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Table 1 Examples of HCs used in Clinical Trials for Approvals by Regulatory Agencies

From: A roadmap to using historical controls in clinical trials – by Drug Information Association Adaptive Design Scientific Working Group (DIA-ADSWG)

Drug CandidateCarglumic Acid or CARBAGLUProtein C Concentrate (Human) or CEPROTINLepirudin or REFLUDANAntithrombin [Recombinant] or ATRYN
IndicationHyper-ammonaemiaProtein C deficiencyImmunologic type of Heparin-associated thrombocytopeniaHereditary anti-thrombin deficient patients
Prevalence of the disease<  10 patients (US)
<  50 (worldwide)
<  20 patients (US)N/AN/A
Other treatmentsNoNoNoNo
Approved2010200719982009
DivisionFDA-CDERFDA-CDERFDA-CDERFDA-CDER
Study DesignRetrospective Case SeriesN/AUncontrolled studyTwo prospective, single-arm, open-label studies
Number of subjects23 subjects18 subjectsTwo studies with 39 and 33 Subjects31 subjects
EndpointAmmonia levelsResponse for thromboembolic eventsPlatelet count recoveryIncidence of thromboembolic events
Type of HCNatural history dataN/ARegistry data which PI establishedProspectively designed retrospective chart review
Source of the HCSubject at baselineN/ASubjects not treated with recombinant hirudin 
Size of HC23 subjects21 subjects91 subjects35 Subjects
Method of applicationDescriptive statisticsDescriptive StatisticsDirect comparisonMatching
Note  HC was used only for secondary endpoint due to the less availability of platelet data 
Drug CandidateAnagrelide or AGRYLINAlglucosidase Alfa or MYOZYME/LUMIZYMEMiglustat or ZAVESCABlinatumomab or BLINCYTO
IndicationReduction of the elevated platelet count, thrombosis and ameliorate-associated symptoms.Pompe diseaseType I Gaucher diseaseAdults relapsed/refractory Acute Lymphoblastic Leukaemia
Prevalence of the diseaseN/A1/40,000 live births1/100,0001–2/100,000 adults
Other treatmentsNoNoAvailableNo
Approved1997200620032017
DivisionFDA-CDERFDA-CDERFDA-CDERFDA-CDER
Study DesignSelf-controlled studyRCT with two dose groupsSelf-controlled studySingle arm trial
Number of subjectsAbout 300 subjects18 (9 subjects per dose group)Three studies include 28, 18 and 36 subjects189 subjects
EndpointN/AInvasive ventilator-free survival and survival ratePercentage change from baseline in liver organ volumeComplete remission
Type of HCNatural history data at baselineNatural history data (Cross-sectional NH)Natural history data at baselineSeveral kinds of data
Source of the HCSubject at baselineNatural history dataSubject at baselineInvestigator database
Size of HCAbout 300 subjects62 subjects82 subjects1112 subjects
Method of applicationN/ADirect comparison for non-inferiority inference.Descriptive StatisticsHC was used to show the validity of efficacy threshold by meta analytic approach.
Note Historical data collected over a 20-year span and time trend observed. For EMA, analysis with propensity score was also performed.
Drug CandidateArsenic trioxide or TRISENOXEteplirsen or EXONDYS 51Elbasvir and Grazoprevir or ZEPATIERNitisinone or ORFADIN
IndicationAcute promyelocytic leukaemiaDuchenne muscular dystrophy (DMD)Treatment of Chronic Hepatitis C genotypes 1, 4 or 6 in adultsHereditary Tyrosinemia 1
Prevalence of the disease6/10,000,000 per year20 / 100,000N/A1/100000
Other treatmentsYesNoNewly available during the developmentNo
Approved2010201620162002
DivisionFDA-CDERFDA-CDERFDA-CDERFDA-CDER
Study DesignSingle arm trialPlacebo controlled study followed by extension studyParallel or single arm studySingle arm study
Number of subjects40 subjects12 subjects1294 subjects from 3 studies207 subjects
EndpointComplete remissionControlled trial: change from baseline of dystrophin positive fibers
Extension study: 6MWT
Sustained virologic responseSurvival
Type of HCRegistry dataRegistry dataPrevious clinical trial dataRegistry data
Source of the HCHospital stored dataMatching from 2 DMD patient registriesPrevious clinical trial dataSurvey result
Size of HC27 subjects13 subjectsDepending on the trials108 subjects
Method of applicationJust showed as referenceDirect comparisonOne sample testing.
HC was used for efficacy threshold.
Just showed as reference
Note Initially agency and advisory panel voted against the approvalNot a rare disease.Large improvement against historical data
Drug CandidateSodium Ferric Gluconate Complex or FERRLECITSebelipase Alfa or KANUMAAsfotase Alfa or STRENSIQCerliponase Alfa or BRINEURA
IndicationIron deficiency anemia undergoing chronic hemodialysisLysosomal acid lipase (Wolman disease)Hypophosphatasialate infantile neuronal ceroid lipofuscinosis type 2
Prevalence of the diseaseN/A1/500,0001/100,0001/100,000
Other treatmentsYesNoNoNo
Approved2001201520152017
DivisionFDA-CDERFDA-CDERFDA-CDERFDA-CDER
Study DesignMultiple dose historical control studyHistorical control studySingle-armSingle arm trial
Number of subjects88 subjects from 2 dosing groups9 subjects70 subjects from 2 studies22 subjects
EndpointChange in HemoglobinTime to DeathOverall survivalResponse rate
Type of HCRegistry dataNatural history dataNatural history dataNatural history data
Source of the HCSubjects with oral IronRetrospective clinical chart reviewsRetrospective clinical chart reviewsNatural history cohort
Size of HC25 subjects21adjudicated as appropriate for comparison48 subjects42 subjects
Method of applicationDirect comparisonDirect comparison by survival analysisDirect comparison by survival analysisMatched analysis with HC
NoteAnother study also supported the efficacy