Table 3 Comparison of FDA and EMA guidance

RA

FDA 2013 guidance [65]

Key RA domains:

(i) Clinical response: ACR20 to demonstrate reduction in disease activity.

Supportive evidence of efficacy: (a) higher levels of response, measured by ACR50, ACR70

(b) measures of low disease activity (LDA): DAS28

(ii) Improvement in physical function: HAQ-DI

Other domains:

(i) Prevention of structural damage progression: Radiographic data using validated scoring methods.

(ii) (ii) Clinical remission: ACR/EULAR Provisional Definition of Remission criteria may be acceptable.

EMA 2017 guidance [66]

Primary endpoint(s):

(i) Remission (3–6 months): by a combined measure (studies on the treatment of naïve patient)

(ii) LDA (3–6 months): In patients with inadequate response to synthetic or biologic DMARD treatment: DAS28-CRP, DAS28-ESR, SDAI or CDAI

Secondary endpoints:

(i) ACR20, ACR50, ACR70 responder rates

(ii) Structural joint damage by X-rays (e.g. Sharp-van der Heijde scores)

(iii) Physical function (e.g. HAQ-DI)

(iv) Remission/LDA rates defined by SDAI, CDAI, DAS28-ESR or-CRP (if not already not chosen as primary endpoint)

Others:

(i) CRP

(ii) Pain: VAS or Numeric Rating Scale

(iii) Quality of Life: SF-36, AIMS

(iv) Fatigue: FACIT-F

(v) Ultrasonography of the joints

(vi) MRI of the joints (RAMRIS scale)

SLE

FDA 2010 guidance [68]

Primary Efficacy Endpoints:

(i) Reduction in disease activity: BILAG is the preferred index. SLEDAI, SELENA-SLEDAI, SLAM, ECLAM. The primary efficacy analysis can be based on the outcome of major clinical response (MCR) or partial clinical response (PCR)

(ii) Complete clinical response or remission

(iii) Reduction in flare/increase in time to flare

(iv) Reduction in concomitant steroids

(v) Treatment of serious acute manifestations

Secondary endpoints:

(i) PRO instruments: No existing PRO instrument was considered optimal for measurement of fatigue symptom complex.

Others:

(i) An assessment of damage caused by manifestations of SLE least 1-year duration (SLICC/ACR Damage Index measures)

(ii) Biomarkers

EMA 2015 guidance [67]

Primary outcomes:

(i) Control of the disease activity (SLEDAI and BILAG, SLE Responder Index [SRI] or BICLA

(ii) Prevention of flares (Criteria for flares should be predetermined in the protocol: using SLEDAI-2 K, SELENA-SLEDAI, BILAG score; time to a new flare or the frequency/annual rate of flares)

(iii) Prevention of long-term damage (the SLICC/ACR damage index, clinical trial should be at least 12 months)

Secondary endpoints:

(i) When a composite endpoint is used as a primary outcome measure components of this composite endpoint should be analysed separately as secondary outcomes

(ii) Decrease in steroid dose

(iii) Patients and investigators reported outcomes:

(a) HRQOL – SF-36 and any of: Lupus QoL, SLE symptom checklist, SLE QOL; WPAI Lupus score; FSS; FACIT-F or BFI; ADL for change in physical function

(iv) Biomarkers

jSLE

FDA SLE 2010 [68] referencing PRINTO core set of domains:

(i) A DAI: e.g. ECLAM, SLEDAI, SLAM, BILAG

(ii) Renal function: 24-h proteinuria

(iii) Parent’s global

(iv) Physician’s global

(v) Health status: CHQ physical summary score

EMA 2015 [67] referenced the PRINTO domains:

(i) Physician’s global assessment of disease activity

(ii) A global DAI (e.g. ECLAM, SLEDAI, SLAM, BILAG

(iii) 24-h proteinuria. Alternatively, the spot urine protein: creatinine ratio on first morning void urine sample

(iv) Patient’s/Parent’s global assessment of the overall patient’s wellbeing

(v) HRQOL: CHQ physical summary score

UC

FDA 2016 [70]

Primary endpoints:

(i) Clinical remission (responder definition based on stool frequency, rectal bleeding and endoscopy scores). This is the recommended one.

Until a valid PROM for UC signs and symptoms and a valid clinician rating scale for mucosal inflammation in UC become available, a modified Mayo or modified UCDAI score (omitting the physician’s global or disease activity ratings) can be used as an endpoint measure.

Secondary endpoints:

(i) Changes between the treatment arms of each of the subscores (Stool Frequency, Rectal Bleeding and Endoscopy)

(ii) And/or the total score (i.e. sum of the Stool Frequency, Rectal Bleeding and Endoscopy subscores).

(iii) Corticosteroid-free remission (based on a justified minimum duration of time over which a patient is considered to be both corticosteroid-free and in clinical remission)

(iv) Endoscopic Appearance of the Mucosa - There are currently limitations of histologic scoring systems and of community standards for definitions of histologic improvement; thus, there are currently no criteria for histological assessment of mucosal healing.

EMA 2018 [69]

Stressed that the total Mayo score including physician’s global assessment is not of primary interest.

Primary endpoint:

(i) Proportion of patients with symptomatic remission

(ii) Proportion of patients with endoscopic remission

Secondary endpoints:

(i) Patients achieving both MH and symptomatic remission

(ii) Patients achieving response: Response should be defined according to the instruments used for evaluating symptoms and endoscopic appearance.

(iii) Patients achieving remission defined more stringently than for the primary endpoint or vice versa

(iv) In studies where steroids are not tapered at time of evaluation of the primary endpoint, (a) proportions of patients in whom either or both symptomatic and endoscopic remission are achieved without concomitant steroid treatment (b) proportions of patients in whom either or both symptomatic and endoscopic remission are achieved at particular doses of concomitant steroid treatment

(v) Numerical, separate evaluations of the individual components of the symptom score and of MH score

(vi) Histological evaluation of mucosal inflammation, including number of patients achieving histological normalisation

(vii) Individual patients achieving MH, judged endoscopically, as well as combined symptomatic, biomarker and histological normalisation

(viii) Changes in stool frequency

(ix) Laboratory measures of inflammation (e.g. faecal calprotectin)

(x) Time to remission (symptom scores and biomarkers only)

(xi) Time to response (symptom scores and biomarkers only)

Other secondary endpoints:

(xii) Validated QoL measurement, e.g. inflammatory bowel disease questionnaire (IBDQ)

(xiii) Reduction in number of colectomies (primarily relevant in studies of acute severe ulcerative colitis).