Role of external evidence in monitoring clinical trials: experience from a perinatal trial.
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ABSTRACT:
SUBMITTER: Brocklehurst P
PROVIDER: S-EPMC1117916 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background Evidence from previous studies is often used relatively informally in the design of clinical trials: for example, a systematic review to indicate whether a gap in the current evidence base justifies a new trial. External evidence can be used more formally in both trial design and analysis, by explicitly incorporating a synthesis of it in a Bayesian framework. However, it is unclear how common this is in practice or the extent to which it is considered controversial. In this qualitative study, we explored attitudes towards, and experiences of, trialists in incorporating synthesised external evidence through the Bayesian design or analysis of a trial. Methods Semi-structured interviews were conducted with 16 trialists: 13 statisticians and three clinicians. Participants were recruited across several universities and trials units in the United Kingdom using snowball and purposeful sampling. Data were analysed using thematic analysis and techniques of constant comparison. Results Trialists used existing evidence in many ways in trial design, for example, to justify a gap in the evidence base and inform parameters in sample size calculations. However, no one in our sample reported using such evidence in a Bayesian framework. Participants tended to equate Bayesian analysis with the incorporation of prior information on the intervention effect and were less aware of the potential to incorporate data on other parameters. When introduced to the concepts, many trialists felt they could be making more use of existing data to inform the design and analysis of a trial in particular scenarios. For example, some felt existing data could be used more formally to inform background adverse event rates, rather than relying on clinical opinion as to whether there are potential safety concerns. However, several barriers to implementing these methods in practice were identified, including concerns about the relevance of external data, acceptability of Bayesian methods, lack of confidence in Bayesian methods and software, and practical issues, such as difficulties accessing relevant data. Conclusions Despite trialists recognising that more formal use of external evidence could be advantageous over current approaches in some areas and useful as sensitivity analyses, there are still barriers to such use in practice. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-021-05759-8.
| S-EPMC8577005 | biostudies-literature
Project description:Real-Time PCR (qPCR) testing is recommended as both a diagnostic and outcome measurement of etiological treatment in clinical practice and clinical trials of Chagas disease (CD), but no external quality assurance (EQA) program provides performance assessment of the assays in use. We implemented an EQA system to evaluate the performance of molecular biology laboratories involved in qPCR based follow-up in clinical trials of CD. An EQA program was devised for three clinical trials of CD: the E1224 (NCT01489228), a pro-drug of ravuconazole; the Sampling Study (NCT01678599), that used benznidazole, both conducted in Bolivia; and the CHAGASAZOL (NCT01162967), that tested posaconazole, conducted in Spain. Four proficiency testing panels containing negative controls and seronegative blood samples spiked with 1, 10 and 100 parasite equivalents (par. eq.)/mL of four Trypanosoma cruzi stocks, were sent from the Core Lab in Argentina to the participating laboratories located in Bolivia and Spain. Panels were analyzed simultaneously, blinded to sample allocation, at 4-month intervals. In addition, 302 random blood samples from both trials carried out in Bolivia were sent to Core Lab for retesting analysis. The analysis of proficiency testing panels gave 100% of accordance (within laboratory agreement) and concordance (between laboratory agreement) for all T. cruzi stocks at 100 par. eq./mL; whereas their values ranged from 71 to 100% and from 62 to 100% at 1 and 10 par. eq./mL, respectively, depending on the T. cruzi stock. The results obtained after twelve months of preparation confirmed the stability of blood samples in guanidine-EDTA buffer. No significant differences were found between qPCR results from Bolivian laboratory and Core Lab for retested clinical samples. This EQA program for qPCR analysis of CD patient samples may significantly contribute to ensuring the quality of laboratory data generated in clinical trials and molecular diagnostics laboratories of CD.
| S-EPMC5703561 | biostudies-literature
Project description:The mechanisms and brain regions underlying error monitoring in complex action are poorly understood, yet errors and impaired error correction in these tasks are hallmarks of apraxia, a common disorder associated with left hemisphere stroke. Accounts of monitoring of language posit an internal route by which production planning or competition between candidate representations provide predictive signals that monitoring is required to prevent error, and an external route in which output is monitored using the comprehension system. Abnormal reliance on the external route has been associated with damage to brain regions critical for sensory-motor transformation and a pattern of gradual error 'clean-up' called conduite d'approche (CD). Action pantomime data from 67 participants with left hemisphere stroke were consistent with versions of internal route theories positing that competition signals monitoring requirements. Support Vector Regression Lesion Symptom Mapping (SVR-LSM) showed that lesions in the inferior parietal, posterior temporal, and arcuate fasciculus/superior longitudinal fasciculus predicted action conduite d'approche, overlapping the regions previously observed in the language domain. A second experiment with 12 patients who produced substantial action CD assessed whether factors impacting the internal route (action production ability, competition) versus external route (vision of produced actions, action comprehension) influenced correction attempts. In these 'high CD' patients, vision of produced actions and integrity of gesture comprehension interacted to determine successful error correction, supporting external route theories. Viewed together, these and other data suggest that skilled actions are monitored both by an internal route in which conflict aids in detection and correction of errors during production planning, and an external route that detects mismatches between produced actions and stored knowledge of action appearance. The parallels between language and action monitoring mechanisms and neuroanatomical networks pave the way for further exploration of common and distinct processes across these domains.
| S-EPMC6513694 | biostudies-literature
Project description:BackgroundSome level of monitoring is usually required during a clinical trial to protect the rights and safety of trial participants and to safeguard the quality and reliability of trial results. Although there is increasing support for the use of risk-proportionate approaches to achieve these aims, the variety of methods and lack of an empirical evidence base can present challenges for clinical trial practitioners.MethodsThis paper describes the monitoring methods and procedures that are utilised by a non-commercial clinical trials unit which coordinates a range of clinical trials across a variety of clinical areas with different associated risks.ResultsMonitoring activities and approaches should be selected to be proportionate to the risks identified within a trial. A risk-proportionate approach to monitoring is described giving details of methods that may be considered by clinical trial practitioners during the development of a trial monitoring plan. An example risk assessment and corresponding monitoring plan for a low risk (type A in the Medicines and Healthcare Products Regulatory Agency (MHRA) classification system) pediatric trial is provided for illustration.ConclusionWe present ideas for developing a monitoring plan for a clinical trial of an investigational medicinal product based on our experience. Alternative approaches may be relevant or preferable in other settings based on inherent risk.
| S-EPMC4022377 | biostudies-literature
Project description:In the presented study, in order to unravel gut microbial community multiplicity and the influence of maternal milk nutrients (i.e., IgA) on gut mucosal microbiota onset and shaping, a mouse GM (MGM) was used as newborn study model to discuss genetic background and feeding modulation on gut microbiota in term of symbiosis, dysbiosis and rebiosis maintenance during early gut microbiota onset and programming after birth. Particularly, a bottom-up shotgun metaproteomic approach, combined with a computational pipeline, has been compred with a culturomics analysis of mouse gut microbiota, obtained by MALDI-TOF mass spectrometry (MS).
2016-10-13 | PXD004033 | Pride
Project description:Renal cell carcinoma (RCC) is considered an immunogenic tumor with a prominent dysfunctional immune cell infiltrate, unable to control tumor growth. Cytokine-based immunotherapies, including interferon-? and interleukin-2, have been used for the treatment of metastatic RCC (mRCC). Long-term responses and complete remissions were observed, but durable clinical benefit efficacy in the overall population was limited and associated with significant toxicity. As a consequence, new generation agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways replaced interferon alpha (IFN-?). Strategies of tumor immune evasion include T-cell suppression by negative signals deriving from the interaction between programmed death-1 (PD-1) on the T cell and its ligand (PDL-1) on the tumor cells. Nivolumab, a programmed death 1 checkpoint inhibitor, blocks this pathway, thus reversing T-cell suppression and activating antitumor responses. The aim of this review is to summarize the safety and efficacy data of nivolumab in mRCC. Objective responses and safety profile of single-agent nivolumab are favorable in both previously treated and treatment-naïve mRCC patients. Despite toxic effects, combination therapies with nivolumab have shown promising results, indicating a potential role in the treatment of mRCC. Tailoring immunotherapy on a patient-to-patient basis represents a major challenge for the future.
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Project description:The treatment of metastatic renal cell carcinoma (mRCC) is rapidly changing. During first-line treatment with targeted therapy, patients ultimately develop resistance to therapy and the disease progresses. Recently, cabozantinib has demonstrated a better response rate, progression-free survival and overall survival compared with everolimus after failure of prior targeted therapy in patients with advanced or metastatic renal cell carcinoma (RCC). Cabozantinib is a small-molecule tyrosine kinase inhibitor (TKI). It exerts inhibition of MET, vascular endothelial growth factor receptor type 2, AXL, and many other receptor tyrosine kinases that are also implicated in tumor pathobiology, including RET, KIT, and FLT3. MET drives tumor survival, invasion, angiogenesis, and metastasis through several downstream signaling pathways. AXL has recently been described as an essential mediator of cancer metastasis that mediates crosstalk and resistance to TKIs. MET and AXL are thought to be anti-vascular endothelial growth factor receptor (VEGF) resistance pathways and thus cabozantinib represents a logical choice after progression on initial VEGF therapy. Subgroup analyses examining those with good performance status or visceral and bone metastases indicate that the hazard ratios may be better when using cabozantinib versus everolimus. However, there were no clear statistically significant differences between any subgroups.
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Project description:Paul Pinsky of the US National Cancer Institute and colleagues describe the implementation and outcomes of web-based data sharing from the PLCO and NLST cancer screening trials.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease associated with significant morbidity and mortality. Previously, IPF has been managed using immunosuppressive therapy; however, it has been shown that this is associated with increased mortality. In the last 5 years, two disease-modifying agents have been licensed for use in IPF, namely pirfenidone and nintedanib. Nintedanib is a tyrosine kinase inhibitor with antifibrotic properties that has also been shown to significantly reduce the progression of the disease. The scientific evidence shows that nintedanib is effective and well tolerated for the treatment of IPF in mild, moderate and severe stages of the disease. Real-world experiences also support the findings of previously conducted clinical trials and show that nintedanib is effective for the management of IPF and is associated with reducing disease progression. Gastrointestinal events, mainly diarrhoea, are the main adverse events caused by the treatment. Recent real-word studies also suggest that nintedanib stabilizes lung function till lung transplantation, with no increased surgical complications or postoperative mortality after lung transplantation. In this review, we will discuss the clinical trial evidence and real-world experience for nintedanib in the management of IPF.
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Project description:Clinical trials are paramount to improving human health. New trial designs and informed consent issues are emerging as a result of genomic profiling and the development of molecularly targeted agents. Many groups and individuals are responsible for ensuring the protection of research participants and the quality of the data produced. The specialty role of the clinical trials nurse (CTN) is critical to clinical trials. Oncology CTNs have competencies that can help guide their practice; however, not all oncology clinical trials are supervised by a nurse. Using the process of engagement, one organization has restructured oncology CTNs under a nurse-supervised model.
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