Clinical trial protocol review checklist

A section-by-section checklist for reviewing a clinical trial protocol before it reaches an ethics committee, sponsor, or regulator. Organized around the SPIRIT 2013 reporting items and the design questions that most often surface problems late.

How to use this checklist

Work top to bottom, but treat the objectives → endpoints → analysis → sample size chain as a single unit: most serious protocol problems are not missing text, they are inconsistencies between sections. A protocol can have every required heading and still be unapprovable if the primary endpoint in the objectives doesn't match the one the sample size was powered on.

1. Background & rationale

• Is there a clear, referenced scientific rationale, and an explanation of why the trial is needed now (e.g. a systematic review of existing evidence)?
• Is the benefit–risk rationale stated, and consistent with the investigator's brochure or prior data?

2. Objectives & endpoints

• Is there one clearly designated primary objective, with the primary endpoint defined precisely (measure, metric, timepoint, method of aggregation)?
• Do secondary and exploratory endpoints map to secondary objectives — and are they labeled as such, so they aren't later promoted post hoc?
• Is the estimand defined (population, variable, intercurrent-event handling, summary measure) per ICH E9(R1)?

3. Design

• Is the design (parallel, crossover, factorial, adaptive), allocation ratio, and framework (superiority, non-inferiority, equivalence) stated — and appropriate to the question?
• For non-inferiority/equivalence: is the margin pre-specified and justified?
• Is there a schematic and a schedule of assessments that agrees with the narrative?

4. Population & eligibility

• Are inclusion/exclusion criteria unambiguous, individually verifiable, and free of overlap or contradiction?
• Is the target population consistent with the indication and the generalizability the trial claims it will support?

5. Interventions

• Are dose, route, schedule, duration, and modification/discontinuation rules fully specified for every arm (including comparator/placebo)?
• Are permitted and prohibited concomitant therapies listed, and is adherence measured?

6. Randomization & blinding

• Is the method of sequence generation described, and is allocation concealment specified separately (the mechanism that hides the next assignment)?
• Who is blinded, how, and what is the unblinding procedure for emergencies?

7. Statistics & sample size

• Does the sample-size calculation state effect size, variability, alpha, power, and dropout — and are those assumptions justified and consistent with the primary endpoint and analysis?
• Are the analysis populations (ITT, per-protocol, safety) defined, and is the primary analysis method pre-specified?
• Is the handling of missing data defined, with sensitivity analyses?
• Are interim analyses, stopping rules, and multiplicity control specified?

8. Safety & oversight

• Are AE/SAE definitions, collection windows, and reporting timelines specified?
• Is a DSMB/DMC and its charter referenced where the risk profile warrants one?

9. Ethics, consent & data

• Informed-consent process, IRB/IEC approval, and any vulnerable-population safeguards described?
• Data management, confidentiality, trial registration, and a publication/data-sharing plan present?

Frequently asked questions