Dose-escalation and dose-finding study
Which doses or regimens merit further investigation under prespecified safety and activity criteria?
When to use this project
Study early dose or regimen selection using a reviewed rule-based, model-assisted or model-based design with safety constraints and defined decision authority.
How it differs
The objective is dose selection and characterization, not necessarily a definitive treatment-effect claim. A maximum tolerated dose and an optimal biologic or recommended dose need not coincide.
Decisions before you start
- Define toxicity, activity, assessment windows and the target selection criterion.
- Specify escalation, de-escalation, expansion, holds and stopping, including delayed outcomes and the possibility of no acceptable dose.
- Evaluate the complete design by simulation and retain clinician oversight and an auditable decision process.
How the flows work together
Each flow below links to its diagram, steps and tables. Flow order organizes the project; it does not imply that all work is strictly sequential. Data assessment, analysis planning and protocol refinement may inform one another.
1. Dose-finding study overview
Overview · Question through dose recommendation
Use this overview to state the purpose and link to detailed decisions. Keep a versioned protocol and decision register, and add evidence references for the rationale.
2. Eligibility and cohort enrollment
Selection · Track evaluability and replacement rules
Evaluable participants are a subset of enrolled participants, not a disjoint group. Specify replacement and hold rules, and retain safety information from people who do not complete the formal evaluation window.
3. Dosing and assessment windows
Conduct · Specify schedules toxicity and activity
Define toxicity and activity ascertainment and their windows before enrollment. Delayed outcomes and dose modifications affect decision readiness; missing follow-up must not be mistaken for absence of toxicity.
4. Escalation and stopping rules
Statistics · Define permitted decisions and safeguards
Rule-based, model-assisted and model-based designs use different decision mechanisms. Document allowed actions and safety constraints, including hold, stop and no acceptable dose. The diagram records decisions; it does not authorize dosing.
5. Design simulations and assumptions
Statistics · Evaluate operating characteristics across scenarios
Simulate the full enrollment and decision process under plausible dose-response shapes, delays and accrual. Assess overdosing, selection, sample size and failure to identify an acceptable regimen, not only correct-dose selection.
6. Safety review and dose selection
Statistics · Integrate evidence into dose recommendations
Selection should use the protocol-defined evidence and authorized review. A recommended regimen need not be the maximum tolerated dose; include uncertainty, pending outcomes and the possibility of no recommendation.
Equations and statistical interpretation
These explanations describe notation and assumptions. Flow does not calculate these values.
Observed dose-specific toxicity proportion
y_d is the number with the protocol-defined toxicity at dose d and n_d is the specified evaluable denominator for that window.
This descriptive proportion is not an escalation algorithm. Pending outcomes, replacement and model-based borrowing need explicit rules; small cohorts produce considerable uncertainty.
Published example
Topalian et al. (2012), Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer
Examine the early-phase dose cohorts, safety windows and expansion objectives. Distinguish exploratory activity from a randomized efficacy comparison.
This publication illustrates a study design, not an endorsement of every method or a reproduction of its results. Follow its protocol, supplement and update history when studying the example.
Hypothetical scenario
An early development team wants to identify a tolerable regimen for a later trial while collecting preliminary activity information.
- Dose-finding study overview: Specify the dose question, approvals, registration and review responsibilities.
- Eligibility and cohort enrollment: Define enrollment, evaluability, replacement and holds without hiding incomplete follow-up.
- Dosing and assessment windows: Set permissible regimens and prespecified toxicity and activity windows.
- Escalation and stopping rules: Document the reviewed algorithm, safety constraints and authorized actions.
- Design simulations and assumptions: Simulate dose-response, accrual and delayed-outcome scenarios before selecting the design.
- Safety review and dose selection: Review accumulated evidence, including pending outcomes, and document the rationale for a recommendation or no selected dose.
Deliver a populated protocol, decision log, data specification, and planned outputs. Enter numerical findings only after analysis and verification. Keep decisions made before seeing results distinguishable from later amendments.
Sources
- CONSORT-DEFINE: early phase dose-finding trials (2023)
- CONSORT-DEFINE: explanation and elaboration (2025)
- WHO: clinical trials and prospective registration
- WHO: primary registries in the trial registry network
- ISRCTN: what the clinical study registry records
- ClinicalTrials.gov: about the registry
Source check: 2026-09-17. Record the version of each reporting or appraisal tool used in your actual protocol.
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