it is possible to search for pharmacogenomics studies, thereby providing clinicians
opportunitiestolearnmoreaboutthelatestinclinicalpharmacogenomicsresearchandpossiblyprovide
theirpatientswithopportunitiestoenrollinspecifictrials.
There are also an increasing number of resources that are specifically targeted toward equipping
specifichealthcareprofessionalswithknowledgeandinformationaboutpharmacogenomicsandhowto
use it in clinical settings, such as the Community Pharmacist Pharmacogenetics Network
(https://rxpgx.wordpress.com).
Box7.3 SelectedPharmacogenomicsInformationResourcesforClinicians
CDCOfficeofPublicHealthGenomics:https://www.cdc.gov/genomics/default.htm
ClinicalPharmacogenomicsImplementationConsortium:https://cpicpgx.org/guidelines/
CommunityPharmacistPharmacogeneticsNetwork:https://rxpgx.wordpress.com
Dutch Pharmacogenomics Working Group Guidelines:
https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica/pharmacogenetics1/pharmacogenetics
FDA Table of Pharmacogenomic Biomarkers inDrug Labeling: https://www.fda.gov/drugs/science-
and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling
NationalLibraryofMedicineDailyMedProject:https://dailymed.nlm.nih.gov/dailymed/
PharmacogenomicsKnowledgeBase,PharmGKB:www.Pharmgkb.org
UbiquitousPharmacogenomics(U-PGx):http://upgx.eu
CASESTUDY1
J.T. suffers from an irregular heartbeat called atrial fibrillation. On a Sunday afternoon, his wife
noticedasJ.T.waswatchingafootballgameontelevisionthathisfacestartedtodroopandhisspeech
seemed abnormal. She asked him to smile andhis smile was all ofsudden very uneven. After he
arrivesatthehospital,itisdeterminedheishavingastrokeasaconsequenceofhisnewlydiagnosed
atrialfibrillation.
1.ThetherapyofchoiceforJ.T.inthisparticularcaseiswarfarin.However,followingafewhoursof
warfarintherapy, J.T.’s wifenotice excessive nose bleedsandbruisingappearingunderhis skin
that seemedto be coming outof nowhere.Fromthefollowingoptions givenandfrom a genetic
standpoint,whatcouldbehappeningtoJ.T.?
a.HecouldhaveamutationinhisliverCYP2C19enzyme,causinga90%decreaseinwarfarin
clearance,leavingmoreS-warfarininhisblood,causingexcessivebleeding.
b.HecouldhaveamutationinhisliverCYP2C9enzyme,causinga90%decreaseinwarfarin
clearance,leavingmoreS-warfarininhisblood,causingexcessivebleeding.
c.HecouldhaveamutationinhisliverCYP2C9enzyme,causinga90%decreaseinwarfarin
clearance,leavingmoreR-warfarininhisblood,causingexcessivebleeding.
d.HecouldhaveamutationinhisliverCYP1A1enzyme,causinga90%decreaseinwarfarin
clearance,leavingmoreS-warfarininhisblood,causingexcessivebleeding.
Answer:b.
2. Surprisingly, following genetic testing, it was discovered that J.T. can metabolize warfarin
perfectlythroughhisliverasallofhisCYPenzymescamebacknormal(nomutations).Whichof
thefollowingoptionscouldthusexplainhisexcessivebleeding?
a.J.T.isAhaplotypeforVKORC1.
b.J.T.isGhaplotypeforVKORC1.
c.J.T.isThaplotypeforVKORC1.
d.J.T.isChaplotypeforVKORC1.
Answer:a.
3.KnowingJ.T.’sgenetictestingresults,whatshouldbedoneconcerningthedoseofwarfarin?
a.Alowerdoseshouldbegiven.
b.Ahigherdoseshouldbegiven.
c.Nochangeinthedosageisnecessary.
d.NowarfarinshouldbegiventoJ.T.inthefirstplace.
Answer:a.
CASESTUDY2
1.Amandapresentstotheemergencyroomwithdifficultybreathingandstatesintensechestpain.She
istriagedashavinganacutecoronarysyndrome.Aspartialblockageofhercoronaryissuspected,
sheis givena dualtherapyofclopidogrel andaspirintoinhibit platelet aggregationandprevent
thrombogenesis. Surprisingly, Amanda’s symptoms are not improving at all following the
administrationofthe dual therapy,and animpaired response toclopidogrel is suspected in this
patient.Thus, sheis suspected to be a poor metabolizer of clopidogrel. Whichof the following
nomenclature associated with CYP2C19 mutations do you expect could be the root cause of a
subtherapeuticresponsetoclopidogrelinthispatient?
a.*2/*2
b.*2/*3
c.*3/3*
d.Alloftheabovecouldbeexpected
Answer:d.
2. If Amanda is believed to be a poor metabolizer of clopidogrel, would you expect her liver
CYP2C19tocontainagain-of-functionmutation?
a.Yes
b.No
Answer:b.
3.Whatisthemechanismofactionofclopidogrelatthecellularlevel?
a.ItinhibitsplateletactivationbyirreversiblybindingtotheP2rY12receptoratthesurfaceof
platelets.
b. ItinhibitsplateletactivationbyreversiblybindingtotheP2rY12 receptoratthesurfaceof
platelets.
c.ItpromotesplateletactivationbyirreversiblybindingtotheP2rY12receptoratthesurfaceof
platelets.
d.Noneoftheabove.
Answer:a.
CONCLUSION
Insummary,amongthemostpromisingapplicationsofpharmacogenomicsisthepotentialtominimizeor
preventADRs.Progresshasbeenmadeintheclinicalimplementationofpharmacogenomics,withseveral
molecularcompaniondiagnosticspairedwithtargetedtherapeutics.Manyotherbiomarkersarecurrently
beingtestedtopredictresponsetotherapies.However,todate,theimplementationofpharmacogenomics
inclinicalpracticehaspresentedvariousELSIandpolicychallenges.
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8
TheEconomicsofPharmacotherapeutics
BrianaL.SantanielloandJoshuaJ.Spooner
LearningObjectives
1.Describethehistoricaloriginsandevolutionofhealthinsuranceandmanagedcareorganizationsin
theUnitedStates.
2. Compare and contrast the common types of prescription drug formularies and corresponding
prescriptioncopaymentstrategies.
3. Explain the responsibilities of a pharmacy and therapeutics (P&T) committee and describe the
factorsthatP&Tcommitteesconsiderintheirdecision-makingprocesses.
4. Discuss how formulary management tools (generic substitution, therapeutic interchange, prior
authorization,andsteptherapyprograms)caninfluenceprescribingpatterns.
5.Explainhowemerginghealthtechnologies(electronicprescribing,electronicmedicalrecords,and
telehealth)haveinfluencedthedeliveryofcare.
INTRODUCTION
As few as 100 years ago, health insurance in the United States was a scarce commodity. Although
PresidentGeorgeWashingtonhadsignedalawestablishingprepaidhealthcarein1798,healthinsurance
planswereslowtodevelop.Traditionally,patientsintheUnitedStatespaid healthcareprovidersand
hospitals directly for their services out of their own pocket on a fee-for-service basis. This system
worked well for patientsintimes ofgoodhealth;however,a seriousinjuryorillness couldplace the
patientinseverefinancialperil.
Thegoalofthischapteristoprovideafundamentalunderstandingoftheprinciplesusedbymanaged
care organizations (MCOs) and pharmacy benefit managers (PBMs) to manage pharmacy costs while
providingaccesstoappropriatepatientcare.Thischapterprovidesabriefreviewofpharmacoeconomic
principles, educates the reader about the strategies used by MCOs and PBMs to manage health care
expenditures, explains how these strategies are developed and implemented, and reviews how MCOs
evaluate the performance of contracted providers. Through a better understanding of the practices,
benefits, andchallenges of MCOs andPBMs, practitioners can betterprescribe appropriate and costeffectivemedicationsfortheirpatients.
ORIGINSOFMANAGEDCARE
Theoriginsofmodernhealthinsurancecanbetracedto1929, whentheBaylor UniversityHospital in
Dallas,Texas,begantoofferschoolteachersupto21daysofhospitalcareayearforanannualpayment
(premium) of $6 per person (Starr, 1982). Other groups also entered into agreements to prepay for
Baylor’sservices.Shortlythereafter,severalotherDallasareahospitalsfollowedsuitandofferedsimilar
plans.OtherearlyhealthinsuranceplansincludedtheKaiserHealthPlans(earlytomid-1930s)andthe
GroupHealthAssociationinWashington,DC(1937).Asthecountryslidintothedepressionandhospital
revenues plummeted by 75% per patient, hospitals began to rely on insurance payments for a greater
proportionoftheiroperatingbudget(Starr,1982).
Most healthplans offeredindemnityinsurance(also knownasfee-for-service insurance), inwhich
patientspaidforhealthcareexpensesoutoftheirownpocketsandthenrequestedreimbursementfromthe
insurer(oftenreceivingreimbursementfor80%ofincurredexpenses).However,indemnityinsurancedid
littletocontrolhealthcareexpendituresbecausephysiciansandhospitalsreceivedpaymentsproportional
to the volume of services they provided. Concerned with the rising cost of providing health care,
insurance providers sought ways to slow the increases in health care expenditures. After extensive
lobbyingandnegotiationsinCongress,PresidentRichardNixonsignedthefederal HealthMaintenance
Organization(HMO)Actintolawin1973.Thisactencouragedthegrowthofmanagedcarebyproviding
grantsandloanstodevelopHMOs,overturnedrestrictivestatelawsregulatinghealthproviders,defined
a basic packageof services that HMOs were required to offer, andestablished procedures by which
HMOscouldbecomefederallyqualified.
BecauseHMOscoulddelivercost-effectivehealthcarebenefitswhilemaintainingareasonablequality
of care, they were viewed as an attractive health insurance alternative for employers. The rate of
enrollment in HMOs grew rapidly during the 1980s and 1990s, growing to rival preferred provider
organizations(PPOs)astheleadingsourceofemployer-sponsoredhealthinsuranceintheUnitedStatesin
thelate1990s.ThefederalgovernmentalsoencouragedtheuseofHMOstomanagethehealthcarecosts
ofMedicare-eligible beneficiaries;HMOswerereimbursedona prospective basisbythegovernment.
The states soonfollowed suit,offeringHMO-based optionstoMedicaid recipients. Oflate,there has
beena significantdeclineinemployer-sponsored HMO enrollment,with a shiftinfavor of PPOs and
high-deductiblehealthplans(KaiserFamilyFoundation,2019).
OVERVIEWOFPHARMACOECONOMICS
WhenMCOsmakedecisionsrelatedtowhatmedicationsarecoveredandplacedonformularies,those
decisionscouldimpacthundredsofthousandsofmembers.Applyingeconomicprinciplestoanalyzethe
impactofa medicationon the MCO’soverall healthcare cost and disease managementof the patient
population is essential to appropriate decision making. Pharmacoeconomic research assesses the
“overallvalue”ofmedicationsinthetreatmentorpreventionofthedisease(s)theyareintendedtotreat
(Navarroetal.,2009).Becausetheyevaluatebothcostandhumandata,studiesonpharmacoeconomics
areimportanttoolsforMCOsinmakingdrugtherapydecisions.Toprovideanoverview,somedifferent
pharmacoeconomicstudydesignsaredescribedinthefollowingsections.
Cost–BenefitAnalysis
Acost–benefitanalysisisusedtodeterminetheoverallcostofaparticular interventionorprotocolby
evaluating all pertinent data and convertingthedata to a monetary endpoint(e.g., U.S. dollars or EU
Euros). Most often, this type of analysis is used to compare two different programs that also have
differentunitsforendpointsbecausethedatacanthenbe convertedtoonecommonmonetaryunit.The
limitationtothisanalysisinvolvestheevaluationof“intangible”endpoints,ordatathatcannotbeequated
toamonetaryvalue.
CostMinimizationAnalysis
Acostminimizationanalysisevaluatesthecostoftwoormoreinterventionswithequivalentcomponents
orendpointsanddetermineswhichinterventionisleastcostly.Themostappropriateuseforsuchanalyses
involves situationsinwhicheveryaspectofcomparedinterventionsis identical exceptthecostofthe
intervention. Because efficacy and safety are identical, the cost of each intervention becomes the
differentialoutcome.Theoutcomesoftheseanalysesarealsoexpressedinamonetaryendpoint.
Cost-EffectivenessAnalysis
A cost-effectiveness analysis mayhelp determinethe best program or intervention,where thedesired
outcome is a combination of both a monetary endpoint and a nonmonetary endpoint relative to an
improvementinhealth(e.g.,lifeexpectancy,bloodglucosemeasurements).Anexampleofthiswouldbe
dollarsspentperlife-yearsaved.
Cost–UtilityAnalysis
Acost–utilityanalysis,whichiscloselyrelatedtoacost-effectivenessanalysis,measuresdataintermsof
qualityoflife.Qualityoflifeisanassessmentofapatient’swell-beingandsocialfunctioning,whichcan
assistpractitionersindeterminingapatient’sresponsetodrugtherapy(Hunteretal.,2015).Alongwith
traditionalclinical results(e.g.,laboratoryvalues, blood pressure, serum glucoselevel), acost–utility
analysis provides a more complete evaluation of a patient’s progress and compares the cost of an
intervention or program in terms of more intangible endpoints, rather than dollars. These analyses
predominantly use quality-adjusted life-years (QALYs) gained as a major outcome. The QALY is
symbolic of healthy years of life and is the unit of measurement that encompasses outcomes (e.g.,
morbidityandmortality) inpreferential sequence. This methodhas beenverysuccessful in evaluating
variousprocedurescomparedwithdrugtherapyinwhichapatient’squalityoflifeisthechosenoutcome
(Hunter et al., 2015). The Institute for Clinical and Economic Review, a non-partisan research
organization that objectively evaluates the value of health care, has identified the QALY as the gold
standardformeasuringhowwellamedicaltreatmentimprovesandlengthenspatients’lives(Institutefor
ClinicalandEconomicReview,2018).
Pharmacoeconomicresearchcomparescostandconsequencewithrespecttopharmaceuticalproducts
andtheirimpactonindividuals,thehealthcaresystem,andsociety.Suchparametersareseldomanalyzed
inmoststudies.
FORMULARIESANDPHARMACYANDTHERAPEUTICSCOMMITTEES
Anevaluationof Americanhealth expenditures identified$3.6 trillionin total health carespending in
2018 (Centers for Medicare &Medicaid Services [CMS],2019a), whichaccounted for 17.7% ofthe
nationalgrossdomesticproduct(GDP).Ofthis$3.6trillioninhealthexpenditures,$335billion(9.9%)
was spent on prescription drugs. Although this represents a minor portion of overall health care
expenditures,itremainsatargetforinterventionbyMCOsduetolargeannualincreasesinprescription
drugspending. Prescriptiondrugspending in the UnitedStates tripled during the 1980s, tripled again
duringthe1990s,anddoubledduringthefirstdecadeofthe21stcentury(CMS,2019b).
Formularies
OneofthemosteffectivemethodsbywhichanMCOcanimprovethequalityofcareprovidedtopatients
andmitigatetheincreasingcostsofprovidingaprescriptionbenefitisbyimplementingaformulary.Also
knownasapreferreddruglist,amedicationformularyis alistofpreferredmedicationsapproved for
use within an HMO, a third-party payer, or a PBM (Navarro et al., 2009). Formularies are usually
organizedbytherapeuticareaandmedicationclass,withtheformularystatusandreimbursementcategory
listedforeachmedication.
Formulariesencouragetheuseofmedicationsconsideredtobesafer,moreclinicallyeffective,ormore
cost-effectivethanothermedicationswithinthesametherapeuticcategory.WhenanMCOwantstolimit
theuseofa drugforaspecific reason(safety, efficacy,orcost),theformularyallows theflexibilityto
implement restrictions or limitations on utilization. Examples of such restrictions include prior
authorizations,steptherapies,quantitylimitations,andtieredcopayments.
EvolutionofFormularies
The useof formularies canbe traced back to1925, when thephysicians andpharmacists of Syracuse
University Hospital collaborated to establish a formulary system to monitor drug use and reduce
therapeuticduplication(theunnecessaryuseoftwoormoremedicationstotreatthesamecondition)in
theirdrugtherapyprogram(Sonnedecker,1976).Bythe1960s,formularieswerebeingimplementedin
hospitals throughout the country with the guidance of the American Hospital Formulary Service, a
prominent set of formulary development materials published by the American Society of Hospital
Pharmacists. FollowingtheHMOActof1973, manyHMOsadoptedthehospital formularytomonitor
medicationuse.Formularies wereinitiallyusedbyMCOsasaninventorycontrol mechanismfor staff
model HMOs (Navarro et al., 2009), but they have evolved into effective tools for monitoring and
regulatingmedicationutilizationforalltypesofMCOs.
StructureofFormularies
Althoughformatsmaydifferamongplans,aformularyusuallycontainsthesamefundamentalinformation.
Formularies usually begin with a basic plan summary and detailed key points of reference and then
proceed to the list of drugs. The drugs are most oftencategorized within their respective therapeutic
classes, with the therapeutic classes listed in alphabetic order. The order of the drugs within each
therapeuticclass canvary,butthedrugsareoftenlistedalphabetically, eitherincompletealphabetical
order (generic and brand drugs intermixed) or as generic drugs listed before brand-name drugs.
Additionalinformationusuallydetailedforeachdrugincludesthebrand/genericstatus;thedrug’srelative
cost(oftensymbolizedbydollarsigns,withone$representingthelowestcostmedicationandadditional
$s representing increasingly costly medications); copay tier; and any potential utilization management
programs.AnexampleofaformularyisshowninTable8.1. Aformularymedicationisa drugthatis
covered(reimbursed)bythehealthplan;formularymedicationscanbesubdividedintodifferentgroups
suchaspreferredandnonpreferredagents.Preferredagentsaredrugsthatthehealthplanwouldprefer
thatthepractitionerprescribe,duetosafety,efficacy,and/orrelativecost.Nonpreferreddrugsarenotthe
preferreddrugsofthehealthplanbutwillnonethelessbecoveredbytheplanatahigherout-of-pocket
costtothepatient.Mostformularieshavedifferenttieredcopaysforpreferredandnonpreferreddrugs,in
which preferred drugs have a lower-cost tiered copay than the nonpreferred drugs. Nonformulary
medications are drugsthat areexcluded fromtheformulary; healthplans generally do not publishthe
nonformularymedicationsontheirformularies.Prescribersmustusuallyprovidejustificationforapatient
toreceivereimbursementforanonformularymedication.
TABLE8.1
ExampleofaFormulary
PA,priorauthorization;QL,quantitylimits;ST,steptherapy;Tier1,generic;Tier2,preferredbranddrug;Tier3,nonpreferredbranddrug;Tier
4,specialtyinjectable.
Formularies can be grouped into three different categories: closed, open, and tiered formularies.
Closedformularieslimitclinicianstoprescribingfromalimitedlistofpreferred agents(Edlin,2015).
Openformulariesusuallydonotinvolveapreferredgroupofagents;instead,theyallowtheprescriberto
selectanycovered medication.Tiered formulariesare essentiallythecompromise betweenclosed and
open formularies. Tiered formularies are open formularies that set different copay tiers for generic,
preferred,andnonpreferredmedications(Edlin,2015).
ImpactofFormulariesonPatients
The price that consumers pay for prescription medications varies from plan to plan. Patients are
commonlyrequired topay a portion of the cost of the prescription,also knownasthecopayment, or
copay. Copay amounts can differ from plan to plan and by geographic region. Closed and open
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