Applicable Regulatory Requirements Research Articles

STANDARDIZATION AS AN INTEGRAL COMPONENT OF THE QUALITY MANAGEMENT SYSTEM IN AN ENTERPRISE

It was conducted an analysis of the impact of standardization, as an integral and important component of the quality management system of the State Enterprise “State Road Transport Research Institute”, on the enterprise’s scientific and industrial-and-economic activities, in particular from the viewpoint of maintaining its competitiveness on the of road transport services market. Standardization, as a type of the State Road Transport Research Institute’s activity, is aimed at achieving the optimal degree of orderliness in the regulatory support of the enterprise’s activities. In accordance with its Policy, the enterprise ensures high-quality performance of work by providing services that meet customer requirements and also applicable legislative and regulatory requirements. It has been considered the standardization activity in the State Road Transport Research Institute, which can be conditionally presented in four separate directions. The first direction is, in general, the organizational work for standardization. This also includes work on the development of normative documents of the enterprise, as well as national standards harmonized with international ones, and revision of current normative documents. Another direction is related to maintaining and updating the fund of normative documents of the enterprise, including the fund of normative documents of the Inland Transport Committee of the UN Economic Commission for Europe. And finally, important from the point of view of the enterprise’s image, the direction of agency activity and also the activity of the Secretariat of the Technical Committee of Standardization TC 80 “Road transport”, the functions of which is entrusted to State Road Transport Research Institute.

Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials

IntroductionImmunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While...

Non-ischaemic preservation of the donor heart in heart transplantation: protocol design and rationale for a randomised, controlled, multicentre clinical trial across eight European countries

IntroductionIschaemic cold static storage (ICSS) is the gold standard in donor heart preservation. This ischaemic time frame renders a time constraint and risk for primary graft dysfunction. Cold oxygenated heart...

An Open Label Study Comparing Photobiomodulation Therapy to Cryotherapy in Patients at High Risk for Drug-Induced Oral Mucositis

Background and rationale Oral mucositis (OM) is one of the most common side effects of chemotherapy and may lead to weight loss and increased risk for infection ultimately impairing overall survival. Evaluated options for mucositis prophylaxis in patients receiving a high-dose chemotherapy include oral cryotherapy (CT) and photobiomodulation therapy (PBMT) using laser diodes to reduce incidence and severity of OM. However, standards of mucositis prophylaxis in German hospitals differ substantially. While CT has been standard of care in melphalan treated patients, the German guidelines for supportive oncology do not recommend the use of PBMT for patients receiving high-dose chemotherapy. Several clinical trials have demonstrated the beneficial effect of PBMT, however, no randomized clinical trials (RCT) exist to compare the efficacy of oral CT versus PBMT. Study design This is a single-center, open-label, randomized, two-arm interventional trial to evaluate the efficacy of PBMT and CT as prophylaxis of OM in patients with hematological malignancies receiving high-dose chemotherapy as part of a conditioning regimen prior to hematopoietic cell transplantation (HCT) or high-dose methotrexate (MTX, defined as ≥ 500 mg/m 2). Randomization will occur 1:1, stratified according to conditioning regimen/chemotherapy protocol. The primary endpoint of the trial is rate of severe OM as assessed by the world health organization (WHO) OM grading scale grade 3 or higher. Key secondary endpoints include duration of OM, patient reported pain, total parenteral nutrition, opioid usage, weight loss, length of in-patient stay and overall survival. Eligible patients randomized to receive PBMT will undergo daily laser therapy at 4 J/cm² of the oral mucosal areas most frequently affected by OM, starting on the first day of the administration of chemotherapy, until neutrophil engraftment or resolution of OM, whatever occurs first. Eligible patients randomized to oral CT will receive ice chips (IC) made from filtered tap water or flavored ice popsicles on days of chemotherapy infusions only, starting 5 min prior to chemotherapy until 30 min after the end of infusion. Patients ≥ 18 years of age, receiving therapies with high potential to induce OM, including the conditioning regimen high-dose melphalan, carmustine/etoposide/cytarabine/melphalan (BEAM), thiotepa/etoposide/cytarabine/melphalan (TEAM), fludarabine/thiotepa/melphalan (FTM) and fludarabine/melphalan (FM) or chemotherapy protocols with high-dose MTX, are included in this trial. The trial tests the null hypothesis (H 0) that the observed rate of severe OM with PBMT and CT prophylaxis are equal versus the alternative hypothesis (H 1) that the observed rate of severe OM differs between CT and PBMT. We estimate a rate of severe OM of 45 % in our trial population (H 0). With a power of 80 %, a type 1 error rate of 5 %, and an expected difference in severe OM rate of 30 % considered relevant between both arms, with an expected dropout rate of 5 %, n = 86 patients should participate in the study to ensure discrimination of H 0 and H 1. Conclusion This study aims to compare PBMT and CT with regard to their effectiveness in the prevention of severe OM in a randomized trial for the first time. Our objective is to provide data that may guide the development of a standardized OM prophylaxis for patients undergoing high-dose chemotherapy. At the time of abstract submission, 8 patients have been randomized in the study. Acknowledgments This is an independent academic trial conducted under the sponsor role of the University Cancer Center Schleswig-Holstein, Germany. This study is conducted in compliance with the protocol, Good Clinical Practice (GCP), all applicable regulatory requirements and the ethical principles of the Declaration of Helsinki.

Siting tidal energy projects through resource characterization and environmental considerations

The development of tidal energy technologies has progressed to where devices can be deployed, operated, maintained, and recovered with some level of assurance that they will and produce adequate levels of power. Equally important to further the tidal energy industry is the ability to site and gain regulatory permission to deploy and operate these devices. This paper sets out a framework for reaching preliminary siting of tidal devices, drawing from case studies from three locations in the US where research studies have provided information in support of tidal deployments.
 Through the TEAMER funding opportunity in the US, tidal energy device and project developers were able to engage US Department of Energy national laboratory scientists and engineers to provide technical assistance for investigating potential tidal deployment sites within US waters. The bodies of water of interest had already been determined by the proponents at the start of the project and constraints and opportunities within those bodies of water were examined to optimize siting capabilities for the developers. Using numerical models and field observations, we characterized tidal resources at a scale that will allow for optimization of energy extraction. We examined the natural and human infrastructure constraints for deploying and operating tidal devices and arrays including channel widths, bathymetry, vessel traffic, ferry lanes, and grid interconnects, in order to narrow siting options. We also examined the biological resources in the water bodies of interest, with a focus on populations of endangered marine mammals and fish, and the critical habitats that support them. The biological resources were then related to the applicable regulatory requirements in place in US for federal and state statutes in areas where the tidal applicants wish to deploy. Based on these analyses, preferred deployment locations were delineated and processes for meeting regulatory requirements laid out, including post-installation monitoring plans that will be needed. This initial assessment of logistical, regulatory, and environmental conditions for the deployment of a tidal technology is a first step toward the achievement of regulatory compliance for tidal energy projects.
 Three locations were considered for tidal energy development in the US. The first one included the area around an archipelago of islands in the northern portion of Washington State, near the US-Canada border, with the intent of installing one or more floating tidal devices to add energy resilience and independence for the single utility that services the isolated islands. The second location was in the coastal waters of Maine where tidal power would be added to the local electrical grid. The third location was in Cook Inlet, Alaska, where the applicant seeks to deploy multiple floating tidal devices to provide renewable energy in place of conventionally generated power for the city of Anchorage.

Pendampingan Pembuatan NIB UMKM melalui Sistem Online Single Submission (OSS) di Kelurahan Karangtengah

Legality is the identity of a business to legalize a business so that it can be recognized by the public. Business legality is very important for Micro, Small and Medium Enterprises (MSMEs) because it can provide many benefits. To obtain complete and legal business legality, MSMEs must fulfill all applicable legal and regulatory requirements. The Thematic Real Work Lecture (KKNT) activities for MSMEs in Karangtengah Village involve several MSMEs that have been recorded and surveyed. The purpose of this community empowerment program itself is so that business actors can better understand the importance of NIB and can take advantage of government programs that can facilitate online legality permits. After registering business legality, it is hoped that business actors will consider the importance of licensing business entities, there needs to be more attention to training and socialization of business licensing in Karangtengah Village.

The Metreleptin Effectiveness and Safety Registry (MEASuRE): concept, design and challenges

BackgroundMetreleptin, a recombinant analog of human leptin, is an approved therapy, adjunct to diet, to treat the metabolic complications of leptin deficiency in patients with lipodystrophy – a group of rare diseases characterized by a paucity of adipose tissue. MEASuRE (Metreleptin Effectiveness And Safety Registry) is a post-authorization, voluntary registry that gathers long-term safety and effectiveness data on metreleptin. Here, we present the aims and evolution of MEASuRE.MethodsMEASuRE was established to collect data from patients receiving commercially supplied metreleptin in the United States (US) and European Union (EU). MEASuRE aims to determine the incidence and severity of safety events and describe the clinical characteristics and therapeutic outcomes in the metreleptin-treated population. A key feature of MEASuRE is that it accumulates data from different sources to meet post-authorization objectives. US data are received directly from treating physicians via a contract research organization-mediated electronic data capture system. In the EU, data are received via the European Registry of Lipodystrophies managed by the European Consortium of Lipodystrophies (ECLip), a platform established by researchers and physicians to advance the knowledge of lipodystrophy. MEASuRE complies with applicable regulatory requirements governing privacy, and the storage, management, and access of data.ResultsLeveraging processes, infrastructure, and data from the ECLip registry presented several challenges that were addressed during MEASuRE’s development, including the expansion of the ECLip registry to accommodate MEASuRE-specific data elements, extensive data matching processes to ensure data consistency regardless of source, and rigorous data validation following the amalgamation of global data. Through the support of ECLip, MEASuRE is now a fully operational registry with the capacity for gathering and integrating standardized US- and EU-derived data. As of 31st October 2022, 15 US and four EU sites have participated in the MEASuRE, enrolling 85 patients globally.ConclusionsOur experiences show that a post-authorization product registry can be successfully integrated into an existing patient registry. We propose that, through collaboration with existing registries and use of their established resources, patient enrolment timelines and data collection for new registries can be expedited. The learnings presented here may be applicable to other registries with similar objectives.Trial registrationNCT02325674; Registered 25 December 2014 - Retrospectively registered’. https://clinicaltrials.gov/ct2/show/NCT02325674.

High-level disinfection, sterilization, and hand hygiene: What do accreditation surveyors want to see?

Health care organizations accredited by the Joint Commission should follow a standardized approach to the development of infection prevention and control-related processes, policies, and protocols. This approach should start with applicable regulatory requirements and may incorporate evidence-based guidelines and consensus documents chosen by the Health care organizations. Surveyors follow this approach when assessing compliance.

IMPLEMENTASI KEBIJAKAN MEMENUHI KETERWAKILAN PEREMPUAN PADA PEMILIHAN UMUM LEGISLATIF TAHUN 2019 DI KABUPATEN BIAK NUMFOR

The purpose of this study is to describe and find out the implementation of policies to fulfill women's representation in the 2019 legislative general election in Biak Numfor Regency and also to find out the level of supporters and obstacles in fulfilling women's representation in Biak Regency. The type of research used in this study is descriptive qualitative. Data collection techniques used in collecting research data are in-depth interviews, observation, and document studies. The results of the research on Policy Implementation meet the representation of women in the Biak Numfor district. The implementation of the policy on the placement or implementation of women's representation in the general election of the legislature requires the need for gender justice in party management and implementing a 30% quota policy for women's representation in the list of legislative candidates. Power interests and strategies involved in policy implementation. It is also necessary to take into account the strengths of the actors involved to facilitate a policy. Inhibiting and supporting factors in implementing policies to fulfill women's representation are more on structural, institutional, and cultural constraints that must be more organized so that they can provide sufficient space for an applicable regulatory requirement so that it can meet the requirements in implementation. election

A Systematic Review on Clinical Research and Approval Process

Drug discovery is a key step or process by which lead molecule is been optimized for further preclinical and clinical trial studies. Drug development process involves target identification, target validation, lead identification, and lead optimization. Once the lead molecule is optimized the HIT compound is been analyzed further in preclinical trial in animals and clinical trial in human subjects. The development of a new drug till marketing authorization should gone through several stages in order to make the drug safe, effective and should posses best quality to get approve for applicable regulatory requirements. The overall theme of our article is to review and state the process from drug discovery to approval for marketing of drug. The process from drug discovery till marketing authorization is time taking, complex and expensive so each target should be consider for development of new drug and new research tools must be used for any new drug development process. It takes around 10-15 years and US$ 1 billion for a new lead compound to make it as a medicine and to get marketing approval for general public use. On an average million lead molecules are been scrutinized to make a HIT compound, so that it can be use for further preclinical and clinical studies to make it available in market. This article provides a brief outline on stages from drug development to clinical research.

Patient-reported well-being in value-based care using tildrakizumab in a real-world setting: protocol of a multinational, phase IV, 1-cohort prospective observational study (the POSITIVE study)

IntroductionPsoriasis is a chronic inflammatory skin disease that negatively impacts the quality of life of patients and their families. However, the most commonly used decision-making tools in psoriasis, Psoriasis Area...

Use of Machine Learning to classify clinical research to identify applicable compliance requirements

Background and objectiveDifferent regulatory requirements apply for clinical research activities, thus identifying the applicable regulatory requirements is one of the cornerstones of regulatory compliance. Typically, classification is a very manual and time-consuming process. To make the classification more efficient, precise and dynamic, we proposed to automate the classification process using an advanced Machine Learning algorithm which follows a set of logical decision steps. The main objective of the project was to prove or reject the hypothesis of whether a Machine Learning model can be trained to automatically classify clinical research. MethodsMultiple Machine Learning models based on Natural Language Processing Classifiers including Random Forest, Support Vector Machine, and Logistic Regression were trained to classify Interventional Clinical Trials, Non-interventional Studies and other Real-world evidence research activities based on the text extracted from a Research Plan or a Study Protocol/Synopsis. Starting with Data Exploration and Data Preparation, for Data Preprocessing, the Term Frequency-Inversed Document Frequency (Tf-idf) column transformation was performed. To assess the performance of the models and choose the most efficient one, the accuracy, precision, recall (also known as sensitivity) and f1-score were calculated for each model. ResultsAll models showed sufficient performance. However, the Random Forest Classification model outperformed the other solutions tested and therefore was implemented in our Machine Learning application. The hypothesis was accepted based on a recall score of 1.00 as well as a 0.94 accuracy. The probability score of the result was analysed from the perspective of prioritisation of compliance needs minimising the false negatives for interventional and non-interventional studies. This Machine Learning model was then applied directly to achieve successful Clinical Research classification. ConclusionThus, we have demonstrated that the implementation of the Machine Learning approach helps in the acceleration of the classification process and at the same time increasing compliance with applicable regulatory requirements. This model can benefit the biopharmaceutical industry and individual researchers.

Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)-Registry Identify New Chances and Challenges in Lenalidomide Treatment of Patients With MDS del(5q).

Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)-Registry Identify New Chances and Challenges in Lenalidomide Treatment of Patients With MDS del(5q).

A Novel User-Centred Framework for the Holistic Design of Therapeutic Medical Devices

AbstractNumerous and complex sequence of activities in medical device development often result in time consuming and expensive engineering processes. In this study, patient and designer requirements were identified and integrated within a novel framework which supports medical device design through a consolidated understanding of user-experience whilst directly coalescing the applicable regulatory requirements in terms of product compliance and certification. This assists in the development of safe and reliable products which reflect the need for increased usability considerations during design.

Reliability and feasibility of centralized monitoring approach in source data verification during clinical trials

As per ICH GCP, monitoring can be defined as “The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).” Clinical experiments are important for deeper understanding of how interventions work in humans. The aim of the monitoring of the clinical trial is to avoid errors that may compromise patient safety and results of the trial and enables more frequent monitoring of the integrity of the trial and could improve safety concerns by detecting errors earlier than expected. Risk-based monitoring in clinical trials is the process of identification, assessment, monitoring and mitigation of risks that could affect the quality or safety of a study. Centralized monitoring has a direct impact on the clinical trials. One of the most basic and fundamental need of centralized monitoring is to avoid the repetition in clinical trials, saving both time and Money. Central monitoring greatly influences the Patient safety, data integrity and monitoring costs in a clinical trial. This helps in increasing the effectiveness of the monitoring process reducing the burden on the sponsor. The basic and fundamental priority of a clinical trial is to ensure the safety and well-being of the subject. In this article, we will be focusing on how Centralized monitoring can increase the effectiveness and efficiency of the monitoring process and source data verification (SDV) in clinical trials with a special emphasis on Risk based monitoring (RBM).

Antibiotic prescribing rate after optimal near-patient C-reactive protein testing in acutely ill children presenting to ambulatory care (ARON project): protocol for a cluster-randomized pragmatic trial

IntroductionChildren become ill quite often, mainly because of infections, most of which can be managed in the community. Many children are prescribed antibiotics which contributes to antimicrobial resistance and reinforces...

Guided self-determination intervention versus attention control for people with type 2 diabetes in outpatient clinics: a protocol for a randomised clinical trial

IntroductionIn the management of type 2 diabetes, autonomy-supporting interventions may be a prerequisite to achieving more long-term improvement. Preliminary evidence has shown that the guided self-determination (GSD) method might have...

QMS external quality auditors’ education framework: findings from an iterative Delphi study

PurposeThe paper aims to describe the development of an open curriculum framework of external quality auditors (EQAs) education. The study was commissioned by accreditation body JAS-ANZ, with the objective of improving EQA audit performance, resulting in more effective audits that can add value to client organisations.Design/methodology/approachThe key sets of knowledge, skills and attributes that auditors should possess were identified from the literature and an initial survey, and validated through several rounds of experts' opinion using the Delphi technique. The Delphi panel consisted of: top managers; quality practitioners; academicians; quality auditors, consultants and managers; a financial auditor and other managers. Kendall's coefficient of concordance (Kendall's W) was used to measure the level of agreement of the experts' ranking scores.FindingsPanelists believed there is a need for EQAs to be more broadly grounded in certain knowledge, skills, and attributes. The knowledge requirements for EQAs were: audit principles, process and methods; quality management principles, system, and standards; risk management; business process and operations management; applicable legal, regulatory and contractual requirements; strategic planning; and performance measurement. EQAs need strong skills in communication, auditing, people relations, critical thinking, report writing, leadership, coaching and coordination. The attributes considered essential are objectivity, integrity, ethics and professionalism; being observant, perceptive, articulate and confident; having good judgement; being flexible, adaptive, diplomatic, fair and open-minded. Based on these outcomes, the curriculum framework of EQAs was developed.Originality/valueThis study highlights the core elements required in a syllabus to prepare EQAs for value-added auditing in the present and future. The educational framework can be adopted by accreditation and certification bodies to evaluate and improve their auditors' audit performance.

Basics of Methodology of Creating and Developing the Class of Natural Engineering Systems in Water Resources Management

This study uses the system approach as a method of describing the relations and interaction among natural and technogenic objects and the people to elaborate the basics of the methodology of creating and developing the Natural Environment-Object of Activity-Population (NENV-OA-PPL) class of natural engineering systems (NES) for managing water resources in various branches of economy. The methodological basics elaborated for the class of natural engineering systems in question have been translated into practice in designing, building, and running water-management facilities, referred to as objects of activity, in conformity with applicable regulatory environmental requirements in effect. The basic system notions defined for the considered class of systems according to the study results are structure, component, element, and the paramount role of the whole that includes the notions of natural and technogenic constituents and environmental acceptability. The study results were time-tested in the course of designing and building the Zelenchukskaya Hydroelectric-Pumped Storage Power Plant (HPSPP) located in the basin geosystem of the Upper Kuban in the Karachay-Cherkess Republic in the North Caucasus.

Aquatic toxicity of waterpipe wastewater chemicals

IntroductionThe recent increase in U.S. popularity and use prevalence of water pipe (WP) tobacco smoking raises concerns about the potential environmental impacts of WP waste disposal and the need for strategies to reduce such impacts. The U.S. Food and Drug Administration (FDA) is required to assess the environmental impacts of its tobacco regulatory actions per the U.S. National Environmental Policy Act (NEPA). The purpose of this study was to identify and quantify specific chemical constituents in WP wastewater and to determine their potential aquatic toxicity. MethodsUsing a modified Beirut smoking regimen, five different WP charcoal brands (n = 70) and ten WP tobacco brands (n = 35) were smoked separately using a WP smoking machine in which smoke was passed through the WP base water. We analyzed and quantified specific chemical constituents in the WP bowl wastewater through standardized U.S. Environmental Protection Agency's (EPA) Hazardous Waste Test Methods. We then characterized the ecological hazard for acute and chronic aquatic toxicity posed by the specific chemicals through compilations of Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and hazardous concentration values (concentration affecting 50% of the species). ResultsAmong the list of 31 specific chemicals analyzed, we detected 22 and 11 chemicals in wastewater from WP tobacco and WP charcoal smoking, respectively. Nearly half of the 22 WP wastewater chemicals were classified as “very toxic” or “toxic” for acute and chronic aquatic toxicity per GHS classification. The most hazardous compounds with acute and chronic toxicity in aquatic organisms include acrolein, acrylonitrile, and metals (cadmium, lead, chromium, nickel, cobalt) found in both WP tobacco and charcoal wastewater, and N-nitrosonornicotine, nicotine, crotonaldehyde and selenium were additionally found in WP tobacco wastewater. All the identified chemicals are considered harmful or potentially harmful constituents in tobacco products and tobacco smoke per FDA's list, and seventeen of them represent hazardous waste per EPA's list. ConclusionOur study expands the identification and quantifies several WP wastewater chemical constituents. It characterizes the ecological hazard of these chemicals and identifies chemicals of concern, aiding our evaluation of the environmental impacts of WP waste products. Our results add to the existing evidence that WP wastewater is a source of toxins that could affect water quality and aquatic organisms, and bioaccumulate in the environment if disposed of into public sewers, on the ground, or in an onsite septic system. These findings highlight the importance of concerted efforts to raise awareness of appropriate WP waste disposal practices in both retail and residential settings, and applicable regulatory compliance requirements for WP retailer establishments, thereby limiting hazards from WP wastewater.