Purpose
Systematically diagnose a clinical trial protocol against regulatory guidance and design best practices, surfacing gaps most likely to trigger regulatory queries, protocol amendments, enrollment failures, or data integrity problems — each rated by severity and paired with a specific, citable fix. Turns a subjective protocol read into a structured, defensible gap register a program team can act on before finalization.
When to Use
Invoke this skill when the user asks to:
- Review a draft protocol before IND/CTA submission or IRB/EC review
- Identify design gaps or regulatory risks in an existing protocol
- Assess a protocol against ICH E8(R1), E6(R3), or FDA/EMA guidance
- Predict where a protocol is likely to require amendments or generate regulatory queries
- Stress-test endpoints, eligibility, or statistical assumptions before finalizing
- Prepare a gap remediation list for a protocol handoff or vendor review
Inputs Required
Before starting, collect:
- Protocol summary or full text: Synopsis at minimum; full protocol preferred
- Phase and indication: e.g., Phase 2, moderate-to-severe atopic dermatitis
- Trial design type: Randomized/single-arm, blinding, controlled/uncontrolled, parallel/crossover/adaptive
- Primary and key secondary endpoints: As currently written, including timing
- Target regulatory regions: FDA (US), EMA (EU), PMDA, other — determines applicable guidance
- Population and eligibility highlights: Key inclusion/exclusion criteria and enrollment target
- Statistical assumptions: Sample size, power, effect size, and any interim analysis plan
If full protocol text is unavailable, work from the synopsis and flag any domain that cannot be fully assessed as "Insufficient information — cannot verify."
Instructions
Step 1: Establish the Regulatory Baseline
Identify the applicable guidance framework before analyzing.
- Confirm target regions and map to primary guidance: ICH E8(R1) (design quality), ICH E6(R3) (GCP/quality by design), ICH E9 (statistical principles), FDA guidance by therapeutic area, EMA scientific guidelines
- Note phase-specific expectations — early-phase safety focus vs. late-phase confirmatory rigor
- Identify the estimand framework (ICH E9 R1) expectation: is the protocol's treatment effect definition explicit?
- State which frameworks the analysis is measured against so every gap is traceable to a source
Step 2: Analyze Across 10 Protocol Domains
For each domain, identify gaps against guidance and best practice. Assign a severity to each finding:
- Critical — likely to block submission, trigger a clinical hold risk, or invalidate the primary result
- Major — likely to generate a regulatory query or force a protocol amendment
- Minor — best-practice improvement or clarity issue unlikely to block progress
Domain 1 — Objectives & Estimands Do objectives map cleanly to endpoints? Is the estimand (population, variable, intercurrent event handling, summary measure) explicitly defined per ICH E9(R1)? Flag missing intercurrent event strategies.
Domain 2 — Endpoint Design Is the primary endpoint clinically meaningful, validated/qualified, and measurable at the stated timepoint? Are secondary endpoints ranked and multiplicity-controlled? Flag surrogate endpoints lacking regulatory precedent.
Domain 3 — Study Design & Control Is the control arm appropriate (placebo, active, standard of care)? Is blinding adequate and justified? For adaptive/interim designs, is the adaptation pre-specified with type I error control? Flag single-arm designs where a control is feasible.
Domain 4 — Population & Eligibility Are inclusion/exclusion criteria justified and non-restrictive to the point of harming enrollment or generalizability? Are diversity/representativeness expectations (FDA Diversity Action Plan, ICH E8 broader inclusion) addressed? Flag criteria that exclude the intended-use population.
Domain 5 — Statistical Analysis Plan Alignment Are sample size assumptions justified with cited effect sizes? Is power ≥80% (typically 90% for confirmatory)? Is the analysis population (ITT/mITT/PP) defined and consistent with the estimand? Flag unjustified effect sizes and missing missing-data handling.
Domain 6 — Safety Monitoring & Risk Management Are stopping rules, DSMB/DMC charter references, dose-modification rules, and AE/SAE reporting timelines defined? Is there a risk-based/proportionate monitoring plan per E6(R3)? Flag absent safety run-in or stopping criteria in first-in-population studies.
Domain 7 — Schedule of Assessments & Operational Feasibility Is the visit schedule feasible for sites and participants? Is patient burden proportionate? Are assessment windows defined? Flag overloaded visits likely to cause protocol deviations.
Domain 8 — Data Integrity & Quality by Design Are critical-to-quality factors identified per E6(R3) quality-by-design? Are source data, eCRF, and data flow defined? Flag missing data management plan references and undefined key data.
Domain 9 — Regulatory & Ethical Compliance Are informed consent elements, benefit-risk justification, and applicable regional requirements present? Is the protocol consistent with the investigator's brochure and prior-phase data? Flag benefit-risk statements unsupported by cited data.
Domain 10 — Amendment & Protocol Deviation Risk Identify the 3–5 elements most likely to require a future amendment (overly specific eligibility, aggressive timelines, unvalidated endpoints) and pre-empt them.
Step 3: Build the Gap Register
Consolidate all findings into a single ranked table sorted by severity (Critical → Major → Minor). For each gap record: domain, finding, severity, regulatory basis (specific guidance/section), risk consequence, and recommended fix (concrete and implementable).
Step 4: Deliver a Submission-Readiness Verdict
State an overall verdict: Submission-ready, Ready with minor revisions, Requires major revision, or Not ready — critical gaps present. Justify with the count of gaps by severity and name the top 3 must-fix items before any further step.
Output Format
- Structure: Regulatory baseline statement → 10-domain findings → consolidated ranked gap register (table) → readiness verdict with top 3 must-fixes
- Length: 1,000–1,500 words
- Format: Prose analysis per domain; gap register as a table (Domain | Finding | Severity | Regulatory Basis | Recommended Fix)
- Sections: Regulatory Baseline → Domain Analysis (10) → Gap Register → Submission-Readiness Verdict
- Tone: Regulatory affairs reviewer — precise, citation-anchored, direct about risk; no hedging on severity
Quality Checklist
Before delivering output, verify:
- [ ] All 10 domains are assessed (or explicitly marked "Insufficient information" with reason)
- [ ] Every gap carries a severity rating (Critical / Major / Minor) — none unrated
- [ ] Every gap cites a specific regulatory basis (guidance name and section/principle), not "best practice" alone
- [ ] Every gap has a concrete, implementable recommended fix — not a restatement of the problem
- [ ] Gap register is sorted by severity with counts stated in the verdict
- [ ] A single readiness verdict is issued with the top 3 must-fix items named (no hedging)
Notes
- The highest-value findings usually sit in estimand definition and endpoint-to-objective alignment — these drive the most regulatory queries and are the least visible on a casual read
- Overly restrictive eligibility is the most common cause of both enrollment failure and mid-study amendments; scrutinize exclusion criteria hard
- This analysis is a design-quality review, not a substitute for formal regulatory affairs sign-off, biostatistics review, or a health authority meeting — recommend those for Critical findings
- When target regions differ (FDA vs. EMA), flag any gap where the two frameworks diverge so the team can reconcile before parallel submissions
How to use this skill
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Installing in Claude Code:
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Restart Claude Code or open a new session to register.
Using in Claude.ai, ChatGPT, Gemini, or other AI tools:
- Drag this file into a new chat, or copy and paste its contents
- Send your task or request as your next message — the AI will apply the skill where it fits
For Claude Code skill details: https://docs.anthropic.com/en/docs/claude-code/skills