Table 4.
External control arm methodology in single-arm studies
| Study ID | Indication | Statistical methods for generating ECA | Outcome(s) compared with ECA | Outcome timepoint (weeks) | Evidence of treatment benefit compared with ECA* | Rationale for using an ECA |
| Baker and Jewell, 198929 | IBD | Unadjusted | Efficacy (severe attack rate) | 6 | No | Well-characterised disease course |
| Rosenberg et al, 199030 | UC | Unadjusted | Efficacy (response and surgical rates) | >1 | No | NR |
| Stenger et al, 199831 | RA | Unadjusted | Efficacy (cumulative CRP-AUC, median change in Sharp-score) Safety (AEs) |
104 | Yes | NR |
| Marotte et al, 200732 | RA | Matching | Efficacy (DAS28 response rate) | 52 | Yes | Unethical to use internal placebo arm |
| Shen et al, 200734 | Pouchitis | Unadjusted | Efficacy (PDAI clinical remission and response rates) Safety (AEs) |
4 | Yes | NR |
| Moul et al, 200733 | PsO | Unadjusted | Efficacy (PASI 50 and PASI 75 response rates) | 12 | No | Small study sample size |
| van der Heijde et al, 200836 | AS | Matching | Efficacy (median change in mSASSS) | 104 | No | Unethical to use internal placebo arm |
| Boyle et al, 200835 | IBD | Matching | Safety (LOS, postoperative hospitalizations) | LOS | Yes | Impractical to use internal placebo |
| van der Heijde et al, 200937 | AS | Unadjusted | Efficacy (median change in mSASSS) | 104 | No | Unethical to use internal placebo arm |
| Garg et al, 201138 | IBD | Unadjusted | Safety (AEs) | >1 | NA | NR |
| Yong et al, 2011†39 | PsO | NR | Safety (SAEs) | NR | NA | ECA methodology study |
| Carter et al, 201240 | RA | Unadjusted | Safety (acute infusion reactions) | >1 | Yes | Small study sample size |
| Kwok and Leung, 201241 | RA | Unadjusted | Efficacy (DAS20 and ACR response rate) | 52 | Yes | NR |
| Baraliakos et al, 201443 | AS | Unadjusted | Efficacy (mean change in mSASSS) | 8 years | No | Unethical to use internal placebo arm |
| Horneff et al, 201444 | Multiple‡ | Unadjusted | Efficacy (JIA ACR 30 response rate) | 12 | Yes | Unethical to use internal placebo arm |
| Lichtenstein et al, 201445 | UC | Unadjusted | Safety (AEs) | 104 | Yes | Unethical to use internal placebo arm |
| Gardenbroek et al, 201542 | UC | Unadjusted | Efficacy (anastomotic healing, closure of anastomotic defect and function pouch rates) | 24 | Yes | Impractical to use internal placebo |
| Mahajan et al, 201848 | UC | Unadjusted | Efficacy (clinical, endoscopic, and steroid-free clinical remission rates) Safety (AEs) |
22 | Yes | NR |
| Rozette et al, 201849 | Multiple § | Unadjusted | Safety (adverse infusion reactions) | > 1 | NA | NR |
| Tweehuysen et al, 201850 | Multiple¶ | Unadjusted | Efficacy (CRP and DAS28-CRP response rates) Safety (AEs) |
24 | No | NR |
| Horneff et al, 201846 | JIA | Unadjusted | Efficacy (JADAS10 response rate) Safety (AEs) |
NR | NA | Unethical to use internal placebo arm |
| Inui et al, 201847 | RA | Unadjusted | Efficacy (DAS28-ESR and Sharp score response rates) | 52, 104 | No | NR |
| Braun et al, 201951 | AS | Unadjusted | Efficacy (mean change in mSASSS) | 104 | No | Unethical to use internal placebo arm |
| Kawashiri et al, 2020**52 | RA | Unadjusted | Efficacy (DAS28-ESR clinical relapse rate) | 24 | NA | HESDE previously established |
| Muskens et al, 202053 | Multiple¶ | Unadjusted | Safety (AEs) | 52 | NA | NR |
| Sanchez-Hernandez et al, 202054 | IBD | Unadjusted | Efficacy (treatment failure and IBD-related surgery and hospitalisation rates) Safety (AEs, acute infusion reactions) |
156 | Yes | NR |
| Sagami et al, 202157 | IBD | Unadjusted | Safety (AEs) | 104 | NA | Impractical to use internal placebo arm |
| Gasparetto et al, 202156 | IBD | Unadjusted | Efficacy (dose escalation rate) | 52 | Yes | NR |
| Danese et al, 202155 | UC | Propensity score weighting | Efficacy (Mayo endoscopic score) | 14 | Yes | Impractical to use internal placebo arm; low recruitment |
| Holland et al, 202259 | CD | Matching | Efficacy (mPCDAI response rate) | 26, 52, 78 | No | NR |
| Huang et al, 202260 | RA | Propensity score matching | Efficacy (SDAI, RA-CDAI and DAS28 response rates) | 12, 26, 52, 104 | Yes | NR |
| Truong et al, 202258 | IBD | Unadjusted | Safety (postoperative complications) | 4 | No | Lack of large single-institution studies |
| Takei et al, 202261 | RA | Propensity score matching | Efficacy (ACR20, DAS28-ESR, SDAI response rates) | 24 | Yes | NR |
*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.