Evidence map›Paper›PMID 42050422›Full record

ArticleBMC medical research methodology2026

How to design a ROCI (Response Over Continuous Intervention) randomised trial: guidance and a case study.

Matteo Quartagno, Ehsan Ghorani, Tim P Morris, Henry Bern, Michelle N Clements, A Sarah Walker, James R Carpenter, Ian W White, Koen B Pouwels, Michael J Seckl and 1 more

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In one paragraph

Article in BMC medical research methodology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0cells of the map it votes in
0citing papers in PubMed
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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Matteo QuartagnoMRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, Second Floor, London, WC1V 6LJ, UK. m.quartagno@ucl.ac.uk.ORCID http://orcid.org/0000-0003-4446-0730
Ehsan GhoraniDepartment of Medical Oncology, Charing Cross Hospital Campus of Imperial College London, London, UK.
Tim P MorrisMRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, Second Floor, London, WC1V 6LJ, UK.ORCID http://orcid.org/0000-0001-5850-3610
Henry BernMRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, Second Floor, London, WC1V 6LJ, UK.
Michelle N ClementsMRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, Second Floor, London, WC1V 6LJ, UK.
A Sarah WalkerMRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, Second Floor, London, WC1V 6LJ, UK.ORCID http://orcid.org/0000-0002-0412-8509
James R CarpenterMRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, Second Floor, London, WC1V 6LJ, UK.ORCID http://orcid.org/0000-0003-3890-6206
Ian W WhiteMRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, Second Floor, London, WC1V 6LJ, UK.ORCID http://orcid.org/0000-0002-6718-7661
Koen B PouwelsNuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
Michael J SecklDepartment of Medical Oncology, Charing Cross Hospital Campus of Imperial College London, London, UK.
Mahesh Kb ParmarMRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, Second Floor, London, WC1V 6LJ, UK.ORCID http://orcid.org/0000-0003-0166-1700

Funding

Medical Research Council MC_UU_00004/05Medical Research Council MC_UU_00004/07MRC TMRP DTP MR/W006049/1National Institute for Health and Care Research NIHR133011
6 · The paper itself

Abstract

backgroundAn important challenge in late-phase drug development is selection of the optimal parameters for treatment administration, including dose, duration and frequency. Whilst these are (near-)continuous parameters, conventional non-inferiority trial designs are not well suited to explore multiple options across a range of values. The ROCI (Response Over Continuous Intervention) randomised trial design is an alternative to standard non-inferiority trials, addressing limitations in selecting optimal treatment regimens, but practical guidance in its application is limited.

methodsWe outline key design considerations for ROCI trials, including modelling the treatment–response relationship, selecting treatment levels and arms, defining optimality criteria, and determining power and sample size. A flexible fractional polynomial approach is recommended to estimate the treatment–response relationship, and two power definitions—optimal and acceptable—are considered. We apply these principles to REFINE-Lung, which investigates whether extended pembrolizumab dosing intervals in advanced non-small cell lung cancer (NSCLC) maintain efficacy while reducing unnecessary overtreatment. Sample size calculations use simulation-based methods or an analytic formula for binary outcomes.

resultsREFINE-Lung was designed with five administration frequency arms, exploring the range within which the optimal frequency is likely to exist (6-, 9-, 12-, 15-, and 18-weekly dosing), with the primary endpoint 2-year overall survival. Initial sample size calculations targeted 1,750 patients to provide 80% optimal power, but in order to accelerate completion this was adjusted to 1,100 patients targeting acceptable power. An interim analysis strategy allowed adaptation based on early data on progression-free survival. This approach balances statistical robustness with feasibility while ensuring ethical equipoise in dose de-escalation.

conclusionsThe ROCI design is an efficient alternative to standard non-inferiority trials for optimising continuous aspects of treatment administration. By sharing information across multiple treatment levels and leveraging flexible modelling approaches, ROCI trials improve efficiency and reliability in identifying optimal treatment regimens. The REFINE-Lung trial case study demonstrates applying these principles, providing a framework for future trials aiming to refine treatment administration strategies.

Indexed as

Carcinoma, Non-Small-Cell LungLung NeoplasmsRandomized Controlled Trials as TopicResearch DesignEquivalence Trials as TopicHumansSample SizeTreatment OutcomeClinical trialsDuration designNon-inferiorityROCISample size

Identifiers

PMID42050422
PMCPMC13270560

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.