Safety Profile Of Drugs Research Articles

КАРЦИНОМА ИЗ КЛЕТОК МЕРКЕЛЯ: СОВРЕМЕННЫЕ ТЕНДЕНЦИИ ВРАЧЕБНОЙ ПРАКТИКИ

Merkel cell carcinoma (CM) is a rare but very dangerous (rapidly progressive) malignancy. The need for early detection of CM determines the importance and relevance of informing dermatologists, cosmetologists, doctors of other specialties about the current aspects of the diagnosis and treatment of this disease, despite its relatively rare occurrence. The review highlights modern approaches to the diagnosis and treatment of CM. Early treatment of CM is vital because the disease progresses extremely rapidly with the formation of distant metastases. For the treatment of CM at localized stages, positive results in terms of prognosis in patients are brought by the use of the standard of combined treatment: surgery with adjuvant radiation therapy. A good alternative is also to use of RT only. Effective therapy for late variants of CM includes the appointment of immune response checkpoint inhibitors. Immunotherapy provides a sustained response in a significant proportion of patients with metastatic or recurrent disease. However, in the population of elderly and debilitated patients, the use of immunotherapy is limited due to the development of adverse events. The tasks of determining the optimal therapy regimens with the best efficacy and drug safety profiles have been included in the programs for further clinical research and development.

JAK inhibitors for the treatment of inflammatory bowel disease: results of an international survey of perceptions, attitudes, and clinical practice.

Janus kinase inhibitors (JAKi) are small molecule drugs with demonstrated efficacy in inflammatory bowel disease (IBD). However, widespread utilisation may be hindered by safety concerns. This is the first study assessing risk-benefit perceptions and clinical practices of those using JAKi for IBD. A prospective, cross-sectional study was conducted using a 23-item survey distributed to IBD healthcare providers worldwide. Of 385 respondents from 48 countries, 72% were tertiary-centre based and 50% were gastroenterologists with ≥10 years experience. JAKi were commonly used outside market authorisation (31%), though many (17%) were unconfident discussing JAKi risk-benefit profile and 7% had never prescribed JAKi. If venous thromboembolism risks were present, 15% preferentially referred for surgery than initiate JAKi; 21% would do this even if the patient was already anticoagulated. For patients relapsing on dose reduction, 8% would switch treatment rather than dose escalate. Conversely, 45% felt that cardiovascular safety concerns from post-marketing studies were irrelevant to IBD. Despite the lack of detailed, long-term safety data, safety profiles of JAK1-selective drugs were perceived to be favourable to tofacitinib by most (62%). The study indicates that while clinical practice appears to be in keeping with international guidance, a significant minority remain deterred by safety concerns.

Using Reference Reagents to Confirm Robustness of Cytokine Release Assays for the Prediction of Monoclonal Antibody Safety.

New immunostimulatory antibody drugs designed to either directly stimulate specific immune cells or indirectly enhance the immune response by blocking or activating an endogenous regulator of the immune system have the potential to cause serious immune-related adverse events such as cytokine release syndrome (CRS). It is, therefore crucial to assess the safety profile of such drugs with a combination of in vivo and in vitro experiments before first-in-human dose administration. Cytokine release assays (CRAs), where the proposed antibody therapeutic is co-cultured with human immune cells (such as peripheral blood mononuclear cells (PBMCs), whole blood, or otherwise) and the amount of inflammatory cytokine produced is measured, are critical for hazard identification. However, different labs using different control antibodies can threaten the harmonization of CRAs, and clinically relevant controls (such as TGN1412) can be difficult to source, which can lead to less accurate or reliable results or data which are difficult to compare between laboratories. The inclusion of positive and negative controls in a CRA can ensure the accuracy and reliability of the results. The National Institute for Biological Standards and Control (NIBSC) has produced a panel of lyophilized antibody controls intended for use in various CRA platforms to harmonize results across various laboratories and assay methods. A set of three different positive control antibodies include anti-CD52, anti-CD3, and anti-CD28 superagonist (SA), which are known to induce dose-dependent CRS in patients. Each antibody is provided with an isotype-matched negative control antibody. This panel of reference reagents has previously been shown to have good inter-lab reproducibility and are suitable controls to increase the confidence and robustness of safety data from a variety of CRA platforms.

Safety assessment of fluorescently labeled anti-EGFR Nanobodies in healthy dogs.

Introduction: Surgical resection is one of the main treatment options for several types of cancer, the desired outcome being complete removal of the primary tumor and its local metastases. Any malignant tissue that remains after surgery may lead to relapsing disease, negatively impacting the patient's quality of life and overall survival. Fluorescence imaging in surgical oncology aims to facilitate full resection of solid tumors through the visualization of malignant tissue during surgery, following the administration of a fluorescent contrast agent. An important class of targeting molecules are Nanobodies® (Nbs), small antigen-binding fragments derived from camelid heavy chain only antibodies. When coupled with a fluorophore, Nbs can bind to a specific receptor and demarcate tumor margins through a fluorescence camera, improving the accuracy of surgical intervention. A widely investigated target for fluorescence-guided surgery is the epidermal growth factor receptor (EGFR), which is overexpressed in several types of tumors. Promising results with the fluorescently labeled anti-EGFR Nb 7D12-s775z in murine models motivated a project employing the compound in a pioneering study in dogs with spontaneous cancer. Methods: To determine the safety profile of the study drug, three healthy purpose-bred dogs received an intravenous injection of the tracer at 5.83, 11.66, and 19.47 mg/m2, separated by a 14-day wash-out period. Physical examination and fluorescence imaging were performed at established time points, and the animals were closely monitored between doses. Blood and urine values were analyzed pre- and 24 h post administration. Results: No adverse effects were observed, and blood and urine values stayed within the reference range. Images of the oral mucosa, acquired with a fluorescence imaging device (Fluobeam®), suggest rapid clearance, which was in accordance with previous in vivo studies. Discussion: These are the first results to indicate that 7D12-s775z is well tolerated in dogs and paves the way to conduct clinical trials in canine patients with EGFR-overexpressing spontaneous tumors.

The rapidly evolving landscape of HCC: Selecting the optimal systemic therapy.

Over the past years, there has been a remarkable advance in the systemic treatment options for advanced HCC. The overall survival has gradually increased over time, with larger benefits for patients with sensitive tumors and preserved liver function, the latter being an essential condition for the delivery of sequential lines of treatment and optimization of clinical outcomes. With the approval of new first-line agents and the introduction of immune checkpoint inhibitor-based therapies, the treatment landscape of advanced HCC is becoming wider than ever. Atezolizumab plus bevacizumab and, more recently, durvalumab plus tremelimumab have entered the clinical practice and are the current standard of care for treatment-naïve patients, surpassing sorafenib and lenvatinib monopoly. As no head-to-head comparisons are available among all the first-line treatment options, the recommendation for the most appropriate choice and sequence is patient-driven and integrates efficacy data with clinical comorbidities, background liver disease, and the safety profile of available drugs. In addition, predictive biomarkers for successful patients' stratification are yet to be available and constitute the focus of ongoing research. The treatment algorithm is likely to become even more complex since systemic therapeutic approaches are now being translated into earlier stages of the disease, with an impact on the evolution of the sequential treatment of patients with HCC.

Bifidobacterium longum 68S mediated gut-skin axis homeostasis improved skin barrier damage in aging mice

BackgroundBifidobacterium as probiotics, play important roles in skin status, while the potential mechanisms interaction remains unknown. The study further explored the potential mechanism of B. longum 68S in ameliorating skin barrier damage from the perspective of the gut-skin axis in aging mice. MethodsB. longum 68S supplied natural aging mouse model and fecal microbiota transplantation (FMT) experiment proves the key role of intestinal microbiota in B. longum 68S up-regulating the production of ceramide synthesis key enzyme (SPT1) and ceramide level and improving skin barrier damage. Moreover, B. longum 68S supplied SPT1 gene deletion mouse model to investigate the mechanism of B. longum 68S on improving skin barrier damage. ResultsTranscriptome analysis and 16S rRNA high-throughput pyrosequencing demonstrated that aging mice exhibited skin barrier dysfunction and intestinal dysbiosis. Meanwhile, aging mice exhibited an up-regulation in the trans epidermal water loss (TEWL) and a down-regulation in the level of SPT1, ceramide and skin barrier-related proteins (Loricrin, Keratin 10 and Desmoglein 1). Similarity, the FMT from aging mice to normal mice and SPT1 gene deletion mice could rebuild skin barrier damage and B. longum 68S supplementation exerted a positive effect on it. Further, B. longum 68S-mediated SPT1-derived ceramide production prevented impaired ceramide synthesis-induced endoplasmic reticulum stress and apoptotic response, ultimately improving skin barrier damage in vitro. ConclusionEmerging anti-aging therapies are necessary given the poor safety profiles of current pharmaceutical drugs. B. longum 68S may be better alternatives, considering the association between the gut microbiota and healthy aging. The findings suggested that B. longum 68S-mediated gut-skin axis homeostasis, thereby exhibiting an anti-aging effect and facilitate a better understanding of the mechanisms governing the various beneficial effects of B. longum 68S.

Application of artificial intelligence and machine learning in early detection of adverse drug reactions (ADRs) and drug-induced toxicity

Adverse drug reactions (ADRs) and drug-induced toxicity are major challenges in drug discovery, threatening patient safety and dramatically increasing healthcare expenditures. Since ADRs and toxicity are not as visible as infectious diseases, the potential consequences are considerable. Early detection of ADRs and drug-induced toxicity is an essential indicator of a drug's viability and safety profile. The introduction of artificial intelligence (AI) and machine learning (ML) approaches has resulted in a paradigm shift in the field of early ADR and toxicity detection. The application of these modern computational methods allows for the rapid, thorough, and precise prediction of probable ADRs and toxicity even before the drug’s practical synthesis as well as preclinical and clinical trials, resulting in more efficient and safer medications with a lesser chance of drug’s withdrawal. This present review offers an in-depth examination of the role of AI and ML in the early detection of ADRs and toxicity, incorporating a wide range of methodologies ranging from data mining to deep learning followed by a list of important databases, modeling algorithms, and software that could be used in modeling and predicting a series of ADRs and toxicity. This review also provides a complete reference to what has been performed and what might be accomplished in the field of AI and ML-based early identification of ADRs and drug-induced toxicity. By shedding light on the capabilities of these technologies, it highlights their enormous potential for revolutionizing drug discovery and improving patient safety.

The modern aspects of the optimal therapeutic strategy of hyperemesis gravidarum

Although, nausea and vomiting in early pregnancy is very common, affecting approximately 80% of pregnancies, hyperemesis gravidarum (HG) is a severe form that complicates up to 2.2% of pregnancies. HG is one of the most common indications for hospitalization during pregnancy. In addition to the insufficient nutrition both for the mother and fetus, the severity of HG symptoms causes a serious psychosocial stress, which leads to depression, anxiety and even the development of perinatal pathology. The aim of this meta-analysis was to study available randomized controlled trials about therapeutic strategies by HG, their evaluation based on both subjective and objective measures of efficacy, maternal and fetal/neonatal safety, and economic costs.A systematic data search was conducted using the databases MEDLINE, ISI Web of Science, PubMed, Scopus, Google Scholar, Cochrane Database of Systematic Reviews and publications in professional editions of Ukraine for 2013–2023. The search was conducted using the following keywords: pregnancy, nausea and vomiting of pregnant women, excessive vomiting of pregnancy, hyperemesis, antiemetic therapy during pregnancy, infusion therapy and the safety profile of medications prescribed during pregnancy in various combinations.The main outcome was: the effectiveness of therapeutic strategies (reduction or stopping nausea/vomiting); detailing by safety profile of antiemetic drugs; optimization of infusion therapy; additional clinical strategies that help to improve the quality of care for pregnant women; adverse effects and side effects of drugs for HG for the mother/fetus/newborn.The results presented in this meta-analysis can be used in the creation of a national clinical guideline, protocol, consensus or clinical recommendations regarding the clinical management of hyperemesis gravidarum.

DHA/EPA (Omega-3) and LA/GLA (Omega-6) as Bioactive Molecules in Neurodegenerative Diseases

Neurodegenerative diseases are characterized by neuroinflammation, neuronal depletion and oxidative stress. They coincide with subtle chronic or flaring inflammation, sometimes escalating with infiltrations of the immune system cells in the inflamed parts causing mild to severe or even lethal damage. Thus, neurodegenerative diseases show all features of autoimmune diseases. Prevalence of neurodegenerative diseases has dramatically increased in recent decades and unfortunately, the therapeutic efficacy and safety profile of available drugs is moderate. The beneficial effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) polyunsaturated fatty acids (omega-3 PUFAs) are nowadays highlighted by a plethora of studies. They play a role in suppression of inflammation, gene expression, cellular membrane fluidity/permeability, immune functionality and intracellular/exocellular signaling. The role of omega-6 polyunsaturated fatty acids, such as linoleic acid (LA), gamma linolenic acid (GLA), and arachidonic acid (AA), on neuroprotection is controversial, as some of these agents, specifically AA, are proinflammatory, whilst current data suggest that they may have neuroprotective properties as well. This review provides an overview of the existing recent clinical studies with respect to the role of omega-3 and omega-6 PUFAs as therapeutic agents in chronic, inflammatory, autoimmune neurodegenerative diseases as well as the dosages and the period used for testing.

Improving the Accuracy of Biologic Drug Survival Data: The Increasing Prevalence of Off-Label Dosing Must Be Considered when Reporting Drug Effectiveness and Safety

Improving the Accuracy of Biologic Drug Survival Data: The Increasing Prevalence of Off-Label Dosing Must Be Considered when Reporting Drug Effectiveness and Safety

Uncovering Knowledge Gaps in the Safety Profile of Antiangiogenic Drugs in Cancer Patients: Insights from Spontaneous Reporting Systems Studies.

Global repositories of postmarketing safety reports improve understanding of real-life drug toxicities, often not observed in clinical trials. The aim of this scoping review was to map the evidence from spontaneous reporting systems studies (SRSs) of antiangiogenic drugs (AADs) in cancer patients and highlight if the found disproportionality signals of adverse events (AEs) were validated and thus mentioned in the respective Summary of product Characteristics (SmPC). This scoping review was conducted according to PRISMA guidelines for scoping reviews. A knowledge gap on the safety of AADs was found: firstly, several cardiovascular AEs were not mentioned in the SmPCs and no pharmacovigilance studies were conducted despite the well-known safety concerns about these drugs on the cardiovascular system. Second, a disproportionality signal (not validated through causality assessment) of pericardial disease was found in the literature for axitinib with no mention in SmPC of the drug. Despite the exclusion of pharmacoepidemiological studies, we believe that this scoping review, which focuses on an entire class of drugs, could be considered as a novel approach to highlight possible safety concerns of drugs and as a guide for the conduction of a target postmarketing surveillance on AADs.

Are enrollment criteria for phase II and III clinical trials in acute myeloid leukemia arbitrarily restrictive?

6525 Background: Ethical clinical research requires fair subject selection and a favorable risk-benefit ratio. Enrollment criteria can unfairly exclude patients if they are not based in safety. There are few data regarding variability within criteria, which can also represent unfair exclusion, or for acute myeloid leukemia (AML). Methods: We assessed enrollment criteria use and variability for frontline phase II and III therapeutic AML trials from 2010-2019 listed on Clinicaltrials.gov. Drug safety profiles were obtained from protocols, publications, and FDA labels. FDA publications guided a standardized abstraction and coding process. Associations between criteria and safety profiles were identified using X2 and t-tests. Regression modeling identified differences in infectious disease (ID) exclusion by sponsor adjusted for trial phase, year, size, and safety profiles. Results: 190 trials were eligible; 159 (84%) were phase II and 32 (17%) phase III. Trials were sponsored by the National Institutes of Health (NIH; 50; 26%), industry (109; 57%), and academic investigators (AI; 108; 57%). Exclusions and variability are shown in the table. ID exclusions were for HIV (96; 51%) and hepatitis B (60; 32%) and C (64; 34%). Older adults were considered as over 60 (42 trials; 39%), 65 (23; 21%), 70 (13; 12%), or 75 years (18; 17%). There was no association between QTc limits and the use of QTc prolonging drugs (criteria presence p=0.2; mean 450 vs 474 ms, p=0.3) or renal function limits and nephrotoxic drugs (presence p=0.2; mean 1.65 vs 1.67 ULN, p=0.8). Hepatitis B and C exclusions were associated with the use of drugs linked to viral reactivation (OR 2.1 [95% CI 1.1,3.9], 2.0 [95% CI 1.1,3.7]). This was not the case for HIV (OR 1.2 [95% CI 0.7,2.2]). Industry sponsorship was independently associated with hepatitis B and C exclusion (OR 3.0 [95% CI 1.2,7.3], 3.3 [95% CI 1.4,4.7]) and AI sponsorship with HIV exclusion (OR 2.5 [95% CI 1.4,5.5]). Conclusions: There is substantial variability in enrollment criteria for AML clinical trials. Many criteria are related to risks, but some exclusions and variability are not clearly based in safety. Avoiding arbitrary exclusions will likely enhance trial representativeness and enrollment rates. [Table: see text]

The Prevalence and Features of Medications With Actionable Pharmacogenomic Biomarkers Prescribed to Kidney Transplant Recipients

Genetic variants are associated with pharmacokinetic and pharmacodynamic changes, leading to variability in drug effects and safety profiles in the clinical response. The role of genetic variants in kidney transplant recipients (KTRs) has not been extensively studied. Here, we explored the potential of incorporating pharmacogenomic (PGx) gene biomarkers into prescription practices for KTRs. This study analyzed 490 KTRs participating in the Taiwan Precision Medicine Initiative program and used medications with actionable PGx biomarkers. The analysis included prescriptions issued between January 2000 and December 2021 with 206 CPIC-recommended level A or B gene-drug pairs, encompassing 363 single or combination drug products. All KTRs had the potential to receive at least one prescription that could be adjusted based on their genetic profiles after the day of surgery. The top 5 medications prescribed within the first 3 months after transplantation were mycophenolic acid, tacrolimus, pantoprazole, labetalol, and tramadol. These findings highlight the significant potential of PGx-guided prescriptions for KTRs. Additionally, some drug-gene pairs, such as tramadol/CYP2D6, pantoprazole/CYP2C19, and atorvastatin/SLCO1B1, were considered high-quality evidence by the Clinical Pharmacogenetics Implementation Consortium and were included in the Food and Drug Administration's drug labels, indicating that they have the potential for clinical application. Overall, this study demonstrated the potential of incorporating PGx gene biomarkers into prescribing practices for KTRs, which could improve personalized pharmacotherapy for these patients.

Рациональная фармакотерапия артериальной гипертензии в реальной клинической практике: диуретики сквозь призму лекарственной безопасности

The use of diuretics in arterial hypertension is pathogenetically justified, which is due to the significant role of an increase in the volume of circulating blood and the retention of sodium ions in the internal environment of the body, in increasing blood pressure. In clinical guidelines, the choice of a diuretic for the treatment of hypertension is limited to 3 drugs: hydrochlorothiazide, chlorthalidone and indapamide. Thiazide and thiazide-like diuretics are often combined into a single group of "thiazides", however, they have significant differences in the mechanism of their action, clinical effects, drug safety profile, partly in the parameters of the effectiveness of blood pressure control, as well as the evidence base in randomized clinical trials. In the first part of the review, along with evidence of the effectiveness of the use of diuretics in arterial hypertension, various aspects of the drug safety of drugs in this group are considered, both possible metabolic disorders and more rare, but possible disorders of the organ of vision, skin adverse reactions and the risk of acute respiratory distress. -syndrome. The second part of the review considers the efficacy and safety of the thiazide-like diuretic indapamide.

SARS-CoV-2 infection dysregulates the expression of clinically relevant drug metabolizing enzymes in Vero E6 cells and membrane transporters in human lung tissues.

SARS-CoV-2-mediated interactions with drug metabolizing enzymes and membrane transporters (DMETs) in different tissues, especially lung, the main affected organ may limit the clinical efficacy and safety profile of promising COVID-19 drugs. Herein, we investigated whether SARS-CoV-2 infection could dysregulate the expression of 25 clinically relevant DMETs in Vero E6 cells and postmortem lung tissues from COVID-19 patients. Also, we assessed the role of 2 inflammatory and 4 regulatory proteins in modulating the dysregulation of DMETs in human lung tissues. We showed for the first time that SARS-CoV-2 infection dysregulates CYP3A4 and UGT1A1 at the mRNA level, as well as P-gp and MRP1 at the protein level, in Vero E6 cells and postmortem human lung tissues, respectively. We observed that at the cellular level, DMETs could potentially be dysregulated by SARS-CoV-2-associated inflammatory response and lung injury. We uncovered the pulmonary cellular localization of CYP1A2, CYP2C8, CYP2C9, and CYP2D6, as well as ENT1 and ENT2 in human lung tissues, and observed that the presence of inflammatory cells is the major driving force for the discrepancy in the localization of DMETs between COVID-19 and control human lung tissues. Because alveolar epithelial cells and lymphocytes are both sites of SARS-CoV-2 infection and localization of DMETs, we recommend further investigation of the pulmonary pharmacokinetic profile of current COVID-19 drug dosing regimen to improve clinical outcomes.

Assay development considerations to improve drug tolerance in direct competitive ligand binding neutralizing antibody assays, pretreatment strategies

Neutralizing anti-drug antibodies (ADAs) may affect safety, efficacy, and pharmacokinetic profile of a biotherapeutic drug and thus their assessment is of particular importance during immunogenicity testing. Neutralizing antibody (NAb) assays typically rely on NAbs ability to block the drug-target interaction. Higher NAb concentration and/or higher binding affinity of NAb to the drug, lowers the drug-target binding interaction. However, in the presence of high concentrations of residual circulating drug, as often seen for drugs with longer half-lives or in repeat-dose studies, NAbs may exist as drug bound complexes. In direct NAb assay formats, the NAb-drug complexes present in the sample could result in the NAb being unable to block the drug-target interaction eventually leading to a false negative response. The residual free circulating drug present in the sample may bind to the target in the NAb assay thereby competing with the drug used in the assay and inhibiting the assay signal, leading to a false positive response. For traditional ADA assays, multiple approaches involving acid treatment have been described to mitigate circulating drug interference issue. Here, we report two acid-treatment approaches that utilize the Dynabeads extraction with acid dissociation and Affinity Capture Elution (ACE) principle to improve drug tolerance in NAb assays.

Safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of subcutaneous and intravenous ALXN1720 in healthy volunteers: a phase 1, randomized, double-blind, placebocontrolled, single and multiple ascending dose study (P1-5.016)

<h3>Objective:</h3> To report the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of subcutaneous (SC) ALXN1720 in healthy volunteers (HVs) (NCT04920370). <h3>Background:</h3> ALXN1720, a novel 28 kD bispecific variable domain on a heavy chain (VHH) antibody, binds complement component 5 (C5), inhibiting its cleavage into C5a and C5b. ALXN1720 also binds to albumin, which extends its half-life. The low molecular weight of ALXN1720 enables SC injection, designed for self-administration. <h3>Design/Methods:</h3> HVs aged 18–45 years were recruited into 12 cohorts at a single site in the UK. In each cohort, participants were randomized (3:1) to receive ALXN1720 or placebo. HVs received either SC ALXN1720 as a single dose (30–1700 mg), multiple doses (100 or 300 mg) once weekly for three weeks, or a single dose of IV ALXN1720 (300 mg). One cohort received SC 900 mg loading dose then 600 mg maintenance doses once weekly for seven weeks. Primary objective was the evaluation of ALXN1720’s safety and tolerability in healthy adults. <h3>Results:</h3> The study enrolled 97 HVs. ALXN1720 was well tolerated with no serious adverse events (SAEs) reported. All AEs were mild in severity. Dose proportionality was concluded across the range of single doses. ALXN1720 serum exposure increased dose dependently over 3 weekly doses of 100 mg and 300 mg. Single doses ≥100 mg and extended multiple dosing achieved complete terminal complement inhibition (serum free C5 &lt; 0.5 ug/mL). Low-titer, treatment-emergent (TE)-anti-drug antibodies were observed in 12% (9/73) of participants who received ALXN1720 SC. There was no indication that TE-anti-drug antibodies had any impact on drug concentration (PK) or safety profiles. Mean absolute bioavailability of SC ALXN1720 was 96%. <h3>Conclusions:</h3> Healthy adults tolerated ALXN1720 well. ALXN1720 exposure was dose-proportional and was associated with corresponding decreases in serum free C5 concentrations. Immunogenicity was low. <b>Disclosure:</b> Dr. Ortiz has received personal compensation for serving as an employee of Alexion/AstraZeneca Rare Disease. Dr. Ortiz has stock in Alexion. Dr. McEneny has received personal compensation for serving as an employee of Alexion Pharmaceuticals Inc.. Dr. McEneny has stock in Alexion Pharmaceuticals. Dr. Amancha has nothing to disclose. Mrs. Rice has received personal compensation for serving as an employee of AstraZeneca. Mrs. Rice has stock in AstraZeneca. Dr. Scholz has received personal compensation for serving as an employee of Alexion AstraZeneca Rare Disease. Dr. Scholz has stock in Alexion AstraZeneca Rare Disease. Dr. Scholz has stock in Biogen. Dr. Rakhade has received personal compensation for serving as an employee of Alexion Pharmaceuticals . Dr. Rakhade has stock in Alexion Pharmaceuticals. Dr. Rakhade has stock in Astra Zeneca. Dr. Rakhade has received intellectual property interests from a discovery or technology relating to health care. Dr. Yee has nothing to disclose.

Definition and rationale for placebo composition: Cross-sectional analysis of randomized trials and protocols published in high-impact medical journals.

Inadequate description of trial interventions in publications has been repeatedly reported, a problem that extends to the description of placebo controls. Without describing placebo contents, it cannot be assumed that a placebo is inert. Pharmacologically active placebos complicate accurate estimation and interpretation of efficacy and safety data. In this study, we sought to assess whether placebo contents are described in study protocols and publications of trials published in high-impact medical journals. We identified all placebo-controlled randomized clinical trials (RCTs) published in 2016 in Annals of Internal Medicine, The BMJ, the Journal of the American Medical Association (JAMA), The Lancet, and the New England Journal of Medicine (NEJM). We included all trials with publicly available study protocols. From journal publications and associated study protocols, we searched and recorded: description of placebo contents; the amount of each placebo ingredient; and investigators' stated rationale for selection of placebo ingredients. We included 113 placebo-controlled RCTs. Of the 113 trials, placebo content was described in 22 (19.5%) journal publications and 51 (45.1%) study protocols. The amount of each placebo ingredient was described in 15 (13.3%) journal publications and 47 (41.6%) study protocols. None of the journal publications explained the rationale for the choice of placebo ingredients, whereas a rationale was provided in 4 (3.5%) study protocols. The stated rationales were to ensure the placebo was visually indistinguishable from the experimental intervention (N = 3) and ensure comparability with a previous study (N = 1). There is no accessible record of the composition of placebos for approximately half of high-impact RCTs, even with access to study protocols. This impedes reproducibility and raises unanswerable questions about what effects-beneficial or harmful-the placebo may have had on trial participants, potentially confounding an accurate assessment of the experimental intervention's safety and efficacy. Considering that study protocols are unabridged, detailed documents describing the trial design and methodology, the fact that less than half of the study protocols described the placebo contents raises concerns about clinical trial transparency. To improve the reproducibility and potential of placebo-controlled RCTs to provide reliable evidence on the efficacy and safety profile of drugs and other experimental interventions, more detail regarding placebo contents must be included in trial documents.

Safety Surveillance During Drug Development: Comparative Evaluation of Existing Regulations.

Drug safety monitoring is essential for developing efficient and safe treatments. It starts with preclinical toxicology studies and continues with the observation and analysis of potentially harmful effects in humans throughout the whole drug life cycle. Safety surveillance during the clinical phase is of paramount importance for protecting the health of clinical trial (CT) participants at a period when relatively little is known about the drug safety profile, and for reassuring that detected risks are minimized when the product obtains marketing approval. This review aimed to investigate current safety surveillance methods during drug development worldwide, in order to identify potential gaps and opportunities for amelioration. To this end, international guidelines, standards, and local legislations about CTs were reviewed and compared. Our review revealed common strategies, mainly in alignment with international guidelines, especially concerning the systematic collection, assessment, and expedition of adverse events by investigators and sponsors and the preparation of periodic aggregate safety reports by sponsors, as a means to inform health authorities (HAs) about the evolving benefit-risk balance of the investigational product. Inconsistencies in safety surveillance mainly concerned local expedited reporting requirements. Significant gaps were identified in the methodologies for aggregate analyses and the responsibilities of HAs. Addressing the regulatory discrepancies and harmonizing the safety surveillance processes at a global level would increase the usability of safety data accumulated by clinical studies worldwide, thus enabling and hopefully accelerating the development of safe and efficient drug therapies.

Nirmatrelvir/ritonavir (Paxlovid®): French pharmacovigilance survey 2022

Nirmatrelvir/ritonavir (Paxlovid®) is currently one of the few therapeutic options for coronavirus disease 2019 (COVID-19) curative treatment in non-oxygen-requiring adult patients at-high risk of progressing to severe disease. This recently approved boosted antiviral therapy presents a significant risk of drug-drug interactions (DDI). As part of the enhanced surveillance program in France for COVID-19 drugs and vaccines, the French national pharmacovigilance database (BNPV [base nationale de pharmacovigilance]) was queried in order to better characterize the drug safety profile, with a special focus on DDI. The aim of the study was to describe the adverse drug reactions reported through the BNPV. All nirmatrelvir/ritonavir reports validated in the BNPV from the first authorization in France (January, 20th 2022) to December, 3rd 2022 (date of the query) were considered. An analysis of the scientific literature (PubMed®) and from the WHO pharmacovigilance database (Vigibase) was also performed. Over this period (11 months), 228 reports (40% of serious reports) were registered with a sex ratio of 1.9 female/1 male and a mean age of 66 years old. DDI reports account for more than 13% of reports (n=30) and were mainly related to immunosuppressive drugs overexposure (n=16). A total of 10/228 reports with fatal outcomes were reported in complex clinical settings. The main reported unexpected adverse drug reaction (ADRs) were high blood pressure (n=7), confusion (n=5), acute kidney injuries (AKI, n=7) and various skin reactions (n=22). Apart from situations of disease recurrence (not found in this analysis), data from Pubmed® and Vigibase also reported the above-mentioned events of interest. Overall, this analysis shows that nirmatrelvir/ritonavir safety profile was conform to current summary of product characteristics (SmPC). The main concern was the risk of DDI. Therefore, SmPC and expert recommendations should be systematically consulted before initiation of this antiviral, which is particularly indicated in polypharmacy patients. A case-by-case multidisciplinary approach including a clinical pharmacologist is required in these complex situations. Blood pressure elevation, confusion, cutaneous reactions and AKIs were the main unexpected ADRs of interest to follow, but need to be confirmed with a qualitative approach over time and new reports.