Postmarketing data collection and evidence evaluation

AIFA Monitoring Registries (wMRs) constitute a collection of drug registries (product registries) deployed to physicians and pharmacists through a national web platform. They have been adopted in the clinical practice since 2005 and are used to define the population for which the drug is available under the umbrella of the National Health Service (NHS - Servizio Sanitario Nazionale SSN), monitor prescription appropriateness and ensure the rapid access to potentially priority medicines allowing the implementation of patient-based managed entry agreements (MEAs). Each registry consists of specific data entry forms, collecting data at the patient level and filled in by authorized clinicians and pharmacists. The required information includes: 1. Registration form with patient personal data (anonymized after registration);2. Eligibility and clinical data form;3. Prescription and administration forms;4. Evaluation of disease status and treatment update form;and 5. End-of-treatment form. Evaluation and end-of-treatment forms provide main safety and effectiveness data at a patient level. Moreover, since entry forms are the same throughout the nation, this platform allows access to treatment in a homogeneous manner throughout the country. Recently, a new type of registry has been released, with the primary aim of monitoring the pregnancy prevention programme (PPP) following the prescription of potentially teratogenic medicinal products. All this information is collected in a national database that represents a key source of postmarketing evidence that is frequently exploited to answer both administrative and clinical questions, such as drug utilization among a specific pharmacological class or the effectiveness of a drug in a census consisting of all Italian patients treated with that medicinal product. For example, given the prospective nature of the data contained inside the wMRs, AIFA together with members of the relevant scientific associations were able to evaluate the effect of the COVID- 19 pandemic and lockdown measures on the new prescription (i.e. first prescription) of some cardiovascular drugs in Italy and suggest new studies to analyse the occurrence of new cardiovascular- related events resulting from the decline in the activation of these treatments. Equally important is the work assessing the effectiveness of tyrosine kinase inhibitors in chronic myeloid leukaemia (CML) patients in Italian clinical practice, which was able to highlight important aspects on both expected mortality and consequential use in first and second line TKIs in Italy. Finally, the wMRs were also a critical instrument in the management of the COVID-19 medicinal products since 29 October 2020, providing essential evidence on drug availability through the country, predicting possible shortages and publishing hundreds of freely available reports on the utilization trend of COVID-19 drugs in the different Italian Regions. In conclusion, the wMRs represent a key tool to generate pharmaco-epidemiological evidences in the Real-world setting and monitoring drug appropriateness for expensive, innovative drug.

Multicenter post-marketing clinical evaluation on the clinical performance of the five domestic fast nucleic acid detection reagents for 2019-nCoV.

Objective This multicenter clinical evaluation analyzed the clinical performance of five fast nucleic acid detection systems for 2019-nCoV. Methods Clinical performance of the five fast nucleic acid detection reagents approved in China was evaluated in the present study. Fifty-seven throat swabs samples from COVID-19 patients and fifteen throat swabs samples from healthy people were collected from the First Affiliated Hospital of Zhejiang University school of Medicine, Tongji Hospital of Tongji Medical College of HUST, and National Institute of Viral Disease Control and Prevention of CDC to evaluate the positive coincidence rate, negative coincidence rate, total coincidence rate, the detection time and retest rate as well as the relation between positive intensity and positive coincidence rate of the five fast nucleic acid detection systems in November 2020. Results The positive coincidence rates of the five kits were 92.59% (50/54), 83.64% (46/55), 98.25% (56/57), 94.44% (51/54) and 98.18% (54/55);and the negative coincidence rates were 93.33% (14/15), 93.33% (14/15), 86.67% (13/15), 100% (14/14) and 93.33% (14/15);and the total coincidence rates were 92.75% (64/69), 85.71% (60/70), 95.83% (69/72), 94.20% (65/69) and 97.14% (68/70), respectively. The positive coincidence rate of the five kits reached 100% for the strong-positive (90/90) and medium-positive samples (84/84), but only 82.18% (83/101) for weak-positive samples (cycle threshold value>33), and the retest rate of two kits were 15.28% (11/72) and 12.50% (9/72), which were both higher than 10%. Total time from sample extraction to amplification was between 32.33-65.33 minutes for these five kits. Conclusion The five fast nucleic acid detection reagents have good performance and can be used as a supplement to routine nucleic acid detection reagents.Copyright © 2022 Chinese Journal of Laboratory Medicine. All rights reserved.

34th Annual Meeting of the Japanese Society for Neuroimmunology (JSNI)

The proceedings contain 14 papers. The topics discussed include: MOG-positive anti-NMDA receptor encephalitis with no demyelinating lesions: two case reports;safety and tolerability of rozanolixizumab in the randomized phase 3 MycarinG study;Outcomes from RAISE: A randomized, phase 3 trial of zilucoplan in generalized myasthenia gravis;efficacy and safety of zilucoplan in myasthenia gravis: responder analysis from the randomized Phase 3 RAISE trial;distinct effects among calcium-binding proteins for microglia to produce chemokines associated with the clinical severity of ALS;astroglial connexin 43 is a novel therapeutic target for a chronic multiple sclerosis model;targeting lymphocytes in SPMS: Th cell populations as a biomarker to predict the efficacy of Siponimod;CSF lysophospholipids as a novel biomarker in relapsing-remitting multiple sclerosis;the immune response to SARS-COV-2 MRNA vaccines in siponimod-treated patients with secondary progressive multiple sclerosis;patient characteristics of siponimod-treated SPMS patients in Japan: interim results from post-marketing surveillance;and efficacy of ravulizumab across sex and age subgroups of patients with generalized myasthenia gravis: a post hoc analysis of the CHAMPION MG study.

Structure of Adverse Events Following Immunisation against Coronavirus Infection (COVID-19) in the Kyrgyz Republic.

There is considerable interest worldwide in developing safe and effective vaccines against COVID-19. Pharmacovigilance of adverse events following immunisation (AEFIs) is a key to making informed decisions regarding the global COVID-19 vaccination campaign. In the Kyrgyz Republic, there have been developed a national immunisation information system (IIS) for automated recording of vaccines, vaccinated persons, and AEFIs and a mobile application for AEFI reporting, called Den Sooluk. The aim of the study was to analyse the pattern of AEFIs against COVID-19 in the Kyrgyz Republic. Material(s) and Method(s): the study analysed the spontaneous safety reports submitted to the national IIS database through the Den Sooluk mobile application from 29.03.2021 to 25.09.2022. Result(s): according to the data available by 25.09.2022, the total number of vaccinated people in the country amounted to 2,940,082. At the time, the IIS database included 2111 AEFIs: 1 fatal (and coincidental), 3 severe and 2108 minor ones. AEFIs were more frequent in the young and middle-aged population (81.5%), than in the elderly (18.5%). The following AEFIs were reported: injection site pain (21.25%), fatigue (20.7%), headache (19.8%), body temperature above 38 C (10.10%), miscellaneous symptoms (5.12%), chills (4.41%), dizziness (4.32%), sore throat (3.36%), myalgia (2.9%), and nausea (2.2%). Conclusion(s): all COVID-19 vaccines used in the Kyrgyz Republic can be considered adequately safe. Pharmacovigilance of AEFIs is an integral part of the requirements to ensure the safe use of vaccines, and collecting of spontaneous reports on AEFIs supports adequate functioning of the post-marketing surveillance system. It is essential to provide access to electronic information platforms to health professionals and patients in order to ensure vaccination transparency and coordination and enable quick and safe reporting of AEFIs associated with the use of COVID-19 vaccines.Copyright © NEICON ISP LLC. All rights reserved.

Safety monitoring of COVID-19 therapy and vaccines

Since late 2019, the pandemic of COVID-19, caused by SARS-CoV-2, has resulted in high morbidity and mortality worldwide. During 2020, safety monitoring of medicinal treatments for this novel disease was performed by Uppsala Monitoring Centre (UMC) in VigiBase, WHO's global database of suspected adverse drug reactions, which is the largest international repository of reported ADRs. Initially, COVID-19 treatments included numerous repurposed medicines previously approved for other indications, such as chloroquine and hydroxychloroquine. Although chloroquine is a widely used drug which has been on the market for a very long time, the efficacy and safety profile have not been thoroughly studied in COVID-19 patients. In early 2020, chloroquine and hydroxychloroquine were authorized by major regulatory agencies for emergency use, or only for use within clinical trials. Given the interest over the use of these drugs in COVID-19, the ADR reports in VigiBase for them were summarized and communicated to reiterate their toxicities, in particular the cardiac reactions which may result in fatal outcomes.1 Remdesivir, the first novel antiviral drug authorized for use in treatment for COVID-19, was the most commonly reported COVID-19 medicine within VigiBase during 2020. Employing indication- focused descriptive statistics (disproportionality analysis), together with the use of a comparator tocilizumab with a known safety profile, it was possible to identify known safety information for both remdesivir and tocilizumab and suggest potential safety concerns for remdesivir. The most reported adverse events were liver dysfunction, kidney injury, death and bradycardia.2 In late 2020, several new vaccines for COVID-19 were developed, received emergency authorization and rolled out on a large scale. The vaccines used novel technology and a rapid and vast deployment was anticipated. For this scale of activity, a well-functioning international postmarketing safety surveillance system is essential. The unprecedented volume of reports of suspected adverse events following immunization has led to the development of new routines and the use of new tools at UMC, for example, a digital reporting form designed for mobile devices was implemented;more frequent updates of VigiBase data allowed timely data analyses;a COVID-19 vaccine-specific standardized drug grouping (SDG) was created enabling the data analysis on a vaccine platform level;and a monthly descriptive report regarding COVID-19 vaccine reporting in VigiBase was made available for member countries of the WHO Programme for International Drug Monitoring (PIDM).3 UMC regularly screened VigiBase for previously unknown or incompletely documented COVID- 19 vaccines adverse reactions. These signals were shared with all WHO PIDM members to complement their signal detection and support local action to protect patients from harm. Some signals were also published outside the WHO PIDM to raise awareness or encourage data collection.4,5 In summary, successful adaptations were made at UMC in a short period to handle the COVID- 19 pandemic situation. However, the pandemic has not ended yet and further challenges are anticipated. The safety monitoring of COVID- 19 therapies and vaccines still needs to continue.

Multicenter post-marketing clinical evaluation on the clinical performance of the five domestic fast nucleic acid detection reagents for 2019-nCoV

Objective This multicenter clinical evaluation analyzed the clinical performance of five fast nucleic acid detection systems for 2019-nCoV. Methods Clinical performance of the five fast nucleic acid detection reagents approved in China was evaluated in the present study. Fifty-seven throat swabs samples from COVID-19 patients and fifteen throat swabs samples from healthy people were collected from the First Affiliated Hospital of Zhejiang University school of Medicine, Tongji Hospital of Tongji Medical College of HUST, and National Institute of Viral Disease Control and Prevention of CDC to evaluate the positive coincidence rate, negative coincidence rate, total coincidence rate, the detection time and retest rate as well as the relation between positive intensity and positive coincidence rate of the five fast nucleic acid detection systems in November 2020. Results The positive coincidence rates of the five kits were 92.59% (50/54), 83.64% (46/55), 98.25% (56/57), 94.44% (51/54) and 98.18% (54/55);and the negative coincidence rates were 93.33% (14/15), 93.33% (14/15), 86.67% (13/15), 100% (14/14) and 93.33% (14/15);and the total coincidence rates were 92.75% (64/69), 85.71% (60/70), 95.83% (69/72), 94.20% (65/69) and 97.14% (68/70), respectively. The positive coincidence rate of the five kits reached 100% for the strong-positive (90/90) and medium-positive samples (84/84), but only 82.18% (83/101) for weak-positive samples (cycle threshold value>33), and the retest rate of two kits were 15.28% (11/72) and 12.50% (9/72), which were both higher than 10%. Total time from sample extraction to amplification was between 32.33-65.33 minutes for these five kits. Conclusion The five fast nucleic acid detection reagents have good performance and can be used as a supplement to routine nucleic acid detection reagents.

Structure of Adverse Events Following Immunisation against Coronavirus Infection (COVID-19) in the Kyrgyz Republic

There is considerable interest worldwide in developing safe and effective vaccines against COVID-19. Pharmacovigilance of adverse events following immunisation (AEFIs) is a key to making informed decisions regarding the global COVID-19 vaccination campaign. In the Kyrgyz Republic, there have been developed a national immunisation information system (IIS) for automated recording of vaccines, vaccinated persons, and AEFIs and a mobile application for AEFI reporting, called Den Sooluk. The aim of the study was to analyse the pattern of AEFIs against COVID-19 in the Kyrgyz Republic. Materials and methods: the study analysed the spontaneous safety reports submitted to the national IIS database through the Den Sooluk mobile application from 29.03.2021 to 25.09.2022. Results: according to the data available by 25.09.2022, the total number of vaccinated people in the country amounted to 2,940,082. At the time, the IIS database included 2111 AEFIs: 1 fatal (and coincidental), 3 severe and 2108 minor ones. AEFIs were more frequent in the young and middle-aged population (81.5%), than in the elderly (18.5%). The following AEFIs were reported: injection site pain (21.25%), fatigue (20.7%), headache (19.8%), body temperature above 38 ºC (10.10%), miscellaneous symptoms (5.12%), chills (4.41%), dizziness (4.32%), sore throat (3.36%), myalgia (2.9%), and nausea (2.2%). Conclusions: all COVID-19 vaccines used in the Kyrgyz Republic can be considered adequately safe. Pharmacovigilance of AEFIs is an integral part of the requirements to ensure the safe use of vaccines, and collecting of spontaneous reports on AEFIs supports adequate functioning of the post-marketing surveillance system. It is essential to provide access to electronic information platforms to health professionals and patients in order to ensure vaccination transparency and coordination and enable quick and safe reporting of AEFIs associated with the use of COVID-19 vaccines.

DRUG-INDUCED PNEUMONITIS IN THE SETTING OF SARS-COV-2 INFECTION

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Interstitial pneumonitis (ILD) is inflammation of lung interstitium leading to scarring and pulmonary fibrosis. Various etiologies include idiopathic, connective tissue disorders, sarcoidosis and drug induced1. Many chemotherapy agents have been implicated in drug related ILD such as bleomycin, taxanes. However, newer chemotherapeutic drugs such as molecular agents such as anti-VEGF, anti-EGFR (panitumumab) could be causative of drug induced ILD. CASE PRESENTATION: A 75-year-old female with stage IV sigmoid colon cancer treated with surgery, adjuvant FOLFOX chemotherapy and Panitumumab. She presented to the emergency department with shortness of breath and hypoxia after known COVID-19 exposure. Initial imaging with chest radiography showed bilateral ground glass opacities. A chest CT pulmonary embolism protocol was negative for pulmonary embolism but showed bilateral ground glass opacities (GGOs) and some interstitial thickening (L>R) not typical of COVID-19 infection. She was treated with remdesivir and dexamethasone, however her oxygen requirements continued to rapidly escalate. A repeat CT chest without contrast showed bilateral asymmetric interstitial thickening and GGOs. Given persistence of CT chest abnormalities, workup for interstitial lung disease was initiated. The results include ANA titer 1:80, otherwise negative ANCA profile, rheumatoid factor, anti-CCP, Scl-70, Sjogren antibodies. Given clinical history and imaging findings, diagnosis of ILD was suspected, and she was started on solumedrol 1 mg/kg. Her oxygen requirements decreased significantly over the next 2 days, and she was discharged home on oral steroid taper and pneumocystis pneumonia prophylaxis. DISCUSSION: Panitumumab is a fully humanized monoclonal antibody against EGFR. Approved by the US Food and Drug Administration in 2006 for advanced or recurrent colorectal cancer exhibiting wild-type KRAS mutation.2 ILD is rarely reported with panitumumab monotherapy, but higher incidence when used as a combination treatment such as with FOLFOX or FOLFIRI. A Japanese post-marketing surveillance study from 2010-2015 showed an ILD incidence of 1.3% but mortality rates of 51.3%.2 EGFR is expressed on basal cells and non-cilia cells of the bronchioles and type II cells of the alveolus. EGFR mediated mechanisms are important in tissue repair.3 Therefore inhibition of this pathway has been postulated to play a role in development of ILD. Another mechanism was decreased surfactant production by type II cells in pre-clinical study.4,5 ILD secondary to Panitumumab can occur at any point during therapy and up to 1 year after administration of drug.6 The role of infectious processes, in this case, COVID-19 pneumonia, could synergistically worsen ILD presentation. CONCLUSIONS: Although the incidence of ILD is low, the mortality rate is high, therefore early recognition and treatment is associated with improved clinical outcomes. Reference #1: Mudawi D, Heyes K, Hastings R, Rivera-Ortega P, Chaudhuri N. An update on interstitial lung disease. Br J Hosp Med (Lond). Jul 2 2021;82(7):1-14. Reference #2: Osawa M, Kudoh S, Sakai F, et al. Clinical features and risk factors of panitumumab-induced interstitial lung disease: a postmarketing all-case surveillance study. Int J Clin Oncol. Dec 2015;20(6):1063-1071. Reference #3: The FASEB Journal - 2000 - Puddicombe - Involvement of the epidermal growth factor receptor in epithelial repair in asthma.pdf. DISCLOSURES: No relevant relationships by Navitha Ramesh No relevant relationships by Uba Udeh

SEVERE HYPONATREMIA AS A MANIFESTATION OF A NEUROLOGIC DISORDER ASSOCIATED WITH THE COVID-19 VACCINE

SESSION TITLE: Issues After COVID-19 Vaccination Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: More reports are indicating a temporal association between Bell's palsy and the mRNA vaccine for coronavirus disease 2019 (COVID-19). Therefore, collecting vaccine history is becoming important in post-marketing surveillance to monitor the safety of vaccines in real-world settings. We report the case of concomitant occurrence of Bell's palsy and glossopharyngeal neuralgia leading to severe symptomatic hyponatremia in a previously healthy patient. CASE PRESENTATION: A 60 year-old-female without significant medical history presented to the hospital with odynophagia, and generalized weakness for two weeks. She decreased her oral intake due to stabbing pain in the back of her throat triggered by swallowing. She reported hyperacusis and frequent shooting pain in the left cheek managed with non-steroidal anti-inflammatory drugs. The symptoms occurred several days after the first dose of the mRNA vaccine for COVID-19. She denied previous COVID-19 infection and herpes zoster. Examination revealed dry mucosa, left facial muscle weakness, inability to raise the left eyebrow or lift the labial commissure, effacement of the nasolabial fold, and left-sided frontal wrinkles. Laboratory investigation revealed sodium of 110. Computerized Tomography of the brain revealed negative findings for intracranial abnormalities. Severe symptomatic hyponatremia was managed with hypertonic saline. The neurologist made the diagnosis of Bell's palsy and glossopharyngeal trigeminal neuralgia leading to poor oral intake. We initiated acyclovir, prednisone, and gabapentin. The patient recovered from hyponatremia and experienced improvement of neurological symptoms with initiated medications. DISCUSSION: High morbidity and mortality of patients with COVID-19 accelerated the development and production of the vaccines. During the pandemic, mRNA COVID-19 vaccines reduced asymptomatic and prevented severe symptomatic COVID-19 infection and its complications. Although the benefits and protective effects of the COVID-19 vaccines outweighed the risks associated with them, we have reports of associations between vaccines and certain disorders such as Bell's palsy. Glossopharyngeal neuralgia is defined as sudden severe brief pain in the distribution of the glossopharyngeal nerve. It can be described as transient stabbing pain experienced in the ear, tonsillar fossa, and base of the tongue. Unusual presentation is fear to eat as this can be a precipitating cause of the pain. It overlaps with trigeminal neuralgia and can create a diagnostic dilemma. CONCLUSIONS: In summary, it is unknown what causal relationship exists between the mRNA COVID-19 vaccine and neurological diseases such as Bell's palsy and glossopharyngeal neuralgia. Glossopharyngeal neuralgia is frequently overlooked as a diagnosis. This is a unique case of concomitant glossopharyngeal neuralgia and Bell's palsy that is coincidental with a history of COVID-19 vaccine. Reference #1: El Sahly HM, Baden LR, Essink B, et al. Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase. New England Journal of Medicine. 2021;385(19):1774-1785. doi:10.1056/NEJMoa2113017 Reference #2: Singh PM, Kaur M, Trikha A. An uncommonly common: Is glossopharyngeal neuralgia. Ann Indian Acad Neurol. 2013;16(1):1-8. doi:10.4103/0972-2327.107662 Reference #3: Cellina M, D'Arrigo A, Floridi C, Oliva G, Carrafiello G. Left Bell's palsy following the first dose of mRNA-1273 SARS-CoV-2 vaccine: A case report. Clin Imaging. 2022;82:1-4. doi:10.1016/j.clinimag.2021.10.010 DISCLOSURES: No relevant relationships by Nemanja Draguljevic No relevant relationships by Katherine Hodgin No relevant relationships by Kristina Menchaca No relevant relationships by Catherine Ostos Perez

DISSEMINATED HERPES ZOSTER VIRUS INFECTION FOLLOWING BARICITINIB IN COVID-19

SESSION TITLE: COVID-19 Co-Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Baricitinib with Remdesivir has been Food and Drug Administration (FDA) approved for hospitalized COVID-19 pneumonia patients requiring supplemental oxygen and is used across the United States. However, limited post-marketing surveillance data is currently available for these drugs. We present a case of an unvaccinated, immunocompetent patient with Herpes-Zoster virus (HZV) infection following baricitinib administration. CASE PRESENTATION: A 66-year-old African-American male with unknown vaccination status for Herpes zoster presented with worsening shortness of breath for 1 week. He had an SpO2 85% on presentation however had to be subsequently intubated due to worsening hypoxia in the ER. Cardiorespiratory exam was remarkable for diminished bibasilar breath sounds. Lab work was significant for positive COVID-19, elevated leukocytes and deranged inflammatory markers. CT chest showed bilateral ground glass opacities. He received a 14 day course of baricitinib, 10 days of dexamethasone and 5 days of remdesivir during his hospital stay. Tracheostomy and percutaneous endoscopic gastrostomy were performed due to prolonged vent dependence. On day 37 of hospitalization, the patient developed vesicular rashes over his left shoulder and anterior chest. Disseminated HZV infection was confirmed based on serologic testing. Patient received 7 days of valacyclovir with complete resolution. He was eventually discharged to a pulmonary rehabilitation center. DISCUSSION: Baricitinib was first developed for patients with rheumatoid arthritis and has been used in the treatment of rheumatoid arthritis and acts by reversible inhibition of JAK1 and JAK2. These proteins have been implicated in COVID-19 pathophysiology;promoting intracellular assembly of SARS-CoV-2 and subsequent cytokine release. Baricitinib in COVID-19 leads to the inhibition of proinflammatory cytokine release, antibody production, monocyte activation and viral proliferation. [1] There have been several studies published in support of Baricitinib induced HZV infection in rheumatoid arthritis patients, however there is little data available in COVID patients. Nonetheless, immunomodulatory action is the same. A study comparing the incidence rate (IR) of Baricitinib emergent HZV infection per 100 patient years (PY) vs placebo found IR/100PY 4.3 (p<_0.01) vs 3.1 (p not significant) [2]. Another study found the HZV IR vs placebo of 4.3 vs 1.0, with all-bari-RA IR was 3.2 (95% CI 2.8-3.7) [3]. In our case, the patient developed HZV infection after baricitinib treatment, demonstrating its immunomodulatory effects. CONCLUSIONS: This case demonstrates the ability of baricitinib to cause immunosuppression and hence causing HZV infection in COVID-19 affected patients. Reference #1: Schwartz DM, Bonelli M, Gadina M, O'shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12(1):25. Reference #2: Kevin L, Masayoshi H, Mark C et al. Infections in baricitinib clinical trials for patients with active rheumatoid arthritis. Ann Rheum Dis.2020 Oct;79(10):1290-1297. Reference #3: Joseph S, Mark C, Tsutomu T et al. Safety profile of Baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. The Journal of Rheumatology January 2019, 46 (1) 7-18;DOI: https://doi.org/10.3899/jrheum.171361 DISCLOSURES: No relevant relationships by Mark Aloysius No relevant relationships by Gursharan Kaur No relevant relationships by Mohammed Musa Najmuddin No relevant relationships by mashu shrivastava

Development of vaccines and vaccines for pandemic threats (in particular for COVID19)

Vaccines, currently used for prophylactic purposes, prevent more than three million deaths every year from diseases like diphtheria, pertussis, tetanus, poliomyelitis, measles and influenza. The general six stages of the development of a new vaccine are: i) Exploratory stage;ii) Pre-clinical stage;iii) Clinical development;iv) Regulatory review and approval;v) Manufacturing;vi) Quality control. Clinical development is a three/four-phase process. During Phase I, small groups of people receive the trial vaccine. In Phase II, the clinical study is expanded. In Phase III, the vaccine is given to thousands of people and tested for efficacy and safety. Many vaccines undergo Phase IV formal, ongoing studies after the vaccine is approved and licensed. Phase IV studies, also referred to as postmarketing surveillance studies (PMS). These processes are very similar to drug developments. However, there are several differences compared to drug development, namely: i) unlike drugs, which are given to patients, vaccines are received by healthy individuals, thus the safety margin should be very high;ii) as vaccines have to be stored under refrigeration, there are always logistical challenges during clinical trials;iii) Adjuvants are incorporated into vaccine formulations to modulate and improve the immune response (antigen/adjuvant formulation are important aspects of clinical development);iv) The immune response primarily measured during early stages of vaccine development (Phase I/II) should evaluate: Humoral/ cell-mediated/ cross-reactive antibodies or immune complexes/ immune landscape. A challenge in responding to pandemic diseases is that vaccines may not exist for them. For newly emerging threats without licensed vaccines, such as SARS, MERS, Marburg virus, Nipah virus, SARS CoV-2 and the like, the time required to develop and produce a safe, effective vaccine is unknown and would depend on the nature of the threat and the state of current vaccine research for that threat. In almost all cases, several months would be needed to respond with the first doses of vaccines. Unfortunately, six month later than WHO declared the public health emergency of international concern (27/01/2020) there are five important questions, essential for vaccine development that remain open for scientists, namely: 1) Why do people respond so differently to infection? 2)Has the virus developed any worrying mutations? 3)How well will a vaccine work? 4)Can we develop immunity and if so, how long does it last? 5)What is the origin of the virus? Until a safe, effective vaccine was ready, other public health and medical measures (social distancing, quarantine, and aspecific medications) would need to be employed to try to limit disease spread.

Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): A new safety concern

Introduction: In recent clinical trials some cardiac arrhythmias were reported with use of remdesivir for COVID-19. To address this safety concern, we investigated whether use of remdesivir for COVID-19 is associated with an increased risk of bradycardia. Material and methods: Using VigiBase®, the World Health Organization Global Individual Case Safety Reports database, we compared the cases of bradycardia reported in COVID-19 patients exposed to remdesivir with those reported in COVID-19 patients exposed to hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. All reports of patients with COVID-19 registered up to the 23 September 2020 were included. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% CI. Results: We found 302 cardiac effects including 94 bradycardia (31%) among the 2603 reports with remdesivir prescribed in COVID-19 patients. Most of the 94 reports were serious (75, 80%), and in 16 reports (17%) evolution was fatal. Compared with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids, the use of remdesivir was associated with an increased risk of reporting bradycardia (ROR 1.65;95% CI 1.23-2.22). Consistent results were observed in other sensitivity analyses. Discussion/Conclusion: This post-marketing study in a real-world setting suggests that the use of remdesivir is significantly associated with an increased risk of reporting bradycardia and serious bradycardia when compared with the use of with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. This result is in line with the pharmacodynamic properties of remdesivir.

Dysgeusia and Appetite Loss: Thinking Beyond MDD and COVID-19

Background: Dysgeusia is a distortion of taste sensation. Etiologies can include medications and Covid-19, among others. Dysgeusia may lead to appetite loss which is nonspecific and can have multiple causes, including major depressive disorder (MDD) (Coulter, 1988). Although post-marketing data revealed no association between nifedipine and dysgeusia (Ackerman, 1997), case reports of dysgeusia from nifedipine exist (Ackerman, 1997). We present a case of nifedipine-induced dysgeusia mistaken for depression. Case Report: A 42-year-old man with hypertension and diabetes was admitted to the hospital following right thalamocapsular and intraventricular hemorrhages. Hypertension was managed with metoprolol, lisinopril, nifedipine, and chlorthalidone. Levetiracetam was started for seizure prophylaxis. Medications included pantoprazole, simethicone, transdermal lidocaine, insulin, metformin, docusate, senna, and subcutaneous heparin. Psychiatric consultation was requested out of concern that appetite loss indicated depression. The day before psychiatric evaluation, mirtazapine 15 mg at bedtime for mood and appetite was started. Nifedipine 90 mg daily had been started 9 days prior to his first complaint of decreased appetite. The patient reported feeling disconnected from his family and “sad" for ∼10 years, complaining that family members “talk behind his back.” He was otherwise without paranoia. He denied insomnia, anhedonia, hopelessness, poor concentration, suicidal ideation, homicidal ideation, guilt, mania, or hallucinations. He reported poor appetite due to epigastric discomfort and bad taste to foods. Covid-19 testing was not yet widely available. No other signs or symptoms suggestive of Covid-19 were present. Although alert and fully oriented, concentration was impaired with sometimes tangential thought processes. Affect was full without depression. A diagnosis of adjustment disorder was made. The psychiatry team suspected nifedipine-induced dysgeusia and advised discontinuing nifedipine. Appetite improved two days later. Discussion: This case highlights the importance of considering alternative causes of nonspecific symptoms of depression, including decreased appetite, that may have non-psychiatric causes. Dysgeusia is widely recognized as a symptom of Covid-19. Other causes, including medications may be underrecognized and amenable to intervention. Conclusion: It would be helpful to consider medication side-effects as potential causes for taste distortion alongside psychiatric diagnoses, and COVID-19. References: 1. Coulter DM: Eye pain with nifedipine and disturbance of taste with captopril: a mutually controlled study showing a method of post marketing surveillance BMJ 1988;296: 1086–8. 2. Ackerman BH, Kasbekar N: Disturbances of taste and smell induced by drugs. Pharmacotherapy 1997;17(3):482-96.

A Comprehensive Review on Efficacy and Adverse Events Associated With Different Covid-19 Vaccines

To combat COVID-19, various health agencies around the world gave emergency approval for vaccines. Therefore, the long-term protective effect and the potential adverse effects of the vaccines on immunocompromised patients, pregnant women and geriatrics might not be well-established. The aim of this review was to assess the safety and efficacy of a number of the most commonly approved vaccines all over the world. A review was made to identify clinical trials that studied the vaccines’ efficacy and case reports of potential suspected vaccine-related adverse events. The electronic databases searched to identify relevant studies were Science Direct, PubMed/Medline, Scopus and MedRxiv. Seven randomized controlled trials which assessed the efficacy of COVID-19 vaccines and case reports which reported the vaccines’ adverse events were included in the review. The efficacy of the vaccines was found to be 94.6% for Pfizer vaccine, 94.1% for Moderna vaccine, 66.1% for Johnson and Johnson’s, 76.4% for Covishield, 91.6% for Sputnik, and 77.8% for Covaxin. No severe adverse events were reported in the studies. All the reported adverse events were mild, self-sustaining and did not require any medical intervention. All the COVID-19 vaccines demonstrated promising immunogenicity profile, different degrees of protective effectiveness and a tolerable safety profile. However, further research to evaluate the efficacy and safety in vulnerable populations including immunocompromised patients, pregnant women and geriatric populations are needed. The long term post marketing surveillance becomes a very important part of identifying the efficacy and side effects among different populations.

Analysis of Medical Device Reports Involving Ventilator-Related Incidents in a Clinical Setting: Insights and Lessons Learned

Continuous ventilators are a critical resource for the treatment and management of respiratory diseases, particularly in the midst of the COVID-19 pandemic. Healthcare technology management professionals (HTMs) are instrumental toward protecting the safety of patients by ensuring that ventilators and ventilator accessories (ventilator-related medical devices) remain functional during their lifetime. This article discusses a retrospective analysis on the failure modes described in ventilator-related medical device reports that were submitted to the US Food and Drug Administration Medical Product Safety Network (MedSun). In addition, the article also examines MedSun case studies, obtained from medical device reports, to provide HTMs with a comprehensive analysis of the lifecycle of a safety signal and how their input is essential to improve the safety and effectiveness of medical devices. Postmarket medical device surveillance in a constantly changing medical device ecosystem benefits from the first-hand knowledge that HTMs contribute to the cross-functional collaboration between the clinical community, medical device manufacturers, and the US Food and Drug Administration.

H2C2 (HOME HOSPITAL AND CRITICAL CARE) - A 2.5 YEAR EXPERIENCE USING A NEW MODEL OF HOSPITAL AT HOME: DEVELOPMENT AND IMPLEMENTATION

Background: The CMS Hospital at Home (H@H) program during the COVID 19 pandemic was successfully applied as a suitable alternative to unnecessary admissions in lower risk patient populations. As the top 5% pts ($50,000/Year) account for 50% of the US healthcare expenditure over 15 years (5:50 Rule), we sought to investigate the long-term clinical and financial effectiveness and sustainability of new model of home hospital and critical care (H2C2) on the top 5% patients. Methods: 68 consecutive pts with top 5% annual cost profile (~4 admissions/pt with severe chronic dx [CHF, CAD, CODP, sepsis] +/-ventilator, PEG, dialysis, LifeVest) were enrolled in a multiple MSO program. On-site & On-line care started 3/2019 via patented processes and individualized protocols/devices (24/7 monitoring + ICU level Telemetry, 12-lead ECG). All Medicare Part A, B & D costs, admissions and LOS for pts were computed and normalized per phase (PRIOR, DURING, POST H2C2) to determine effectiveness and sustainability. Results: Of the 68 patients, 90% discharged to PCP, 6% admitted to hospice and 4% remained on the program for continuous care. There were no deaths at home. Compared to baseline, H2C2 had an over 70% sustained total cost reduction. Conclusion: This is 1st study to assess long-term clinical & financial impacts of H2C2 in top 5% of high-risk/cost pts. H2C2 was safe with a significantly sustained reduction of admissions and costs both during and 1.5 years post H2C2. Further studies are warranted for scalability. [Formula presented]

5th European Pharmacovigilance Congress

The proceedings contain 26 papers. The topics discussed include: updates from the UMC: new organization, roles and opportunities;updates from the pharmaceutical information and pharmacovigilance association (PIPA);strategies to improve signal detection: quality of information and causality assessment;signal detection in post-marketing studies in the older patient population: the role of machine learning;what is the most appropriate signal management system for a company and its products?;global drug safety: the role of the UMC in times of the COVID-19 vaccines;communicating vaccine safety in the age of COVID-19;and the growing area of telehealth and pharmacovigilance.

WORLDWIDE POST-MARKETING SAFETY SURVEILLANCE EXPERIENCE WITH TOFACITINIB IN ULCERATIVE COLITIS

Background: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. First market authorization was received in the US in May 2018. Post-marketing surveillance (PMS) is an important part of monitoring adverse events (AEs). Here, we report an analysis of PMS case safety reports for tofacitinib in patients with UC.Methods: We analyzed the worldwide tofacitinib PMS reports received in the Pfizer safety database from May 30, 2018 to August 25, 2020. The type and estimated reporting rate (RR) of serious AEs (SAEs) of interest, incl. infection, vascular, respiratory, neoplasm, and cardiac events, were reviewed. Patient-years of exposure (PY) was estimated based on worldwide sales data and the calculated daily regimens of tofacitinib 5 or 10 mg twice daily, immediate or extended-release formulations.Results: During the 27-month reporting period, worldwide post-marketing exposure to tofacitinib was 8,916 PY. Overall, 4,226 case reports were received and included 12,103 AEs, of which 1,839 were SAEs. Among the cases reported, 1,141 (27.0%) included an SAE and 18 (0.4%) were fatal. Of cases with reported gender (88.1%) or age (81.6%), 46.5%occurred in men and the median age was 45 years (range 9–93). When analyzed by tofacitinib formulation, proportions of SAE cases were similar (Table 1). Table 2 presents a summary of AEs and SAEs by MedDRA system organ class. Among the 1,839 SAEs, RRs per 100 PY were 3.28 for infection events, 1.26 for vascular events, 0.74 for respiratory events, 0.55 for neoplasm events, and 0.50 for cardiac events. The most commonly reported serious infection events (MedDRA preferred term [PT] n≥8) were 2 PTs within the high level term (HLT) of Clostridia infections (C. difficile colitis/infection), pneumonia, COVID-19, cytomegalovirus, and herpes zoster. The most commonly reported serious vascular events (n≥10) included hemorrhage, thrombosis, and deep vein thrombosis. Most serious respiratory events were pulmonary embolism. The most commonly reported serious neoplasm events (n≥3) were 2 PTs within the HLT of breast and nipple neoplasms malignant (breast cancer female/breast cancer), colon cancer, lymphoma, malignant melanoma, neoplasm malignant, and prostate cancer. The most commonly reported serious cardiac events (n≥4) were 3 PTs within the HLT of ischemic coronary artery disorders (acute myocardial infarction/myocardial infarction, angina pectoris) and pericarditis.Conclusion: Based on this review of PMS data for tofacitinib in UC, the types of AEs and RRs were consistent with the known tofacitinib safety profile, with no new potential risks identified. Limitations of PMS reports, low numbers of case reports for extended-release formulation, and reliance on estimated RRs due to lack of precise values for exposure, required for incidence rate calculation, should be considered when interpreting these results.(Table Presented)(Table Presented)