Table 4

External control arm methodology in single-arm studies

Study IDIndicationStatistical methods for generating ECAOutcome(s) compared with ECAOutcome timepoint (weeks)Evidence of treatment benefit compared with ECA*Rationale for using an ECA
Baker and Jewell, 198929IBDUnadjustedEfficacy (severe attack rate)6NoWell-characterised disease course
Rosenberg et al, 199030UCUnadjustedEfficacy (response and surgical rates)>1NoNR
Stenger et al, 199831RAUnadjustedEfficacy (cumulative CRP-AUC, median change in Sharp-score)
Safety (AEs)
104YesNR
Marotte et al, 200732RAMatchingEfficacy (DAS28 response rate)52YesUnethical to use internal placebo arm
Shen et al, 200734PouchitisUnadjustedEfficacy (PDAI clinical remission and response rates)
Safety (AEs)
4YesNR
Moul et al, 200733PsOUnadjustedEfficacy (PASI 50 and PASI 75 response rates)12NoSmall study sample size
van der Heijde et al, 200836ASMatchingEfficacy (median change in mSASSS)104NoUnethical to use internal placebo arm
Boyle et al, 200835IBDMatchingSafety (LOS, postoperative hospitalizations)LOSYesImpractical to use internal placebo
van der Heijde et al, 200937ASUnadjustedEfficacy (median change in mSASSS)104NoUnethical to use internal placebo arm
Garg et al, 201138IBDUnadjustedSafety (AEs)>1NANR
Yong et al, 2011†39PsONRSafety (SAEs)NRNAECA methodology study
Carter et al, 201240RAUnadjustedSafety (acute infusion reactions)>1YesSmall study sample size
Kwok and Leung, 201241RAUnadjustedEfficacy (DAS20 and ACR response rate)52YesNR
Baraliakos et al, 201443ASUnadjustedEfficacy (mean change in mSASSS)8 yearsNoUnethical to use internal placebo arm
Horneff et al, 201444Multiple‡UnadjustedEfficacy (JIA ACR 30 response rate)12YesUnethical to use internal placebo arm
Lichtenstein et al, 201445UCUnadjustedSafety (AEs)104YesUnethical to use internal placebo arm
Gardenbroek et al, 201542UCUnadjustedEfficacy (anastomotic healing, closure of anastomotic defect and function pouch rates)24YesImpractical to use internal placebo
Mahajan et al, 201848UCUnadjustedEfficacy (clinical, endoscopic, and steroid-free clinical remission rates)
Safety (AEs)
22YesNR
Rozette et al, 201849Multiple §UnadjustedSafety (adverse infusion reactions)> 1NANR
Tweehuysen et al, 201850Multiple¶UnadjustedEfficacy (CRP and DAS28-CRP response rates)
Safety (AEs)
24NoNR
Horneff et al, 201846JIAUnadjustedEfficacy (JADAS10 response rate)
Safety (AEs)
NRNAUnethical to use internal placebo arm
Inui et al, 201847RAUnadjustedEfficacy (DAS28-ESR and Sharp score response rates)52, 104NoNR
Braun et al, 201951ASUnadjustedEfficacy (mean change in mSASSS)104NoUnethical to use internal placebo arm
Kawashiri et al, 2020**52RAUnadjustedEfficacy (DAS28-ESR clinical relapse rate)24NAHESDE previously established
Muskens et al, 202053Multiple¶UnadjustedSafety (AEs)52NANR
Sanchez-Hernandez et al, 202054IBDUnadjustedEfficacy (treatment failure and IBD-related surgery and hospitalisation rates)
Safety (AEs, acute infusion reactions)
156YesNR
Sagami et al, 202157IBDUnadjustedSafety (AEs)104NAImpractical to use internal placebo arm
Gasparetto et al, 202156IBDUnadjustedEfficacy (dose escalation rate)52YesNR
Danese et al, 202155UCPropensity score weightingEfficacy (Mayo endoscopic score)14YesImpractical to use internal placebo arm; low recruitment
Holland et al, 202259CDMatchingEfficacy (mPCDAI response rate)26, 52, 78NoNR
Huang et al, 202260RAPropensity score matchingEfficacy (SDAI, RA-CDAI and DAS28 response rates)12, 26, 52, 104YesNR
Truong et al, 202258IBDUnadjustedSafety (postoperative complications)4NoLack of large single-institution studies
Takei et al, 202261RAPropensity score matchingEfficacy (ACR20, DAS28-ESR, SDAI response rates)24YesNR
  • *As defined by the included study.

  • †Primary study objective was to examine methodological approaches for complementing prior or concurrent RCT data with external control data.

  • ‡Juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis.

  • §Crohn’s disease, ulcerative colitis and juvenile idiopathic arthritis

  • ¶Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

  • **Protocol for an upcoming single-arm study with an ECA.

  • ACR, American College of Rheumatology; AE, adverse event; AS, ankylosing spondylitis; AUC, area under the curve; CD, Crohn’s disease; CRP, C reactive protein; DAS, disease activity score; ECA, external control arm; ESR, erythrocyte sedimentation rate; HESDE, historical evidence of sensitivity to drug effects; IBD, inflammatory bowel disease; JADAS, Juvenile Arthritis Disease Activity Score; JIA, juvenile idiopathic arthritis; LOS, length of stay; mPCDAI, modified Paediatric Crohn’s Disease Activity Index; mSASSS, modified Stoke Ankylosing Spondylitis Spinal Score; NA, not applicable; NR, not reported; PASI, Psoriasis Area Severity Index; PDAI, Pouchitis Disease Activity Index; PsO, psoriasis; RA, rheumatoid arthritis; RA-CDAI, Rheumatoid Arthritis Clinical Disease Activity Index; SAE, serious adverse event; SDAI, Simplified Disease Activity Index; UC, ulcerative colitis.