ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD) · White paper
Attention Deficit/Hyperactivity Disorder (ADHD) Clinical Trials
Approved therapies, the pivotal-trial endpoints they were judged on, the magnitude of benefit — and the drugs that failed their endpoints, and why.
Indication overview
About attention deficit/hyperactivity disorder (adhd) — and why its trials are hard
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder marked by persistent inattention, hyperactivity, and impulsivity beginning before age 12, coded 6A05 in ICD-11. Global prevalence is roughly 5-7% in children and 2.5-5% in adults, with heritability estimated at 70-80%. Treatment is anchored by stimulants, methylphenidate (1955) and amphetamine/lisdexamfetamine, which remain first-line, complemented by non-stimulants atomoxetine (2002), extended-release guanfacine (2009), and the newer viloxazine (Qelbree, 2021). Efficacy is measured chiefly by the ADHD Rating Scale (ADHD-RS) and clinician CGI ratings, with executive-function, academic, and quality-of-life measures as secondaries. Registration trials consistently show large stimulant effect sizes, though doses above certain thresholds add little benefit. Trial design is complicated by symptom variability across settings, a substantial placebo response, comorbid psychiatric conditions, adherence problems, and pediatric ethical constraints. Candidates that failed or underperformed, including bupropion, Mydayis at low dose, and sedative hypnotics for ADHD-related insomnia, highlight the importance of validated multi-informant endpoints.
Approved therapies & pivotal evidence
What's been approved — and by how much it moved the endpoint
| Drug (brand) | Approved | Setting | Pivotal trial | Primary endpoint | Magnitude of benefit |
|---|---|---|---|---|---|
| Methylphenidate (Ritalin / Ritalin LA) | 1955 | First-line CNS stimulant for pediatric and adult ADHD | Randomized, double-blind, placebo-controlled Ritalin LA study | CADS-T teacher-rated symptom change | Mean change -10.7 points (improvement) vs +2.8 points (worsening) on placebo |
| Lisdexamfetamine (Vyvanse) | 2007 | Long-acting amphetamine prodrug; once-daily stimulant | Pivotal ADHD-RS studies (children, adolescents, adults) | ADHD-RS total score; CGI-I | All doses superior to placebo; 70 mg not superior to 50 mg |
| Amphetamine mixed salts (Adderall XR) | 1996 | First-line extended-release stimulant across age groups | Double-blind, randomized, placebo-controlled ADHD-RS-IV studies | ADHD-RS-IV total score | Significant improvement for all doses; >20 mg/day added no benefit |
| Atomoxetine (Strattera) | 2002 | First non-stimulant for ADHD; selective norepinephrine reuptake inhibitor | Randomized, double-blind, placebo-controlled studies (children and adults) | ADHD-RS (parent/CAARS) total score; time to relapse | Statistically significant improvement; longer time to relapse vs placebo |
| Viloxazine (extended-release) (Qelbree) | 2021 | Newer non-stimulant (SNMA); approved for pediatric ADHD in 2021 and adults in 2022 | Phase 3 pediatric and adult ADHD-RS-5 trials | ADHD-RS-5 total score; CGI-I | Significant ADHD-RS-5 reduction vs placebo (unverified exact value) |
Where trials have failed
Drugs that missed their endpoint — and what contributed
The most instructive lessons in attention deficit/hyperactivity disorder (adhd) development come from programmes that failed the endpoint that mattered.
| Drug / trial | Endpoint outcome | What contributed |
|---|---|---|
| Bupropion — GDCT0153477 | Effective for ADHD but less effective than methylphenidate | Weaker effect size than stimulant comparator; off-label status |
| Mydayis (SHP465, mixed amphetamine salts ER) — NCT03325881 | 6.25 mg dose not superior to placebo in children aged 6-12 | Subtherapeutic dose in a young cohort; dose-selection issue |
| Eszopiclone — NCT00856973 | Did not reduce sleep latency in children with ADHD-related insomnia over 12 weeks | Wrong target population; comorbid insomnia not modified by hypnotic |
Choosing the right endpoint
Primary endpoints that matter in attention deficit/hyperactivity disorder (adhd) trials
- ADHD Rating Scale (ADHD-RS / ADHD-RS-IV / ADHD-RS-5) — Standard primary endpoint measuring core inattentive and hyperactive-impulsive symptoms
- Clinical Global Impression (CGI-S/CGI-I) — Global clinician rating used to corroborate scale-based symptom change
- Conners and SKAMP scales — Parent/teacher (Conners) and classroom analog (SKAMP) ratings capturing cross-setting behavior
- Executive function measures (e.g., BRIEF) — Assess working memory, inhibition, and cognitive flexibility as functional secondaries
- Relapse prevention (randomized withdrawal) — Maintenance endpoint measuring proportion of treatment failures after stabilization
How iNGENū runs attention deficit/hyperactivity disorder (adhd) trials
Physician-led design, built for FDA submission
Endpoint & biomarker strategy
Board-certified specialists design endpoints and patient selection aligned to current FDA guidance for this indication.
FDA-ready data
Built to ICH-GCP and 21 CFR 312.120, with direct FDA submission — data accepted by the FDA, EMA and MHRA.
Faster, lower-cost delivery
~4-week ethics via the TGA CTN scheme, up to 43.5% R&D rebate, and 80–90% below US CRO cost.
The full white paper: approved-product analyses, pivotal endpoints and trial-design strategy. Open-access · no sign-in.
Frequently asked questions
Attention Deficit/Hyperactivity Disorder (ADHD) clinical trials — FAQs
What drugs are FDA-approved for ADHD?
What are the primary endpoints in ADHD trials?
What makes ADHD trials challenging?
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