Postmarketing Surveillance Trial Research Articles

Characterizing Adverse Events of Biologic Treatment of T2 Disease: A Disproportionality Analysis of the FDA Adverse Event Reporting System

Introduction: Over the last 3 years, the FDA has approved dupilumab, omalizumab, and mepolizumab for the treatment of CRSwNP; however, adverse events of these biologics have not been described in post-marketing surveillance trials. By utilizing the FDA Adverse Event Reporting System (FAERS), this study describes and compares biologic-associated adverse events in T2 disease. Methods: This case-non-case study assessed disproportionate reporting rates using reporting odds ratios (RORs). RORs and p values for biologic-associated AEs were categorized and compared among dupilumab, omalizumab, and mepolizumab. This analysis included AEs associated with all treatment indications. Relative AE rates and outcomes were calculated. Results: There were a total of 112,560, 24,428, and 18,741 unique AE reports associated with dupilumab, omalizumab, and mepolizumab, respectively. Omalizumab had the strongest association with anaphylaxis (ROR = 20.80, 95% confidence interval [CI]: 18.58, 23.29). Dupilumab had large relative proportions and positive signals in the ophthalmologic category (7.76%, ROR = 6.20, 95% CI: 6.06, 6.35), such as with blurry vision (ROR = 3.80, CI: 3.52, 4.12) and visual impairment (ROR = 1.98, CI: 1.80, 2.19). Dupilumab was the only biologic associated with injection-site reactions (7.98%, ROR = 8.17, 95% CI: 7.98, 8.37). Discussion/Conclusion: This is the first large-scale comparative analysis of the AE profiles of dupilumab, omalizumab, and mepolizumab. Our data suggest possible relations between dupilumab and ophthalmologic and injection-site AEs. Omalizumab was the only biologic with a positive anaphylaxis signal. This FAERS investigation suggests important AE differences among these biologics.

Post-marketing Surveillance of a Quadrivalent Influenza Vaccine (VaxigripTetra) in South Korea.

IntroductionIn 2017, a quadrivalent inactivated split-virion influenza vaccine (QIV; Vaxigrip Tetra®, Sanofi) was licensed in South Korea for active immunization against influenza A and influenza B viruses in individuals aged 3 years or older, which was subsequently extended to individuals aged 6 months or older in 2018. Post-marketing surveillance trials are mandatory in South Korea to retain drug licensure. Here, we assessed the safety of QIV in routine clinical practice in South Korea.MethodsThis was an open, multicenter, observational, active safety surveillance study conducted between 20 June 2017 and 19 June 2021 at 10 study sites in South Korea in individuals aged 3 years or older who received a single dose of QIV during a routine healthcare visit. The participants or their legally acceptable representatives were instructed to record any adverse reactions (solicited events) and unsolicited non-serious adverse events (AE) in diary cards, and notify study investigators in case of serious adverse events (SAE).ResultsOverall, 663 participants were included in this study. There were no AEs leading to study termination, and no SAEs reported. Injection site pain (278 [41.9%]) was the most frequent solicited injection site reaction, with myalgia (250 [37.7%]) and malaise (236 [35.6%]) the most frequent solicited systemic reactions. Grade 3 solicited injection site and systemic reactions were reported by 8 (1.2%) and 13 (2.0%) participants, respectively; most participants with solicited reactions recovered without the need for further action. Overall, 39 (5.9%) participants experienced 49 unsolicited non-serious AEs with the most frequently reported being nasopharyngitis (19 [2.9%]). Grade 3 unsolicited non-serious adverse events were reported in 1 (0.2%) participant. None of the unsolicited non-serious AEs were considered to be related to QIV.ConclusionThis post-marketing surveillance study confirms that QIV is well tolerated and has an acceptable safety profile in routine practice in South Korea. No unexpected safety concerns were identified.Trial RegistrationClinicalTrials.gov identifier NCT05406180.

How to Assess the Efficacy of Interventions for Actinic Keratosis? A Review with a Focus on Long-Term Results.

Actinic keratoses (AK) are common lesions of the skin caused by cumulative sun exposure. Since AK may progress to invasive cutaneous squamous cell carcinoma (cSCC), guidelines uniformly recommend early and consequent treatment. A variety of interventions are available; however, most randomized controlled trials, meta-analyses, and guidelines focus on outcomes that are usually evaluated 8–12 weeks after the end of treatment. Importantly, these assessments can capture the short-term, transient outcomes, but do not allow any conclusions about long-term results to be drawn and do not reflect the probability of transition towards cSCC. Until now, few studies have assessed the long-term results of interventions for AK. Indeed, finding the most appropriate end-point and adjunct time point for determining the long-term results of interventions for AK remains a challenge. Here, we provide an overview of the different ways of measuring the efficacy of AK treatments, such as using recurrence rates or sustained clearance rates, and discuss methodological aspects. Furthermore, we highlight the importance of evidence from post-marketing surveillance trials for the detection of efficacy values and safety signals. Additionally, we emphasize that a follow-up period of 12 months might not be sufficient to reflect the long-term results and stress the urgent need for a longer follow-up period and regular risk-stratified surveillance.

A Systematic Review and Meta-Analysis of Interventions for Actinic Keratosis from Post-Marketing Surveillance Trials.

Multiple interventions are available for the treatment of actinic keratosis (AK) showing high efficacy in pivotal trials. However, data from post-marketing surveillance studies have received little attention until now. Here, we systematically investigate interventions for AK from post-marketing surveillance trials as a proxy for real-world efficacy and tolerability. A systematic literature search was conducted in Medline, Embase, and CENTRAL. Pertinent trial registers were hand-searched until 25 March 2020. Results were pooled using a random-effects model to calculate pooled proportions and relative risks (RR) or were described qualitatively. Eleven records with a total sample size of n = 4109 were included. Three of the studies had an active-controlled design, while seven were single-armed. Participant complete clearance ranged from 23.1% for diclofenac sodium 3% gel to 88.9% for ingenol mebutate 0.05% gel. The lesion-specific clearance rate for photodynamic therapy (PDT) was 74% (95% confidence interval (CI) 56–87%). The recurrence rate was significantly higher for diclofenac sodium 3% in comparison to imiquimod 5% cream (RR 1.10, 95% CI 1.02–1.1.8) and ranged from 10.6% for ingenol mebutate 0.015% gel to 23.5% for PDT. Few patients discontinued the trials due to adverse events. The results from the majority of the post-marketing surveillance studies deviated from those of pivotal trials.

Post-marketing assessment of generic tamoxifen in Brazilian breast cancer patients.

Generic formulations of tamoxifen are commonly prescribed to oestrogen receptor-positive breast cancer patients at the Brazilian National Cancer Institute (INCA). We carried out a post-marketing surveillance of the generic tamoxifen formulation in current use at INCA, by comparing plasma concentrations of the parent drug and metabolites obtained with the generic vs the reference formulation. Thirty patients participated in an open-label, bracketed protocol, comprising 3 successive phases of 30-32days each: the generic formulation was used in phases 1 and 3 and the reference formulation in phase 2. Two blood samples were collected in the last 4days of each phase, for LC-MS/MS quantification of tamoxifen and metabolites in plasma. The median plasma concentrations (ng/mL) for the reference formulation were as follows: tamoxifen, 135.0 (CI 95% 114.2-155.8); endoxifen, 35.3 (30.0-40.8); and 4-hydroxytamoxifen, 4.8 (4.2-5.4). The endoxifen/tamoxifen plasma concentration ratio was 0.27 (0.21-0.25). ANOVA detected no statistically significant difference in plasma concentrations of tamoxifen, metabolites or the endoxifen/tamoxifen ratio among the three phases. The genetic component (rGC) of the CYP2D6-mediated conversion of tamoxifen into endoxifen, estimated using the repeated drug administration procedure across the three phases, was 0.87, pointing to an important component of genetic variability. In conclusion, this first post-marketing surveillance trial of oncologic generic drugs carried out in Brazilian patients verified the switchability between the reference and the generic tamoxifen formulation currently used at our institution. The adopted bracketed protocol adds confidence to this conclusion and may serve as a frame for future trials of post-marketing assessment of other generic drug products.

Post-Marketing Surveillance of Hepatitis A Virus Vaccine (Avaxim® 160U) in South Korea from 2011 to 2015

IntroductionHepatitis A, caused by hepatitis A virus (HAV), is one of the leading causes of acute hepatitis in South Korea. Avaxim® 160U is an inactivated hepatitis A vaccine that has been proven to be highly effective and well tolerated. It is licensed for use in more than 90 countries, and was approved for use in South Korea in 2011. Clinical trial and approval processes may not fully assess the safety and efficacy of a vaccine. Post-marketing surveillance (PMS) aims to provide a complete safety profile of a vaccine in a real-life setting. PMS trials are mandatory in South Korea to retain drug licensure.MethodsThis post-marketing observational study (NCT01838070) was conducted over 4 years at 16 centres in South Korea, and aimed to observe and record all types of adverse events (AE) occurring in an adult population after vaccination with Avaxim® 160U. This included solicited events, unsolicited non-serious events, unexpected events and serious events.ResultsCase report forms were collected from 614 vaccinees, all of whom completed 30 days of follow-up post-vaccination, of whom 36 (5.9%) experienced 53 solicited and unsolicited AEs, 17 (2.8%) experienced 22 of the solicited AEs, while there were no reports of AEs of severe intensity. A total of 31 unsolicited AEs were reported in 22 patients (3.6%), and no unexpected adverse drug reactions were reported.ConclusionNo new safety issues were identified and the safety profile obtained from this study was comparable to that of previous studies for HAV vaccine.Trial RegistrationClinicalTrials.gov identifier, NCT01838070.FundingSanofi Pasteur.

Medicines Regulation in Africa: Current State and Opportunities.

Sound regulatory systems are critical for protecting public health against use of medical products which do not meet international standards of quality, safety and efficacy. This review provides a summary of the current status of National Medicines Regulatory Authorities (NMRAs) in Africa, and various initiatives that have been established to improve their performance. All countries in Africa (except Sahrawi Republic), have NMRAs but their organizational set-up and functionality is variable. Some are located within Ministries of Health and others are semi-autonomous. There is progressive improvement in regulatory capacity, particularly in quality control and post-marketing surveillance, pharmacovigilance and clinical trials oversight. The African Vaccines Regulatory Forum, African Medicines Regulatory Harmonization Initiative, Network of Official Medicines Control Laboratories and WHO Prequalification Scheme have helped countries strengthen their regulatory capacities. The potential establishment of the African Medicines Agency (AMA) in 2018 is an opportunity to improve NMRAs’ capacity in Africa.

Pitavastatin: an overview of the LIVES study

The Livalo® (Livazo® in Europe) Effectiveness and Safety (LIVES) study, a postmarketing surveillance trial conducted in 20,279 Japanese patients with hypercholesterolemia, is the largest trial evaluating the efficacy and safety of pitavastatin 1–4 mg/day. Elderly patients (aged ≥65 years) accounted for approximately 50% of participants, and about 75% of all patients had concomitant diseases, including hypertension and Type 2 diabetes. During 2 years of follow-up, only 10.4% of patients developed adverse drug reactions (ADRs), most of which were mild in severity. No previously unknown ADRs were identified, and laboratory abnormalities such as elevated serum creatine phosphokinase (2.74%), alanine aminotransferase (1.79%), aspartate aminotransferase (1.5%) and myalgia (1.08%) represented the most common ADRs. Importantly, the ADR incidence did not differ significantly based on either concomitant drug use or age. Furthermore, subgroup analyses of the LIVES study showed that pitavastatin has beneficial effect...

Effectiveness of omalizumab in patients 50 years and older with severe persistent allergic asthma

Omalizumab is approved for the treatment of severe allergic asthma. To compare the efficacy of omalizumab therapy in patients 50 years or older with patients younger than 50 years. Between November 2005 and November 2007 a total of 174 asthma patients 50 years or older (40.7% male, 51.1% taking oral corticosteroids, and mean [SD] serum IgE level of 315 [353] U/L) and 297 asthma patients younger than 50 years (40.0% male, 50.5% taking oral corticosteroids, and mean [SD] serum IgE level of 363 [431] U/L) who met the European Union criteria for add-on therapy with anti-IgE were treated prospectively with omalizumab for 4 months as part of 2 postmarketing surveillance trials. Compared with the pretrial period omalizumab treatment reduced the rate of severe exacerbations in patients 50 years or older by 68.9% (P < .001) and in patients younger than 50 years by 75.4% (P < .001). After 4 months there was a marked reduction of daily asthma symptoms and nocturnal awakenings by 67.8% and 72.6% in the older and by 79.3% and 82.5% in the younger patients, respectively (P < .001, all 4 comparisons). In 60% of patients 50 years or older lung function improved compared with 69% of patients younger than 50 years. Efficacy of omalizumab was rated as excellent or good by most physicians in patients 50 years or older (68.4%) and younger than 50 years (76.8%, P = .05 elderly vs younger). Adverse events were reported in 35.5% of patients 50 years or older and 32.1% of patients younger than 50 years. There was a higher rate of discontinuation of omalizumab therapy in older patients (20.9% vs 11.1%, P = .006). The present study confirms the clinical efficacy of omalizumab in patients with severe allergic asthma irrespective of age in a real-life setting outside the omalizumab trial program.

Omalizumab in patients with severe persistent allergic asthma in a real-life setting in Germany

Omalizumab is a humanized monoclonal anti-immunoglobulin E (IgE) antibody indicated in Europe for the treatment of uncontrolled severe persistent allergic (IgE-mediated) asthma despite optimal therapy with inhaled corticosteroids and long-acting beta(2) agonists. Between 2005 and 2007 280 patients (58% female, mean age 44+/-16 yrs., 46% on oral corticosteroids, median serum IgE level 235IU/ml) who met the EU criteria for add-on therapy with anti-IgE were treated prospectively with omalizumab by 134 physicians as part of a post-marketing surveillance trial and were followed-up for 6 months. The median follow-up time was 195 days, the patients were treated with a median dose of 450mg omalizumab every 4 weeks. After 6 months there was a marked effect of omalizumab treatment on daily (-76%) and nocturnal symptoms (-84%), exacerbations (-82%), unscheduled health care contacts (-81%), hospitalizations (-78%) and quality of life (Mini-AQLQ: score increase from 2.9 to 4.5). Overall, efficacy of omalizumab was rated as excellent or good by the majority of physicians (82%) and patients (86%). In 19 patients (7%) omalizumab-related adverse events were recorded. This post-marketing surveillance trial confirms the marked and clinically relevant effect of omalizumab on asthma symptoms and level of asthma control in the majority of patients with severe persistent allergic (IgE-mediated) asthma in a real-life situation.

Efficacy and safety of butterbur herbal extract Ze 339 in seasonal allergic rhinitis: Postmarketing surveillance study

The efficacy and safety of the butterbur leaf extract Ze 339 (carbon dioxide extract from the leaves of Petasites hybridus L., 8 mg petasines per tablet) were tested in patients with seasonal allergic rhinitis. In an open postmarketing surveillance study, 580 patients were treated with an average of 2 tablets of Ze 339 daily for 2 weeks. Symptoms of rhinorrhea, sneezing, nasal congestion, itchy eyes and nose, red eyes, and skin irritation were evaluated on a visual analogue scale. Symptoms of seasonal allergic rhinitis improved in 90% of patients. Differences observed before and after therapy were significant and clinically relevant for all symptoms. Improvement reported by the end of the study was found to be inversely related to symptom severity as described at baseline. Efficacy, tolerability, and improvement in quality of life were positively rated by 80%, 92%, and 80% of patients, respectively. A total of 44% of patients were given an antiallergic comedication. This combination did not result in a better effect than was attained with Ze 339 monotherapy. Adverse events occurred at a rate of 3.8%, and gastrointestinal complaints were predominantly nonspecific. Results of this postmarketing surveillance trial are consistent with observations documented in previous randomized, double-blind, prospective, controlled trials of the same extract that were conducted according to Good Clinical Practice (GCP). Butterbur leaf special extract Ze 339 was confirmed by 3 GCP trials and 2 postmarketing surveillance trials to be safe and efficacious in the treatment of patients with seasonal allergic rhinitis.

Safety update: Focus on cough

Overall, angiotensin-converting enzyme (ACE) inhibitors have a very low side-effect profile. However, several reports in the literature cite cough as a possible complication of ACE inhibitor therapy. These reports have prompted speculation that the risk of cough may differ among ACE inhibitors and that the risk may be greater in patients with renal impairment, perhaps because of excessive drug accumulation. However, these hypotheses have not been tested in prospective, controlled studies. Fosinopril is a long-acting ACE inhibitor with a unique chemical structure and an elimination profile that is associated with stable clearance, regardless of the degree of renal impairment. Favorable clinical experience with fosinopril led to the evaluation of this agent's cough profile in a prospective, open-label study. This study focused on the frequency of cough in patients with mild-to-moderate hypertension who had previously experienced cough while taking another ACE inhibitor. Whereas most prior controlled studies and postmarketing surveillance trials measured the frequency of cough through spontaneous adverse-event reporting, in this study a methodology previously validated in antitussive and mucolytic studies was adapted to provide an accurate and sensitive measure of fosinopril's cough profile. Twenty-four patients were switched from another ACE inhibitor to fosinopril, 10 mg once daily for 6 weeks. At study end, the mean occurrence of cough, frequency of cough, and cough severity significantly changed from baseline (p ≤ 0.0002). Thus, fosinopril use was associated with a less frequent, less severe cough in patients who experienced cough white taking other ACE inhibitors.

Experience with digoxin immune Fab (ovine) in patients with renal impairment

Digibind is a purified antigen binding fragment (Fab) of immunoglobulin G antibodies raised to bind digoxin. Studies in animals suggest renal excretion accounts for a substantial portion of Fab's elimination. Thus it is expected that elimination of antidigoxin Fab fragments would be prolonged in patients with renal impairment; it remains unclear whether digoxin might be released with possible recurrence of toxicity. To shed light on this potential for recrudescent digitalis toxicity following release of bound digoxin, the author scrutinized the records of patients with impaired renal function who were treated with Digibind. Data are available from three sources: the original multicenter investigation of Digibind in 150 patients with life-threatening digoxin or digitoxin toxicity, a postmarketing surveillance study of 745 patients treated with Digibind, and all other reports in the literature or to Burroughs Wellcome Co of physician experience with any antidigoxin Fab. Sixty percent of patients in the multicenter trial and 80% of patients in the postmarketing surveillance trial had some degree of renal impairment. Patients with poor renal function had no evidence of decreased effectiveness or safety either in terms of percent of patients responding, onset of effect or evidence of recrudescence. From all sources the authors identified 28 patients treated with Fab who were functionally anephric. Twenty-seven of these patients had no evidence of recrudescent toxicity. One patient was reported to have complete resolution of digoxin-induced third-degree atrioventricular (AV) block, but AV block recurred 10 days after Fab treatment and persisted for 10 days thereafter. Although this case offers the only clinical evidence suggesting recrudescence can occur, there were no likely alternative explanations for the clinical findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperkalemia in diabetes mellitus. Effect of a triamterene-hydrochlorothiazide combination

• Hyperkalemia is known to occur with increased frequency in the patient with diabetes mellitus and in the elderly when agents that interfere with renal potassium excretion are employed, but the precise frequency has not been established. We employed data from a post-marketing surveillance trial following the introduction of a triamterene-hydrochlorothiazide (Maxzide) combination to estimate the frequency. In patients normokalemic at baseline, hyperkalemia developed with a frequency of 0.59% in 20 809 nondiabetics and in 1.08% of 922 diabetics. Hyperkalemia was threefold to fivefold more likely in those more than 60 years of age, and all of the excess hyperkalemia in diabetics occurred in the elderly. The severity of hyperkalemia was not influenced by the diabetes mellitus. Hypokalemia occurred with a frequency of about 5% and was not influenced by either age or diabetes. In patients who were hypokalemic prior to treatment, hypokalemia was corrected in more than two thirds and hyperkalemia occurred less frequently. Although hyperkalemia indeed occurs with increased frequency in the elderly diabetic when a potassium-sparing combination is employed, the frequency is not so great that such agents should be avoided routinely when their use could be beneficial. Renal function and serum potassium concentration should be assessed prior to instituting treatment and repeated within a few days and a few weeks thereafter in the patient at risk, especially when renal function is suspected, and in the elderly. (<i>Arch Intern Med.</i>1989;149:1327-1330)

Hyperkalemia in Diabetes Mellitus

Hyperkalemia is known to occur with increased frequency in the patient with diabetes mellitus and in the elderly when agents that interfere with renal potassium excretion are employed, but the precise frequency has not been established. We employed data from a post-marketing surveillance trial following the introduction of a triamterene-hydrochlorothiazide (Maxzide) combination to estimate the frequency. In patients normokalemic at baseline, hyperkalemia developed with a frequency of 0.59% in 20,809 nondiabetics and in 1.08% of 922 diabetics. Hyperkalemia was threefold to fivefold more likely in those more than 60 years of age, and all of the excess hyperkalemia in diabetics occurred in the elderly. The severity of hyperkalemia was not influenced by the diabetes mellitus. Hypokalemia occurred with a frequency of about 5% and was not influenced by either age or diabetes. In patients who were hypokalemic prior to treatment, hypokalemia was corrected in more than two thirds and hyperkalemia occurred less frequently. Although hyperkalemia indeed occurs with increased frequency in the elderly diabetic when a potassium-sparing combination is employed, the frequency is not so great that such agents should be avoided routinely when their use could be beneficial. Renal function and serum potassium concentration should be assessed prior to instituting treatment and repeated within a few days and a few weeks thereafter in the patient at risk, especially when renal function is suspected, and in the elderly.