Global Clinical Trials Playbook. Management and Implementation when resources are limited

294 Pages·2012·19.395 MB·English

by  Menghis Bairu and Richard Chin (Eds.)

1
CHAPTER
Introduction
Menghis Bairu
Elan Biopharmaceuticals, San Francisco, California, USA
Wherever in the world we stand, the majority of clinical trials are being
conducted somewhere else in the world, under a different regulatory
framework and in different cultural settings. However, we all rely on the
sametrialstomakedecisions;asregulators,toallowordisallowmarketing
authorizations, and, as patients and healthcare providers, to use or not to
use a medicine.
FergusSweeney,HeadofInspectionsattheEuropeanMedicinesAgency(September2010)
Thirtyyearsago,theUnitedStatesFoodandDrugAdministration(FDA)formalizedaprocess
fortheinclusionofdataderivedfromclinicaltrialsconductedoverseasthatcouldbeincluded
3
in anewdrug application (NDA)submitted for marketingapprovalbypharmaceutical
sponsors.TheimpetusforthisnewFDAguidelinederivedfromclinicaltrialsbeingsponsored
byUS governmentagencies,academic research medical centers,and USpharmaceutical
companies which werebeing conductedoutside the USA. Atthat time, 41 foreign clinical
investigatorswereconductingdrugresearchunderaninvestigationalnewdrugapplication.By
1999, over 4400foreign investigators wereparticipating in US-sponsored research, and by
2008,morethan200,000patientswereenrolledinover6500research sites outsidethe USA
for over 80 percent ofthe NDAssubmitted to the FDAthatyear.
This trend in globalization of clinical trial researchwasbyno means limited to regulatory
submissionsin the USA. During the years2005e2009,registration studies submitted tothe
European MedicinesAgency(EMA)involved more than 44,000 investigator sites in 89
countries.Only 38.8 percent of patientswithinthe EuropeanUnion or European Economic
Areawereenrolledinstudiessponsoredbylocalinstitutions.Theremainderofpatientswere
recruited offshore.
The forces that havedriventhe globalization of clinical trial researchare multifactorial,with
potential benefitfor patients,sponsors,local communities,and foreign governments.
Government-,non-government-,andpharmaceuticalindustry-sponsoredresearchconducted
inemergingnationsreflectsthedesiretostudymedicinesinpopulationswithlocallyendemic
diseases and infections which mayalso be found indeveloped countries.In addition, for
pharmaceutical companies thatanticipate selling in keyglobalmarkets, the impetusto use
overseasstudysitesundoubtedlyreflectsthepotentialtoreduceoperationalcostsandrecruit
largernumbersofdrug-na¨ıvepatientsovershorterperiods,while establishingaresearch and
marketing presence inthese developing countries.
Nevertheless,the globalization of clinical trial researchhasrevealed significantchallenges,
especially in developing countries,with regard tounderstandinggood clinical practice,
GlobalClinicalTrialsPlaybook.DOI:10.1016/B978-0-12-415787-3.00001-1
Copyright(cid:1)2012ElsevierInc.Allrightsreserved.
SECTION 1
Clinical Trials
informedconsent,patientsafety,ethicsreviewcapacity,accesstomedicalequipment,integrity
ofacquired data, and regulatoryoversight. Low-and middle-income countries inwhich
clinicaltrialsareconductedvarysubstantiallyintheextentoftheircapabilitiesandexperience
withclinical trial research. Manydeveloping countrieshavelimitedor no institutional regu-
latoryinfrastructureandethicsreviewboardstooverseetheconductofclinicaltrialsatglobally
acceptedstandards.Local clinical investigators have varyingdegreesof skill, training, and
experiencerequisite tosupervise the conductof aclinical trial. The extentof understanding
and sophistication ofpatients,coupledwithlocalcultural idiosyncrasies, affects informed
consent, study participation, and overall expectations.
Recognitionofthesechallengesoverthepastdecadehasledtoavarietyofpublications,
workshops,trainingprograms,andguidelinesinanefforttoenhancethequalityoftheclinical
trialenterpriseindevelopingcountries.Keystakeholders,includingregulatoryagenciesin
developednations,theWordHealthOrganization(WHO),ministriesofhealth,academia,the
pharmaceuticalindustry,non-governmentalorganizations(NGOs),contractresearchorgani-
zations(CROs),andnon-profitfoundations,haveforgedavarietyofpartnershipstoadvance
thequalityofclinicalresearch.Forexample,theStrategicInitiativeforDevelopingCapacityin
EthicalReview(SIDCER)wasorganizedin2001“.todevelopcompetent,independent,in-
countrydecisionmakingforpromotingresponsibleconductofhumanresearchandtomonitor
thequalityandeffectivenessofethicalreviewworldwide,withmutualunderstandingand
respectforcultural,regionalandnationaldifferences”.TheEuropeanandDevelopingCoun-
triesClinicalTrialsPartnership(EDCTP)wascreatedin2003“.toacceleratethedevelopment
ofneworimproveddrugs,vaccines,microbicidesanddiagnosticsagainstHIV/AIDS,malaria
andtuberculosis,withafocusonphaseIIandIIIclinicaltrialsinsub-SaharanAfrica”.TheUS
FDAholdsongoingtrainingprogramssuchas“TraintheTrainerGoodClinicalPractices”,to
enhancetheregulatoryoversightofclinicaltrialsinvariousregionsaroundtheworld.Although
theseexamplesillustratetheenormousstridesthathavebeentakentoimprovethequalityof
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clinicaltrialsconductedindevelopingnations,therehasyettobetheconsolidationofbest
practicesregardingthevariouscomponentsoftheclinicalresearchenterprisethatmaybe
resourcedforestablishinghigh-qualityclinicalresearchinstitutions.
Thisbook waswritten toprovide resources under one coverwhich elucidate the various
elementsrequiredforthesuccessfulimplementationofclinicaltrialsindevelopingcountries.
Forthe firsttime, thereader hasapracticalmanualfor developing and enhancing the
infrastructureandprocessesrequiredtoconductclinicalresearchindevelopingcountries.This
book is divided into eight sections addressing the essential aspects ofhowto build and
enhance global clinical trialscapacity inemerging markets and developing countries.In
Section 1, anintroductionto the subject of global clinical trialsis provided, with afocus on
design and planning. The African perspectiveofappropriateand necessary training ingood
clinicalpracticeofallpersonnelinvolvedinconductingclinicaltrials,inbothurbanandrural
localesinAfricancountries,isdiscussed.Clinicaltrialsitecapabilitiesandtheimportanceof
establishingadequate standard operatingprocedures in sub-Saharan Africa are discussed,
while addressing the challenges of informed consent,clinical execution byprincipal investi-
gators and staff, partneringwithlocalpharmacy, and processingof laboratoryspecimens,
practicesthat should be intended toendure from trial to trial. Building and strengthening
clinical trial site capabilitiesand capacity in other developing/emergingmarkets, including
India,China,EasternEurope,Singapore,andTurkey,arecoveredinSection2.Partneringwith
therightcontractresearchorganizationisavitalcomponentinconductingasuccessfulclinical
trial; the different perspectives ofworkingwithglobaland niche CROsand the options
available for choosing aCROwhenconducting anoverseas clinical trial are presented. The
finalchapters of this section provide the reader with guidelinesfor prioritizing clinical trial
research based on nationalinterests,as wellas addressing the managementof resources,
budgets,andpersonnel,withanemphasisonfutureplanningtosustaintheclinicalresearch
enterprise locally.
CHAPTER 1
Introduction
Section3providesaroadmapforlocalregulatoryagenciestobuildandenhancetheircapacity
to evaluateinvestigative newdrug and NDAapplications,with recommendations of best
practicestodevelop the regulatorycapacity for the monitoring, oversight, enforcement,and
approval ofclinical trials.Section 4 addresses the establishment of infrastructure, operating
procedures,and personnel training for pharmacovigilanceand risk management bylocal
government agencies.
The challengesand opportunities for outsourcing of electronicdata collection and data
management in developing countries,withexamples of best practices for minimizing data
dilution, arepresented in Section 5.Section6 containsachapter dealingwith theimportant
conceptof the establishment and maintenanceof highly functioning investigational review
boards,with special consideration of vulnerable populations in developing nations.The
criticalimportanceofidentifyinglocaltalent,optimizingrecruitmentandretentionofstaffto
ensurecontinuityduringaclinicaltrialandfromtrialtotrial,andthemeansforensuringthe
protection ofintellectual propertyare also discussed. Section 7 addressesbestpracticesand
challengesforacquiringandmanagingclinicaldataofhighqualitythroughstrategicplanning,
andtheprocessandpreparationforexternalmonitoringbysponsorsandregulatoryagencies.
Finally,inSection8(Appendices),samplesofstudyprotocol,aconsentform,jobdescriptions,
casereport forms,and astatistical analysisplan, as wellas the International Committee on
Harmonisation (ICH) guidelines,are provided.
This book is the first ofits kind toprovideguidelinesand best practicestothe reader for
enhancing the capacityofdeveloping countries toparticipate in clinical trial research at the
highestlevel.Asacomplement to the recently published Global Clinical Trials: Effective
ImplementationandManagementbythesameauthors,thisbookisaimedatindividualsinthe
WHO,ministriesofhealth,pharmaceuticalcompanies,clinicalresearchersinacademia,non-
profit organizationssuch as the Billand Melinda Gates Foundation, the World Bank,and
NGOswhoareinvolvedinclinicalresearcharoundtheworld,andwillserveasavitalreference 5
foranyoneinterestedinbuildingandenhancingclinicalandresearchcapacityindeveloping
countries.
2
CHAPTER
Global Clinical Trials:
Study Design and Planning
Richard Chin
UCSF School of Medicine, San Francisco, California, USA
CHAPTER OUTLINE
Introduction 7 PatientSelection 12
Principles of Clinical Study Design 8 Reference 17
Endpoint 8
Dosing 10
Materialin this chapteris based on or excerpted withpermission from Chin and Lee.1 7
INTRODUCTION
Thedesignofanystudyhasdirecteffectsontheexecutionofthestudyandthequalityofthe
study results.Awell-designed and well-written study protocolis clearon the inclusion and
exclusion criteria, and it is clear on the procedures to be followed. It does not demand
unreasonableorinfeasiblystringentcriteriaonschedulesandprocedurestobefollowed,and
it takes into account the limitations thatthe sitemayface. Such aprotocolfacilitates
asmoothlyrunstudy.Awell-designedstudyalsomakesitpossibletointerprettheresultsand
drawclear conclusions.
Thischapterdiscussesthefundamentalsofclinicalstudydesignandplanning.Thismaterialis
drawnfromand is discussed in more detail in Chin and Lee.1
Whilethefundamentalsofgoodstudydesignarethesameforstudiesconductedindeveloped
and developing countries,there are severalconsiderations that must be taken into account
whenconductingtrials indeveloping countries.
First,thereareclinicalpracticedifferencesbetweencountries.Apatientwithcongestiveheart
failuremayreceivedifferentcareindifferentcountries.Standardsofcarecandiffersignificantly
evenwithinthesamecountrydependingongeographyandthesocialandeconomicstrataof
the patients.
Second,there are genetic, dietary,and other differencesin populations between different
countries.Genetic or dietarydifferencesmayresultin different responses todrugs,including
metabolic differences. Another difference is variation inweight.Patientsin developing
countrieswhohavealowercaloricintakemayhavesmallerstaturesandlowerratesofobesity.
Rates ofbackground diseases,including tuberculosis,can varyfromcountryto country.
GlobalClinicalTrialsPlaybook.DOI:10.1016/B978-0-12-415787-3.00002-3
Copyright(cid:1)2012ElsevierInc.Allrightsreserved.
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Clinical Trials
Insome countries,manyof the womenof childbearingage maybe pregnant or nursing,
makingitdifficulttorecruityoungwomenifexclusioncriteriaexcludepregnantandnursing
women.It is importanttocarefullyassessthe differencesand todetermine whether such
differences mayrequirerevisions in the studydesign.
Third, there maybe regulatorydifferencesbetween countriesand jurisdictions.Laws on
privacy,collectionofgeneticmaterial,andotherissuesmayvaryfromcountrytocountryand
mayrequirechangesinthestudy.Insomejurisdictions,thereisarequirementthatthesponsor
payforallmedicalcareforthepatient.Insomecases,theethicalconsiderationsmayrequire
additional prudence,as discussed inChapter 15.
Fourth,thefacilitiesandtrainingoftheinvestigatorsandthesitepersonnelmaylimitthetypes
ofstudiesand procedures that can be performed. Forexample,magnetic resonance imaging
(MRI) is not widelyavailable in manycountries.Manysites maynot have readyaccessto
anearbyacute care facility for adverseevents. In rural areas,reliableelectricitymaynot be
available, necessitatingthatdiesel generatorsbe provided. However, indevelopingcountries,
theprincipalinvestigatormaybemuchmoreactivelyinvolvedinthestudythanindeveloped
countries,andsometimes,therefore,amorecomplicatedstudyispossible.Inaddition,clinical
diagnostic skillssuch asauscultation andophthalmic examinationskillsmaybemuch more
sophisticated in asetting where echocardiograms and other types ofdiagnostic machineare
not readilyavailable.
Fifth, transportation in developing countries,especially in rural areas,can be challenging.
Apatientmayneedtowalkforanentiredaytoreachtheclinic.Insuchcases,studiesthatare
normallyoutpatientmayneed to be conducted as inpatient studies.Communication can
sometimesbeachallengeaswell,buttheavailabilityofcellphonesisnowalmostubiquitous
and contacting sites and patients hasbecome significantly less challenging.
8 Sixth,culturaland nationalcalendars maymake itdifficulttoconduct studiesduring certain
periods.Just as it is difficult to recruit patients during AugustinFrance,recruiting patients
during Ramadanin Muslim countriesor during October in India can be achallenge.
Being awareofthe potential issuesand workingwith the local medical director,contract
researchorganization(CRO),orinvestigatorduringthedesignofthestudywillmakethestudy
much more likelytosucceed.
PRINCIPLES OF CLINICAL STUDY DESIGN
There are three key parameters inthe design ofaclinical trial: endpoint, dosing, and patient
selection. Althoughthere are multipleadditional parameters that can be modified in atrial,
thesethreeaccountfornearlyallofthedifferencesbetweenstudydesignsthatleadtosuccess
and those thatdo not.
Endpoint
The first criticalfactor, endpoint, is the clinical orsurrogate item thatyouare assessing to
determine whether the drug or intervention iseffective. This item can be adisease character-
istic, health state,symptom, sign, or test (e.g.laboratory, radiological) results.Regulatory
agencies basedrug and device approval decisionson clinical trial endpoints.Earlyinthe
development and evaluationof an intervention, endpoints are usedto determine the safety
and biological activityofan intervention. Later on, endpoints help investigators to decide
whether adrug providesaclinical benefit.
There are severalkeycharacteristics ofagoodclinical endpoint. Itshould:
l be clinicallyrelevant
l closelyand comprehensivelyreflect the overalldisease being treated
l be rich in information
CHAPTER 2
Global Clinical Trials: Study Design and Planning
l be responsive (sensitiveand discriminating, withgooddistribution)
l be reliable (precise and reproducible, withlowvariability),evenacross studies
l be robust to dropouts and missing data
l not influence the treatmentresponse or have abiological effect inand ofitself
l bepractical(implementableatdifferentsites,measurableinallpatients,economical,and
non-invasive).
Theendpointmustcloselyandcomprehensivelyreflecttheoveralldiseasebeingtreated,andit
must be clinicallyrelevant.Anendpoint that onlycaptures oneaspect or component of
adisease maynot suffice. Forexample, if the disease beingtreated weresystemic lupus
erythematosus(SLE),anendpointfocusingjustonskinmanifestationsmaymissthecardiac,
pulmonary,and renal manifestations of lupus.Ifthe intention ofthe therapywereto
improve the overallstatus ofapatient with SLE, a skin manifestations measure wouldbe an
inappropriate endpoint. However, if the drug wereonly intended to improveskin manifes-
tations, this endpoint maybe acceptable.
One of the most importantaspects ofselectingand defininganendpoint is its clinical rele-
vance.Themostsensitiveandreliablemeasureisoflittleuseiftheresultsdonothaveclinical
meaning or cannot be extrapolatedto anendpoint thathas clinical meaning. Clinicalrele-
vanceis dependent on severalfactors,includingthe importance of the endpoint being
measured,themagnitudeofthechange,andfunctionaloutcome.Ultimately,though,whatis
clinically relevant is whatmatters to the patient.
The choice of clinicallyrelevantendpoints often depends on the type of disease. What is
relevanttoonediseasemaynotberelevanttoanotherdisease.Reductioninsymptomswould
beabetterendpointthanmortalityforacute,self-limited,non-fataldiseasessuchasseasonal
allergiesorcolds;butmortalitywouldbeamoreappropriateendpointforpotentiallyrapidly
fatal diseasessuch asaneurysmruptures or myocardial infarctions.
9
Theendpointshouldcaptureenoughappropriateinformationthatcanbeusedtoanalyzeand
todrawappropriateconclusions,anditshouldberesponsive.Ingeneral,knowingmoreuseful
informationisbetter.Forexample,knowingtheactualcardiacejectionfractionbypercentage
is usuallybetter than justknowingwhetherthe ejection fractionwasnormalor reduced.
Responsiveness(i.e.sensitivityofthemeasuretoactualchangesinaphenomenon)isacritical
characteristicofagoodendpoint.Whenthereisachangeinthephenomenon,thevalueofthe
endpoint should change as well.
Endpoints with good responsiveness(i.e.largechanges inthe endpoints when the phenom-
enonchanges)allowsmallersamplesizesandpermitabetterestimateoftheclinicalbenefit.
Of course, when the endpoint is too sensitive, it maydetect too manysmallclinicallyinsig-
nificantchanges,such as athree percentdecrease in tumor size or asix-hour increase inthe
median survival.The keyis balancing responsivenessand clinical significance.
The endpoint shouldbe reliable. Reliability is the “consistency” or “repeatability” ofthe
endpoint. Repeated measurements for anendpoint should producesimilar values,i.e. the
endpoint should be reproducible and verifiable. The measurementshould not varysignifi-
cantlydependingonwho measuresit.
Theendpointshouldberobusttodropoutsandmissingdata.Patientswilldropoutoftrials.
Datawillbe lost. Soyouwill haveto predict what measurementswouldhavebeen. For
example, all-cause mortalityis relatively robust to afewdropouts becauseyoumaycount
dropoutsasdeaths.However,frequencyofflareisnotrobustbecauseyoucannotpredicthow
manyflaresdropouts would have had duringthe study.
Finally,theendpointshouldnotinfluencetreatmentresponseorhaveabiologicaleffectonthe
patient; the endpointshouldbe practical froman implementation, economic, and patient
comfortstandpoint.
SECTION 1
Clinical Trials
Surrogate endpoints are measuresthat correlate withand canreplace measuring clinically
important outcomes inatrial.They include:
l pharmacokinetic/pharmacodynamic measures
l invivobiomarkers (e.g. CD4 count,viralload, glucose level, cholesterol level)
l clinical surrogates(e.g. blood pressure)
l ex vivomeasures
l minimal inhibitoryconcentration (MIC) of anantibacterialagent
l adenosinediphosphate (ADP)-induced platelet aggregation inhibition
l non-clinicalmeasures[e.g. forced expiratory volumein 1 second (FEV1),radiographic
findings].
Surrogate endpoints are used when it isnot practical or feasibleto use real clinical outcome
endpoints.Itmaytaketoomuchtime(whentheoutcomeoccursinthedistantfuture)ortoo
many patients (when the outcomeis relatively uncommon) to see areal clinical outcome
endpoint. Theyare also used whenit maybe too costlyor cause too much discomfort to
measurearealclinical outcome.
Surrogate endpoints commonly guide treatment decisions in clinical practice; for example,
a95percentstenosisinacoronaryarterymayleadtoapercutaneouscoronaryintervention,
high glycosylated hemoglobin levels may lead to an increase in the insulin dose, and
active urine sediment may precipitate aggressive immunosuppression in a lupus patient.
Therefore, many clinical trials use surrogate endpoints, and their results often can drive
clinical practice.
BOX 2.1 EXAMPLE OF A FAILED SURROGATE ENDPOINT: CARDIAC
ARRHYTHMIA SUPPRESSION TRIAL (CAST) STUDY
10
Highratesofprematureventricularcontractions(PVCs)arepredictiveofsuddendeathaftermyocardial
infarction.SeveraldrugsweredevelopedwithsuppressionofPVCsasthegoal,withtheultimategoalof
reducingdeathaftermyocardialinfarction.TheCASTstudywasinitiatedin1987withflecainide,
moricizine,andencainide,whichhadbeenshowntobehighlyeffectiveatreducingPVCs.Atinitiationof
thetrial,therewasdebateoverwhetheritwasethicaltorandomizepatientstoplacebowhenthedrugs
hadbeendemonstratedtoreducePVCs.Inall,2309patientswererandomized.
TheDataSafetyMonitoringBoard(DSMB)stoppedthestudyearlybecausethepatientsreceiving
antiarrhythmictherapyhadanunacceptablyhighmortality.Therelativerisk(RR)ofdeathandnon-fatal
eventsat10monthswas4.6infavorofplacebo.
Asanaside,therateofmortalityseenintheantiarrhythmicgroupwaslowerthanhistoricalcontrols.Ifit
hadbeendeemedunethicaltoconductaplacebo-controlledtrial,thenwemightstillbeusingthese
drugsinpost-myocardialinfarctionpatients.
However, asurrogate endpoint is neveras informativeas the clinical endpoint, and in many
instances,surrogateendpointshaveturnedoutnottobepredictiveofclinicalresponseatall.
Forexample,antiarrhythmicsthat preventprematureventricular contractions have actually
increasedmortality. Some drugs thatlower blood pressure donot lower the risk of cardio-
vascularproblems.Moreover, asurrogateendpoint thatworksfor one drug maynot for
another drug with adifferent mechanism of action. Asaresult,regulatoryauthorities and
manyclinicians insist on clinical rather than surrogate endpoints.
Dosing
The second critical parameterinclinical studydesign is dosing. Adose isthe amount of
anintervention administered. There are severalaspects todosing: the amount ofdosing
CHAPTER 2
Global Clinical Trials: Study Design and Planning
can vary;the route ofadministration can vary (oral, intravenous, subcutaneous,etc.);the
dosingintervalcan vary; and, for interventions that are administered over along period, the
rateanddurationofadministrationcanvary.Infusing500mgofamedicationover10minutes
(whichmayresult inhigher levelsof medication inthe blood at agiventime) can be very
differentfrominfusing500mgoveronehour(whichmayresultinlowerlevelsoveralonger
period).
Theoverallgoalofdoseselection,exploration,andcharacterizationisnotjusttoidentifydoses
that are safe and effectivebut also topaintacomprehensivepictureof:
l the relationships between dose and differentefficacy, safety, and convenience parameters
l the parameters that affect these relationships
l the dosingregimensthat appropriately balance efficacyand safety.
Researchersneedtounderstandfullyhowdifferentdosesbehaveinawidevarietyofsituations,
such as the distribution of efficacyand toxicity inthe population and whether the patients
experiencingadverseeventsarethoseexhibitingaresponse.Beingabletopredict(ifpossible)
whichpatientswillrespondandwhichwillsuffertoxicitywouldallowclinicianstoselectthe
right doses and appropriate measuresto avoidoralleviate adverseeffects.
Designingappropriatedosingregimensrequiresclosecollaborationwithpharmacokineticists,
toxicologists,and preclinical scientists.Data from preclinicalexperiments such as animal,
modeling, and pharmacokinetic data help todetermine the dosingintervaland the initial
dosesinearlyclinicaldevelopment.Lateroninclinicaldevelopment,theclinicalefficacyand
safetyprofilesfromearly-phasestudiesplayamuchlargerroleinguidingdoseselection,but
understandingpharmacokinetics,toxicology, and preclinicalinformation is still important.
Whengreat heterogeneity in patient responseor anarrowtherapeutic windowexists,any
numberof methodsmayhave tobe used tocustomize thedose.
11
l Dosingbybaselinecharacteristic.Customizingdosesbybaselinephysiologicalfactorsis
the most common method. Forexample, if you find that drug responsevariesbypatient
weight,youmayhave togiveheavierpatients higher dosesthan lighter patients.
l Titratingto an endpoint. Analternativemethod is choosing arelevantclinical endpoint
(i.e.outcome)andadjustingthedoseforeachpatientuntiltheendpointreachesacertain
value(e.g.changing the medication dose untilacertainblood pressureis achievedor
acertain plasma levelof the drug is reached).
l Dosingbysubpopulation.Another method isto identifysubpopulationsthat may
responddifferentlytothedrugandgivingeachsubpopulationadifferentappropriatedose
(e.g.menmayreceivehigherdosesthanwomen,AfricanAmericansmayrequiredifferent
dosesthan Latinos,or patientswith liverfailure mayonly toleratelower doses).In some
cases, the drug maynot be indicated or safe for certain subpopulations.
Convenienceand practicabilityare extremelyimportantbut often underappreciated facets of
choosingtherightdoseregimen.Theoptimaldosefromapureriskebenefitstandpointisnot
necessarilyconvenientor practical.Forexample, manyoral medications wouldbe more
effectiveand less toxic if givenintravenously, since intravenousadministration deliversthe
drugdirectlytothebloodstream.However,takingoralmedicationsismuchmoreconvenient
and requires significantlyless time and effort. Similarly, frequentlytitratingthe dose to
apatient’sdailyfluctuations in body weight,temperature,blood pressure,fluidintake, and
urineoutputcouldimprovetheriskebenefitratioofamedicationbutwouldbeconfusingand
impractical for apatient.
Adoseeresponsecurveisanxeygraphthatplotsthedose(orthelogarithmofthedose)on
thex-axisandtheresponse(whichcanbeanymeasureorendpoint)onthey-axis.Figure2.1
illustrates atypical doseeresponsecurve. Commonly, the x-axisplots the dose (in units of
interventionperunitmassoftestsubject)ordosefunction(thelogofthedose)andthey-axis
SECTION 1
Clinical Trials
FIGURE 2.1
Doseeresponsecurve.(Pleaserefertocolorplatesection)
plots the percentage ofthe population that exhibits the response(e.g. desiredeffect or
toxicity).Themorepowerfultheintervention,thesteeperthecurvebecomes.Theclinicaltrial
generatesdatapointstoplotthedoseeresponsecurve.Ingeneral,thetrialshouldprovideas
manydata pointsas possible todrawan accurate curve.
Byplottingadoseeresponsecurveinwhichresponseisthedesiredeffectoftheintervention,
anumberofimportantefficacyparameterscanbedetermined.Thethresholddoseisthelowest
dose at which there is anyresponse.This is the pointat which the vertical height ofthe
12
doseeresponsecurvefirststartstoriseabovezero.So,ifyouwereusingadoseeresponsecurve
todemonstratetheeffectivenessofabloodpressuremedication,thethresholddosewouldbe
the dose at which anydecreasein blood pressurein anytest subject occurs.Usuallyslightly
higherthanthethresholddoseistheminimaleffectivedose(MED),thelowestdosethatwill
generateaspecific effect. Ifthespecific desired effect is lowering the blood pressure by
20mmHg,thenthe MED will be thedose at which at leastone test subject’sblood pressure
decreasesbyat least20mmHg.FindinganMEDis especiallyimportant when toxicityis of
concern(e.g.smallmoleculedrugsthattendtohavetoxicitiesatalmostalldosesorcompletely
noveldrugsthat must be developed quickly to fill an importantunmet need). Forsmall
molecules,theMEDtendstobethedosewheretheefficacyandsafetycurvesdivergethemost.
Patient Selection
Thethirdcriticalparameterinclinicalstudydesignispatientselection.Therearemanyways
to define patient populations and diseases. It is not always optimal to define the patient
population bya previously recognized disease category, as disease categories are arbitrary
intellectual constructs. Disease categories are based on a number of possible criteria,
including:
l histologicalchanges(e.g.Crohn’sdiseaseandulcerativecolitisaltertheintestinalliningin
different ways)
l pathophysiological mechanisms(e.g. lack of insulin secretion results in type 1 diabetes
while lack ofresponse toinsulinresults intype2 diabetes)
l causativeagent (e.g. hepatitis Ais caused bythe hepatitis Avirus,asbestosis is caused by
asbestos)
l physicalmanifestations (e.g. rheumatological conditions are defined bythe joints they
affect and howtheyaffect them)
CHAPTER 2
Global Clinical Trials: Study Design and Planning
l symptomsandsigns(e.g.stableangina isthepresence ofchestpainduringexertion and
unstable angina is the presence of chest pain at rest)
l bodypart,organ,ororgansystemaffected(e.g.iritisisinflammationoftheirisanduveitis
is inflammation of the uvea)
l predisposing, preceding,or concurrent conditions (e.g. concussions occur after head
trauma, frostbite occurs withextreme cold)
l prognosisandnaturalhistory(e.g.cancerousmassescanspreadtodistantlocationswhile
benignmasses donot)
l measurement thresholds (e.g. hypertension is definedas asystolic blood pressureabove
140mmHg and adiastolicpressureabove90mmHg).
l response to treatment: twoverysimilar conditions mayhavedifferent treatments
(e.g. STand non-STelevationmyocardialinfarction) or severalconditions with very
differentmechanismsandclinicalmanifestationswillbedefinedasasinglediseaseiftheir
treatments are the same (e.g. schizophrenia includes catatonic and paranoid
schizophrenia).
Of the above, the most commonwayto classifydisease is byresponse totherapy. Several
distinctconditions withverydifferentpathophysiologyand clinical manifestations maybe
classified as the same disease if the treatment is the same (or,more commonly, if no good
treatments exist for anyof the conditions). Forexample, schizophreniahasverydifferent
possible manifestations that range from catatonicto paranoidschizophrenia. Thesecondi-
tionsallfallundertheumbrellaofonedisease,partlybecausetheyrespondtosimilartherapy.
Classifying diseases based on the availabletreatment options is often more pragmatic (e.g.
distinguishingbetween STelevationmyocardial infarction and non-STelevationmyocardial
infarctionwasunnecessarybeforethrombolyticswereshowntobeeffectiveinonebutnotthe
other;since thatdiscovery,one disease hasbecome two).
So,itisimportanttothinkcarefullyaboutthe“disease”thataclinicaltrialistargeting.Atrial 13
mayhave tobe expanded beyondthe normalconfinesof adisease (e.g.bygrouping all
patients with arterial atherosclerosistogether,including patients requiringcoronaryartery
bypasssurgery, percutaneous coronary interventions, and stroke interventions) or limitedto
asubgroupofpatients(e.g.classicoroccultage-relatedmaculardegeneration).Therearemany
different waystogroupconditions together.Forexample,conditions that have:
l the same symptoms(e.g. patientswith joint pain)
l anycombination ofsigns orsymptoms fromalist of criteria (e.g.different lupus patients
havedifferent symptoms.but allmust have aminimal numberof symptomsfroman
established list)
l the same pathophysiological criteria(e.g.apositiveblood culturefor an organism)
l the same cause (e.g. patientswithtuberculosismayhave pulmonaryor gastrointestinal
manifestations)
can be grouped together.
Usingetiology to group conditions can be problematic. Althoughassigning asingle causeto
diseases iscommon, veryfewdiseases havejust one cause. Most are the resultof interaction
amongthe environment, genes,and other factors.Hereare three examples:
l Helicobacter pylori:Helicobacterpyloriispresentinmanypeople.Althoughitcausespeptic
ulcers,manyinfectedpatientsdonothaveulcers.Otherfactorsmustbepresentforulcersto
result.
l Phenylketonuria(PKU):PKUisoftencalledageneticdisease.Butifthe“normal”human
diet had verylowlevelsofphenylalanine, evenpeoplewhowerehomozygous for the
recessivePKUgenewouldnotdemonstrateanysignsofPKU.Onlypeoplewithabnormally
highlevelsofphenylalaninewouldexhibitPKU.Therefore,itmaybesaidthatanabnormal
diet causes PKU.