Post-authorization Safety Studies Research Articles

COVID-19 vaccination and lethality reduction: a prospective observational study in Venezuela during the last two waves

BackgroundIn Venezuela, the predominant vaccines administered are BBIBP-CorV and Gam-COVID-Vac. Despite robust evidence from randomized clinical trials validating the effectiveness of COVID-19 vaccines in mitigating hospitalization and mortality, there is still a lack of post-authorization safety studies conducted within this demographic population.MethodsA prospective observational study from October 5, 2021 to March 31, 2022 encompassed COVID-19 vaccinated and unvaccinated patients from four sentinel hospitals in Venezuela. Patient lethality was predicted using Charlson Comorbidity index. Clinical outcomes were assessed through WHO’s COVID-19 Clinical Progression Scale.ResultsOut of the 175 patients assessed, 85 (48.6%) were vaccinated. The median Charlson Comorbidity index was 3 points, with no statistically significant differences observed between the groups (p = 0.2). A total of 50 (28.6%) patients died during the study period, with higher proportion of deaths in unvaccinated patients (35.6% vs. 21.2%, p = 0.035). Advanced age (OR = 1.043, 95% CI = 1.015–1.071, p = 0.002) was associated with increased death risk, whereas vaccination against COVID-19 (OR = 0.428, 95% CI = 0.185–0.99, p = 0.047), high oxygen saturation (OR = 0.964, 95% CI = 0.934–0.995, p = 0.024), and enoxaparin administration (OR = 0.292, 95% CI = 0.093–0.917, p = 0.035) were associated with decreased death risk.ConclusionDuring the third and fourth waves of the pandemic, COVID-19 vaccination was associated with a 57% reduction in lethality among patients in four public hospitals in Venezuela.

Limitations Reported in Evaluating Effectiveness of Risk Minimization Measures in the EU during 2018-2021: A Qualitative Analysis of Industry-Sponsored Post-Authorization Safety Studies.

Marketing-authorization holders evaluate the effectiveness of risk minimization measures (RMM) for medicines through the conduct of post-authorization safety studies (PASS). Earlier studies show that concluding on RMM effectiveness is challenging. The aim of this study was to describe reported limitations associated with RMM effectiveness assessments of industry-sponsored PASS that did not render a conclusion. We conducted a thematic analysis of study limitations extracted from assessment reports and study reports finalized by the Pharmacovigilance Risk Assessment Committee between 2018 and 2021. In 39 (61.0%) of the PASS a conclusion on RMM effectiveness was drawn, where 25 (39.0%) PASS was inconclusive. Most PASS had a cross-sectional design with surveys as primary data sources (73.4% and 65.6% respectively). Four main themes emerged: (i) survey-specific limitations, (ii) limitations specifically related to secondary use of data, (iii) general limitations related to study design, and (iv) limitations not related to study design. In general, frequently reported limitations were survey-related, such as selection bias or information bias. Interestingly, well-known study limitations related to secondary use of data such as missing or misclassification of data were more often presented in inconclusive compared with conclusive PASS. Given that about 40% of PASS did not allow a conclusion on RMM effectiveness, our results suggest prioritization for strategies to mitigate limitations related to the secondary use of data at the protocol stage, for example, through feasibility assessments. Although many databases may have incomplete registration of some variables, feasibility testing prior to conducting a PASS could contribute to meeting study objectives and concluding on RMM effectiveness.

CAR T-cell Resistance to Oncogenic Transformation.

In this commentary, we discuss the investigation into reports of T-cell malignancies following chimeric antigen receptor T-cell therapy. We argue that although these cases should be thoroughly examined, current data suggest that such risks with autologous chimeric antigen receptor T cells are remarkably low compared with other cancer treatments. We also emphasize the importance of continued research, transparent reporting, and participation in postauthorization safety studies.

Comparison design and evaluation power in cohort and self-controlled case series designs for post-authorization vaccine safety studies.

Post-authorization safety studies (PASSs) of vaccines are important. PASSs enable the evaluation of association between vaccination and adverse events following immunization through common study designs. Clinical trials during vaccine development typically include a few thousand to 10,000 participants while a PASS might aim to detect a few adverse events per 100,000 vaccine recipients. While all available data may be utilized, prior consideration of power analyses are nonetheless crucial for interpretation in cases where statistically significant differences are not found. This research primarily examined cohort study design and self-controlled case series (SCCS) design, estimating the power of a PASS under plausible conditions. Both the cohort study and SCCS designs necessitated large sample sizes or high event counts to guarantee adequate power. The SCCS design is particularly suited to evaluating rare adverse events. However, extremely rare events may not yield sufficient occurrences, thereby resulting in low power. Although the SCCS design can more efficiently control for time-invariant confounding in principle, it solely estimates relative measures. A cohort study design might be preferred if confounding can be adequately managed as it also estimates absolute measures. It may be an easy decision to use all the data at hand for either design. We found it necessary to estimate the sample size and number of events to be used in the study based on a priori information and anticipated results.

The Critical Intersect of Regulations, Health Technology Assessment, and Drug Safety Assessments.

Health technology assessment (HTA) is a multidisciplinary process that determines the value of health technology at different points in its lifecycle. Safety issues have become more important since regulatory authorities are increasingly adopting flexible standards, processes, and evidentiary requirements for drug approval. In this article, we compared the different role of regulatory authorities and HTA agencies. Additionally, the experience of regulatory-HTA collaboration for assessment and/or decision-making on safety issues in the lifecycle of a health technology is illustrated, including olmesartan (angiotensin II receptor antagonist) and the direct-acting hepatitis C virus (HCV) antiviral agents. Post-licensing data can be derived from various sources such as electronic health records, medical claims, drug and disease registries, post-authorization safety studies (PASS) or post-authorization safety efficacy studies (PAES), periodic benefit-risk assessment reports, as well as HTA reassessment reports, which incorporate utilization information from patients in a real-world setting and provide crucial evidence for various purposes. With the ongoing accumulation of safety and efficacy information during post-regulatory approval, a standardized process for continuous data collection and active reassessment of risk and benefit becomes crucial for managing the lifecycle of health technologies. In order to define evidence requirements clearly, reduce uncertainty, and minimize delays in HTA approval, early engagement and collaboration of HTA agencies in the regulatory review processes have become more common. However, there is currently limited interaction and collaboration between regulatory authorities and HTA agencies. This article aims to identify the challenges faced by regulators and HTA agencies today, emphasizing the significance of conducting regulatory reviews and health technology assessments throughout a technology's lifecycle, underlining the value of utilizing real-world data and evidence, and emphasizing the necessity of enhancing collaboration between regulatory authorities and HTA agencies, all within the overarching context of drug safety.

MSR161 Quantifying the Impact of Exposure Prevalence and Selection Bias to Optimize Patient Selection Criteria in Post-Authorization Safety Studies

MSR161 Quantifying the Impact of Exposure Prevalence and Selection Bias to Optimize Patient Selection Criteria in Post-Authorization Safety Studies

Landscape review of global real-world data sources for studying medication use in pregnancy and lactation that support regulatory decision making.

Most pregnant people take at least one medication during gestation or while breastfeeding, however data are lacking on the safety of medication use in these populations. We conducted a landscape review of real-world data sources specific to medication use in pregnancy and breastfeeding populations that have met, or have potential to meet, health authorities' requirements for post-authorization safety studies. A 2-phase approach identified data sources from literature, publicly available registers of non-interventional post-authorization studies of pregnant women, existing database inventories, and emerging data sources known to the authors. Required key attributes were assessed according to current regulatory guidance, resulting in selection of 49 suitable data sources. All global regions were represented, with North America (37%) and Europe (33%) most common; 12% of the data sources included pregnancy information from low-to middle-income countries. Administrative healthcare claims (25%) and electronic healthcare records (21%) comprised the largest types of data sources. Across data sources, 53% were managed by national or regional governments, 27% by industry, and 20% by academic institutions. Maternal age, diagnoses, prenatal care, and reproductive history were available in most, whereas fewer included demographic data (e.g., race/ethnicity). Breastfeeding data were collected in 37% of the final data sources. We conducted a systematic approach to data source evaluation of pregnancy and breastfeeding to be used as a resource for investigators to consider when designing pregnancy-related research studies to satisfy regulatory requirements.

Review of Studies Evaluating Effectiveness of Risk Minimization Measures Assessed by the European Medicines Agency Between 2016 and 2021.

The European Medicines Agency (EMA) supervises medicines' safe and effective use throughout the product's life cycle by, for example, monitoring the implementation of risk minimization measures (RMMs). Limited information is available on factors associated with effectiveness of RMMs. This study reviews post-authorization safety studies (PASS) evaluating the effectiveness of RMMs assessed by the Pharmacovigilance Risk Assessment Committee (PRAC) between 2016 and 2021. PASS assessment reports finalized by PRAC between January 1, 2016, and December 31, 2021, were compiled from non-public EMA databases and PASS characteristics were extracted. Of the 93 PASS included, 62.4% aimed to measure healthcare professionals' awareness, knowledge, and behavior regarding RMMs. There were 67.7% of the 93 PASS that used primary data, 24.7% used secondary data sources, and 7.5% used both. A cross-sectional study design was most frequently applied (77.4%), followed by a cohort study design (29.0%). Nearly 40% of the included PASS did not render a conclusion on RMM effectiveness. Of the 60% that did render a conclusion, 82.1% were deemed effective. Only minor differences in characteristics were found when stratified by outcome (i.e., effective RMM, ineffective RMM, and no conclusion on RMM effectiveness). To conclude, 4 out of 10 PASS assessing impact of RMMs did not render a conclusion on RMM effectiveness. No clear differences in PASS characteristics were found in relation to their outcomes, indicating that additional research is needed to understand better the underlying reasons for PASS being inconclusive.

The characteristics and regulations of adaptive designs from 2008 to 2020: An overview of European Medicines Agency approvals.

The aim of this study was to identify and characterize all European Medicines Agency (EMA) approvals derived from adaptive designs in clinical trials and to provide an update of the current status of these drugs. Relevant files were identified in the EMA database for annual reports for the period between 2008 and 2020 using a list of suitable keywords related to adaptive designs. We recorded trial characteristics from drug approvals and used Fisher exact test to compare the characteristics. A total of 1,054 EMA approvals were identified, and the percentage of EMA approvals planned with adaptive trial designs increased from 1.85% in the period 2008-2012 to 6.19% in between 2017-2020. A total of 41 approvals were identified among 91 original EMA files that contained adaptive designs. The types of adaptive designs used in clinical trials increased after 2017 where the most common type used was the most common (17/41). Most approvals (32/41) comprised pivotal trials, and most assessments had not been accelerated (38/41). Of 32 confirmatory trials planned with adaptive designs, the proportion of those with additional monitoring (AM) increased significantly (p<0.0001) from 0% in the 2008-2012 period to 90.48% in the 2017-2020 period. The percentage of approved antitumor drugs in approved drugs in ongoing clinical trials was 82.35%, compared to 20.83% in trials that were completed (p=0.0001). The proportion of drug approved but where clinical trials were still ongoing in companies requiring post-authorization safety studies (PASSs) or post-authorization efficacy studies (PAESs) or who were granted conditional marketing authorization (CMA) significantly differed from the group of drugs approved where clinical trials were completed (p=0.0230). A trend showing an increased number of EMA approvals related to adaptive designs was observed for the period from 2008 to 2020. Different types of adaptive trial designs could be encouraged for the designation of clinical trials, especially for antitumor drugs; meanwhile, more stringent monitoring regulations seemed to be conducted for ongoing trials of antitumor drugs with adaptive design.

The readiness of the spontaneous reporting system for COVID-19 vaccines safety monitoring in Croatia.

We aimed to identify whether a spontaneous reporting system (SRS) in Croatia could timely identify and confirm signals for COVID-19 vaccines. Post-marketing spontaneous reports of adverse drug reactions (ADRs) following COVID-19 immunisation reported to the Agency for Medicinal Products and Medical Devices of Croatia (HALMED) were extracted and analysed. 6624 cases reporting 30 655 ADRs following COVID-19 immunisation were received from 27th December 2020 to 31st December 2021. Available data in those cases were compared with data available to the EU network at the time when signals were confirmed and minimisation measures were implemented. 5032 cases, reporting 22 524 ADRs, were assessed as non-serious, and 1,592 cases, reporting 8,131 ADRs as serious. The most reported serious ADRs, which were listed in the MedDRA Important medical events terms list, were syncope (n = 58), arrhythmia (n = 48), pulmonary embolism (n = 45), loss of consciousness (n = 43), and deep vein thrombosis (n = 36). The highest reporting rate had Vaxzevria (0.003), followed by Spikevax and Jcovden (0.002), and Comirnaty (0.001). Potential signals were identified, however, they couldn't be timely confirmed solely on cases retrieved by SRS. In order to overcome the limitations of SRS, active surveillance and post-authorisation safety studies of vaccines should be implemented in Croatia.

Post-Authorization Safety Studies of Acute Liver Injury and Severe Complications of Urinary Tract Infection in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting.

At the time of dapagliflozin's approval in Europe (2012) to treat patients with type 2 diabetes mellitus, concerns regarding acute liver injury and severe complications of urinary tract infection (sUTI) led to two post-authorization safety (PAS) studies of these outcomes to monitor the safety of dapagliflozin in real-world use. To investigate the incidence of hospitalization for acute liver injury (hALI) or sUTI (pyelonephritis or urosepsis) among patients initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). These two noninterventional cohort studies identified initiators of dapagliflozin and comparator GLDs in November 2012-February 2019 using data from three longitudinal, population-based data sources: Clinical Practice Research Datalink (UK), the HealthCore Integrated Research Database (USA), and the Medicare database (USA). Outcomes (hALI and sUTI) were identified with electronic algorithms. Incidence rates were estimated by exposure group. Incidence rate ratios (IRRs) were calculated comparing dapagliflozin to comparator GLDs, using propensity score trimming and stratification to address confounding. The sUTI analyses were conducted separately by sex. In all data sources, hALI and sUTI incidence rates were generally lower in dapagliflozin initiators than comparator GLD initiators. The adjusted IRR (95% confidence interval) pooled across data sources for hALI was 0.85 (0.59-1.24) and for sUTI was 0.76 (0.60-0.96) in females and 0.74 (0.56-1.00) in males. Findings from sensitivity analyses were largely consistent with the primary analyses. These real-world studies do not suggest increased risks of hALI or sUTI, and they suggest a potential decreased risk of sUTI with dapagliflozin exposure compared with other GLDs.

Federated analyses of multiple data sources in drug safety studies.

Studies of rare side effects of new drugs with limited exposure may require pooling of multiple data sources. Federated Analyses (FA) allow real-time, interactive, centralized statistical processing of individual-level data from different data sets without transfer of sensitive personal data. We review IT-architecture, legal considerations, and statistical methods in FA, based on a Swedish Medical Products Agency methodological development project. In a review of all post-authorisation safety studies assessed by the EMA during 2019, 74% (20/27 studies) reported issues with lack of precision in spite of mean study periods of 9.3 years. FA could potentially improve precision in such studies. Depending on the statistical model, the federated approach can generate identical results to a standard analysis. FA may be particularly attractive for repeated collaborative projects where data is regularly updated. There are also important limitations. Detailed agreements between involved parties are strongly recommended to anticipate potential issues and conflicts, document a shared understanding of the project, and fully comply with legal obligations regarding ethics and data protection. FA do not remove the data harmonisation step, which remains essential and often cumbersome. Reliable support for technical integration with the local server architecture and security solutions is required. Common statistical methods are available, but adaptations may be required. Federated Analyses require competent and active involvement of all collaborating parties but have the potential to facilitate collaboration across institutional and national borders and improve the precision of postmarketing drug safety studies.

Minority Patients in the US Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy: A SEER-Based Simulation on Representation and Impact of Proximity to Authorized Treatment Center (ATC)

Background Patients (pts) of minority race or ethnicity are often underrepresented in oncology clinical trials (Awidi et al. JCO Oncol Pract. 2021) despite differences in the incidence of most cancer types, including B-cell malignancies, across races and ethnicities (Teras et al. CA Cancer J Clin 2016; Feng et al. Am J Epidemiol 2021). Both clinical trials and real-world (RW) studies have demonstrated significant clinical benefits of CAR T-cell therapy for pts with B-cell malignancies. To understand potential underrepresentation of minority pts, we conducted a series of simulations to estimate proportions of minority pts potentially eligible for either CAR T-cell trials or receiving standard-of-care CAR T-cell therapy in RW settings. We also assessed whether proximity to a CAR T-cell ATC is a barrier for treatment. Methods Race/ethnicity demographics (mutually exclusive groups of non-Hispanic White [NHW], non-Hispanic Black [NHB], non-Hispanic Other [NHO], and Hispanic [any race]) for US pts ≥ 20 years old with large B-cell lymphoma (LBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and B-cell precursor acute lymphoblastic leukemia (B-ALL) were estimated for both trial and RW settings based on 5-year limited-duration prevalence prior to January 1, 2019 from the SEER Research Plus Data (17 registries, November 2021 submission), and US County Population Data (1969-2020). Estimated proportions and 95% confidence intervals (CIs) were simulated based on 3000 random samples per cancer type. Sample sizes for trial settings corresponded to US enrollment in clinical trials of axicabtagene ciloleucel (axi-cel) and brexucabtagene autoleucel (brexu-cel), while those for RW settings were based on accrual targets for post-authorization safety studies (PASS) using the CIBMTR registry (Table). Sampling was performed for counties within 50 miles [mi] of trial-associated ATCs or commercial ATCs for trial or RW settings, and for the entire US. Results As of January 1, 2019, approximately 177 million of 246 million people (72%) ≥ 20 years old lived within 50 mi of a commercial ATC in the US, of which 13% were NHB and 17% were Hispanic (Table). In clinical trial settings, the estimated proportion of NHB pts ≤ 50 mi of an ATC ranged from 5% in FL to 7% in LBCL (Table). The estimates were numerically higher, but not statistically significant, compared with actual enrollment in trials, except in B-ALL (7% [3%-12%] estimated vs 3% enrolled). Compared with actual trial enrollment, the estimated proportions (95% CI) of Hispanic pts were statistically higher across all indications (LBCL, 14% [10%-18%] estimated vs 7% enrolled; FL, 15% [9%-21%] estimated vs 5% enrolled; and B-ALL, 39% [30%-48%] estimated vs 29% enrolled) except in MCL (12% [4%-19%] estimated vs 15% enrolled). In RW settings, the estimated proportions of NHB pts were comparable to those in trial settings across all indications, whereas estimates of Hispanic pts were numerically lower (Table). The reported proportion of NHB pts with LBCL in PASS (5%) was statistically lower than the estimated proportion (8% [95% CI 7%-9%]). To further assess the impact of proximity to ATCs, the estimated proportions were compared between regions ≤ 50 mi of an ATC and the entire US. Proportions of NHB pts ≤ 50 mi of an ATC across all disease types were comparable with the estimates of the entire US, regardless of trial or RW settings (Table). While for Hispanic pts, the estimated proportions ≤ 50 mi of an ATC were numerically higher compared with the estimates of the entire US; but the estimates were comparable in RW settings. Conclusions This is the first simulation study to estimate the proportions of minority pts by considering disease prevalence and proximity to CAR T-cell ATCs. The possibility of patient underrepresentation is raised as the actual enrolled proportions of minority pts with certain B-cell malignancies were numerically lower than simulation-based estimates, even though most findings were not statistically significant. Based on the simulation, the estimated proportions of minority pts were comparable or even higher in regions close to ATCs indicating that proximity to ATCs may not be a key barrier for trial participation and accessibility of care. Further investigation into other factors influencing diversity in trials and accessibility of state-of-the-art cancer care in RW settings is warranted. MG and Z-HH contributed equally. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Postauthorization safety study of betaine anhydrous

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N=54) and partially responsive (N=7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N=21) deficiency and cobalamin C (N=48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

Regulator-Requested Non-Interventional Postauthorization Safety and Effectiveness Studies for Oncology Drugs: A Systematic Review.

There has been a growing number of oncology drug approvals. Non-interventional postauthorization safety/effectives studies (PASSs/PAESs) aim to provide real-world evidence on the safety/effectiveness of oncology drugs postapproval. To understand the current landscape, a comprehensive search as of March 1, 2021, was conducted in major register/databases. We found that requested studies increased from 1 in 2006-2010 to 47 in 2016-2020. Of 78 total studies identified, 50 focused on safety/risk assessment (64.1%), 6 on effectiveness (7.7%), 3 on drug utilization (3.8%), 1 on disease epidemiology (1.3%), and 18 on effectiveness of additional risk minimization measures (23.1%). For safety/risk assessment studies, 58.9% focused on nonspecific end points (e.g., frequency of adverse events). For effectiveness studies, the leading primary outcome was overall survival. Overall, safety/risk assessment studies concerning nonspecific end points for vascular endothelial growth factor (receptor) inhibitors were most requested. Regarding data sources, though a majority (71.8%) used primary data collection, a growing proportion utilized secondary data sources. Among 23 studies with information available on study design, 10 (43.5%) were single-arm cohort studies, 9 (39.1%) were cross-sectional studies, 3 (13.1%) were comparative cohort studies, and 1 (4.3%) was a nested-case-control study. In conclusion, there was an increasing number of oncology-specific non-interventional PASSs/PAESs, with a majority on safety/risk assessment. Although most utilized primary data collection, there was an increasing use of secondary real-world data sources. Few conducted comparative analyses, and most used single-arm designs. Future efforts are needed to assess how findings of these studies would impact regulatory decisions and improve knowledge of toxicity for clinical/translational development.

Safety and Persistence of Nalmefene Treatment for Alcohol Dependence. Results from Two Post-authorisation Safety Studies.

AimsTwo post-authorisation studies assessed the safety and persistence of patients’ use of nalmefene.MethodsThe START study (EUPAS5678) was a non-interventional, multi-country, prospective, 18-month (8 follow-up visits) cohort study including outpatients initiating nalmefene for the first time. The multi-database retrospective cohort study (MDRC, EUPAS14083) included baseline and follow-up data from German, Swedish and UK healthcare databases. Both studies permitted ‘all comers’ without explicit exclusion criteria; predefined subgroups of interest included the elderly (≥65 years) as well as patients with significant psychiatric and/or somatic comorbidities.ResultsSTART study: Overall, the mean duration of nalmefene treatment was 10.3 ± 7.3 months (N = 1348), with 49.0% of patients treated for ≥1 year; frequent reasons for treatment discontinuation were ‘goal reached’ and ‘drug cost’. The most frequently reported adverse drug reactions (ADRs) were nausea (4.7%), dizziness (3.2%) and insomnia (2.0%). ADR rates appeared higher in the elderly subpopulation (18.6% reported ≥1 ADR vs. 12.0% in the total population) but were not higher in the other predefined subgroups.MDRC study: The database follow-up analysis followed 2892 patients over 18 months for whom the duration of nalmefene treatment was between 2 and 3 months and <5% of patients used nalmefene for ≥1 year.ConclusionsDespite the inclusion of a wider patient population (e.g. elderly patients and those with relevant co-morbidities), the safety and tolerability profile of nalmefene given in routine practice was consistent with previous clinical studies. The differing rates of persistence beyond 1 year likely reflect the different methodologies and highlight the relevance of psychosocial support at follow-up visits.

Long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease: aggregate data from two post-authorization safety studies

ABSTRACT Background Enzyme replacement therapy in Fabry disease has been available in Japan since 2004. Two post-authorization safety studies were conducted to evaluate agalsidase beta in Japanese patients with Fabry disease in real-world practice. Research Design and Methods The Special Drug Use Investigation monitored the long-term safety and efficacy of agalsidase beta, and the Drug Use Investigation monitored safety in patients not participating in the Special Drug Use Investigation. Safety and efficacy evaluations included adverse drug reactions (ADRs), infusion-associated reactions and hypersensitivity reactions, and change in blood GL-3 level over time. Results Of 396 patients in the aggregated data set, safety and efficacy analysis sets comprised 307 and 196 patients, respectively. ADRs occurred in 93 (30.3%) patients and serious ADRs occurred in 25 (8.1%) patients, with general disorders and administration site conditions (n=55, 17.9%), nervous system disorders (n=30, 9.8%) and skin and subcutaneous tissue disorders (n=23, 7.5%) the most common. Reductions in blood GL-3 levels occurred over the study, irrespective of age or disease phenotype. Conclusions Agalsidase beta demonstrated acceptable safety and tolerability, with sustained reductions in blood GL-3 levelsin Japanese patients with Fabry disease in real-world clinical practice Clinical Trial Registration NCT00233870/AGAL03004 (Special Drug Use Investigation of Agalsidase beta)

Editorial introductions

Editorial introductions

Italian multiple sclerosis register as the basis for post-authorization safety studies

Abstract While the safety and efficacy of Disease Modifying Therapy (DMT) in multiple sclerosis (MS) are assessed in clinical trials, these are of relatively short duration and always confined to highly selected patient groups. The evaluation of real-world data such as patient registries, is vital as it offers long-term data collection and is patient rather than product-focused during the lifetime of MS, and allows to document a patient's treatment history throughout the disease course. Patient registries can play an important role in monitoring the safety of drus. Regulators and the pharmaceutical industry have shown interest in complementing or even replacing phase 4 clinical studies with data from MS registries. The Italian MS Register (IMSR), in collaboration with the Big MS Data initiative, that also includes the national MS registries of Denmark, France, and Sweden and the international database network MSBase, came together with industry to conduct studies on post-authorization safety (PASS) and treatment effectiveness. The IMSR includes the clinical history of approximately 55,000 patients, or approximatively 45% of the estimated cases of MS in Italy. More than 10,000 patients have a follow-up duration of over 10 years. A Core Protocol outlining principles of PASS projects was created in which aggregated results made available to sponsors and health authorities. The Core Protocol specifies variables, emphasizes improved capture of adverse events, in particular cancer, non-melanoma skin cancers and immunosuppression-related infections, all MedDRA-coded. EUROCAT codes for pregnancy outcomes are also documented. Regulators, the pharmaceutical industry and national-level registries have jointly identified a format of collaboration on PASS for DMT in MS to benefit patients and the larger society. In this way, we hope to contribute to a framework that will include emerging and existing registries with the common goal of contributing to the advancement of knowledge in MS. Key messages The real-world data can contribute to understanding of the impact of disease-modifying therapy on long term. A format of collaboration among clinical research, regulators and pharmaceutical industry could be a winning framework to improve the knowledge on safety and treatment effectiveness in MS.

Drug Safety in Pregnancy: Review of Study Approaches Requested by Regulatory Agencies

We reviewed postauthorization pregnancy safety studies requested by regulatory agencies to explore which study approaches have been typically requested and to what extent these have changed over time. The most common study approach requested by the US Food and Drug Administration (FDA) is pregnancy exposure registries (observational cohorts with prospective data collection), per the FDA’s Postmarketing Requirements and Commitments (PMR/PMC) database. Since 2017, this requirement has often been paired with a request for a database study (observational study using preexisting electronic health care data), both approaches assessing pregnancy and fetal outcomes. From studies registered in the European Union electronic Register of Post-Authorisation Studies, we observed a similar number of pregnancy exposure registries and database studies, both approaches also assessing pregnancy and fetal outcomes. In requests for drugs approved since 2014, preference appears to have shifted toward studies using preexisting electronic health care databases from multiple countries. Pregnancy exposure registries have been the most commonly requested study approach on drug safety in pregnancy. Recent regulatory requests and activities denote an increasing interest in other approaches.