Risk-benefit Balance Research Articles

On the Concepts, Methods, and Use of "Probability of Success" for Drug Development Decision-Making: A Scoping Review.

Drug development is a lengthy process with considerable uncertainty at each milestone. Several trials are needed to progress to confirmatory evaluation and establish a positive benefit-risk balance. One of the critical milestones is the decision to progress to phase III based on phase II trial results. Use of probability of success is becoming standard in pharmaceutical companies to support this decision. However, the lack of consistency in terminology makes it difficult to assess the comparative value of different approaches. By leveraging the availability of high-quality external data (e.g., real-world data, historical clinical trial data, etc.), probability of success-based procedures may further improve decision-making. We performed a scoping review of approaches to calculate the probability of success of a phase III trial depending on the available data sources and the availability of specific endpoints. Calculation of probability of success is relatively straightforward if data for the primary endpoint of the phase III trial are also available in phase II trials. Often, phase II trials are based on biomarker or surrogate outcomes, due to challenges associated with study duration and required sample size. Probability of success-based procedures as reviewed can incorporate external data sources, for example, from clinical trials testing the same or similar drug or real-world data on the targeted population-optimizing the calculation of probability of trial success and the projected drug candidate value. We conclude the paper by reflecting on alternative approaches and ideas for uses within pharmaceutical companies and academia.

Gadolinium‐Based Contrast Agents (GBCAs) for MRI: A Benefit–Risk Balance Analysis from a Chemical, Biomedical, and Environmental Point of View

Gadolinium‐Based Contrast Agents (GBCAs) for MRI: A Benefit–Risk Balance Analysis from a Chemical, Biomedical, and Environmental Point of View

A Real-World Data Analysis of Alglucosidase Alfa in the FDA Adverse Event Reporting System (FAERS) Database.

Alglucosidase alfa for injection is used as an enzyme replacement therapy for the treatment of Pompe disease. The safety profile of alglucosidase alfa-associated adverse events requires a comprehensive evaluation. In this study, we aimed to identify drug safety alert signals and investigate the real-world safety of alglucosidase alfa to guide clinical decision making and optimize the risk-benefit balance. The adverse event reports from the first quarter of 2006 to the fourth quarter of 2023 were selected by exploring the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The new and unexpected potential adverse event signals were detected using a disproportionality analysis, including the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Then, the Medical Dictionary for Regulatory Activities was used to systematically classify the results. After analyzing 16,945,027 adverse event reports, a total of 4326 cases of adverse events related to alglucosidase alfa were identified, spanning 27 system organ classes. A total of 359 preferred terms of adverse events for glucosidase alpha were detected. Pyrexia ranked first, followed by pneumonia, dyspnea, respiratory failure, and disease progression according to occurrence frequency. The top three system organ classes were general disorders and administration-site conditions (n = 2466), respiratory, thoracic, and mediastinal disorders (n = 1749), and infections and infestations (n = 1551). In addition to adverse effects mentioned in the product label, our study also discovered rare but high signal intensity adverse events such as chronic recurrent multifocal osteomyelitis. There are many adverse events associated with the clinical use of alglucosidase alfa, which should be closely monitored in the FAERS database. As the most effective enzyme replacement therapy for Pompe disease, it is crucial to closely monitor these adverse events. Ensuring patient safety while balancing drug effectiveness is particularly important.

Muscle relaxants: uncertain risk-benefit balance in chronic pain syndromes.

Muscle relaxants: uncertain risk-benefit balance in chronic pain syndromes.

Cancer-Therapy-Induced Cardiotoxicity: Results of the Analysis of the UK Yellow Card Adverse Drug Reaction (ADR) Reporting.

Background: Non-small cell lung cancer (NSCLC) is a predominant cause of oncological mortality in the United Kingdom. There is a diverse spectrum of therapeutic options available, such as chemotherapies, targeted therapies and immunotherapies, which have significantly advanced patient prognoses. However, despite these advancements, there is an escalating concern regarding the potential cardiotoxic effects associated with these treatments. Objectives: This study aimed to explore the association between non-small cell lung cancer treatments and cardiotoxicity. Methods: A pharmacovigilance study was conducted utilising the UK Yellow Card System. The proportional reporting ratio (PRR) and reporting odds ratio (ROR) were calculated to detect signals. Results: Among the 56 shortlisted NSCLC drugs, the total number of adverse events reported was 128,214 with 6133 reports being cardiovascular adverse reactions. Among all the drugs analysed, alectinib demonstrated the highest ROR and PRR values, indicating the strongest signal for potential cardiovascular adverse events. Conclusions: This result was comparable to previous studies which also detected a signal of alectinib related to cardiovascular events using the WHO pharmacovigilance database, VigiBase. However, clinical studies demonstrated that alectinib largely improved progression-free survival (PFS) and overall survival in patients. Therefore, it is important to continue monitoring the real-world use of alectinib, so that a benefit-risk balance can be maintained.

P108 Immunotherapy of psoriasis in the context of underlying malignant disease: risk–benefit balance?

Abstract The recently established immunotherapeutic approaches to various malignant tumours have dramatically improved patient survival and tumour responses. Yet, they may result in a number of severe unwanted effects on various organs including the skin, which in fact makes up 20–30% of these side effects. Induction or exacerbation of psoriasis is frequent among these. Interdisciplinary care is needed to efficiently approach both tumour and organ-related side effects. This complex issue may be intensively discussed within local interdisciplinary clinical boards on chronic inflammatory diseases (ICB) and is addressed with this case report. A 67-year-old patient was diagnosed with multifocal metastasing small cell lung cancer (SCLS) of his left upper lung lobe and osseous, hepatic and soft tissue metastases. Radiochemotherapy was initiated with cumulative doses of 34 Gy and four cycles of carboplatin and etoposide as well as atezolizumab (anti-PD-L1), the latter continued for maintenance therapy. After 2 years of treatment, no pathologic lymphnodes nor organ metastases could be found with residual pneumonic condensation in his right lung. After 1 year of immune checkpoint inhibition (ICI) both psoriasis arthritis and skin psoriasis appeared with an initial PASI of 20 and a DLQI of 15 and above. The appropriate treatment within this tumour context was intensively discussed by the local ICB. Four injections of guselkumab were well tolerated, yet without any clinical effect. After 7 months of distinct improvement of both skin and joint symptoms upon bimekizumab, clinical effects waned and the therapy was changed another time to injections of adalimumab. This was well tolerated with slow improvement of skin and joint symptoms. The tumour parameters remained unchanged over time. This case demonstrates the induction of psoriasis and psoriasis arthritis by ICI, the critical risk-benefit balance of immunomodulation for psoriasis in the context of underlying malignant disease and the clinical benefit of interdisciplinary discussion within a board on chronic inflammatory diseases.

Litigation in Cardiovascular Surgery: Risk Management Considerations in the Italian Context

Background/Objectives: Malpractice in cardiovascular surgery was addressed from the forensic pathology perspective, offering reflections on risk prevention in the Italian context. Litigation and risk management in healthcare, following the Italian law on safety of care, clinical risk management and professional liability, should be viewed in an integrated manner. Methods: We conducted a narrative review on litigation data and the principal areas of complaint in Italy regarding the cardiovascular field. The aim is to discuss human, communicative, organisational, technological and regulatory factors that may play a role in this phenomenon. Results: We discuss the importance of information and consent and the management and monitoring of competences, particularly in specialised activities, given the current human capital deficit. Furthermore, we focus on the centrality of the surgical indication focusing on benefit-risk balance in light of clinical guidelines and team-based evaluation, such as by an emergency heart team, to better tailor care to patients. At the facility level, the minimum volume of activity and the requirements for human resources, specialisations, technologies and organisation standards needed for health activity authorisation are highlighted as foundational to risk prevention. Furthermore, we discussed the availability of the minimum diagnostic and care tools in compliance with guidelines and the role of company clinical and organisational protocols. Conclusions: In the surgical, time-sensitive, highly specialised and technologically advanced sector, the importance of enterprise risk prevention and broad, value-based governance to ensure healthcare quality and safety is emphasised.

Recent and future advances in intracerebral hemorrhage

Spontaneous intracerebral hemorrhage (ICH) is defined by the rupture of a cerebral blood vessel and the entry of blood into the brain parenchyma. With a global incidence of around 3.5 million, ICH accounts for almost 30 % of all new strokes worldwide. It is also the deadliest form of acute stroke and survivors are at risk of poor functional outcome. The pathophysiology of ICH is a dynamic process with key stages occurring at successive times: vessel rupture and initial bleeding; hematoma expansion, mechanical mass effect and secondary brain injury (peri-hematomal edema). While deep perforating vasculopathy and cerebral amyloid angiopathy are responsible for 80 % of ICH, a prompt diagnostic work-up, including advanced imaging is require to exclude a treatable cause. ICH is a neurological emergency and simple therapeutic measures such as blood pressure lowering and anticoagulant reversal should be implemented as early as possible as part of a bundle of care. Although ICH is still devoided of specific treatment, recent advances give hope for a cautious optimism. Therapeutic approaches under the scope are focusing on fighting against hemorrhage expansion, promoting hematoma evacuation by minimally invasive surgery, and reducing secondary brain injury. Among survivors, the global vascular risk is now better established, but optimal secondary prevention is still unclear and is based on an individual benefit-risk balance evaluation.

Safety and effectiveness of lenalidomide in Japanese patients with relapsed/refractory ATLL: post-marketing surveillance

Lenalidomide is an oral immunomodulatory agent approved for the treatment of relapsed/refractory adult T-cell leukemia/lymphoma (ATLL) in Japan. Post-marketing surveillance (PMS) was conducted to confirm its safety and effectiveness. From April 2017 until April 2020, safety data were obtained for 77 patients and effectiveness data for 65 patients (31.2% of patients had progressive disease as the best response to their most recent prior regimen). Forty-nine patients (63.6%) in the safety analysis set experienced an adverse drug reaction (ADR). Grade ≥ 3 ADRs occurred in 42.9%. The most common Grade ≥ 3 ADRs were neutrophil count decreased/neutropenia and platelet count decreased/thrombocytopenia (11.7% each). Serious ADRs occurred in 26 patients. Five patients had previously received allogeneic hematopoietic stem cell transplantation. Among these, one experienced acute graft versus host disease (GvHD) during lenalidomide administration and two responded to lenalidomide. Effectiveness analysis showed that an objective response was achieved in 29.2% of patients. No statistically significant differences were observed in the objective response rates of patients aged < 70 versus those aged ≥ 70 years (33.3% vs 28.0%, respectively; p = 0.6904). No new safety signals were observed in this PMS, and lenalidomide demonstrated a favorable benefit-risk balance in Japanese patients with ATLL.

Baseline Characteristics of Participants in STAREE: A Randomized Trial for Primary Prevention of Cardiovascular Disease Events and Prolongation of Disability-Free Survival in Older People.

The risk-benefit balance of statin use in healthy older people is uncertain. We describe the baseline characteristics of the STAREE (Statins in Reducing Events in the Elderly) trial, which is a randomized, double-blind, placebo-controlled trial among community-dwelling older people; the trial evaluated the effect of atorvastatin 40 mg for the prevention of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke), and on disability-free survival (survival free of both dementia and persistent physical disability). STAREE enrolled people aged ≥70 years from 1583 general practices across Australia with no history of clinical cardiovascular disease, diabetes, or dementia. Baseline data collected included demographic, clinical, cognitive (Modified Mini-Mental State Examination), psychological (Center for Epidemiologic Studies Short Depression Scale), lifestyle, medical, physical, blood and urine measures, and quality of life. Demographic and clinical characteristics of study participants were then compared with publicly available landmark statin trials. A total of 9971 participants were recruited (mean±SD age 74.7±4.5 years, 4023 (40%) ≥75 years, 52% women) between July 2015 and March 2023. The mean low-density lipoprotein cholesterol was 3.27 mmol/L (SD=0.72; 126 mg/dL). Hypertension was reported by 43% of participants and the mean blood pressure was 136/80 mm Hg. Compared with previous landmark statin trials that included primary prevention cohorts, STAREE is unique in including such a large number of older (≥75 years) independent-living people. STAREE is the largest primary prevention trial of statins powered to address the important clinical outcomes of major cardiovascular events, disability-free survival, and cognition in older people. https://www.clinicaltrials.gov; Unique identifier: NCT02099123.

Adjuvant therapy for renal cell carcinoma : Relevant patient and tumor factors

The gold standard in the treatment of localized and locally advanced renal cell carcinoma is surgery. Nevertheless, there is still arisk of tumor relapse. Reducing the risk of recurrence and extending overall survival is the goal of subsequent adjuvant treatment. The aim of this work is to discuss the current and future landscape of adjuvant therapy, taking into account the risk-benefit balance in the individual patient selected for adjuvant treatment. The immune checkpoint inhibitor (CPI) pembrolizumab demonstrated asignificant increase in disease-free and overall survival after surgery for the first time. However, other CPI studies demonstrated no improvement. Patient selection for adjuvant treatment is currently based on the parameters of the TNM system. Prospective biomarkers are currently not available. Here, kidney injury molecule‑1 (KIM-1) represents an initial promising biomarker in the prediction of adjuvant immunotherapy.

Necrosectomy and its timing in relation to clinical outcomes of endoscopic ultrasound-guided treatment of walled-off pancreatic necrosis: a multicenter study

Background and AimsEndoscopic ultrasound (EUS)-guided transmural drainage with on-demand endoscopic necrosectomy (EN) is increasingly utilized to manage walled-off necrosis (WON). It has not been fully elucidated how EN and its timing are correlated with treatment outcomes compared to the drainage-based approach. MethodsWithin a multi-institutional cohort of 423 patients with pancreatic fluid collections including 227 patients with WON, we identified 153 patients who received the step-up treatment following the initial EUS-guided drainage of symptomatic WON, including 102 EN patients and 51 non-EN (drainage) patients. Using the competing-risks multivariable proportional hazards regression model with adjustment for potential confounders, we calculated subdistribution hazard ratios (SHRs) for clinical treatment success (WON resolution) by the use of EN and its timing. ResultsCompared to drainage alone, the EN-based treatment was associated with a shorter time to clinical success with a multivariable SHR of 1.66 (95% confidence interval, 1.12–2.46). Despite a higher risk of procedure-related bleeding in the EN group, there were no differences in the rates of severe adverse events (7.8% vs. 5.9% in the EN and non-EN groups, respectively) and mortality (6.9% vs. 9.8%). In the EN-treated patients, the timing of EN was not statistically significantly associated with the time to clinical success (Ptrend = 0.34) ConclusionAmong patients receiving EUS-guided treatment of symptomatic WON, the use of EN in addition to drainage procedures was associated with earlier disease resolution. Further research is desired to determine the optimal timing of initiating EN considering a risk-benefit balance and cost-effectiveness.

Corticosteroid therapy: a multidisciplinary approach to patient care?

As corticosteroids can cause diabetes, it is important to assess the benefit-risk balance for patients before introducing them, and to monitor the development of hyperglycemia in people treated with this therapeutic class. As soon as cortico-induced diabetes is discovered, multidisciplinary, cross-disciplinary management improves follow-up conditions.

Evolución de la terapia fotodinámica en el manejo de la queratosis actínica ¿qué tan efectiva y segura es según la evidencia actual?

Actinic keratosis is a premalignant dermatological condition characterized by the potential to progress to squamous cell carcinoma. To date, there is no treatment with an adequate benefit-risk balance. Photodynamic therapy is proposed as one of the most effective therapeutic tools. However, there is still divergence regarding the quality of available evidence. The objective of this review is to analyze the most recent evidence on the therapeutic performance of photodynamic therapy in the management of actinic keratosis. A literature search was conducted in the PubMed, Scopus, and MEDLINE databases. Based on the most recent randomized controlled trial comparing the use of dynamic phototherapy combined with aminolevulinic acid without incubation versus incubation for one hour, it was found that the intervention group had a higher percentage of lesion resolution compared to the control group (49.5% vs. 34.9%, p=0.002), as well as less pain in the intervention group (p=0.03). In addition, a similar trend was observed in other studies, suggesting that this therapy could be effective and beneficial in the management of actinic keratosis. Despite the limited and heterogeneous evidence regarding the use of dynamic phototherapy and its various combined regimens for the management of actinic keratosis, there is a clear trend towards potential benefits compared to other therapies.

Femoroacetabular Impingement: A Literature Review

Femoroacetabular impingement (FAI) is a hip condition characterized by abnormal contact between the femoral head and the acetabulum, often leading to joint damage and osteoarthritis. This literature review explores the pathophysiology, diagnosis, and treatment options for FAI, synthesizing current research findings from clinical and biomechanical studies. FAI is classified into two primary types: cam impingement, caused by deformity of the femoral head, and pincer impingement, due to acetabular over-coverage. Mixed types involving both mechanisms are also common. Advancements in imaging modalities, such as MRI and CT, have improved diagnostic accuracy, allowing for earlier detection and better differentiation between types of FAI. Conservative treatment options, including physical therapy and anti-inflammatory medications, are often first-line therapies. However, surgical intervention, particularly arthroscopy, has gained prominence for symptomatic patients, demonstrating favorable outcomes in restoring hip function and delaying the progression of osteoarthritis. Despite the success of surgical interventions, challenges remain in understanding the long-term outcomes, particularly concerning the recurrence of symptoms and the risk of joint degeneration. This review also highlights controversies regarding the optimal management of asymptomatic FAI, as the risk-benefit balance of surgical treatment in such cases remains unclear. Overall, FAI remains a significant clinical issue requiring a multidisciplinary approach to optimize patient outcomes, and further longitudinal studies are necessary to assess the efficacy of treatment strategies over time. Keywords: Femoroacetabular, Impingement, Joint

Efficacy of Thiocolchicoside for Musculoskeletal Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Despite the fact that thiocolchicoside has been widely used in the treatment of musculoskeletal pain, its efficacy has never been systematically evaluated. We carried out a systematic review and meta-analysis of randomized clinical trials (RCTs) to appraise the existing evidence on the efficacy of thiocolchicoside for musculoskeletal pain management. Methods: The literature search was performed on multiple databases, extracting reports of RCTs evaluating the efficacy of thiocolchicoside compared to placebo or no exposure. The reduction in pain intensity was evaluated through between-groups mean differences (MDs) in Visual Analogue Scale (VAS) scores after the intervention. The pooled effect estimates were compared to a minimally important difference (MID) of 1 point on a scale from 0 to 10. Results: We retrieved eight RCTs, including a total of 1397 patients. All the included studies were determined as being at high risk of bias. Seven trials evaluated patients with acute low back pain. After 2-3 days of treatment, the pooled MD in VAS score was -0.49 (95%CI = -0.90; -0.09) compared to controls. After 5-7 days of treatment, the summary MD was -0.82 (95%CI = -1.46; -0.18). Conclusions: Although thiocolchicoside was found to significantly reduce patient-reported low back pain, the clinical impact was very small, as the pooled effect estimates were below the MID, and the overall certainty of evidence was very low. In light of the safety concerns raised by the European Medicine Agency, an in-depth analysis on the risk-benefit balance of thiocolchicoside is required.

Location specific rupture risk of intracranial aneurysms: case of ophthalmic aneurysms

BackgroundAneurysm location is a key element in predicting the rupture risk of an intracranial aneurysm. A common impression suggests that pure ophthalmic aneurysms are under-represented in ruptured intracranial aneurysms (RIAs)....

Public deliberation to assess patient views on biosimilar medication switching for the treatment of inflammatory bowel disease

BackgroundBiosimilars are highly similar, but not identical, versions of originator biologic medications. Switching patients to biosimilars presents an opportunity to mitigate rising drug costs and expand patient access to important biologic therapies. However, decreased patient acceptance and adherence to biosimilar medications have been reported, which can lead to loss of treatment response, adverse reactions, and inefficient resource utilization. Understanding patient perceptions of biosimilars and biosimilar switching is needed to inform patient-centered care strategies that promote efficient resource utilization.MethodsWe used democratic deliberation methods to solicit the informed and considered opinions of patients regarding biosimilar switching. Patients with inflammatory bowel disease (IBD; n = 29) from the Veterans Health Administration (VHA) participated in 5-hour deliberation sessions over two days. Following educational presentations with experts, participants engaged in facilitated small group discussions. Transcripts and facilitators’ notes were used to identify key themes. Participants completed surveys pre- and post-deliberation to collect sociodemographic and clinical features as well as to assess IBD treatment knowledge and attitudes toward care and approaches to biosimilar switching.ResultsFive major themes emerged from the small group discussions in the context of biosimilar switching: 1) concerns about adverse consequences and unclear risk-benefit balance; (2) importance of communication and transparency; (3) desire for shared decision making and patient involvement in treatment decisions; (4) balancing cost-saving with competing priorities; and (5) advocating for individualized care and prioritization based on risk levels. These views led participants to favor approaches that prioritize switching the sickest patients last (i.e., those with poorly controlled disease) and that offer patients control and choices around biosimilar switching. Participants also expressed preferences for combining elements of different approaches to maximize fairness.ConclusionsApproaches to biosimilar switching should consider patients’ desires for transparency and effective communication about biosimilar switching and engagement in their medical decision-making as part of patient-centered care. Incorporating patient preferences around biosimilar switching is critical when navigating the quality and affordability of care in resource constrained settings, both within the VHA and in other healthcare systems.

Post-Vaccine Myocarditis: Clinical Insights and Epidemiological Trends

Myocarditis is a rare but key adverse event linked to mRNA COVID-19 vaccines, predominantly in young males. Epidemiological data indicate an incidence of approximately 12.6 cases per million doses administered to patients aged 12-39 years, mostly following the second dose of the vaccine. Most patients present with elevated levels of cardiac biomarkers, chest pain, and abnormal ECG findings within a few days of vaccination. Proposed mechanisms for the exact pathophysiology of this include molecular mimicry between the SARS-CoV-2 spike protein and cardiac antigens, activation of immune pathways, and dysregulated cytokine expression. Despite these findings, the overall benefit-risk balance for COVID-19 vaccination remains positive, as the majority of patients recover fully. In contrast, COVID-19-associated myocarditis is more common and more severe, with an estimated incidence of 1,000-1,400 cases per 100,000 infections. Clinical presentation of vaccine-associated myocarditis is usually mild and self-limiting, and most patients do recover without significant long-term effects. Treatment is usually supportive in nature and has an emphasis on ruling out acute coronary syndrome and symptomatic management for heart failure or arrhythmias if present. Given its low incidence and the generally good outcome, vaccination against COVID-19 is recommended from 12 years of age and above, with provision for ongoing surveillance for monitoring and management of rare adverse events like myocarditis.

Aging well with diabetes

The care of elderly people with diabetes has become a real public health issue due to the growing number of patients. In these patients, the complications of the pathology are often combined with more particularly gerontological manifestations. It is therefore essential to adapt the therapeutic objectives according to the clinical presentation of each of them. If the new drug classes are promising because they are effective in terms of cardiovascular and renal protection, it is crucial to evaluate their benefit-risk balance for each individual. The quality of care for these elderly patients relies on a well-trained multidisciplinary medical and paramedical team.