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Audits in GCP and Beyond
Methods and ExperiencesAudits stellen ein wichtiges Tool für die Qualitätssicherung in der Entwicklung von Arzneimitteln und Medizinprodukten im Hinblick auf das Wohlergehen der Studienteilnehmer, der Integrität und Validität der Studienergebnisse sowie der Transparenz von Prozessen dar.
Das vorliegende Buch bietet bereits in der 3., überarbeiteten und erweiterten Auflage einen umfassenden Überblick über die Methoden und Verfahren des Auditing im klinischen Bereich (GCP) sowie den daran anknüpfenden Bereichen, wie z. B. der Herstellung (GMP), der Pharmakovigilanz (GVP), der Labore (GCLP) sowie bei Nicht Interventionellen Studien (NIS) und Studien mit Medizinprodukten.
Alle Phasen von der Planung bis zum Abschluss werden beschrieben und die verschiedenen Audit-Typen in klinischer Forschung und verwandten Gebieten vorgestellt. Weitere Bereiche sind das Auditieren von Computersystemen und Archiven. Auch die Themen Risikomanagement und Inspektionen werden hier angesprochen. Jeder, der in der Pharma-/Biotech-Branche, in Contract Research Organisations (CROs) und Hochschulinstitutionen oder kommerziellen Einrichtungen tätig ist, profitiert vom umfassenden Knowhow der Autoren, die ihre ganze QA-Erfahrung in allen Bereichen des Auditing hier offerieren.
Auditoren können ihr Fachwissen vertiefen und erweitern; wer ein Audit erwartet, erfährt, worauf Auditoren in den unterschiedlichen Audits das Augenmerk richten.
Kapitel 1: Quality Management Systems in Clinical Drug Development
.... Audits May Contribute Regina Freunscht Quality is usually defined as the level of compliance to a set of predefined conditions or specifications. A Quality Management System (QMS) consists of ...
.... or specifications. A Quality Management System (QMS) consists of various elements, business processes, and tools in an organisational structure focused on achieving quality objectives, the implementation of quality management, ...
.... Organisational Charts—provide an overview of the entire organisation,outlining all major functions and divisions and how they interact with each other. All individuals in an organisation are able to identify ...
.... each other. All individuals in an organisation are able to identify whom they have to report to, who their peers are and to which part of the organisation they ...
.... belong. The position of the quality-assurance (QA) unit is generally recognised as being critical to ensure independence of audits and auditors, as per section 5.19 of ICH E6. Today’s ...Insgesamt 109 Fundstellen in 61 Textabschnitten
Kapitel 10: Audit in the Medical-analytical Laboratory
.... 10 Audit in the Medical-analytical Laboratory Volker El-Samalouti, Susanne Plate, Ralf Schaltenbrand, and Karin Renneisen Clinical laboratory parameters are important ...
.... be reflected by Quality Assurance (QA) measures applied within the scope of clinical trials to ensure the quality of selected laboratories and their analytical data. Although there are certain, ...
.... and their analytical data. Although there are certain, quite similar national regulations for medical-diagnostic laboratories established in European countries, none of the accepted laboratory quality standards (ISO/IEC 17025:2005, ISO ...
.... (ISO/IEC 17025:2005, ISO 15189:2013, ISO 9000, GLP or CAP) have the status of an obligatory regulation for these laboratories. Therefore, a variety of implemented standards and quality management systems ...
.... variety of implemented standards and quality management systems can be observed in medical analytical laboratories. In the following, an overview of the quality-relevant areas in medical analytical laboratories is ...Insgesamt 489 Fundstellen in 246 Textabschnitten
Kapitel 11: Audits of Specialised Laboratories and Centralised Reader Institutions
.... 11 Audits of Specialised Laboratories and Centralised Reader Institutions Approaches, Problems, and Solutions Andreas Edelmann, Karen Edelmann-Stergiou, and Roland ...
.... exposure and pharmacodynamic biomarkers reflecting the biological response during treatment are determined in specialised laboratories that have acquired specific analytical expertise. Response biomarkers are also analysed in specialised central ...
.... MRI, PET, CT, DXA scans, sonographic, echocardiographic videos, ECG, EEG readings or performing quantitative histomorphometry. Personalised medicine is getting more and more important and, therefore, analyses of genomic biomarkers ...
.... is getting more and more important and, therefore, analyses of genomic biomarkers are used to determine predisposition for possible metabolic reactions and for stratification of clinical trial participants by ...
.... clinical trial participants by analysing DNA/RNA samples. Those biomarkers provide valuable exposure-response information for regulatory health authorities in their decision-making process and contribute significantly to patient safety.Therefore, their analytics ...Insgesamt 477 Fundstellen in 281 Textabschnitten
Kapitel 12: Audits of Early Phase Clinical Trials and Clinical Pharmacology Units
.... 12 Audits of Early Phase Clinical Trials and Clinical Pharmacology Units John Norton, Barbara Heumann, and Rita Hattemer-Apostel Results of early phase clinical trials provide the foundation ...
.... Rita Hattemer-Apostel Results of early phase clinical trials provide the foundation for subsequent clinical studies in a drug development program. With only few trial subjects enrolled and of short ...
.... and of short duration,phase I trials are usually not the primary target of QualityAssurance auditors.However,sources for potential errors and weaknesses are numerous and,because of the many areas which are ...
.... potential errors and weaknesses are numerous and,because of the many areas which are unique to clinical pharmacology units and trials,conducting audits in this area has its merits. This article ...
.... clinical trials, provides ideas for auditing such trials and units as well as questions to ask during audits. 1. Introduction Phase I clinical trials (human pharmacology) include studies to ...Insgesamt 522 Fundstellen in 287 Textabschnitten
Kapitel 13: Systems Audits in Pharmacovigilance for Medicinal Products
.... Pharmacovigilance for Medicinal Products Michaela Rittberger 1. Introduction The purpose of pharmacovigilance (PhV) is to provide accurate, complete, and timely information about the benefit-risk profile of medicinal products throughout ...
.... complete, and timely information about the benefit-risk profile of medicinal products throughout their life-cycle to interested parties (e.g., company management, trial subjects, consumers, health-care professionals, authorities). Therefore, marketing authorisation ...
.... Therefore, marketing authorisation applicants (within this chapter: MAAs) and marketing authorisation holders (MAHs) need to maintain a system that ensures • Active, systematic, and continuous monitoring of safety information ...
.... detection of any regular safety signals or crisis situations • Appropriate actions are taken to minimise risks and prevent harm to trial subjects and consumers. The chapter focuses on ...
.... legislative requirements, whereas in reality pharmacovigilance processes and procedures of multinational operating companies have to fulfil national as well as international legal requirements. Accordingly local and global demands within ...Insgesamt 301 Fundstellen in 183 Textabschnitten
Kapitel 14: Auditing Clinical Databases, Trial Reports, and Related Systems
.... Alexander Both Audits of clinical databases have changed substantially during the last decade. Clinical studies with paper based CRFs (pCRF) are becoming rarer and the use of electronic data-capture ...
.... the scope of database audits as well as the time point of these audits. However, database audits have become more complicated for auditors specialised in Good Clinical Practice (GCP) ...
.... have not changed but involve the review of a multitude of different documents related to data management, statistics, and medical writing. The scope and procedures for conducting audits in ...
.... focus on database audits and clinical trial report audits as these elements, in addition to the overall workflow and systems to be assessed, are considered essential for system audits ...
.... Clinical Data Management and biostatistics are the most prominent procedures in a clinical study to collect and analyse clinical data.To a high extent, the quality of these procedures contributes ...Insgesamt 394 Fundstellen in 259 Textabschnitten
Kapitel 15: Audits of Computerised Systems
.... Poland 1. Introduction In the context of clinical trials, computers are used as a tool for efficient performance of a broad range of tasks.The amount of data and documents ...
.... for efficient performance of a broad range of tasks.The amount of data and documents to be handled and exchanged is steadily growing. So it is quite natural that auditors ...
.... encounter the use of computers wherever they perform quality-assurance work and audits. They have to deal with the systems, their development and implementation as well as their usage. They ...
.... with the systems, their development and implementation as well as their usage. They have to assess the environment in which the systems are used, the fulfilment of regulatory requirements ...
.... risks are minimised and data and information are not compromised. The challenges for the auditor are to identify the most “critical” properties of a computer system and its use ...Insgesamt 707 Fundstellen in 409 Textabschnitten
Kapitel 16: Quality Management and Audits in Noninterventional Trials
.... Management and Audits in Non-interventional Trials Gudula Petersen and Günter Minkus Non-interventional Trials (NIT)—used to collect real-life data on licensed medicinal products—are receiving increasing interest from the perspective of ...
.... collect real-life data on licensed medicinal products—are receiving increasing interest from the perspective of regulatory authorities and that of the Marketing Authorisation Holder (MAH). In addition to legal obligations, ...
.... Holder (MAH). In addition to legal obligations, several national and international guidelines are available to support conduct of NIT. These aspects of quality management in NIT have to be ...
.... Training of personnel • Reviewing of documents • Management of study sites and on-site monitoring • Safety reporting • Data management • Reporting and auditing, if appropriate. Trust in ...
.... is followed. 1. Introduction The discussion about the value of Non-interventional Trials (NIT) is contradictory—they are often accused of being designed to influence prescription habits of physicians.At the same ...Insgesamt 127 Fundstellen in 75 Textabschnitten
Kapitel 17: Auditing Medical-device Trials in the EU
.... EU Andreas Grund and Dieter R. Dannhorn 1. Introduction The pharmaceutical and the medical-device sectors have to be regarded as two separate sectors, which differ in history, culture, organisational ...
.... which differ in history, culture, organisational structure, legislation, and even in language. In contrast to pharmaceuticals, medical devices will require clinical data only in certain cases where medical-device manufacturers ...
.... cannot rely on already published clinical data of substantially equivalent medical devices. Therefore, the regulatory basis for CE-marking (Communauté Européenne = French for European Communion) is a clinicalevaluation document ...
.... Européenne = French for European Communion) is a clinicalevaluation document that summarises all clinical-investigation results,history of human use as well as results from scientific literature. The certification of medical ...
.... within Europe. Notified Bodies are not Competent Authorities but rather independent commercial companies [1].According toAnnex X, Clause 1 of the European Medical Device Directive 93/42/EEC and according to national ...Insgesamt 282 Fundstellen in 164 Textabschnitten
Kapitel 18: Auditing Trials in Vulnerable Subject Populations
.... children and minors, patients in emergencies or for mentally disabled persons.The definition of whom to consider as a vulnerable subject and the regulations for their participation and protection vary ...
.... their own, independent definition of “legally designated representatives of incapacitated persons and minors”.These local regulatory differences represent a great challenge for auditors, especially when providing quality-assurance services in multi-centre/ ...
.... Directive 2001/20/EU (CTD) and the subsequent EU-Regulation No 536/2014 require that “incapacitated persons” unable to give legal consent serving as subjects in clinical trials should be afforded the best-possible ...
.... even more important than in other subject populations for audit preparation of such trials to consider the country-specific regulatory framework and ethical requirements of the responsible ethic institutions, i.e., ...
.... information and the Informed Consent Form should always be part of a prospective audit.The investigator-site audit is the next step in a systematic approach to control protocol adherence. In ...Insgesamt 103 Fundstellen in 72 Textabschnitten
Kapitel 19: Audits at the Interface Between GCP and GMP
.... and GMP Bettina Pahlen Audits are not only a legal obligation, but also a tool for a sponsor/manufacturing authorisation holder to check compliance with legal requirements and to ensure ...
.... quality of the finished product as well as the quality of the study and to verify that patient rights are adequately protected. Auditing in the GMP (Good Manufacturing Practice) ...
.... and GCP (Good Clinical Practice) environment requires not only qualified, adequately trained and experienced auditors, but depends on the auditor’s ability to cross-link identified GCP issues possibly deriving from ...
.... the auditor’s ability to cross-link identified GCP issues possibly deriving from GMP deficiencies and to maintain the overview of the various requirements of the clinical study. Interfaces between GCP ...
.... of the various requirements of the clinical study. Interfaces between GCP and GMP related to quality management systems as well as investigational medicinal products (IMP) and documentation (including study-related ...Insgesamt 293 Fundstellen in 178 Textabschnitten
Kapitel 2: Auditing in Clinical Research: Aligning Auditing and Risk Management
.... and Risk Management Peter Schiemann, Beat Widler, and Steffen König 1. Introduction The approach to quality management in an environment of Good Clinical Practice (GCP) and Good Pharmacovigilance Practice ...
.... Good Clinical Practice (GCP) and Good Pharmacovigilance Practice (GPvP) has traditionally focused on on-site monitoring, QC verifications, and audits to enforce quality and compliance. However, the latest publications by ...
.... by FDA (US Food and Drug Administration) and EMA (European Medicines Agency) on risk-based monitoring (RbM) [1] and risk-based quality management in clinical trials [2], respectively, put forward a ...
.... risk-based quality management in clinical trials [2], respectively, put forward a more proactive approach to managing quality in clinical trials and ensuring data integrity and patient safety. The proposed ...
.... trials and ensuring data integrity and patient safety. The proposed risk-based approach is superior to the traditional approach because it allows to identify potential problems more rapidly and to ...Insgesamt 140 Fundstellen in 88 Textabschnitten
Kapitel 20: Auditing Contract Archives
.... A requirement of ICH GCP [1] and other guidelines and directives is the obligation to ensure the retention of essential documents for a pre-defined period of time and in ...
.... way that allows accurate reporting, interpretation, and verification of documented data. The sponsor, CRO, investigator or even Ethics Committees are requested to have facilities and procedures in place to ...
.... the Code of Federal Regulation [4] are often underestimated by sponsors or CROs and investigators. In many cases, the need for establishing an archive that meets essential requirements for ...
.... for establishing an archive that meets essential requirements for a long term and secure storage of paper documents or optic and electronic media is only a minor point during ...
.... its significance is often underestimated by CROs and sponsors. Therefore, insufficient facilities for long-term storage of essential documents are often a finding in audits or inspections. Moreover, investigator sites ...Insgesamt 164 Fundstellen in 96 Textabschnitten
Kapitel 21: Auditing in Low and Mid-income Countries
.... in Eastern Europe, Asia, Latin America, and Africa. In some of these countries, the regulatory framework governing clinical trials is relatively new and less well developed than in North ...
.... Europe. The rapidly growing number of trials involving subjects from these countries has led to the situation that the overall compliance of these clinical trials may not be in ...
.... the overall compliance of these clinical trials may not be in line with the regulators’ expectations developed during their previous work within an economically and regulatory mature environment. In ...
.... number of cases, there has indeed been public concern that western sponsors may have conducted clinical trials in countries that were not able to follow basic standards for the ...
.... trials in countries that were not able to follow basic standards for the ethical conduct of clinical trials. This development has mainly been driven by the economic pressure in ...Insgesamt 168 Fundstellen in 91 Textabschnitten
Kapitel 22: Investigating Suspected Scientific Fraud or Misconduct
.... 22 Investigating Suspected Scientific Fraud or Misconduct Regina Freunscht Patients benefit from high-quality conduct on the part of the pharmaceutical drug ...
.... the biomedical research practice.The integrity, probity, skill, and trustworthiness of our work are essential factors to ensure and maintain the confidence in our experience and work. However,in case of ...
.... processes for appropriate actions in case of a reported incident of suspected fraud or misconduct; it does not deal with results of “carelessness”. Fraud or Misconduct usually involves a ...
.... notice of their existence. But it should be remembered that whilst all fraud is misconduct, not all misconduct amounts to fraud, only further detailed investigation can result in a ...
.... can result in a final conclusion. Fraud is a deception practiced deliberately in order to secure unfair or unlawful gain. As a legal construct, fraud is both a civil ...Insgesamt 57 Fundstellen in 34 Textabschnitten
Kapitel 3: Auditing in Clinical Research: Auditing in a Riskmanagement Environment
.... Peter Schiemann 1. Introduction As described in the previous chapter, a more proactive approach to managing quality in pharmacovigilance and clinical trials ensures a more systematic and proactive protection ...
.... data. This chapter provides an overview of an “audit-compliance” strategy if a riskbased approach to managing quality in clinical trials including risk-based monitoring is adopted. It discusses how audits ...
.... including risk-based monitoring is adopted. It discusses how audits should be used in order to provide assurance that the risk-based approach is working as planned and produces consistent results ...
.... 2. Will Audits Become Obsolete—or Will the Role of Quality Assurance and Auditing Need to Change to Accommodate a Risk-based Approach to Clinical Study Management? Audits will not become ...
.... Management? Audits will not become obsolete. For one, they are mandated by GCP and regulatory guidance such as the “EU Guideline on Good Pharmacovigilance Practices (GPvP)” and are also ...Insgesamt 60 Fundstellen in 35 Textabschnitten
Kapitel 4: Preparation, Hosting, and Follow-up of GCP Inspections
.... 4 Preparation, Hosting, and Follow-up of GCP Inspections Dorette Schrag-Floß 1. Introduction GCP-related inspections conducted by inspectors of the US Food and DrugAdministration (US-FDA) have been carried out as ...
.... the U.K. and Germany, have carried out inspections frequently and at least partly intensively, too. However, the number and depth of GCP-related inspections conducted by European countries has increased ...
.... and the GCP Directive [2]. In the meantime, detailed procedures and guidance for the inspectors have not only been implemented but have also been made available publicly [3,36].As clinical ...
.... been implemented but have also been made available publicly [3,36].As clinical trials are being conducted more and more on a global scale, increasingly inspection activities have become international, too.Thus, ...
.... activities have become international, too.Thus, inspections are not only frequently carried out by European inspectors on behalf of the European Medicines Agency (EMA), but also by inspectors of the ...Insgesamt 535 Fundstellen in 297 Textabschnitten
Kapitel 5: Clinical Investigator Audit as Part of the System Audit
.... 5 Clinical Investigator Audit as Part of the System Audit Beat Widler and Carmen Julius This chapter ...
.... Part of the System Audit Beat Widler and Carmen Julius This chapter explains the conduct of a system audit.This systematic approach greatly facilitates the assessment of the methods and ...
.... and processes used in a clinical study. Adequate integration of the various systems—from study protocol through monitoring to data collection, transmission, and reporting as well as disclosure—directly impacts the ...
.... through monitoring to data collection, transmission, and reporting as well as disclosure—directly impacts the investigator’s work and, thus, the quality of the clinical data collected. Early detection of system ...
.... a functioning quality-assurance system. 1. Introduction For a long time, audits of clinical study sites/investigators were the most important, if not the sole task of Clinical Quality Assurance (CQA) ...Insgesamt 165 Fundstellen in 99 Textabschnitten
Kapitel 6: Audit Schedule and Project Auditor in a Clinical Development Program
.... 6 Audit Schedule and Project Auditor in a Clinical Development Program Eva Beate Ansmann, Jürgen-Hans Schmidt, Christine Korbmacher, and Christiane ...
.... an indispensable prerequisite for the clinical development of medicinal products. Clinical Quality Assurance (CQA), however, is still frequently characterised by activities at the study level. Parallel to laying out ...
.... the QA activities for a development program should be planned in view of all studies that are part of the program by establishing an audit schedule in good time. ...
.... good time. This chapter addresses the advantages and disadvantages of this procedure. All project auditors assume responsibility at the project-development program level as adviser for the project teams, communicator ...
.... assume responsibility at the project-development program level as adviser for the project teams, communicator to the QA department, and as auditor. This chapter discusses the responsibilities for this new ...Insgesamt 175 Fundstellen in 95 Textabschnitten
Kapitel 7: Auditing of Clinical Trial Documents
.... are of fundamental importance for any clinical study. Documents can • Be informative, e.g., Investigator’s Brochure (IB), Patient Information Leaflet (PIL) • Be instructive as the Clinical Study Protocol ...
.... as the Clinical Study Protocol (CSP) and study-specific manuals • Serve as a reporting tool, e.g., the integrated Clinical Study Report (CSR). Auditing of these documents should be subject ...
.... e.g., the integrated Clinical Study Report (CSR). Auditing of these documents should be subject to a risk-based approach and may be performed either in the context of an internal ...
.... internal process audit (system audit) or a—study-specific—in-process audit. These audits are of great importance to ensure compliance with the principles of Good Clinical Practice (GCP) and other applicable regulatory ...
.... ultimately accepted by Ethics Committees and/ or competent authorities. Document audits should also serve to demonstrate compliance to all applicable SOPs and templates including effectiveness of Quality Control procedures. ...Insgesamt 421 Fundstellen in 256 Textabschnitten
Kapitel 8: The Investigator-site Audit
.... 8 The Investigator-site Audit Carmen Julius, Beat Widler, Elfriede Lindauer, and Friederike Spengler The progress in Good ...
.... progress in Good Clinical Practice (GCP) guidelines as well as more precise requirements according to the EU Directive [1] and local law(s) has increased the importance of conducting audits ...
.... field of Clinical QualityAssurance (CQA) the introduction of ICH GCP [2] guidelines has led to a globalised and simplified audit methodology and a more systematic approach in the planning ...
.... globalised and simplified audit methodology and a more systematic approach in the planning and conduct of audits.To promote further European harmonisation, the European Parliament and the Council of the ...
.... for human use”on 14 April 2014, repealing Directive 2001/20/EC [4]. This chapter describes the conduct of an investigator-site audit,from the planning stages to the writing of the audit report. ...Insgesamt 375 Fundstellen in 185 Textabschnitten
Kapitel 9: Sponsor Audits at Contract Research Organisations
.... Contract Research Organisations Dagmar Chase and Jürgen-Hans Schmidt 1. Introduction In the past two to three decades, the pharmaceutical industry has become leaner and outsourcing to Contract Research Organisations ...
.... on the size and/or nature of the outsourcing company, reaching from small start-up organisations to big pharmaceutical industry.According to the still valid Biopharm Report 2008 [1] reasons for outsourcing ...
.... of internal expertise coupled with the existence of external expertise in CROs • Desire to save costs • Desire to speed up development by accessing more rapid patient recruitment ...
.... flexible development team than that available in a large centralised R&D organisation • Desire to develop truly strategic relations with a CRO that encompasses transfer of internal personnel to ...
.... single project but taking a long-term view, it is now generally believed that outsourcing to CROs may save money and an increasing number of pharmaceutical companies switch to a ...Insgesamt 665 Fundstellen in 359 Textabschnitten
