Practical risk management in early phase clinical trials

Coates, Simon; Täubel, Jörg; Lorch, Ulrike

doi:10.1007/s00228-018-02607-8

Cited by 10 publications

(5 citation statements)

References 10 publications

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“…Due to the intrinsic characteristics of phase I clinical trials [ 7 , 8 , 9 ], competent authorities pay particular attention to patients’ safety and well-being. Various regulations and guidelines were released to protect phase I study participants from potential health risks.…”

Section: Phase I Clinical Trials: Shaping the Future Of Medicinementioning

confidence: 99%

The Requirements of Managing Phase I Clinical Trials Risks: The British and Italian Case Studies

Di Tonno,

Martena,

Taurisano

et al. 2024

Epidemiologia

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Phase I clinical trials represent a critical point in drug development because the investigational medicinal product is being tested in humans for the first time. For this reason, it is essential to evaluate and identify the Maximum Tolerated Dose (MTD) and the safety of the new compound. To mitigate the possible risks associated with drug administration and treatment, the European Competent Authority issued various guidelines to provide provisions and harmonize risk management processes. In the UK and Italy, particular attention should be paid to the Medicines & Healthcare Products Regulatory Agency (MHRA) phase I accreditation scheme and the specific rules set by the Italian Drug Authority through the AIFA Determination no. 809/2015. Both reference documents are based on the concept of quality risk management while conducting phase I clinical studies. Moreover, the AIFA determination outlines specific requirements for those sites that want to conduct non-profit phase I clinical trials. Indeed, the document reports peculiar activities to the “Clinical Trial Quality Team”, which is a team that should support the clinical site researchers in designing, starting, performing, and closing non-profit phase I studies. In this paper, we provide a general overview of the main European guidelines concerning the management of risks during phase I trials, focusing on the main peculiarities of the schemes and rules set by the MHRA and AIFA.

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Section: Phase I Clinical Trials: Shaping the Future Of Medicinementioning

confidence: 99%

The Requirements of Managing Phase I Clinical Trials Risks: The British and Italian Case Studies

Di Tonno,

Martena,

Taurisano

et al. 2024

Epidemiologia

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“…Compound 5 demonstrated a notable inclination towards hepatotoxicity and immunotoxicity, whereas compound 8 was projected to possess no detectable toxicity. Thus, the significance of this study lies in its ability to predict toxicity, which is of particular importance in the pharmaceutical industry [57].…”

Section: Drug-likeness Adme and Toxicity Propertiesmentioning

confidence: 99%

Cytotoxicity effect, network pharmacology, molecular docking, and molecular dynamics simulation of new mono-chalcone compounds for breast cancer

Ismail,

Khairuddean,

Alidmat

et al. 2023

Preprint

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Chalcones are flavonoids' derivatives and have a wide range of biological functions. Chalcones' anticancer efficacy arises from their capacity to operate on several targets. Hence, the purpose of this study was to examine cytotoxicity, network pharmacology, molecular docking, and molecular dynamics (MD) simulations of newly synthesized mono-chalcone compounds related to breast cancer. To achieve this objective, the cytotoxicity of mono-chalcone compounds in relation to breast cancer cells, specifically MCF-7 and MDA-MB-231, was investigated. The results demonstrated that the compounds were significantly suppressed in both breast cancer cells. Subsequently, the compounds were subjected to a network pharmacology analysis. The findings showed that both the compounds and the breast cancer target network shared 160 protein targets. In addition, it was discovered that most of the targeted proteins are involved in cancer pathways. The apoptosis proteins known as BCL2, MDM2, and CASP3 were the enriched genes identified in this analysis. Molecular docking analysis showed that the compounds had high binding affinities for their respective protein receptors. Therefore, the protein-ligand conformations were subjected to a 100 ns MD simulation at 310 K. Comparatively to the reference proteins, the protein-ligand conformation complexes exhibited greater stability, compactness, and negligible structural changes. The results indicate that both mono-chalcone compounds are of great significance and shed light on the molecular interactions between these compounds and proteins involved in the apoptosis breast cancer pathway.

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“…Use of the CRM has been shown to be more efficient in determining MTD and ensuring more patients are treated close to MTD, compared to the 3 + 3 design [67]; however, expert statistical support is required. Appropriate stopping rules must also be defined, usually based on number and severity of adverse events, to ensure the safety of trial participants [68].…”

Section: Safetymentioning

confidence: 99%

Early-Phase Interventional Trials in Oral Cancer Prevention

McCarthy

Fedele

Ottensmeier

et al. 2021

Cancers

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The increasing breadth of molecular targets, promise of immune-targeted therapies and repurposed agents have heightened interest in cancer prevention. While, to date, testing of oral cancer chemoprevention strategies has failed to deliver therapeutic agents for routine clinical practice, there remains an urgent need for further clinical research to overcome this hurdle. Patients at the greatest risk of disease stand to benefit the most from inclusion in clinical trials; therefore, there is a need to carefully define this population using validated clinical and molecular markers. Safety, tolerability and the efficacy of interventions is assessed through carefully selected endpoints. These endpoints may include pharmacodynamic, clinical, histological and on-target molecular modifications as an individual or as a composite endpoint. Early-phase trials provide an area of opportunity to explore novel and repurposed agents in the setting of oral cancer chemoprevention, eventually leading to phase III trials with clinical endpoints such as transformation and clinical outcome; these studies are large, lengthy and expensive and should be reserved for the most promising of agents. This paper will explore current evidence in oral cancer chemoprevention, drug repurposing, selection of appropriate endpoints for early-phase trials and novel therapeutic angles in oral cancer chemoprevention.

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Practical risk management in early phase clinical trials

Cited by 10 publications

References 10 publications

The Requirements of Managing Phase I Clinical Trials Risks: The British and Italian Case Studies

The Requirements of Managing Phase I Clinical Trials Risks: The British and Italian Case Studies

Cytotoxicity effect, network pharmacology, molecular docking, and molecular dynamics simulation of new mono-chalcone compounds for breast cancer

Early-Phase Interventional Trials in Oral Cancer Prevention

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