Potential Safety Signals Research Articles

Reporting Medical Device Events

The Food and Drug Administration (FDA) is responsible for protecting public health by regulating medical devices, radiation-emitting electronic devices, drugs, biologics, food, tobacco, and cosmetics. After a product reaches the market, the Agency continues to evaluate a product's safety by monitoring adverse events. FDA's Center for Devices and Radiological Health facilitates reporting of medical device events and complaints by manufacturers, importers, healthcare facilities, and the general public to help FDA identify potential safety signals and/or improve medical device performance. FDA has established 2 reporting mechanisms (1) reporting through the public MedWatch system and (2) direct user facility collaboration via the MedSun program.

Identifiability of Biologicals: An Analysis Using EudraVigilance, the European Union's Database of Reports of Suspected Adverse Drug Reactions.

The relevance of biological therapies for an increasing number of conditions is on the rise. Following the expiry of the initial period of market exclusivity, many of these successful therapies have seen the arrival of biosimilars on the market. The clear identification of the precise medicine responsible for an adverse drug reaction (ADR) report is an important element for pharmacovigilance, allowing timely detection of potential product‐specific safety signals. We looked at the identifiability of biologicals up to the level of commercial product name in ADR reports received from European clinical practice between 2011 and December 2019. A good level of identification (91.5%) was observed overall, but at the same time a downward trend was observed in the last 5 years. This reduction in the level of identifiability of biological products (originators and biosimilars) at the commercial name level in general was driven by five widely used substances, whereas the identification of all other biologics stayed consistent over time (at over 90%). We observed that those five substances were used mostly within oncology. The introduction of the first biosimilar in the market did not appear to affect their identifiability. These results show that although the general level of identification at the commercial product name level in ADRs in Europe is robust and generally stable over time, decreasing trends can be down to a few commonly used substances, which need to be monitored to reverse the trend.

Human Papillomavirus Vaccination and Premature Ovarian Failure: A Disproportionality Analysis Using the Vaccine Adverse Event Reporting System.

IntroductionThere have been public health concerns about a potential association between human papillomavirus (HPV) vaccines and premature ovarian failure (POF) in young women.ObjectiveTo identify a potential safety signal of POF after HPV vaccination using the United States (US) Vaccine Adverse Event Reporting System (VAERS) database.MethodsWe manually selected relevant MedDRA preferred terms related to POF and identified in VAERS all POF reports in women less than 40 years of age between 2 July 1990 and 14 May 2018, followed by a review of narratives to confirm the cases. We conducted descriptive analyses on age, POF type, HPV vaccine type (HPV2, HPV4, HPV9), time to onset of POF, and dose rank. We described trends in reporting over time and assessed a potential safety signal using the proportional reporting ratio (PRR).ResultsOf the 228,341 eligible POF reports, 281 (0.1%) were suspected to be associated with HPV vaccines. Median patient age was 15 years (range 11–39 years). POF events consisted mainly of amenorrhea (80.4%) and premature menopause (15.3%). Mean number of reported POF events significantly increased after the first HPV vaccine launch in 2006 with 22.2 POF cases/year up from 1.4 POF cases/year before the launch. PRR was 46.1 (95% confidence interval: 31.7–67.2) and sensitivity analyses yielded similar estimates.ConclusionOur study suggests the presence of a potential safety signal of POF associated with HPV vaccination, which may only be partly attributed to notoriety bias. Due to the well-known limitations of spontaneous reporting data, further investigations are warranted.

Surveillance of Antidepressant Safety (SADS): Active Signal Detection of Serious Medical Events Following SSRI and SNRI Initiation Using Big Healthcare Data.

IntroductionThe current process for generating evidence in pharmacovigilance has several limitations, which often lead to delays in the evaluation of drug-associated risks.ObjectivesIn this study, we proposed and tested a near real-time epidemiological surveillance system using sequential, cumulative analyses focusing on the detection and preliminary risk quantification of potential safety signals following initiation of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).MethodsWe emulated an active surveillance system in an historical setting by conducting repeated annual cohort studies using nationwide Danish healthcare data (1996–2016). Outcomes were selected from the European Medicines Agency's Designated Medical Event list, summaries of product characteristics, and the literature. We followed patients for a maximum of 6 months from treatment initiation to the event of interest or censoring. We performed Cox regression analyses adjusted for standard sets of covariates. Potential safety signals were visualized using heat maps and cumulative hazard ratio (HR) plots over time.ResultsIn the total study population, 969,667 new users were included and followed for 461,506 person-years. We detected potential safety signals with incidence rates as low as 0.9 per 10,000 person-years. Having eight different exposure drugs and 51 medical events, we identified 31 unique combinations of potential safety signals with a positive association to the event of interest in the exposed group. We proposed that these signals were designated for further evaluation once they appeared in a prospective setting. In total, 21 (67.7%) of these were not present in the current summaries of product characteristics.ConclusionThe study demonstrated the feasibility of performing epidemiological surveillance using sequential, cumulative analyses. Larger populations are needed to evaluate rare events and infrequently used antidepressants.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-021-01110-x.

Safety profile of carbapenems: Data mining ofthe FDA adverse events reporting system.

To learn the safety profile of carbapenems and compare suspected adverse drug reactions (ADRs) among carbapenem classes by data mining the FDA adverse event reporting system (FAERS) database. This retrospective study described the general characteristics of adverse drug event (ADE) reports related to carbapenems in the FAERS during 2015 - 2018. The 95% confidence intervals (CIs) of proportional reporting ratio (PRR), the reporting odds ratio (ROR), and information component (IC) of Bayesian confidence propagation neural network (BCPNN) were calculated to identify potential safety signals. A total number of 5,899 reports associated with carbapenems were submitted to the FAERS from January 1, 2015 to December 31, 2018. The most frequently reported ADE associated with carbapenems was drug ineffective (10.51%). Serious ADEs and death associated with carbapenems were reported in 41.24and 25.12%, respectively. Infections and infestations was the strongest signal detected in both meropenem and imipenem. Nervous system disorders and psychiatric disorders were strongly detected in ertapenem. Hepatobiliary disorders were common in doripenem patients. Carbapenem resistance is alarming in the United States, and carbapenem is more likely to be associated with serious and fatal ADEs among β-lactam antibiotics. Both differences and similarities exist in the safety profile among carbapenems classes. Close attention should be paid to patients with special disease when administrated carbapenems.

Disproportionality analysis of reported drug adverse events to assess a potential safety signal for pentavalent vaccine in 2019 in El Salvador

Detection and surveillance of vaccine safety hazards is a public health staple. In the post-marketing phase, when vaccines are used in mass, it is crucial to monitor potential signals of adverse reactions that may have been missed in the pre-marketing phase. We analysed spontaneous reports of drug adverse events in El Salvador to assess a potential safety signal related to an increase in febrile seizures following the pentavalent (diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenzae Type B) vaccine in 2019.This was a retrospective observational study of adverse event notifications in the national electronic drug safety database from 2011 to 2019. We performed standard disproportionality analysis computing Proportional Reporting Risk (PRR), Reporting Odds Ratio (ROR), Relative Reporting Ratio (RRR), Chi-squared, and Information Component (IC), comparing the pairing of febrile seizures and pentavalent vaccine to all other drugs and adverse events recorded in 2019.The occurrence of febrile seizures following pentavalent vaccination exceeded the WHO expected rate of six cases × 100 000 doses administered from April 2019, with a maximum of 9.2 in September. IC was 4.3, ORR 421.9 (95% Confidence Interval, CI: 123.8–1437.7), PRR 223.5 (95 %CI: 70.2–710.9), RRR was 19.5. The first booster presented the highest rate (14.6 per 100,000 doses) of febrile seizures, more than double than expected. Rates for 2018 remained below expected. Reports of febrile seizures following pentavalent vaccine were also on the increase globally since 2014, with highest rates in 2018 and 2019.There was a disproportion of febrile seizures notifications following pentavalent in El Salvador in 2019, suggesting the existence of a safety signal. This may be due to the change in provider. Further studies should assess the causes of the increase and compute costs and benefits of this vaccination to determine if switching to a less reactogenic vaccine formulation is indicated.

Cardiac Events Potentially Associated to Remdesivir: An Analysis from the European Spontaneous Adverse Event Reporting System.

Remdesivir was recommended for hospitalized patients with COVID-19. As already reported in the Summary of Product Characteristics, most of remdesivir’s safety concerns are hepatoxicity and nephrotoxicity related. However, some cases have raised concerns regarding the potential cardiac events associated with remdesivir; therefore, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency requested to investigate all available data. Therefore, we analyzed all Individual Case Safety Reports (ICSRs) collected in the EudraVigilance database focusing on cardiac adverse events. From April to December 2020, 1375 ICSRs related to remdesivir were retrieved from EudraVigilance, of which 863 (62.8%) were related to male and (43.3%) adult patients. A total of 82.2% of all AEs (N = 2604) was serious and one third of the total ICSRs (N = 416, 30.3%) had a fatal outcome. The most frequently reported events referred to hepatic/hepatobiliary disorders (19.4%,), renal and urinary disorders (11.1%) and cardiac events (8.4%). Among 221 cardiac ICSRs, 69 reported fatal outcomes. Other drugs for cardiovascular disorders were reported as suspected/concomitant together with remdesivir in 166 ICSRs (75.1%), 62 of which were fatal. Moreover, the mean time to overall cardiac event was 3.3 days (±2.2). Finally, disproportionality analysis showed a two-fold increased risk of reporting a cardiac adverse event associated with remdesivir compared to both hydroxychloroquine and azithromycin. This study showed that remdesivir could be associated to risk of cardiac events, suggesting a potential safety signal which has not been completely evaluated yet. Further studies are needed to confirm these findings.

Disease-modifying agents for multiple sclerosis and the risk for reporting cancer: A disproportionality analysis using the US Food and Drug Administration Adverse Event Reporting System database.

While the efficacy of disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS) is established, little is known about their long-term safety. Cancer-risk after DMT use remains unclear. This study aimed to investigate whether the prescription of DMTs for patients with MS increases the risk of reporting cancer. Data from the Food and Drug Administration Adverse Event Reporting System were extracted from 2004 to 2020. After data cleaning, the crude and adjusted reported odds ratios (cROR and aROR) for cancer were calculated for DMTs with Interferon beta-1a as the reference drug. Sensitivity analyses investigated the group of reports with multiple registered DMTs, the effect of indication restriction and the results when using the rest of the DMTs as reference. For malignant tumours, aROR (95% confidence interval [CI]) values were Cladribine 0.46 (0.18-0.95), Dimethyl fumarate 0.30 (0.27-0.34), Fingolimod 0.61 (0.53-0.70), Glatiramer 0.50 (0.43-0.58), Alemtuzumab 0.84 (0.64-1.08), Interferon beta-1b 0.49 (0.42-0.56), Natalizumab 0.36 (0.34-0.39), Ocrelizumab 0.48 (0.29-0.74), Peginterferon beta-1a 0.35 (0.26-0.48), Siponimod 0.89 (0.47-1.54) and Teriflunomide 0.25(0.21-0.30) adjusted to age, gender and concomitant medications. In the sensitivity analysis, when the rest of the drugs were used as a reference, Interferon beta-1a and Peginterferon beta-1a had aROR (95% CI) 2.60 (2.47-2.74, P < .001) and Alemtuzumab had aROR 1.47 (1.13-1.88, I = .003). No safety signal for increased cancer risk was detected among the approved DMTs. A potential safety signal detected in the sensitivity analysis concerning Interferon beta-1a and Alemtuzumab requires further evaluation with more robust evidence.

Association of Facial Paralysis With mRNA COVID-19 Vaccines

This disproportionality analysis uses the World Health Organization pharmacovigilance database to explore the potential safety signal of facial paralysis after COVID-19 vaccination.

A novel data mining application to detect safety signals for newly approved medications in routine care of patients with diabetes.

ABSTRACTBackgroundClinical trials are often underpowered to detect serious but rare adverse events of a new medication. We applied a novel data mining tool to detect potential adverse events of canagliflozin, the first sodium glucose co‐transporter 2 (SGLT2 inhibitor) in the United States, using real‐world data from shortly after its market entry and before public awareness of its potential safety concerns.MethodsIn a U. S. commercial claims dataset (29 March 2013–30 Sept 2015), two pairwise cohorts of patients over 18 years of age with type 2 diabetes (T2D) who were newly dispensed canagliflozin or an active comparator, that is a dipeptidyl peptidase 4 inhibitor (DPP4) or a glucagon‐like peptide 1 receptor agonist (GLP1), were identified and propensity score‐matched. We used variable ratio matching with up to four people receiving a DPP4 or GLP1 for each person receiving canagliflozin. We identified potential safety signals using a hierarchical tree‐based scan statistic data mining method with the hierarchical outcome tree constructed based on international classification of disease coding. We screened for incident adverse events where there were more outcomes observed among canagliflozin vs. comparator initiators than expected by chance, after adjusting for multiple testing.ResultsWe identified two pairwise propensity score variable ratio matched cohorts of 44,733 canagliflozin vs. 99,458 DPP4 initiators, and 55,974 canagliflozin vs. 74,727 GLP1 initiators. When we screened inpatient and emergency room diagnoses, diabetic ketoacidosis was the only severe adverse event associated with canagliflozin initiation with p < .05 in both cohorts. When outpatient diagnoses were also considered, signals for female and male genital infections emerged in both cohorts (p < .05).Conclusions and relevanceIn a large population‐based study, we identified known but no other adverse events associated with canagliflozin, providing reassurance on its safety among adult patients with T2D and suggesting the tree‐based scan statistic method is a useful post‐marketing safety monitoring tool for newly approved medications.

Review of near real-time vaccine safety surveillance

Post-marketing vaccine safety surveillance, including both passive and active surveillances, aims to detect and alert to signals of adverse events following immunization (AEFI), and to further ensure public safety and public confidence in vaccination. Active surveillance could proactively seek information of AEFI and timely investigate the potential safety signals, therefore, it has become the main development trend of post-marketing surveillance worldwide. Nowadays, there is an ongoing interest in developing active surveillance systems that can incorporate and use existing electronic data such as administrative claims and electronic health records. Researchers have also began exploring ways of accruing data closer to "real-time" in order to speed the recognition of potential safety problems.This near real-time vaccine safety surveillance is gradually emerging worldwide. This study reviews the development and methodology of near real-time surveillance and aims to accelerate the foundation of the active surveillance system for vaccine safety in China.

Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database.

Remdesivir is approved for emergency use by the US Food and Drug Administration (FDA) and authorized conditionally by the European Medicines Agency (EMA) for patients with coronavirus disease 2019 (COVID-19). Its benefit-risk ratio is still being explored because data in the field are rather scant. A decrease of the creatinine clearance associated with remdesivir has been inconstantly reported in clinical trials with unclear relevance. Despite these uncertainties, we searched for a potential signal of acute renal failure (ARF) in pharmacovigilance postmarketing data. An analysis of the international pharmacovigilance postmarketing databases (VigiBase) of the World Health Organization (WHO) was performed, using two disproportionality methods. Reporting odds ratio (ROR) compared the number of ARF cases reported with remdesivir, with those reported with other drugs prescribed in comparable situations of COVID-19 (hydroxychloroquine, tocilizumab, and lopinavir/ritonavir). The combination of the terms "acute renal failure" and "remdesivir" yielded a statistically significant disproportionality signal with 138 observed cases instead of the 9 expected. ROR of ARF with remdesivir was 20-fold (20.3; confidence interval 0.95 [15.7-26.3], P<0.0001]) that of comparative drugs. Based on ARF cases reported in VigiBase, and despite the caveats inherent to COVID-19 circumstances, we detected a statistically significant pharmacovigilance signal of nephrotoxicity associated with remdesivir, deserving a thorough qualitative assessment of all available data. Meanwhile, as recommended in its Summary of Product Characteristics, assessment of patients with COVID-19 renal function should prevail before and during treatment with remdesivir in COVID-19.

Retroperitoneal fibrosis and β-blocking agents: Is there an association?

Retroperitoneal fibrosis (RPF) is a rare chronic fibro-inflammatory disorder that may be secondary to certain drugs, including β-blocking agents (BBAs). However, their causative role is unclear. We aimed to investigate this association. Disproportionality analysis was carried out on cases from 1985 to 4 October 2020 in VigiBase, the World Health Organization pharmacovigilance database. The Bayesian-based IC025 metric and reporting odds ratio were used in order to assess the adverse event signal. We also analysed all published case reports from the literature regarding BBA-associated RPF to assess the value of suggested supportive clinical evidence. In total, 1599 individual case safety reports of RPF were reported to VigiBase, of which 132 (32%) concerned 16 different single BBA. For 12 of these agents (75%), reporting of RPF was disproportionate, indicating a potential safety signal. Line listing analysis of individual case safety reports showed no consistent time interval from start of BBA to RPF diagnosis (range 0.7-264 mo). Dechallenge was negative or unknown in the majority of cases (74%). In 18 published cases from the literature, time from start of BBA to RPF diagnosis varied widely (range 3-156 mo). BBA were discontinued 6months before (n=1) or at the time of RPF diagnosis (n=17). Most patients (84%) also received RPF specific treatment. Follow-up duration was short (median 5 mo [range 1-24 mo]) and in most cases (83%) relevant follow-up data were lacking. Although disproportionality analysis indicated a potential safety signal for RPF associated with BBAs, clinical evidence did not support a cause-and-effect relationship.

Safety first: Tracking adverse events associated with new therapies for people with hemophilia

Safety first: Tracking adverse events associated with new therapies for people with hemophilia

5. Observational Study of Routine Use of 9-Valent Human Papillomavirus Vaccine: Safe in More Than 140,000 Individuals

BackgroundNine-valent human papillomavirus (HPV) vaccine (9vHPV vaccine, Gardasil®9) was licensed in the US in Dec-2014. Using a self-controlled risk interval design, we conducted a post-licensure retrospective cohort study within Kaiser Permanente in Northern California (KPNC) to assess 9vHPV safety following routine administration.MethodsWe included KPNC members 9-years or older who received 9vHPV as their first dose of HPV vaccine between Oct-2015 and Sep-2017. Post-vaccination emergency and hospitalization events were compared during risk intervals (days 1–60 and 0–14) with later self-comparison intervals using conditional logistic regression, following all 9vHPV vaccine doses combined, and by dose. We investigated significant findings by assessing post-vaccination timing and medical record reviews. We evaluated and reviewed medical records for all day 0 allergic reaction and syncope events, and all deaths during the study. An independent Safety Review Committee reviewed potential safety signals.ResultsWe studied 140,628 9vHPV-vaccinated individuals, including 69,027 (49%) who received 2 doses and 29,901 (21%) 3 doses, totaling 239,556 doses. Eight categories were significantly increased in at least one analysis (Table). On review, most findings were previously known, preceded vaccination, or were better explained by other medical history. Some day 0 allergic reactions and syncope were potentially related to vaccination. None of the 20 deaths were considered related to 9vHPV.Table. Elevated diagnosis categories comparing risk and self-comparison intervals.Diagnosis CategoriesORs (95% CI)Diabetes mellitus1.66 (1.01, 2.74)DeliriumNE (1.11, NE)Nervous system disorders+21.33 (1.02, 1.72)Digestive disorders+41.21 (1.03, 1.41)Male genital disease1.60 (1.04, 2.46)Skin disorders+11.88 (1.00, 3.53)Congenital anomalies, nervous system5.01 (1.10, 22.83)Symptoms, ill-defined+11.36 (1.13, 1.64) +n indicates number of elevated sub-categories, for a total of 16 categories. NE: not estimable.ConclusionThis large study of individuals who received only 9vHPV vaccine did not identify any new safety events related to 9vHPV administration and provides reassuring evidence of the favorable safety profile of the 9vHPV vaccine.DisclosuresSe Li, PhD, Merck & Co., Inc. (Employee, Shareholder) Christine Velicer, PhD, Merck & Co., Inc. (Employee, Shareholder) Patricia Saddier, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Nicola P. Klein, MD, PhD, GSK group of companies (Research Grant or Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support)Protein Science (now SP) (Grant/Research Support)Sanofi Pasteur (Grant/Research Support)

A pharmacovigilance study to quantify the strength of association between the combination of antimalarial drugs and azithromycin and cardiac arrhythmias: implications for the treatment of COVID-19.

ABSTRACT Background: Hydroxychloroquine, an antimalarial drug, combined with azithromycin has been considered a potential treatment for COVID-19. However, these drugs may cause electrocardiogram QT prolongation (QTp) and torsade de Pointes (TdP). We examined potential safety signals for these cardiac arrhythmias. Methods: Using the OpenVigil 2.1 MedDRA platform, we mined data from the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) from December 2019 to June 2020. We extracted individual case safety reports based on exposures of seven antimalarial drugs, azithromycin, and combinations. All other drugs in FAERS served as controls. Events of interest included QTp and TdP, with associations between drug exposures and events expressed as adjusted Reporting-Odds-Ratios (aRORs) and confidence intervals. The lower end of aROR 95% confidence interval >1 was used as the statistically significant signal detection threshold. Results: QTp safety signals were found for hydroxychloroquine[aROR:11.70 (10.40–13.16)], chloroquine[aROR:18.97 (11.30–31.87)], quinine[aROR:16.66 (10.18–27.25)], atovaquone[aROR:6.91 (4.14–11.56)], azithromycin alone [aROR:28.02 (22.87–34.32)] and hydroxychloroquine + azithromycin [aROR:75.23 (51.15–110.66)]. TdP safety signals were found for hydroxychloroquine [aROR: 5.62 (4.94–6.38)], chloroquine[aROR:49.37 (30.63–79.58)], and hydroxychloroquine + azithromycin[aROR:33.09 (21.22–51.61)]. Conclusion: Hydroxychloroquine/chloroquine and/or azithromycin was associated with QTp/TdP safety signals and their use should be monitored carefully.

A Phase II Pilot Study of Avelumab in Combination with Hypofractionated Radiotherapy in Patients with Relapsed Refractory Multiple Myeloma

Background: Multiple myeloma (MM) is the 2nd most common hematologic malignancy and remains incurable despite significant treatment advances over the last decade. Patients with relapsed/refractory multiple myeloma (RRMM), who have exhausted available therapies, have limited treatment options and a median survival as brief as 6 months (Richardson PG et al., Oncology 2010). Immune checkpoint inhibitors (CPI) have dramatically changed treatment paradigms in multiple cancers, with growing evidence that radiation therapy (XRT) may synergize with these agents via the abscopal effect. MM cells express high levels of PD-L1. Preclinical models have demonstrated rejection of murine myeloma when PD-L1 blockade was combined with XRT (Kearl TJ et al., Journal of Immunology 2013), as well as longer survival in myeloma-bearing mice compared to controls (Jing W et al., Journal for ImmunoTherapy of Cancer 2015). Early phase single arm clinical trials with combinations of immunomodulatory drugs (IMiDs) and CPI showed response rates between 33 and 76% (Pianko MJ et al., Stem Cell Investigation 2017)(San Miguel J et al., Blood 2015)(Badros A et al., Blood 2017). However, subsequent phase 3 studies revealed a potential safety signal of this combination (FDA 2017). Nonetheless, a subset of patients appear to attain durable responses (Badros A et al., Blood Advances 2019). CPI combined with other therapies such as XRT, that help to prime the immune system, hold great promise in the treatment of patients with RRMM. Herein, we describe our phase II study of avelumab, an anti-PD-L1 IgG1 antibody with potential antibody-dependent cellular cytotoxic properties, in combination with XRT in patients with RRMM. Methods: Trial Design: The primary endpoint of this trial is to assess the systemic response rate with the combination of avelumab and XRT in the treatment of extramedullary plasmacytomas or active lytic lesions in patients with RRMM using the 2016 IMWG response criteria. Secondary endpoints include determination of complete response rate, progression-free survival, and overall survival. Patients will undergo bone marrow biopsies and imaging (PET/CT and DW-MRI) at baseline, during disease response evaluations, and at the end of treatment. Treatment: Treatment consists of a 4-week lead-in with avelumab at a flat dose of 800mg IV every 2 weeks followed by concurrent XRT of 5Gy for 5 consecutive days directed toward the plasmacytoma/lytic lesion (Figure 1). Monotherapy avelumab, 800mg IV every 2 weeks, will continue indefinitely until disease progression or unacceptable toxicity. Analysis: This is a single arm trial with a Simon minimax two-stage phase II trial design that will enroll up to 27 patients. The first stage will enroll 13 evaluable patients, and if 0 of the 13 have a clinical response, then no further patients will be accrued due to futility. If 1 or more of the first 13 patients have a response, then accrual will continue until a total of 27 evaluable patients have been treated in the second stage. This will provide a two-sided alpha of 5% and a Power of 80% to rule out an ORR of 5% in favor of a response rate of 20%. Response fractions and time to event endpoints will be reported along with 90 and 95% two-sided confidence intervals with nominal p values. Eligibility: Patients must have previously treated relapsed MM or RRMM refractory to, ineligible for, or intolerant of, available myeloma therapies and have ≥ 1 extramedullary plasmacytoma and/or lytic lesion. Lesions must be amenable to, and clinically indicated for, treatment with localized XRT. Eligible patients must have documented evidence of progressive disease on, or after, their most recent regimen as defined by the IMWG criteria. They must have achieved at least a minimal response to one or more prior regimens. Exclusionary criteria include patients with: clinically unstable lesions where a delay in XRT may be detrimental; active autoimmune diseases or history of serious autoimmune-related disorders; uncontrolled intercurrent illnesses; concurrent use of immunosuppressant medications; and recent or current anti-cancer treatment prior to the first dose of avelumab. Current Enrollment: This study is actively enrolling patients to the first stage. At the time of this submission, 4 patients have been enrolled and have received at least one dose of trial therapy. Clinical trial registry number: NCT03910439. Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: avelumab not approved in myeloma

Bayesian hierarchical model for safety signal detection in multiple clinical trials

Clinical safety signal detection is of great importance in establishing the safety profile of new drugs and biologics during drug development. Bayesian hierarchical meta-analysis has proven to be a very effective method of identifying potential safety signals by considering the hierarchical structure of clinical safety data from multiple randomized clinical trials conducted under an Investigational New Drug (IND) application or Biological License Application (BLA). This type of model can integrate information across studies, for instance by grouping related adverse events using the MedDRA system-organ-class (SOC) and preferred terms (PT). It therefore improves the precision of parameter estimates compared to models that do not consider the hierarchical structure of the safety data. We propose to extend an existing four-stage Bayesian hierarchical model and consider the exposure adjusted incidence rate, assuming the number of adverse events (AEs) follows a Poisson distribution. The proposed model is applied to a real-world example, using data from three randomized clinical trials of a neuroscience drug and examine in three simulation studies motivated by real-world examples. Comparison is made between the proposed method and other existing methods. The simulation results indicate that our proposed model outperforms other two candidate models in terms of power and false detection rate.

Risk of Metformin in Patients With Type 2 Diabetes With COVID-19: A Preliminary Retrospective Report.

The current outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has spread across the world. No specific antiviral agents have been adequately evidenced for the treatment of coronavirus disease 2019 (COVID‐19). Although metformin has been recommended as a host‐directed therapy for COVID‐19, there are some opposite views. The effects of metformin on the disease severity of patients with COVID‐19 with diabetes during hospitalization remains unclear. This study aimed to determine the effect of metformin on disease severity. We enrolled 110 hospitalized patients with COVID‐19 with diabetes prescribed either metformin or non‐metformin hypoglycemic treatment for a case‐control study. The primary outcome was the occurrence of life‐threatening complications. There were no differences between the two groups in age, sex, comorbidities, and clinical severity at admission. Blood glucose and lactate dehydrogenase levels of the metformin group were higher than those of the non‐metformin group at admission. Other laboratory parameters at admission and treatments after admission were not different between the two groups. Strikingly, the percentage of patients who experienced life‐threatening complications was significantly higher in the metformin group (28.6% (16/56) vs. 7.4% (4/54), P = 0.004). Antidiabetic therapy with metformin was associated with a higher risk of disease progression in patients with COVID‐19 with diabetes during hospitalization (adjusted odds ratio = 3.964, 95% confidence interval 1.034–15.194, P = 0.045). This retrospective analysis suggested a potential safety signal for metformin, the use of which was associated with a higher risk of severe COVID‐19. We propose that metformin withdrawal in patients with COVID‐19 be considered to prevent disease progression.

Two-stage Bayesian hierarchical modeling for blinded and unblinded safety monitoring in randomized clinical trials

BackgroundMonitoring and reporting of drug safety during a clinical trial is essential to its success. More recent attention to drug safety has encouraged statistical methods development for monitoring and detecting potential safety signals. This paper investigates the potential impact of the process of the blinded investigator identifying a potential safety signal, which should be further investigated by the Data and Safety Monitoring Board with an unblinded safety data analysis.MethodsIn this paper, two-stage Bayesian hierarchical models are proposed for safety signal detection following a pre-specified set of interim analyses that are applied to efficacy. At stage 1, a hierarchical blinded model uses blinded safety data to detect a potential safety signal and at stage 2, a hierarchical logistic model is applied to confirm the signal with unblinded safety data.ResultsAny interim safety monitoring analysis is usually scheduled via negotiation between the trial sponsor and the Data and Safety Monitoring Board. The proposed safety monitoring process starts once 53 subjects have been enrolled into an eight-arm phase II clinical trial for the first interim analysis. Operating characteristics describing the performance of this proposed workflow are investigated using simulations based on the different scenarios.ConclusionsThe two-stage Bayesian safety procedure in this paper provides a statistical view to monitor safety during the clinical trials. The proposed two-stage monitoring model has an excellent accuracy of detecting and flagging a potential safety signal at stage 1, and with the most important feature that further action at stage 2 could confirm the safety issue.