The 3 + 3 design in dose-finding studies with small sample sizes: Pitfalls and possible remedies

In the last few years, numerous novel designs have been proposed to improve the efficiency and accuracy of phase I trials to identify the maximum-tolerated dose (MTD) or the optimal biological dose (OBD) for noncytotoxic agents. However, the conventional 3+3 approach, known for its and poor performance, continues to be an attractive choice for many trials despite these alternative suggestions. The article seeks to underscore the importance of moving beyond the 3+3 design by highlighting a different key element in trial design: the estimation of sample size and its crucial role in predicting toxicity and determining the MTD. We use simulation studies to compare the performance of the most used phase I approaches: 3+3, Continual Reassessment Method (CRM), Keyboard and Bayesian Optimal Interval (BOIN) designs regarding three key operating characteristics: the percentage of correct selection of the true MTD, the average number of patients allocated per dose level, and the average total sample size. The simulation results consistently show that the 3+3 algorithm underperforms in comparison to model-based and model-assisted designs across all scenarios and metrics. The 3+3 method yields significantly lower (up to three times) probabilities in identifying the correct MTD, often selecting doses one or even two levels below the actual MTD. The 3+3 design allocates significantly fewer patients at the true MTD, assigns higher numbers to lower dose levels, and rarely explores doses above the target dose-limiting toxicity (DLT) rate. The overall performance of the 3+3 method is suboptimal, with a high level of unexplained uncertainty and significant implications for accurately determining the MTD. While the primary focus of the article is to demonstrate the limitations of the 3+3 algorithm, the question remains about the preferred alternative approach. The intention is not to definitively recommend one model-based or model-assisted method over others, as their performance can vary based on parameters and model specifications. However, the presented results indicate that the CRM, Keyboard, and BOIN designs consistently outperform the 3+3 and offer improved efficiency and precision in determining the MTD, which is crucial in early-phase clinical trials

Controlled backfill in oncology dose-finding trials

The use of backfill in early phase dose-finding trials is a relatively recent practice. It consists of assigning patients to dose levels below the level where the study is at. The main reason for backfilling is to collect additional pharmacokinetic, pharmacodynamic and response data, in order to assess whether a plateau may exist on the dose-efficacy curve. This is a possibility in oncology with molecularly targeted agents or immunotherapy. Recommending for further study a dose level lower than the maximum tolerated dose could be supported in such situations. How to best allocate backfill patients to dose levels is not yet established. In this paper we propose to randomise backfill patients below the dose level where the study is at. A refinement of this would be to stop backfilling to lower dose levels when these show insufficient efficacy compared to higher levels, starting at dose level 1 and repeating this process sequentially. At study completion, data from all patients (both backfill patients and dose-finding patients) is used to estimate the dose-response curve. The fit from a change point model is compared to the fit of a monotonic model to identify a potential plateau. Using simulations, we show that this approach can identify the plateau on the dose-response curve when such a plateau exists, allowing the recommendation of a dose level lower than the maximum tolerated dose for future studies. This contribution provides a methodological framework for backfilling, from the perspective of both design and analysis in early phase oncology trials

A Protocol for an economic evaluation of a polypill in patients with established or at high risk of cardiovascular disease in a UK NHS setting: RUPEE (NHS) study

Copyright © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. Introduction: The ‘Use of a Multi-drug Pill in Reducing cardiovascular Events’ (UMPIRE) trial was a randomised controlled clinical trial evaluating the impact of a polypill strategy on adherence to indicated medication in a population with established cardiovascular disease (CVD) of or at high risk thereof. The aim of Researching the UMPIRE Processes for Economic Evaluation in the National Health Service (RUPEE NHS) is to estimate the potential health economic impact of a polypill strategy for CVD prevention within the NHS using UMPIRE trial and other relevant data. This paper describes the design of a modelled economic evaluation of the impact of increased adherence to the polypill versus usual care among the UK UMPIRE participants. Methods and analysis: As recommended by the International Society for Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making modelling guidelines, a review of published CVD models was undertaken to identify the most appropriate modelling approach and structure. The review was carried out in the electronic databases, MEDLINE and EMBASE. 40 CVD models were identified from 57 studies, the majority of economic models were health state transition cohort models and individual-level simulation models. The findings were discussed with clinical experts to confirm the approach and structure. An individual simulation approach was identified as the most suitable method to capture the heterogeneity in the population at CVD risk. RUPEE-NHS will use UMPIRE trial data on adherence to estimate the long-term cost-effectiveness of the polypill strategy. Dissemination: The evaluation findings will be presented in open-access scientific and healthcare policy journals and at national and international conferences. We will also present findings to NHS policy makers and pharmaceutical companies

Toxicity, normal tissue and dose-volume planning parameters for radiotherapy in soft tissue sarcoma of the extremities: A systematic review of the literature

BACKGROUND: Patients with soft tissue sarcoma of the extremities (STSE) are left with high incidence of toxicities after Radiotherapy (RT). Understanding the normal tissue dose relationship with the development of long-term toxicities may enable better RT planning in order to reduce treatment toxicities for STSE. This systematic review of the literature aims at reporting the incidence of acute and late toxicities and identifying RT delineation guidance the normal tissues structures and dose-volume parameters for STSE. METHODS: A literature search of PUBMED-MEDLINE for studies that reported data on RT toxicity outcomes, delineation guidelines and dose-volume parameters for STSE from 2000 to 2022. Data has been tabulated and reported. RESULTS: Thirty of 586 papers were selected after exclusion criteria. External beam RT prescriptions ranged from 30 to 72 Gy. The majority of studies reported the use of Intensity Modulated RT (IMRT) (27%). Neo-adjuvant RT was used in 40%. The highest long-term toxicities were subcutaneous and lymphoedema, reported when delivering 3DCRT. IMRT had a lower incidence of toxicities. Normal tissue outlining such as weight-bearing bones, skin and subcutaneous tissue, corridor and neurovascular bundle was recommended in 6 studies. Nine studies recommended the use of dose-volume constraints, but only one recommended evidence-based dose-volume constraints. CONCLUSION: Although the literature is replete with toxicity reports, there is a lack of evidence-based guidance on normal tissue and dose-volume parameters and strategies to reduce the normal tissues irradiation when optimising RT plans for STSE are poor compared to other tumour sites

Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes.

OBJECTIVES: The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS). BACKGROUND: Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization. METHODS: The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. RESULTS: Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p < 0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04). CONCLUSIONS: Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year.info:eu-repo/semantics/publishedVersio

Achieving optimal adherence to medical therapy by telehealth: Findings from the ORBITA medication adherence sub-study

INTRODUCTION: The ORBITA trial of percutaneous coronary intervention (PCI) versus a placebo procedure for patients with stable angina was conducted across six sites in the United Kingdom via home monitoring and telephone consultations. Patients underwent detailed assessment of medication adherence which allowed us to measure the efficacy of the implementation of the optimization protocol and interpretation of the main trial endpoints. METHODS: Prescribing data were collected throughout the trial. Self-reported adherence was assessed, and urine samples collected at pre-randomization and at follow-up for direct assessment of adherence using high-performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS). RESULTS: Self-reported adherence was >96% for all drugs in both treatment groups at both stages. The percentage of samples in which drug was detected at pre-randomization and at follow-up in the PCI versus placebo groups respectively was: clopidogrel, 96% versus 90% and 98% versus 94%; atorvastatin, 95% versus 92% and 92% versus 91%; perindopril, 95% versus 97% and 85% versus 100%; bisoprolol, 98% versus 99% and 96% versus 97%; amlodipine, 99% versus 99% and 94% versus 96%; nicorandil, 98% versus 96% and 94% versus 92%; ivabradine, 100% versus 100% and 100% versus 100%; and ranolazine, 100% versus 100% and 100% versus 100%. CONCLUSIONS: Adherence levels were high throughout the study when quantified by self-reporting methods and similarly high proportions of drug were detected by urinary assay. The results indicate successful implementation of the optimization protocol delivered by telephone, an approach that could serve as a model for treatment of chronic conditions, particularly as consultations are increasingly conducted online

Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes

Objectives: The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS). // Background: Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization. // Methods: The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. // Results: Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p < 0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04). // Conclusions: Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year