scholarly journals P11 Neonatal and paediatric protocol development and drug safety: points to consider for risk management and safety data collection

2019 ◽  
Vol 104 (6) ◽  
pp. e21.2-e22
Author(s):  
B Aurich ◽  
V Elie ◽  
E Jacqz-Aigrain
Keyword(s):  
Risk Management ◽  
Clinical Trials ◽  
Data Collection ◽  
Drug Safety ◽  
Safety Profile ◽  
Safety Data ◽  
Age Group ◽  
Baseline Trial ◽  
Paediatric Drug ◽  
Protocol Development

BackgroundProtocol development for neonatal or paediatric clinical trials needs to take into account the age group specifics of the study population (e.g. pharmacokinetics, reference values for laboratory data and vital signs). Drug safety and risk management for neonatal/paediatric trials require an understanding of how these change throughout childhood. We were interested in reviewing and summarising the literature to identify publications which provide researchers with practical information of how the neonatal/paediatric drug safety profile informs age group specific safety data collection and risk management in the protocol.MethodsPubmed, Embase and regulatory authority (RA) websites were searched for publications up to 31/12/2018 for children (0–18 years). In addition, the bibliography of included publications was reviewed to identify additional publications.ResultsRA websites provided general and disease specific guidance on neonatal/paediatric clinical trials with sections relating to drug safety. No publication was identified describing the practicalities of how the neonatal/paediatric drug safety profile can be included throughout the various sections of a clinical trial protocol. The existing literature was summarised providing an overview of how the neonatal/paediatric drug safety profile supports the development of the various protocol sections. For example laboratory values in the exclusion criteria and safety monitoring sections need to be adjusted for age. Vital sign and psychomotor assessment should be done at least at baseline, trial completion and follow-up. Monitoring of adverse events of interest requires consideration of how these may present in neonatal/paediatric patients.ConclusionsIn order to support the protocol development with regards to neonatal/paediatric drug safety a dual competence in both paediatrics and drug safety is required. This review provides an overview of the practical aspects related to neonatal/paediatric drug safety during protocol development.Disclosure(s)Nothing to disclose

scholarly journals C4C - Paediatric pharmacovigilance: Methodological Considerations in Research and Development of Medicines for Children – A c4c Expert Group White Paper

2021 ◽  
Author(s):  
Beate Aurich ◽  
Dina Apele-Freimane ◽  
Tobias Banaschewski ◽  
Laurent Chouchana ◽  
Simon Day ◽  
...  
Keyword(s):  
Life Cycle ◽  
Data Collection ◽  
Safety Data ◽  
Expert Group ◽  
Medicinal Products ◽  
Paediatric Drug ◽  
Protocol Development ◽  
Spontaneous Reports ◽  
Data Collection And Analysis ◽  
Methodological Considerations

Children frequently respond differently to therapies compared to adults. Differences also exist between paediatric age groups for pharmacokinetics and pharmacodynamics in both efficacy and safety. Paediatric pharmacovigilance requires an understanding of the unique aspects of children with regards to, for example, drug response, growth and development, clinical presentation of adverse drug reactions (ADRs), how they can be detected and population specific factors (e.g. more frequent use of off-label/unlicensed drugs). In recognition of these challenges a group of experts has been formed in the context of the conect4children (c4c) project to support paediatric drug development. This expert group collaborated to develop methodological considerations for paediatric drug safety and pharmacovigilance throughout the life-cycle of medicinal products which is described in this article. These considerations include practical points to consider for the development of the paediatric section of the risk management plan (RMP), safety in paediatric protocol development and safety data collection and analysis. Furthermore, they describe the specific details of post-marketing pharmacovigilance in children using, for example, spontaneous reports, electronic health care records, registries and record-linkage, as well as the use of paediatric pharmacoepidemiology studies for risk characterisation. Next the details of the assessment of benefit-risk and challenges related to medicinal product formulation in the context of a Paediatric Investigation Plan (PIP) are presented. Finally, practical issues in paediatric signal detection and evaluation are included. This paper provides practical points to consider for paediatric pharmacovigilance throughout the life-cycle of medicinal products for RMPs, protocol development, safety data collection and analysis and PIPs.

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

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Junhao Liu ◽  
Jo Wick ◽  
Renee’ H. Martin ◽  
Caitlyn Meinzer ◽  
Dooti Roy ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Safety ◽  
Safety Data ◽  
Safety Monitoring ◽  
Safety Signal ◽  
Two Stage ◽  
Bayesian Hierarchical ◽  
Potential Safety ◽  
Stage 1

Abstract Background Monitoring 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. Methods In 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. Results Any 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. Conclusions The 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.

Safety profile of poxviral vaccines: NCI experience.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 85-85
Author(s):  
Joseph W. Kim ◽  
Jennifer L. Marte ◽  
Marijo Bilusic ◽  
Nishith K. Singh ◽  
Christopher Ryan Heery ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Safety Profile ◽  
Specific Antigen ◽  
Safety Data ◽  
Treatment Modalities ◽  
Mucin 1 ◽  
Serious Adverse Events ◽  
Scientific Review ◽  
Gm Csf

85 Background: Recombinant poxviruses have been developed as therapeutic cancer vaccines. Here, we report the safety data from NCI clinical trials with poxviral vaccines. Methods: We evaluated all vaccine injections from 215 patients in 8 clinical trials involving poxviral viral vaccines. The Office of Biotechnology Activities, National Cancer Institute (NCI) Institutional Review Board, and NCI Scientific Review Committee approved all of these trials. Vaccines were consisted of recombinant vaccinia and recombinant fowlpox encoded with 3 human costimulatory molecules (TRICOM), and prostate specific antigen (PSA), or carcinoembryonic antigen, and/or mucin-1. Vaccines were administered at doses between 1.2x108 to 2x109 pfu, subcutaneously, in all patients. Twenty-one patients were also vaccinated intra-tumorally. 84 patients also received other concurrent treatment modalities, such as radiation, celecoxib, ipilimumab, samarium-153, or flutamide on 4 of these trials. All 8 clinical trials involved granulocyte-macrophage colony-stimulating factor (GM-CSF) 100mcg, or recombinant fowlpox encoding GM-CSF at 1x 108pfu as an immune adjuvant. Here, we report here the grade 2 or higher adverse events given at least a possible attribution to vaccine. Results: A total of 1,348 poxviral injections were given in 215 patients. No contact transmission, inadvertent inoculation, or any serious adverse events (AEs) related to vaccinia was observed. Below is the summary of proportion of vaccine administrations associated with specific AEs. Conclusions: These data demonstrate a favorable safety profile of the poxviral vaccines at a broad range of doses, routes of administration, in combination with other treatments, and in various tumor types. Clinical trial information: NCT00060528, NCT00096551, NCT00088413, NCT00081848, NCT00113984, NCT00450619, NCT00450463. [Table: see text]

scholarly journals Evaluation of the safety profile of COVID-19 vaccines: a rapid review

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qianhui Wu ◽  
Matthew Z. Dudley ◽  
Xinghui Chen ◽  
Xufang Bai ◽  
Kaige Dong ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Safety Profile ◽  
Meta Analysis ◽  
Safety Data ◽  
Rapid Review ◽  
Protein Subunit ◽  
Serious Adverse Events ◽  
Systemic Reactions ◽  
Reporting Rates

Abstract Background The rapid process of research and development and lack of follow-up time post-vaccination aroused great public concern about the safety profile of COVID-19 vaccine candidates. To provide comprehensive overview of the safety profile of COVID-19 vaccines by using meta-analysis technique. Methods English-language articles and results posted on PubMed, Embase, Web of Science, PMC, official regulatory websites, and post-authorization safety surveillance data were searched through June 12, 2021. Publications disclosing safety data of COVID-19 candidate vaccines in humans were included. A meta-analysis of proportions was performed to estimate the pooled incidence and the pooled rate ratio (RR) of safety outcomes of COVID-19 vaccines using different platforms. Results A total of 87 publications with safety data from clinical trials and post-authorization studies of 19 COVID-19 vaccines on 6 different platforms were included. The pooled rates of local and systemic reactions were significantly lower among inactivated vaccines (23.7%, 21.0%), protein subunit vaccines (33.0%, 22.3%), and DNA vaccines (39.5%, 29.3%), compared to RNA vaccines (89.4%, 83.3%), non-replicating vector vaccines (55.9%, 66.3%), and virus-like particle vaccines (100.0%, 78.9%). Solicited injection-site pain was the most common local reactions, and fatigue and headache were the most common systemic reactions. The frequency of vaccine-related serious adverse events was low (< 0.1%) and balanced between treatment groups. Vaccine platforms and age groups of vaccine recipients accounted for much of the heterogeneity in safety profiles between COVID-19 vaccines. Reporting rates of adverse events from post-authorization observational studies were similar to results from clinical trials. Crude reporting rates of adverse events from post-authorization safety monitoring (passive surveillance) were lower than in clinical trials and varied between countries. Conclusions Available evidence indicates that eligible COVID-19 vaccines have an acceptable short-term safety profile. Additional studies and long-term population-level surveillance are strongly encouraged to further define the safety profile of COVID-19 vaccines.

Long-Term Efficacy and Safety with Deferasirox (Exjade®, ICL670), a Once-Daily Oral Iron Chelator, in Pediatric Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2774-2774 ◽  
Author(s):  
Antonio Piga ◽  
Elliott Vichinsky ◽  
Gian Luca Forni ◽  
Yurdanur Kilinc ◽  
Henry Maseruka ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Sexual Development ◽  
Safety Profile ◽  
Pediatric Patients ◽  
Negative Impact ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Old Patients ◽  
Term Efficacy

Abstract Background: Children with transfusion-dependent anemias will usually require lifelong iron chelation therapy. Establishing the long-term efficacy and safety profile of deferasirox is critically important in children. Presented here are cumulative long-term efficacy and safety data from a cohort of children treated with deferasirox in ongoing clinical trials. Methods: Pediatric patients (<16 years old) with β-thalassemia, sickle cell disease or other transfusion-dependent anemias were enrolled in 4 clinical trials and treated for 1 year with deferasirox (studies 106/108) or randomized to either deferasirox or deferoxamine (DFO; 107/109). Study treatment was extended for 4 years (extension phases); patients either continued deferasirox (deferasirox cohort) or crossed over from DFO to deferasirox (crossover cohort). Doses in the extensions were adjusted based on efficacy and safety parameters. Efficacy was monitored via serum ferritin (SF); safety was assessed by the incidence and type of AEs. Growth and sexual development were evaluated every 6 months. Results: 434 patients aged 2–<16 years (n=289 deferasirox cohort; n=145 crossover cohort) entered the extensions. In the deferasirox and crossover cohorts, respectively, 50 and 20 pediatric patients were ≥2–<6 years old, 123 and 69 were 6–<12 years old, and 116 and 56 were ≥12–<16 years old. Patients in the deferasirox cohort have received treatment for a median 3.5 years. Mean (SD) doses were 9.5 (1.6), 19.5 (2.6) and 29.6 (2.5) mg/kg/d in the 5/10, 20 and 30 mg/kg/d groups at month 1, respectively, and 22.9 (7.7), 24.6 (7.6) and 26.3 (9.5) mg/kg/d at month 42. Until month 12, median SF levels were maintained in the 20 mg/kg/d cohort, decreased in the 30 mg/kg/d cohort and increased in the 5/10 mg/kg/d cohort. After dose escalations at month 12, median SF levels fell below baseline at month 42 in all cohorts (Table). 390 (90%) children continue to receive deferasirox. Of 43 discontinuations, 22 were due to AEs. Two deaths, both considered unrelated to treatment, occurred in the deferasirox cohort. The most common drug-related AEs, including vomiting (n=26), nausea (n=25), abdominal pain (n=21), diarrhea (n=19) and mild/moderate skin rash (n=35), occurred mainly in the core phases. There were no significant changes in markers of liver function in the extension phases and no cases of progressive increases in serum creatinine. Physical and sexual development proceeded normally in all children. Conclusions: Over a median period of 3.5 years, treatment with deferasirox provided dose dependent overall reduction in iron burden in transfusion-dependent children, as measured by SF levels. Deferasirox had a manageable safety profile in children, which was similar to that observed in the 1-year core trials. There was no negative impact on growth and sexual development. Median SF values (ng/mL) in children (deferasirox cohort) Initial dose, mg/kg/d Month 5/10 20 30 All n=129 n=89 n=74 n=292 *Dose adjustments Baseline 2126 2504 3491 2420 1 2041 2488 2976 2451 6 2394 2724 2678 2460 12* 2653 2602 2608 2618 18 3037 2480 2271 2771 24 2929 2651 2106 2522 30 2747 2404 2007 2440 36 1967 1916 2008 1970 42 1830 1812 1889 1831

Analysis of Drug Safety Data From Clinical Trials

2002 ◽  
Vol 36 (1) ◽  
pp. 157-162
Author(s):  
Andrzej Czarnecki ◽  
Katarzyna Zalewska
Keyword(s):  
Clinical Trials ◽  
Drug Safety ◽  
Safety Data

scholarly journals Teduglutide for the treatment of adults with intestinal failure associated with short bowel syndrome: pooled safety data from four clinical trials

2020 ◽  
Vol 13 ◽  
pp. 175628482090576 ◽  
Author(s):  
Ulrich-Frank Pape ◽  
Kishore R. Iyer ◽  
Palle B. Jeppesen ◽  
Marek Kunecki ◽  
Loris Pironi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Short Bowel Syndrome ◽  
Safety Profile ◽  
Safety Data ◽  
Intestinal Failure ◽  
Abdominal Distension ◽  
Clinical Trial Registry ◽  
Data Set ◽  
Short Bowel ◽  
Patient Groups

Background: In multiple clinical studies, teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome–associated intestinal failure (SBS–IF). The objective of this study was to assess adverse events (AEs) from a pooled data set. Methods: Safety data from four prospective clinical trials of teduglutide in patients with SBS–IF were assimilated. AEs were evaluated in patient groups based on treatment received in each study and in populations stratified to create distinct subgroups based on aetiology, bowel anatomy and baseline PS volume requirements. Results: Safety data are reported for up to 2.5 years, totalling 222 person-years exposure to teduglutide. In most patients, AEs were reported as mild or moderate in severity in all patient groups and occurred at comparable rates between patients who received teduglutide or placebo. Several common gastrointestinal AEs, including abdominal pain, nausea and abdominal distension, were reported more frequently earlier in the course of treatment, with their frequency declining over time. Fewer gastrointestinal AEs were reported in patients with vascular causes of SBS–IF and patients with most of their colon-in-continuity than in other patient subgroups. Across the patient stratification subgroups, the predominant treatment-emergent AEs for which patients receiving teduglutide had a significantly increased relative risk were abdominal distension and gastrointestinal stoma complication compared with patients receiving placebo. Conclusions: Teduglutide had a safety profile consistent with prior adult data and no new safety concerns were identified. The most frequently reported AEs were gastrointestinal in origin, consistent with the underlying disease condition and intestinotrophic actions of teduglutide. Clinical Trial Registry information: NCT00081458/EudraCT, 2004-000438-35; NCT00798967/EudraCT, 2008-006193-15; NCT00172185/EudraCT, 2004-000439-27; NCT00930644/EudraCT, 2009-011679-65

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