Exceeding enrolment and mitigating placebo response in Major Depressive Disorder trials
Case study
Overview
ICON partnered with a sponsor to deliver a 14-week multicentre double blind randomised placebo-controlled phase 2 study in Major Depressive Disorder (MDD). The study assessed a fixed dose of an innovative oral compound in 8 countries across 53 sites with 338 participants enrolled against a target of 324.
The program required precise operational control to placebo response risk in a highly competitive CNS landscape.
-
338
participants -
53
sites -
8
countries
Challenge
Delivering consistent high-quality data in MDD trials is inherently challenging, with placebo response representing a key risk to study success in addition to operational and logistical pressures.
Protocol complexity: Therapy restrictions, psychiatrist ECG review requirements, and rigid visit schedules limited site flexibility and increased burden.
Recruitment and enrolment pressure: Low initial site budgets, high screen failure rates of 20%, and two competing MDD studies impacted enrolment performance. Investigational product constraints: Limited IP availability delayed screening for two months and impacted the activation of back-up sites.
Rater training inconsistency: Inconsistent rater experience for screening scale MADRS and primary endpoint HAM-D and variable interpretation of other clinical scales is a primary factor in inter-site variability, compounding the elevated placebo response risk. Without standardisation, differences in training, participant interaction and scoring approach can all impact data consistency and risk masking actual treatment effect, thereby compromising study outcomes.
Solution
ICON implemented an integrated delivery model that combined operational agility with a structured placebo mitigation strategy.
Driving engagement and performance
- Delivered targeted site rater and refresher training through FIRECREST
- Strengthened communication across sponsor, investigators and study teams to maintain alignment and momentum through regular governance meetings, site calls, study newsletters, and ad hoc issue-resolution discussions to ensure timely information sharing, alignment on priorities, and proactive management of study risks and milestones
Restoring supply continuity despite restricted IP availability
- Implemented manual IP shipment triggers to ensure all randomised participants completed treatment
- Maintained close oversight of IP batch availability and pre-screening pipelines
- Prioritised shipments to high potential sites with engaged patient pools
Minimising placebo response through structured rater management
Rigorous rater selection and approval
- Assessed rater capability during feasibility and pre study visits to select experienced sites
- Applied criteria for education, specialisation and MDD experience per scale
- Conducted formal CTM led review and approval of every rater with sponsor oversight for exceptions
Standardised training at scale
- Mandated structured training for all raters via FIRECREST before site activation
- Delivered scale-specific training modules to ensure consistent scoring interpretation. In FIRECREST, three rater trainings were available: one for HMND, one for MADRS and one for «other scale»
- Outside FIRECREST, C-SSRS training certificate (via Kelly Posner official site) was requested.
- Required certification prior to participant assessment
- Applied validated external training for C-SSRS to ensure compliance
Strengthened site activation controls
- Restricted site activation until rater qualification and back up coverage were confirmed
- Embedded rater readiness into activation governance
Consistency through dual rater model
- Required both primary and back up raters for primary endpoint scale at every site
- Ensured back up raters were trained prior to activation to minimise disruption and variability
Controlling variability at participant level
- Maintained the same rater for each participant per scale wherever possible
- Reduced intra-participant variability and scoring drift across visits by training sites to maintain the same
rater for each subject
Centralised oversight and transparency
- Tracked rater training and certification in real time through FIRECREST reporting
- Maintained full documentation in eTMF and investigator site files
- Managed rater changes through controlled updates and CRA oversight
- Enabled complete visibility of rater compliance across all sites through centralised tracking, providing real-time oversight of rater certification status and training completion, allowing identification of training gaps
Outcome
ICON’s integrated approach delivered measurable improvements to this 14-week phase 2 study conducted across eight countries:
- The improvement on active treatment group was statistically significant at final visit and was similar to historic effects for trials with HAM-D 17 as primary endpoint (9.2 points observed vs 9.8 points historically reported in a 2022 meta-analysis in 73,388 subjects).
- The observed improvement in the placebo group (6.4 points) however was 20% lower than the historically observed 8.0 points.1 This 20% reduction in placebo-effects corresponds with similar observations made in a trial where all subjects received placebo for two weeks (while they were told the probability of being on placebo is 50%) and dedicated placebo-minimisation training was applied in a randomised way.2 In other words: our placebo-minimisation measures had very similar impact as it had been observed in a trial specifically designed to measure such effects.
- The sponsor’s increased satisfaction is linked directly to ICON’s overall delivery performance. ICON completed enrolment four weeks ahead of schedule, exceeded original enrolment projections, and reduced placebo response by about 20%.
-
338
participants enrolled -
4
weeks enrolment completed four weeks early -
20%
reduction in placebo response
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References
1. Stone MB, Yaseen ZS, Miller BJ, Richardville K, Kalaria SN, Kirsch I. Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ. 2022;378:e067606. doi:10.1136/ bmj-2021-067606
2. Cohen EA, Hassman HH, Ereshefsky L, Walling DP, Grindell VM, Keefe RSE, Wyka K, Horan WP. Placebo response mitigation with a participant-focused psychoeducational procedure: a randomized, single-blind, all placebo study in major depressive and psychotic disorders. Neuropsychopharmacology. 2021;46(4):779-786. doi:10.1038/s41386-020-00911-5