Reporting of COVID-19 Reinfection and Potential Role of Immunosuppressant/Immunomodulating Agents: A Cross-Sectional Observational Analysis Based on a Spontaneous Reporting Database.

BACKGROUND: The enduring presence of COVID-19 and subsequent increasing incidence of COVID-19 reinfection has prompted evaluation of associated risk factors, particularly the role of immunosuppression. OBJECTIVE: The objective of this study was to characterize cases indicative of COVID-19 reinfection with respect to their reported use of immunosuppressant/immunomodulating agents. METHODS: This cross-sectional observational study leveraged the Pfizer global safety database (SDB) containing adverse event data collected in association with use of Pfizer products between 1 October 2019, and 30 June 2022. Selected Medical Dictionary for Drug Regulatory Activities (MedDRA®) Preferred Terms were used to identify COVID-19 cases; the search was further refined to comprise cases that subsequently reported events potentially indicative of COVID-19 reinfection. RESULTS: Of the cumulative total of 218,242 COVID-19 cases reported into the SDB, 4590 cases (2.1%) involving potential COVID-19 reinfection were identified. Of these 4590 cases of potential Covid-19 reinfection, a total of 134 cases reported COVID-19 specifically during treatment with pharmaceutical products, of which approximately 16% (21/134) of cases reported use of immunosuppressant/immunomodulating agents. Likewise, in the overall dataset (213,652 cases; excluding the 4590 cases involving potential COVID-19 recurrence), the percentage of reported immunosuppressant/immunomodulating agents was low (12%). In applying similar parameters to a dataset that excludes COVID-19 vaccine cases, 18% of cases reported use of immunosuppressant/immunomodulating agents (similar to the aforementioned 16% of cases reported from the overall total dataset that was inclusive of vaccine cases). CONCLUSION: This pharmacovigilance study provides a characterization of cases indicative of COVID-19 reinfection with respect to reported use of immunosuppressant/immunomodulating agents. The observations generated from this cross-sectional observational analysis may prompt further research into the role of immunosuppression in COVID-19 reinfection, in an effort to better inform clinical practice and patient management.

Effects of the COVID-19 Pandemic on Pharmacovigilance Strategy, Systems, and Processes of Large, Medium, and Small Companies: An Industry Survey.

PURPOSE: The COVID-19 pandemic poses an unprecedented threat to global business relationships and dynamics. The pharmacovigilance function of pharmaceutical companies is particularly susceptible to changing external pressures because of its highly structured compliance activities. We conducted an industry-wide survey to provide insights on how the pharmacovigilance function responded to the challenges posed by the pandemic. We compared smaller companies and larger companies regarding impact on portfolios and operational activity metrics. METHODS: We conducted a survey through the Navitas Life Science annual benchmark of pvnetTM, a network of large enterprise (LE) companies, and pvconnectTM, a network of small and medium enterprise (SME) companies, using an online surveying tool during the first quarter of 2021. We collected information on pharmacovigilance activities, including quantitative measures of workload, costs, and key performance indicators, and qualitative data on the effects of the pandemic on product portfolios and operations. FINDINGS: Survey questions were posed to LE (pvnet) network members (n = 12) and SME (pvconnect) network members (n = 18) for the period from January 1 through December 31, 2020. The date of data collection was March 26, 2021. Descriptive median values of parameter metrics included the following: revenue ($28.4 billion for LE companies and $1.6 billion for SME companies), number of products (127 for LE companies and 19 for SME companies), and volume of individual case safety reports (391,000 for LE companies and 13,000 for SME companies). SME companies reported a greater impact on 2 survey categories, remote working and employee well-being, than did LE companies. However, LE companies reported a greater impact than did SME companies on all other survey categories: effect on strategic priorities, shift in product focus, workload changes, changes in sourcing model, effect on case reporting compliance, effect on business continuity, changes in pharmacovigilance technology strategy, impact of interactions with health authorities, effect on resource capacity, and impact on recruitment. IMPLICATIONS: Four major themes emerge from this survey: (1) shift to remote working, (2) recognition of the impact on employee well-being, (3) shift in strategic priorities, and (4) newly recognized aspects of risk mitigation. The COVID-19 pandemic has had a marked effect on every aspect of pharmaceutical companies' pharmacovigilance functions, although the effects appear to be different for LE companies than for SME companies.

Global Safety Database Summary of COVID-19-Related Drug Utilization-Safety Surveillance: A Sponsor's Perspective.

INTRODUCTION: Evidence-based clinical data on coronavirus disease 2019 (COVID-19) pharmacotherapies are scarce. OBJECTIVE: This study documented and characterized COVID-19 cases reported in individuals receiving treatment with Pfizer pharmaceutical products and cases that reported use of Pfizer pharmaceutical products for COVID-19 treatment. METHODS: This retrospective observational review leveraged the Pfizer safety database containing adverse event data collected in association with use of Pfizer products between 1 October, 2019, and 25 June, 2020; the database includes worldwide adverse event data from various sources. Selected Medical Dictionary for Drug Regulatory Activities (MedDRA®) Preferred Terms and subsequent clinical review were used to characterize COVID-19 cases. RESULTS: Over 1500 relevant cases were identified over an 8-month period. In cases that reported COVID-19, immunosuppressant/immunomodulating agents, followed by anticoagulant/antithrombic agents and corticosteroids, were the most frequently reported agents. The frequent reporting of immunosuppressant/immunomodulating agents among cases of COVID-19 suggests increased vulnerability to infection among treated patients, either because of immunosuppressive effects of certain agents or the nature of the underlying treated condition. In cases involving off-label pharmacotherapy use for the treatment of COVID-19-related conditions, the most frequently reported therapeutic classes included antibiotics, antimalarial agents, antivirals/antiretroviral agents, immunosuppressant/immunomodulating agents, corticosteroids, anticoagulants, and immunoglobulin/interferons. The most frequently reported pharmacotherapeutic agents were azithromycin and chloroquine/hydroxychloroquine, followed by lopinavir-ritonavir, ceftriaxone, and tofacitinib. The most frequently reported clinical adverse events associated with azithromycin (as sole therapy or combined with chloroquine/hydroxychloroquine) include electrocardiogram QT prolonged, drug interaction, hepatitis, diarrhea, and hepatitis acute. Regarding cardiac-related events, 19% (120/645) of azithromycin cases reported events associated with QT prolongation/torsade de pointes (which included seven fatal cardiac events). The most frequently reported clinical adverse events associated with other commonly used agents are also presented. CONCLUSIONS: This pharmacovigilance surveillance study provides a unique characterization of cases in which a broad range of pharmaceutical products was reported in relation to COVID-19.

Correction to: Adverse Drug Reaction Case Safety Practices in Large Biopharmaceutical Organizations from 2007 to 2017: An Industry Survey.

The correct name of the second author should be "Moritz Fehrle", and not "Mortiz Fehrle" as given in the original publication of the article.

Trial designs using real-world data: The changing landscape of the regulatory approval process.

PURPOSE: There is a need to develop hybrid trial methodology combining the best parts of traditional randomized controlled trials (RCTs) and observational study designs to produce real-world evidence (RWE) that provides adequate scientific evidence for regulatory decision-making. METHODS: This review explores how hybrid study designs that include features of RCTs and studies with real-world data (RWD) can combine the advantages of both to generate RWE that is fit for regulatory purposes. RESULTS: Some hybrid designs include randomization and use pragmatic outcomes; other designs use single-arm trial data supplemented with external comparators derived from RWD or leverage novel data collection approaches to capture long-term outcomes in a real-world setting. Some of these approaches have already been successfully used in regulatory decisions, raising the possibility that studies using RWD could increasingly be used to augment or replace traditional RCTs for the demonstration of drug effectiveness in certain contexts. These changes come against a background of long reliance on RCTs for regulatory decision-making, which are labor-intensive, costly, and produce data that can have limited applicability in real-world clinical practice. CONCLUSIONS: While RWE from observational studies is well accepted for satisfying postapproval safety monitoring requirements, it has not commonly been used to demonstrate drug effectiveness for regulatory purposes. However, this position is changing as regulatory opinions, guidance frameworks, and RWD methodologies are evolving, with growing recognition of the value of using RWE that is acceptable for regulatory decision-making.

Adverse Drug Reaction Case Safety Practices in Large Biopharmaceutical Organizations from 2007 to 2017: An Industry Survey.

INTRODUCTION: Drug safety remains a top global public health concern. An increase in the number of data sources available has increased the complexity of pharmacovigilance operations, so the US FDA has created draft guidance focusing on optimizing drug safety data for well-characterized medicines. However, to date, no data demonstrating changes in reports have been presented. OBJECTIVES: This study provided data assessing changes in individual case safety reports (ICSRs) and aggregate reports (ARs) for large biopharmaceutical companies from 2007 to 2017. This study also evaluated current trends on the use of advanced machine and deep learning in order to process all data captured for ICSRs as well as opinions from industry thought leaders on creating a sustainable case-processing operation. METHODOLOGY: Using data captured from Navitas Life Science's annual pvnet® benchmark, we calculated workload indicators characterizing pharmacovigilance operations for large biopharmaceutical organizations. Workload indicators included the number of ICSRs by organization, the number of ARs, and the number and types of data sources used. We also conducted structured in-depth interviews with seven biopharmaceutical executives to discover the reasons for changes in workload indicators across time as well as current strategies for increasing efficiencies in drug safety reporting. RESULTS: The median number of ICSRs increased from 84,960 cases in 2007 to over 200,000 cases in 2017; this increase was largely attributable to an increase in both nonserious cases and follow-up cases. Member companies reported using 12 ± 3 data sources for case identification. The number of ARs also increased from a median of 70 reports in 2007 to 258 reports in 2017. To address these increases, 61% of the biopharmaceutical organizations we surveyed planned to adopt machine learning for full ICSR processing; however, as of 2018, none of the organizations surveyed had mechanisms in place. CONCLUSION: This study demonstrated that pharmacovigilance departments are currently burdened by ever-increasing case volumes. With increased guidance from regulatory agencies, as well as improvements in artificial intelligence and natural language processing, biopharmaceutical organizations must determine the most resource-efficient and sustainable methods to process the growing volume of cases.

Innovation in Pharmacovigilance: Use of Artificial Intelligence in Adverse Event Case Processing.

Automation of pharmaceutical safety case processing represents a significant opportunity to affect the strongest cost driver for a company's overall pharmacovigilance budget. A pilot was undertaken to test the feasibility of using artificial intelligence and robotic process automation to automate processing of adverse event reports. The pilot paradigm was used to simultaneously test proposed solutions of three commercial vendors. The result confirmed the feasibility of using artificial intelligence-based technology to support extraction from adverse event source documents and evaluation of case validity. In addition, the pilot demonstrated viability of the use of safety database data fields as a surrogate for otherwise time-consuming and costly direct annotation of source documents. Finally, the evaluation and scoring method used in the pilot was able to differentiate vendor capabilities and identify the best candidate to move into the discovery phase.

Deconstructing the Pharmacovigilance Hype Cycle.

Data science is making increasing contributions to pharmacovigilance. Although the technical innovation of these works are indisputable, efficient progress in real-world pharmacovigilance signal detection may be hampered by corresponding technology life cycle effects, with a resulting tendency to conclude that, with large enough datasets and intricate algorithms, "the numbers speak for themselves," discounting the importance of clinical and scientific judgment. A practical consequence is overzealous declarations regarding the safety or lack of safety of drugs. We describe these concerns through a critical discussion of key results and conclusions from case studies selected to illustrate these points.

Validation of New Signal Detection Methods for Web Query Log Data Compared to Signal Detection Algorithms Used With FAERS.

INTRODUCTION: Post-marketing drug surveillance is largely based on signals found in spontaneous reports from patients and healthcare providers. Rare adverse drug reactions and adverse events (AEs) that may develop after long-term exposure to a drug or from drug interactions may be missed. The US FDA and others have proposed that web-based data could be mined as a resource to detect latent signals associated with adverse drug reactions. METHODS: Recently, a web-based search query method called a query log reaction score (QLRS) was developed to detect whether AEs associated with certain drugs could be found from search engine query data. In this study, we compare the performance of two other algorithms, the proportional query ratio (PQR) and the proportional query rate ratio (Q-PRR) against that of two reference signal-detection algorithms (SDAs) commonly used with the FDA AE Reporting System (FAERS) database. RESULTS: In summary, the web query methods have moderate sensitivity (80%) in detecting signals in web query data compared with reference SDAs in FAERS when the web query data are filtered, but the query metrics generate many false-positives and have low specificity compared with reference SDAs in FAERS. CONCLUSION: Future research is needed to find better refinements of query data and/or the metrics to improve the specificity of these web query log algorithms.

Assessment of dronedarone utilization using US claims databases.

BACKGROUND: A dronedarone utilization study using US MarketScan and InVision Data Mart databases was conducted to estimate the prevalence of the following: (1) dronedarone use in contraindicated patients with worsening heart failure (HF) or hospitalization for HF within 1 month before dronedarone prescription; (2) concomitant prescribing of contraindicated drugs; and (3) recommended creatinine testing after dronedarone initiation among dronedarone users. METHODS: In this retrospective cohort study, data in the MarketScan database between July 20, 2009, and December 31, 2011, and in the InVision Data Mart database between July 20, 2009, and March 31, 2012, were analyzed. The study population included patients who received ≥1 dronedarone prescription during the study period. The following variables were reported: worsening of or hospitalization for HF, concomitant prescribing of potent cytochrome P450 CYP 3A4 inhibitors or QT-prolonging drugs, and creatinine testing. RESULTS: There were 31,408 and 7025 dronedarone users identified in the MarketScan and InVision Data Mart databases, respectively. Approximately 86% to 90% of patients had a diagnosis of atrial fibrillation in each database. In the MarketScan database, 40% were women and 54% were aged ≥65 years. In the InVision Data Mart database, 31% were women and 32% were aged ≥65 years. The corresponding prevalence of worsening or hospitalization for HF was 6.4% (95% CI, 6.2-6.7) and 4.7% (95% CI, 4.2-5.2) in each database, respectively. The corresponding estimates of concomitant prescribing of potent cytochrome P450 CYP 3A4 inhibitors and QT-prolonging drugs within 30 days before initiation or refilling of dronedarone were 2.0% (95% CI, 1.8-2.1) and 10.0% (95% CI, 9.7-10.4), respectively, in the MarketScan database, and 2.3% (95% CI, 2.0-2.7) and 11.2% (95% CI, 10.5-12.0) in the InVision Data Mart database. More than 50% of patients in each database had serum creatinine tests conducted after dronedarone initiation. CONCLUSIONS: The results of the present analysis based on a long-term follow-up (nearly 3 years) were consistent with the previous findings that dronedarone has mostly been used appropriately in compliance with US prescribing in the target populations.

Risk of Cardiovascular Events, Stroke, Congestive Heart Failure, Interstitial Lung Disease, and Acute Liver Injury: Dronedarone versus Amiodarone and Other Antiarrhythmics.

No published studies have evaluated the risks of cardiovascular (CV) events, stroke, congestive heart failure (CHF), interstitial lung disease (ILD), and severe acute liver injury (ALI) related to antiarrhythmics treatment in real-world clinical practice setting. We examined the relationship between the above events and the selected antiarrhythmics in the real-world setting in the US. Using a retrospective cohort design, the hazard ratios of the outcome events were analyzed from 10,455 adult patients with a diagnosis of atrial fibrillation/atrial flutter and a new treatment with dronedarone (comparison drug), amiodarone, sotalol, flecainide, or propafenone between 07/20/2009 and 12/31/2010 from the Clinformatics Data MartTM database. The patients were followed until: 1) switch to another antiarrhythmic drug, 2) occurrence of the outcome event, 3) end of enrollment, or 4) end of the study period, whichever occurred first. No significant differences were observed in the hazard ratios of the outcome events between dronedarone, amiodarone, and the other antiarrhythmics, except that amiodarone was associated with a higher risk of CV events (adjusted HR = 1.7, 95%CI: 1.1-2.4) and stroke (adjusted HR = 2.0, 95%CI: 1.33.2), compared to dronedarone, especially amongst patients without a CHF history (adjusted HR = 2.4, 95%CI: 1.4-3.8 and 2.2, 95%CI: 1.23.9). A higher risk of CHF was also associated with amiodarone in patients without history of CHF at baseline (adjusted HR = 2.7, 95%CI: 2.03.6). In this real-world investigation, no difference in risk was observed between dronedarone, sotalol, and propafenone initiators for CV events, stroke, CHF, ILD, and ALI. Amiodarone was associated with higher risks of CV events, stroke, and CHF than dronedarone in patients without a CHF history, indicating dronedarone could be an alternative therapy option with lower risk of CV events than amiodarone for the above patients.

Amenorrhea due to partial uterine necrosis after uterine artery embolization for control of refractory postpartum hemorrhage.

We report a case of a woman in whom selective embolization of both uterine arteries was performed using gelatin sponge for control of refractory postpartum hemorrhage. Ten months after delivery, the women had not resumed noticeable menstruation. Examination and investigation were consistent with partial uterine necrosis and complete obliteration of the cavity.

The effect of continuous oestradiol with intermittent norgestimate on bone mineral density and bone turnover in post-menopausal women.

OBJECTIVE: To assess in post-menopausal women the efficacy and tolerability of a continuous oestradiol/intermittent norgestimate HRT regimen to prevent and to reverse post-menopausal loss of bone mineral density (BMD) and to determine the effects on serum bone turnover markers markers. METHODS: A 1-year, multicentre, international, placebo-controlled, randomised, double-blind clinical trial was conducted in 146 post-menopausal women with an intact uterus in order to assess the effect on bone loss of continuous oral 17beta-oestradiol (1 mg per day) combined with norgestimate (90 microg per day), for 3 consecutive days out of every 6-day treatment period (E2/iNGM). During a second year extension, all women agreeing to continue were on the E2/iNGM regimen. BMD was assessed prior to treatment and after 1 and 2 years or at the end of treatment in women stopping participation prematurely after at least 6 months of treatment. Serum bone turnover markers were determined prior to and at 1 year of treatment Adverse events were collected at three-monthly intervals during clinic visits over the treatment period. RESULTS: BMD in the lumbar spine, the primary endpoint, was evaluable in 117 subjects completing >6 months of treatment. BMD increased on average by 2.4% in women on the intermittent progestin regimen. It decreased by 1.4% in placebo treated women. The change from baseline and the difference between active and placebo treatment (Delta placebo) were highly significant (P < 0.0001). On E2/iNGM, also the BMD in the total hip increased (+1.49%, Delta placebo 3.73%, P < 0.0001). The serum markers for bone formation osteocalcin and type I collagen N-propeptide were significantly reduced compared to baseline by 31 and 44%, respectively and the bone resorption marker C-terminal crosslinked telopeptide of type I collagen by 59%. Minor increases (<10%) of markers in the placebo group were not significant. During a second year extension of the trial, all subjects were on active treatment. Subjects on placebo who lost (median+/-CI 95%) 0.66% (-2.3 to +0.5) of spine BMD during the first year now gained 4.41% (2.7-7.6). They also gained 1.6% (0.1-0.3.6) in the total hip. Subjects continuously on oestradiol/intermittent norgestimate (E2/iNGM) gained an additional 5.7% (2.3-13.5) in the lumbar spine and +0.1% (-0.6 to +2.2) at the total hip. Side effects reported by women on the intermittent progestin regimen significantly in excess over reports from the placebo group were uterine bleeding, abdominal and breast pain, but not headache. Back pain and weight gain was reported by significantly fewer women on active treatment compared to placebo. CONCLUSION: The continuous oestradiol/intermittent norgestimate HRT regimen is well tolerated, reduces bone turnover and prevents post-menopausal bone loss in healthy post-menopausal women.

Feto-maternal alloimmune thrombocytopenia due to HPA-5b incompatibility: a case report.

Feto-maternal alloimmune thrombocytopenia (FMAIT) results from the maternal production of antibodies against fetal platelets with incompatible antigens inherited from the father. We present a case where this condition was diagnosed prenatally without previously affected siblings. The severe fetal thrombocytopenia was due to anti-HLA-5b maternal alloantibodies. This was treated successfully by intravenous immunoglobulins. Our case reflects that FMAIT due to anti-HPA-5b may be severe and may be corrected successfully with intravenous immunoglogulins.

Norelgestromin as selective estrogen enzyme modulator in human breast cancer cell lines. Effect on sulfatase activity in comparison to medroxyprogesterone acetate.

Human breast cancer tissue contains enzymes (estrone sulfatase, 17beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol (E(2)) formation. In this tissue, E(2) can be synthesized by two main pathways: (1) sulfatase-transforms estrogen sulfates into bioactive E(2), and the (2) aromatase-converts androgens into estrogens. Quantitative assessment of E(2) formation in human breast tumors indicates that metabolism of estrone sulfate (E(1)S) via the sulfatase pathway produces 100-500 times more E(2) than androgen aromatization. In the present study, we demonstrated in T-47D and MCF-7 human breast cancer cells that norelgestromin (NGMN) (a metabolite of norgestimate) is a potent inhibitory agent of the estrone sulfatase activity. After 24h incubation of physiological concentrations of E(1)S (5 x 10(-9)mol/l) the inhibitory effect of NGMN at concentrations of 5 x 10(-9), 5 x 10(-7) and 5 x 10(-5)mol/l was 43+/-7, 74+/-4 and 97+/-2%, respectively, in T-47D cells; 25+/-4, 57+/-5 and 96+/-2% respectively, in MCF-7 cells. Comparative studies using medroxyprogesterone acetate (MPA) showed that this progestin also has an inhibitory effect on sulfatase activity, but significantly less intense than that of NGMN. The inhibition for MPA at concentrations of 5 x 10(-9), 5 x 10(-7) and 5 x 10(-5)mol/l was 31+/-5, 47+/-3 and 61+/-3%, respectively, for T-47D cells; 6+/-3, 20+/-3 and 63+/-4%, respectively, for MCF-7 cells. In conclusion, the present data show that NGMN is a very potent inhibitory agent for sulfatase activity in the hormone-dependent breast cancer cells, resulting in decreased tissue concentration of E(2). The clinical significance of this finding remains to be elucidated.

Intermittent progestin administration as part of hormone replacement therapy: long-term comparison between estradiol 1 mg combined with intermittent norgestimate and estradiol 2 mg combined with constant norethisterone acetate.

BACKGROUND: To decrease exposure to progestin during hormone replacement therapy (HRT), a novel oral regimen consisting of constant 17beta-estradiol (E2) daily plus intermittent norgestimate (NGM) has been developed. METHODS: A multicenter study compared the safety and efficacy of E2 1 mg daily plus intermittent NGM 90 micro g (3 days off, 3 days on) (n = 150) vs. a continuous oral dose of E2 2 mg plus norethisterone acetate (NETA) 1 mg (n = 172) daily, for a period of 2 years. Endometrial biopsies were performed at 1 and 2 years. Subjects recorded the occurrence of vasomotor symptoms, uterine bleeding, and adverse events on diary cards. RESULTS: At 2 years' follow-up, no subject had developed endometrial hyperplasia or cancer. Endometrial atrophy was seen in 75% of subjects using the intermittent NGM regimen and in 78% of women using the constant NETA regimen. Both groups maintained a 96% reduction in vasomotor symptoms up to 2 years. The rates of bleeding and/or spotting showed no difference between the groups, and at 2 years' follow-up, 73% of women in the intermittent NGM group and 83% of subjects in the constant NETA group were amenorrheic. There was a lower incidence of progestin-associated side-effects, such as abdominal discomfort, edema, painful bleeding episodes, and breast symptoms, with the intermittent progestin regimen vs. the constant progestin regimen. Intermittent NGM use was associated with an elevation in HDL- and HDL2-cholesterol, whereas constant NETA reduced these lipoproteins. CONCLUSIONS: The intermittent administration of a progestin, such as NGM, provides a new, well-tolerated regimen to achieve endometrial safety, an adequate rate of amenorrhea, and effective reduction of vasomotor symptoms in postmenopausal women.