Why protocol review changed in 2025–2026
A clinical trial protocol is the master document every other trial document depends on: the SAP, informed consent, case report forms, monitoring plan and CSR. Errors and ambiguities in the protocol become amendments, deviations and inconsistent data later. Three developments have raised the bar for what a good protocol review looks like.
ICH E6(R3). FDA published the final E6(R3) Good Clinical Practice guidance on September 9, 2025, after it took effect in the EU on July 23, 2025. Its emphasis on quality by design, critical-to-quality factors and proportionate, risk-based oversight means reviewers should ask whether the protocol identifies what matters most for participant safety and data reliability.
ICH M11. The CeSHarP protocol template, adopted at Step 4 in November 2025 and effective in the EU from June 11, 2026, standardizes 14 sections, including “Trial Objectives and Associated Estimands” (Section 3) and “Statistical Considerations” (Section 10).
SPIRIT 2025. The updated SPIRIT 2025 Statement (JAMA, August 2025) sets 34 minimum protocol items plus a schedule diagram, adds an open-science section and a patient and public involvement item, and puts more emphasis on harms and on describing interventions and comparators.
Who reviews a protocol, and for what
| Reviewer | Main questions |
|---|---|
| Medical/clinical | Is the scientific rationale sound? Are eligibility criteria, dosing and safety monitoring appropriate? |
| Biostatistics | Are objectives, estimands, endpoints, sample size and analyses aligned? |
| Clinical operations | Is the schedule of assessments feasible at sites? Are visit windows realistic? |
| Data management | Can every endpoint be collected and derived from the planned CRFs and data sources? |
| Regulatory | Does the design support the intended claims and meet regional requirements? |
| Safety/pharmacovigilance | Are adverse event definitions, reporting and stopping rules clear? |
| Quality | Are critical-to-quality factors identified and controlled proportionately? |
| IRB/ethics committee | Do risks, consent and protections meet regulatory criteria? |
The clinical trial protocol review process
- Define critical-to-quality factors first. Agree what could most affect participant safety and the reliability of results, as E6(R3) encourages.
- Structured cross-functional review. Each function reviews against its own checklist, ideally using the M11 section structure so comments map cleanly.
- Protocol review meeting. Resolve conflicting comments (for example, operations wants fewer visits while statistics needs more data points) and record decisions.
- Consistency check. Confirm the synopsis, body, schedule of activities and appendices say the same thing.
- External review. Submit to the IRB or ethics committee and regulators as required.
- Amendment control. After approval, review every amendment for knock-on effects on the SAP, consent form and CRFs.
Protocol review in clinical data management
Data managers should review whether each endpoint can actually be collected and derived: is the data source defined, are visit windows workable, and do derivation rules exist for composite endpoints? Gaps found here are far cheaper to fix before first patient in than through a database change later.
IRB review of a protocol
For FDA-regulated research, an IRB can approve a study only when the criteria in 21 CFR 56.111 are met, including minimized risks through sound design, a reasonable risk–benefit balance, equitable subject selection, informed consent sought and documented, data monitoring where appropriate, privacy protections, and extra safeguards for vulnerable subjects.
Two IRB pathways often come up after approval:
- Expedited review under 21 CFR 56.110 can cover minimal-risk research on FDA’s list of categories and minor changes to previously approved research during the approval period. The chair or designated experienced members review it and may exercise all IRB authorities except disapproval.
- Continuing review under 21 CFR 56.109(f) must happen “at intervals appropriate to the degree of risk, but not less than once per year.”
When writing a protocol for IRB review, make the risk–benefit rationale, consent process, data monitoring plan and privacy protections easy to find, because those map directly to the approval criteria.
Common weaknesses
- Objectives stated without estimands, or estimands that do not match the statistical section.
- Schedule of activities that conflicts with the body text.
- Eligibility criteria that are ambiguous or unverifiable from source documents.
- Safety reporting timelines that differ between sections.
- Critical-to-quality factors never identified, so monitoring is uniform rather than risk-based.
- Amendments approved without updating the SAP, consent form or CRFs.
- Patient burden not assessed, leading to dropouts and missing data.
Checklist: clinical trial protocol review
- Critical-to-quality factors identified and linked to monitoring
- Each objective has an endpoint and estimand, consistent with Section 10
- Synopsis, body, schedule of activities and appendices agree
- Eligibility criteria are specific and verifiable
- Safety definitions, reporting timelines and stopping rules are consistent
- Every endpoint can be collected and derived from planned data sources
- SPIRIT 2025 items covered, including harms, open science and patient involvement
- IRB approval criteria under 21 CFR 56.111 clearly addressed
- Amendment impact on SAP, consent and CRFs assessed
How AskDona helps
Protocol review is a document-consistency problem at scale: dozens of sections, multiple amendments and downstream documents that must match. AskDona reads the protocol against the checklists you choose, such as SPIRIT 2025, the M11 structure or your internal SOP, flags missing items and internal contradictions, and cites the exact section for every finding. Run a sample protocol review against SPIRIT 2025 and M11 before your next protocol review meeting. AskDona shows the evidence; your clinical and regulatory teams decide.
Editor’s note: E6(R3) themes come from an ACRP summary, not the full guideline text; FDA had not set a US compliance date at the time of that article. SPIRIT 2025 details come from the PubMed abstract; the full checklist should be consulted. IRB requirements cited are FDA’s 21 CFR Part 56; studies under the Common Rule (45 CFR 46) have parallel but not identical rules.
FAQ
What is clinical trial protocol review? A structured, cross-functional check that a protocol is scientifically sound, feasible, internally consistent and compliant before it is approved or amended.
What should a protocol review checklist include? Critical-to-quality factors, objective–estimand–endpoint alignment, internal consistency, eligibility, safety reporting, data collection feasibility, SPIRIT 2025 items and IRB approval criteria.
What is a protocol review meeting? A meeting where reviewers from each function resolve conflicting comments and record decisions before the protocol is finalized.
Can protocol changes go through expedited IRB review? Under 21 CFR 56.110, minor changes to previously approved research during the approval period can be reviewed through expedited review.
How often must an IRB review an approved protocol? At intervals appropriate to the risk, but not less than once per year, under 21 CFR 56.109(f).
References
All pages opened and checked by October 19, 2026.
| Source | Type | Used for |
|---|---|---|
| ACRP on FDA’s E6(R3) | Professional association | E6(R3) dates and themes |
| ICH M11 CeSHarP template (EMA) | Regulatory template | Protocol structure |
| RQA: ICH Assembly, Nov 2025 | Professional association news | M11 Step 4 |
| SPIRIT 2025 (PubMed) | Peer-reviewed guideline | Protocol items and changes |
| 21 CFR 56.111 (LII) | Regulation | IRB approval criteria |
| 21 CFR 56.110 (LII) | Regulation | Expedited review |
| 21 CFR 56.109 (LII) | Regulation | Continuing review |