Accuracy of CT-Guided Core-Needle Biopsy in Diagnosis of Thoracic Lesions Suspicious for Primitive Malignancy of the Lung: A Five-Year Retrospective Analysis.

BACKGROUND: Lung cancer represents a heterogeneous group of neoplasms, with the highest frequency and mortality in both sexes combined. In a clinical scenario characterized by the widespread of multidetector-row spiral CT, core-needle biopsy under tomographic guidance is one of the main and safest methods to obtain tissue specimens, even though there are relatively high rates of pneumothorax (0-60% incidence) and pulmonary hemorrhage (4-27% occurrence rates). The aim of this retrospective study is to assess the diagnostic accuracy of CT-guided core-needle biopsy in the diagnosis of primary lung malignancies and to compare our results with evidence from the literature. MATERIALS AND METHODS: Our analysis included 350 thoracic biopsies, performed from 2017 to 2022 with a 64-row CT guidance and 16/18 G needles mounted on a biopsy gun. We included in the final cohort all samples with evidence of primary lung malignancies, precursor lesions, and atypia, as well as inconclusive and negative diagnoses. RESULTS: There was sensitivity of 90.07% (95% CI 86.05-93.25%), accuracy of 98.87% (95% CI 98.12-99.69%), positive predictive value of 100%, and negative value of 98.74% (95% CI 98.23-99.10%). Specificity settled at 100% (93.84-100%). The AUC was 0.952 (95% CI 0.924-0.972). Only three patients experienced major complications after the procedure. Among minor complications, longer distances from the pleura, the presence of emphysema, and the lower dimensions of the lesions were correlated with the development of pneumothorax after the procedure, while longer distances from the pleura and the lower dimensions of the lesions were correlated with intra-alveolar hemorrhage. Immunohistochemistry analysis was performed in 51% of true positive cases, showing TTF-1, CK7, and p40 expression, respectively, in 26%, 24%, and 10% of analyzed samples. CONCLUSIONS: The CT-guided thoracic core-needle biopsy is an extremely accurate and safe diagnostic procedure for the histological diagnosis of lung cancer, a first-level interventional radiology exam for peripheral and subpleural lesions of the lung, which is also able to provide adequate samples for advanced pathologic assays (e.g., FISH, PCR) to assess molecular activity and genetic sequencing.

Monitoring the manufacturing and quality of medicines: a fundamental task of pharmacovigilance.

The collection and assessment of individual case safety reports (ICSRs) is important to detect unknown adverse drug reactions particularly in the first decade after approval of new chemical entities. However, regulations require that these activities are routinely undertaken for all medicinal products, including older medicines such as generic medicinal products with a well-established safety profile. For the latter, the risk management plans no longer contain important risks, considered important safety concerns, on the basis that routine pharmacovigilance activity would not allow their further characterisation. Society assumes that unexpected adverse reactions causally related to pharmacological activity are very unlikely to be detected for such well-established medicines, but important risks can still occur. For these products, a change in the safety profile which is brand or source specific and usually local in nature, associated with failures with the adequate control of quality of manufacturing or distribution are important safety issues. These may be the consequence of manufacturing and pharmacovigilance quality systems that are not fully integrated over the product life cycle (e.g. inadequate control of quality defects affecting one or multiple batches; inadequate impact assessment of change/variation of manufacturing, quality control testing, storage and distribution processes; inadequate control over the distribution channels including the introduction of counterfeit or falsified products into the supply chain). Drug safety hazards caused by the above-mentioned issues have been identified with different products and formulations, from small molecules to complex molecules such as biological products extracted from animal sources, biosimilars and advanced therapy medicinal products. The various phases of the drug manufacturing and distribution of pharmaceutical products require inputs from pharmacovigilance to assess any effects of quality-related issues and to identify proportionate risk minimisation measures that often have design implications for a medicine which requires a close link between proactive vigilance and good manufacturing practice. To illustrate our argument for closer organisational integration, some examples of drug safety hazards originating from quality, manufacturing and distribution issues are discussed. PLAIN LANGUAGE SUMMARY: Monitoring the manufacturing and quality of medicines: the fundamental task of pharmacovigilance Pharmacovigilance is the science relating to the collection, detection, assessment, monitoring, and prevention of adverse reactions with pharmaceutical products. The collection and assessment of adverse reactions are particularly important in the first decade after marketing authorisation of a drug as the information gathered in this period could help, for example, to identify complications from its use which were unknown before its commercialization. However, when it comes to medicines that have been on the market for a long time there is general acceptance that their safety profile is already well-established and unknown adverse reactions unlikely to occur. Nevertheless, even older medicines, such as generic drugs, can generate new risks. For these drugs a change in the safety profile could be the result of inadequate control of their quality, manufacturing and distribution systems. To overcome such an obstacle, it is necessary to fully integrate manufacturing and pharmacovigilance quality systems in the medicine life-cycle. This could help detect safety hazards and prevent the development of new complications which may arise due to the poor quality of a drug. Pharmacovigilance activities should indeed be included in all phases of the drugs' manufacturing and distribution process, regardless of their chemical complexity to detect quality-related matters in good time and reduce the risk of safety concerns to a minimum.

The Unintended Consequences of Adverse Event Information on Medicines' Risks and Label Content.

Patients and prescribers need to be aware of adverse drug events to minimize the risk of their occurrence and the severity with which they appear. However, numerous studies show that being informed about adverse events can increase the possibility of suffering from them. Patients tend to overestimate the likelihood of experiencing the adverse events included in the label, and this can contribute to worsening the negative expectations which are at the root of the nocebo effect. In fact, patients can become anxious after reading the undesirable effects section of the leaflet and, in addition to suffering from the nocebo effect, might not take a drug they could benefit from due to the fear of experiencing adverse events. In addition, patients' attention can focus towards non-specific symptoms of daily living that can be misattributed to the drug and included in the labelling. This article proposes a number of suggestions to reduce the abovementioned unintended effects associated with labelling, namely, an increased focus on the excess risk of experiencing adverse events rather than crude incidence, using attribute framing to help patients to better understand the risk of experiencing adverse events, dividing the undesirable effect section of the leaflet into subsections according to the level of evidence supporting causal relationships and, finally, restricting the addition of non-specific adverse events that are also symptoms of daily living to only those where there is enough evidence to show they have been caused by the drug. More studies on how to minimize the nocebo effect induced by adverse event information should be performed, and these should be done in collaboration with health authorities, to reach a shared consensus on how to better present adverse event information in the label.

Drug Safety in Geriatric Patients: Current Status and Proposed Way Forward.

Elderly patients are the main users of drugs and they differ from younger patients. They are a heterogeneous population that cannot be defined only by age but should rather be stratified based on their frailty. The elderly have distinctive pharmacokinetic and pharmacodynamic characteristics, are frequently polymorbid, and are therefore treated with multiple drugs. They may experience adverse reactions that are difficult to recognize, since some of them present non-specific symptoms easily mistaken for geriatric conditions. Paradoxically, the elderly are underrepresented in clinical trials, especially the frail individuals whose pharmacological response and expected treatment outcome can be different from those of non-frail patients. This means that the benefit-risk balance of drugs used in frail elderly patients is frequently unknown. We present some proposals to overcome the barriers preventing the enrollment of frail elderly patients in clinical trials, and strategies for monitoring their therapy to minimize the risk of adverse reactions. Automated alerts for drug and drug-disease interactions could help appropriate prescribing but should flag only clinically relevant interactions. Pharmaceutical forms should be designed to allow easy dose adjustment and, together with packaging and labeling, should account for the physical and cognitive limitations of frail elderly patients. Aggregate pharmacovigilance reports should summarize the safety profile in the elderly, but rather than presenting the results by age they should focus on patients' frailty, perhaps using the number of comorbidities as a proxy when information on frailty is not available.

Unifying drug safety and clinical databases.

Clinical and drugs safety organisations run their operation independently and use separate databases designed to comply with different data standards. This separation is neither efficient nor effective since investigators need to report serious adverse events both to the clinical and drug safety departments, causing the respective databases to contain partially overlapping data sets containing common elements that need to be reconciled. Electronic data capture provides the opportunity to avoid duplicate storage and obviate reconciliation. It also introduces the risk of non-compliance due to late submission of unexpected serious adverse reactions to competent authorities. This raises the potential for a clinical department to receive a case that the drug safety department is unaware of. However, the most significant inefficiency probably lies in the preparation of aggregate reports and regulatory documents that need to be prepared using data originating from both databases. In a resource-constrained world, unnecessary activities and associated costs are unwelcome, particularly when they are avoidable. The Clinical Data Interchange Consortium (CDISC) has set the standards for clinical trial data, while the International Conference of Harmonization (ICH) dictates drug safety ones. CDISC is expanding its Clinical Data Acquisition Standards Harmonisation (CDASH) model to capture adverse event data associated with ICH E2B. All common data items have two labels that have been mapped. This exercise is showing that there is no scientific justification for data segregation. The differences between these two standards can be attributed to conventions or arise from new technology that renders unnecessary the keying in of certain context information (dates, times and recorder ID). Once this mapping is completed then a common data acquisition process will become feasible. This is the prerequisite to ultimately unifying the two databases and to implementing more efficient processes. The Authors also propose a new workflow to provide safety with the array of benefits that technology and process harmonisation offers and ultimately unifying the clinical drug safety processes.

Using resources for scientific-driven pharmacovigilance: from many product safety documents to one product safety master file.

Current regulations require a description of the overall safety profile or the specific risks of a drug in multiple documents such as the Periodic and Development Safety Update Reports, Risk Management Plans (RMPs) and Signal Detection Reports. In a resource-constrained world, the need for preparing multiple documents reporting the same information results in shifting the focus from a thorough scientific and medical evaluation of the available data to maintaining compliance with regulatory timelines. Since the aim of drug safety is to understand and characterize product issues to take adequate risk minimization measures rather than to comply with bureaucratic requirements, there is the need to avoid redundancy. In order to identify core drug safety activities that need to be undertaken to protect patient safety and reduce the number of documents reporting the results of these activities, the author has reviewed the main topics included in the drug safety guidelines and templates. The topics and sources that need to be taken into account in the main regulatory documents have been found to greatly overlap and, in the future, as a result of the new Periodic Safety Update Report structure and requirements, in the author's opinion this overlap is likely to further increase. Many of the identified inter-document differences seemed to be substantially formal. The Development Safety Update Report, for example, requires separate presentation of the safety issues emerging from different sources followed by an overall evaluation of each safety issue. The RMP, instead, requires a detailed description of the safety issues without separate presentation of the evidence derived from each source. To some extent, however, the individual documents require an in-depth analysis of different aspects; the RMP, for example, requires an epidemiological description of the indication for which the drug is used and its risks. At the time of writing this article, this is not specifically required by other documents. The author has identified signal detection (intended not only as adverse event disproportionate reporting, but including non-clinical, laboratory, clinical analysis data and literature screening) and characterization as the basis for the preparation of all drug safety documents, which can be viewed as different ways of presenting the results of this activity. Therefore, the author proposes to merge all the aggregate reports required by current regulations into a single document - the Drug Safety Master File. This report should contain all the available information, from any source, regarding the potential and identified risks of a drug. It should be a living document updated and submitted to regulatory authorities on an ongoing basis.

How to apply the human factor to periodic safety update reports.

Society has been increasingly intolerant of excuses for systems breakdown in many areas of public life. This is hardly surprising given that there is overwhelming evidence behind why processes fail and mistakes are made, and so, based on this evidence, processes should be designed to mitigate risk. The main root cause of many process failures can be attributed to the human factor, which encompasses all those factors that can influence people and their behaviour. Based on experience from other safety-conscious industries, there is a major move to manage the human factor as part of delivery of safety culture in healthcare systems. Since pharmaceutical companies are healthcare companies, it makes sense that the principles underlying a pharmaceutical safety culture are aligned with those of the healthcare sector. A good place to start applying human factor management to a pharmaceutical safety process would be the complex process required to produce a good quality Periodic Safety Update Report (PSUR) on time and to an acceptable format. This can be achieved by a process aimed at building on an ongoing learning cycle through planning, observing if execution matches expectations and learning from mistakes and through the interdependent teamwork of PSUR contributors providing mutual support. Such a framework of teamwork and communication principles can be applied to the entire process for the preparation and submission of PSURs.