nejm-study-design

Study Design & Registration (nejm-study-design)

When to trigger

• A trial is being written up and you must confirm it was registered before enrollment.
• There is no finalized protocol or statistical analysis plan to submit.
• The design (randomization, blinding, endpoints) needs to be stated rigorously for the Methods.
• An observational study needs its design (cohort / case-control / cross-sectional) named and justified.

The non-negotiable: prospective trial registration

Per ICMJE policy (which NEJM enforces), a clinical trial must be prospectively registered in a public registry — ClinicalTrials.gov or a WHO ICTRP primary registry — before the first patient is enrolled. This is a deal-breaker, not a formatting detail.

• The trial registration number (e.g., an NCT number) is reported in the abstract and Methods.
• Registration must predate enrollment; retrospective registration is generally disqualifying for an Original Article.
• The registered primary outcome must match the reported primary outcome — discrepancies are a top reviewer flag.

If a trial was never prospectively registered, raise it now. It changes venue and framing and cannot be repaired by writing.

Protocol and statistical analysis plan (SAP)

For trials, NEJM expects the full trial protocol and the statistical analysis plan to be submitted (typically as a supplement) and made available to reviewers.

• The SAP must be pre-specified — finalized (and dated) before unblinding / database lock.
• Any deviation from the registered protocol or SAP must be disclosed and explained in the manuscript.
• A CONSORT-aligned trial write-up depends on these documents existing (see nejm-reporting).

Design rigor checklist (trials)

• Randomization — method (e.g., permuted blocks, stratification factors) stated.
• Allocation concealment — mechanism described (central randomization, sealed envelopes).
• Blinding — who was blinded (participants, clinicians, outcome assessors, analysts); if open-label, justify and address bias.
• Primary endpoint — single, pre-specified, patient-important, with a clear definition and time point.
• Secondary endpoints — pre-specified and ordered; multiplicity handled (see nejm-statistics).
• Sample size / power — assumptions, effect size, alpha, power stated; not post hoc.
• Analysis population — intention-to-treat as primary; per-protocol as sensitivity.
• Interim analyses / stopping rules — DSMB, pre-specified boundaries (e.g., O'Brien-Fleming) if used.

Observational studies

• Name the design: cohort (prospective/retrospective), case-control, cross-sectional, or nested designs.
• Pre-specify the primary exposure and outcome; define confounders and the adjustment strategy a priori.
• Address selection bias, information bias, and confounding explicitly; use cautious, non-causal language.
• Report per STROBE (see nejm-reporting); registration of observational protocols is encouraged though not mandated.

Operating pass for New England Journal of Medicine

Use this as a second-pass capability check. First lock the clinical question, population, endpoint, effect size, safety signal, and practice implication; then test whether the manuscript addresses clinical-medicine reviewers who expect practice-changing evidence, patient relevance, safety, and exact reporting discipline.

• Primary move: Return a claim-evidence-risk ledger; every recommendation must point to a manuscript location or missing artifact.
• Decision ledger: return claim / evidence / blocker / next edit rows so the next pass can patch the manuscript directly.
• Neighbor test: compare against JAMA for broad clinical medicine, Lancet for global-health/public-health reach, specialty journals for narrower disease domains; if the neighboring outlet has the stronger audience claim, recommend re-routing before polishing.
• Verification floor: before submission-ready advice, re-open resources/official-source-map.md for volatile rules and name the one unresolved fact that could change the recommendation.

Output format

【Study type】 RCT / other interventional / cohort / case-control / cross-sectional / SR-MA
【Registration】 registry + number + registered BEFORE enrollment? yes/no/UNREGISTERED-FLAG
【Registered vs reported primary outcome】 match? yes/no
【Protocol + SAP】 available, pre-specified, dated? yes/no
【Design rigor gaps】 randomization / concealment / blinding / endpoints / power / ITT
【Protocol/SAP deviations to disclose】 [...]
【Next】 nejm-reporting

Anti-patterns

• Do not write up an unregistered trial as an Original Article without flagging it to the user.
• Do not present a post-hoc analysis plan as if it were pre-specified.
• Do not report a primary outcome that differs from the registered one without disclosing the change.
• Do not treat per-protocol as the primary analysis for a superiority trial — ITT is primary.