In translational research the question arises how to prepare researchers for the requirements of clinical studies in a way that can facilitate the transition of knowledge from basic, preclinical research with animals to clinical studies with humans. The aim of the presented reverse engineering approach is to familiarize basic researchers with the requirements and characteristics of the clinical study culture and in this way to prepare the basic researcher to create a more efficient translational experimental process. The reverse engineering approach consists, anong other help and guidance, of a preclinical evaluation guide for animal models and requirements for cell and gene therapy products prior to start of clinical study; process descriptions including the stages from preclinical research to phase I transition process to be used for analysis of the number of animals and necessary important experimental data to be generated for cell and gene therapy studies; compilations of the necessary legal provisions and advice received from Paul-Ehrlich Institute in Germany and AFSSAPS in France; list of international requirements for animal models, costs of animals for studies, special requirements for biotherapy studies, applicable guidelines for preclinical studies, demands for new investigational medicinal products. The relevance of the animal model is a focus, especially the consideration that a similar response in human and animal cells in vitro, does not guarantee that the in vivo response is similar.
Legal and Ethical Issues of International Clinical TrialsWolfgang Kuchinke
An analysis of regulatory, ethical and international aspects of clinical trials is presented, covering all relevant regulatory and ethical requirements for the conduct of international clinical trials. Our analysis is extended by discussing certain legal and ethical issues that are of importance for personalised medicine, especially for the use of software tools dealing with sensitive patient data and supporting patients in their decision making. Following ethical issues connected to the use of personalised medicine tools are discussed:
Tools that have been completely developed and tested for use in a medical environment and are GCP compliant, tools that capture patient data that have to be accurate, reliable and correct. Compliant clinical data management systems (CDMS) that are based on computer system validation. The ethical environment for GCP compliance in data management (audits, subject identification codes, importance of retention of sponsor-specific essential documents). Security of the portal so that unauthorised persons do not have access; the issue of personal data used in clinical trials and “directly" or "indirectly" identifiable data; legal and ethical issues arising by the deep integration of tools for clinical trials in personalised medicine; and issues caused by software that falls under the medical device law. An important aspect is to ensure patient’s autonomy during use of integrated tools for Patient Empowerment.
In 2006, the Commission on Higher Education (CHED)
released CHED Memorandum Order (CMO) no. 14 which changed the
duration of internship training program to six months as opposed to
the previous memorandum order, CMO no. 27 s. 1998 which required
a one-year internship schedule for Medical Laboratory Science (MLS)
students. Thirty-eight graduates of CMO No. 14 s. 2006 from Lyceum of
the Philippines University-Batangas and 13 chief medical technologists
(CMT) or senior medical laboratory staff from identified affiliate-
hospitals were surveyed about their perception on the attainment of the
objectives, as well as the strengths and weaknesses of the said program.
Results show that objectives were achieved even if the duration of the
training period was shortened. The graduate-respondents favored the 6-month internship training program while the CMT preferred the
one year timetable. This study can be used as a pilot study for other
higher education institutions implementing the same CMO and can
be used as a basis for a curricular reform by assessing the different
parameters that were identified in order to enhance further the six-
month internship training program in producing globally competitive
medical laboratory scientists.
What is ICH- GCP?
Why is GCP important?
Outline the goals of GCP
Provide a historical perspective on GCP
WHO Principles of GCP
Principles: Defines, Application & Implementation.
Legal and Ethical Issues of International Clinical TrialsWolfgang Kuchinke
An analysis of regulatory, ethical and international aspects of clinical trials is presented, covering all relevant regulatory and ethical requirements for the conduct of international clinical trials. Our analysis is extended by discussing certain legal and ethical issues that are of importance for personalised medicine, especially for the use of software tools dealing with sensitive patient data and supporting patients in their decision making. Following ethical issues connected to the use of personalised medicine tools are discussed:
Tools that have been completely developed and tested for use in a medical environment and are GCP compliant, tools that capture patient data that have to be accurate, reliable and correct. Compliant clinical data management systems (CDMS) that are based on computer system validation. The ethical environment for GCP compliance in data management (audits, subject identification codes, importance of retention of sponsor-specific essential documents). Security of the portal so that unauthorised persons do not have access; the issue of personal data used in clinical trials and “directly" or "indirectly" identifiable data; legal and ethical issues arising by the deep integration of tools for clinical trials in personalised medicine; and issues caused by software that falls under the medical device law. An important aspect is to ensure patient’s autonomy during use of integrated tools for Patient Empowerment.
In 2006, the Commission on Higher Education (CHED)
released CHED Memorandum Order (CMO) no. 14 which changed the
duration of internship training program to six months as opposed to
the previous memorandum order, CMO no. 27 s. 1998 which required
a one-year internship schedule for Medical Laboratory Science (MLS)
students. Thirty-eight graduates of CMO No. 14 s. 2006 from Lyceum of
the Philippines University-Batangas and 13 chief medical technologists
(CMT) or senior medical laboratory staff from identified affiliate-
hospitals were surveyed about their perception on the attainment of the
objectives, as well as the strengths and weaknesses of the said program.
Results show that objectives were achieved even if the duration of the
training period was shortened. The graduate-respondents favored the 6-month internship training program while the CMT preferred the
one year timetable. This study can be used as a pilot study for other
higher education institutions implementing the same CMO and can
be used as a basis for a curricular reform by assessing the different
parameters that were identified in order to enhance further the six-
month internship training program in producing globally competitive
medical laboratory scientists.
What is ICH- GCP?
Why is GCP important?
Outline the goals of GCP
Provide a historical perspective on GCP
WHO Principles of GCP
Principles: Defines, Application & Implementation.
National OncoVenture (NOV) is a Korean government funded oncology drug development program. We are focusing on non-clinical and early stage clinical development of promising oncology drug candidates. These candidates are provided by researchers in academics, research institutes, biotech and pharmaceutical companies. We are co-developing the compounds with the originators through a virtual development model. The majority of the development activities are outsourced to domestic and global CRO/CMOs as well as specialized laboratories throughout the world. During the pre-clinical and clinical development, we aim to improve the value of our candidates by out-licensing our development programs to global pharmaceutical companies who can develop them further for the global market.
National OncoVenture, a system-integrated oncology drug development group, was established in June 2011. NOV is supported and located at the National Cancer Center of Ilsan. NOV is a national research and development project group of the Ministry of Health and Welfare.
Their purpose is to carry out the development of oncology drug candidates that were discovered by domestic pharmaceutical companies or academic institutes. NOV aims to develop the candidates into oncology drugs for the global market by providing significant drug development expertise.
National OncoVenture aspires to break through the bottleneck phenomenon in new drug development. Many academic research institutes and small biotechnology or pharmaceutical companies lack the resources to develop new drugs from the preclinical to clinical stage. We, as the non-originators, lead and support the development with experienced experts through an entire new drug development process.
NOV is the first governmental virtual drug development organization as an independent developer of new oncology drugs in South Korea. We select promising drug candidates from originators and lead joint-development projects of new drug candidates with originators utilized by outside networks. These external networks have the necessary know-how and experiences of new drug developments like CROs, CMOs, and consulting firms.
After completing the non-clinical and early clinical phase development, we license out the candidates or projects to domestic and overseas pharmaceutical companies. The profits are shared with the original candidate providers.
National OncoVenture provides consultations to the originators of drug candidates in need of knowledge, information, and experience for oncology market trends, drug candidates licensing, and various other processes.
Outlining the proces and lessons learned in organising the technological infrastructure at the Radboud university medical center, to shape the Radboudumc Technology Centers, supporting our mission in enabling personalized healthcare.
An overview of ICH-GCP guidelines of clinical trials.
Good clinical practice (GCP): a standard for the design , conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.
ICH-GCP is an International Conference on Harmonization Good Clinical Practice.
The guideline was developed with consideration of the current good clinical practices of the European union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the world health organization
Introduction to Good Clinical Practice (GCP) Guidelines: Ensuring Quality in ...ClinosolIndia
Good Clinical Practice (GCP) guidelines are a set of international ethical and scientific standards that define the principles for designing, conducting, recording, and reporting clinical trials involving human participants. GCP guidelines provide a framework to ensure the safety, integrity, and quality of clinical research. Here is an introduction to GCP guidelines and their significance in ensuring quality in clinical research:
Purpose of GCP Guidelines: The primary purpose of GCP guidelines is to protect the rights, safety, and well-being of trial participants. GCP guidelines also aim to ensure the reliability and credibility of trial data, promoting the ethical conduct of clinical research and supporting the development of safe and effective medical interventions.
International Harmonization: GCP guidelines are developed and maintained by international regulatory and scientific organizations, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The ICH GCP guidelines are widely accepted and followed by regulatory authorities and the pharmaceutical industry globally.
Ethical Principles: GCP guidelines are rooted in ethical principles, including respect for the rights and autonomy of participants, minimizing risks, ensuring informed consent, protecting participant confidentiality, and maintaining impartiality and integrity in the conduct of clinical research.
Trial Design and Conduct: GCP guidelines provide recommendations for the design, conduct, and documentation of clinical trials. This includes protocols, study endpoints, inclusion/exclusion criteria, randomization procedures, blinding/masking, sample size determination, and statistical analysis plans. GCP emphasizes the need for scientific rigor, minimizing bias, and ensuring the validity of trial results.
Investigator Responsibilities: GCP guidelines outline the responsibilities of investigators and research staff involved in clinical trials. These responsibilities include obtaining informed consent from participants, conducting the trial in compliance with the protocol, ensuring participant safety, accurate and timely data collection and documentation, and maintaining source data integrity.
Institutional Review Board (IRB) Oversight: GCP guidelines emphasize the importance of independent ethical review and oversight of clinical trials by IRBs or ethics committees. IRBs ensure that the rights, safety, and well-being of trial participants are protected and that the trial design and conduct adhere to ethical principles and regulatory requirements.
Data Integrity and Documentation: GCP guidelines stress the importance of accurate, complete, and timely documentation of all trial-related activities and data. This includes the maintenance of essential documents, such as the protocol, informed consent forms, investigator's brochure, case report forms, and adverse event reports. GCP also emphasizes the need for data valida
2022-11-23 DTL Future of data-driven life sciences, Utrecht, Alain van Gool.pdfAlain van Gool
A pitch on directions to improve experimental reproducibility, illustrated by examples of past experiences. I made the plee to move from 'Proudly invented here' to 'Proudly copyied from', to re-use each other's eperiences in successes and failures.
2023-11-09 HealthRI Biobanking day_Amsterdam_Alain van Gool.pdfAlain van Gool
Examples of lessons learned in Omics-based biomarker studies from myself and colleagues in X-omics and EATRIS, for an audience of biobankers, researchers and diagnostic/clinical chemistry experts.
National OncoVenture (NOV) is a Korean government funded oncology drug development program. We are focusing on non-clinical and early stage clinical development of promising oncology drug candidates. These candidates are provided by researchers in academics, research institutes, biotech and pharmaceutical companies. We are co-developing the compounds with the originators through a virtual development model. The majority of the development activities are outsourced to domestic and global CRO/CMOs as well as specialized laboratories throughout the world. During the pre-clinical and clinical development, we aim to improve the value of our candidates by out-licensing our development programs to global pharmaceutical companies who can develop them further for the global market.
National OncoVenture, a system-integrated oncology drug development group, was established in June 2011. NOV is supported and located at the National Cancer Center of Ilsan. NOV is a national research and development project group of the Ministry of Health and Welfare.
Their purpose is to carry out the development of oncology drug candidates that were discovered by domestic pharmaceutical companies or academic institutes. NOV aims to develop the candidates into oncology drugs for the global market by providing significant drug development expertise.
National OncoVenture aspires to break through the bottleneck phenomenon in new drug development. Many academic research institutes and small biotechnology or pharmaceutical companies lack the resources to develop new drugs from the preclinical to clinical stage. We, as the non-originators, lead and support the development with experienced experts through an entire new drug development process.
NOV is the first governmental virtual drug development organization as an independent developer of new oncology drugs in South Korea. We select promising drug candidates from originators and lead joint-development projects of new drug candidates with originators utilized by outside networks. These external networks have the necessary know-how and experiences of new drug developments like CROs, CMOs, and consulting firms.
After completing the non-clinical and early clinical phase development, we license out the candidates or projects to domestic and overseas pharmaceutical companies. The profits are shared with the original candidate providers.
National OncoVenture provides consultations to the originators of drug candidates in need of knowledge, information, and experience for oncology market trends, drug candidates licensing, and various other processes.
Outlining the proces and lessons learned in organising the technological infrastructure at the Radboud university medical center, to shape the Radboudumc Technology Centers, supporting our mission in enabling personalized healthcare.
An overview of ICH-GCP guidelines of clinical trials.
Good clinical practice (GCP): a standard for the design , conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.
ICH-GCP is an International Conference on Harmonization Good Clinical Practice.
The guideline was developed with consideration of the current good clinical practices of the European union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the world health organization
Introduction to Good Clinical Practice (GCP) Guidelines: Ensuring Quality in ...ClinosolIndia
Good Clinical Practice (GCP) guidelines are a set of international ethical and scientific standards that define the principles for designing, conducting, recording, and reporting clinical trials involving human participants. GCP guidelines provide a framework to ensure the safety, integrity, and quality of clinical research. Here is an introduction to GCP guidelines and their significance in ensuring quality in clinical research:
Purpose of GCP Guidelines: The primary purpose of GCP guidelines is to protect the rights, safety, and well-being of trial participants. GCP guidelines also aim to ensure the reliability and credibility of trial data, promoting the ethical conduct of clinical research and supporting the development of safe and effective medical interventions.
International Harmonization: GCP guidelines are developed and maintained by international regulatory and scientific organizations, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The ICH GCP guidelines are widely accepted and followed by regulatory authorities and the pharmaceutical industry globally.
Ethical Principles: GCP guidelines are rooted in ethical principles, including respect for the rights and autonomy of participants, minimizing risks, ensuring informed consent, protecting participant confidentiality, and maintaining impartiality and integrity in the conduct of clinical research.
Trial Design and Conduct: GCP guidelines provide recommendations for the design, conduct, and documentation of clinical trials. This includes protocols, study endpoints, inclusion/exclusion criteria, randomization procedures, blinding/masking, sample size determination, and statistical analysis plans. GCP emphasizes the need for scientific rigor, minimizing bias, and ensuring the validity of trial results.
Investigator Responsibilities: GCP guidelines outline the responsibilities of investigators and research staff involved in clinical trials. These responsibilities include obtaining informed consent from participants, conducting the trial in compliance with the protocol, ensuring participant safety, accurate and timely data collection and documentation, and maintaining source data integrity.
Institutional Review Board (IRB) Oversight: GCP guidelines emphasize the importance of independent ethical review and oversight of clinical trials by IRBs or ethics committees. IRBs ensure that the rights, safety, and well-being of trial participants are protected and that the trial design and conduct adhere to ethical principles and regulatory requirements.
Data Integrity and Documentation: GCP guidelines stress the importance of accurate, complete, and timely documentation of all trial-related activities and data. This includes the maintenance of essential documents, such as the protocol, informed consent forms, investigator's brochure, case report forms, and adverse event reports. GCP also emphasizes the need for data valida
2022-11-23 DTL Future of data-driven life sciences, Utrecht, Alain van Gool.pdfAlain van Gool
A pitch on directions to improve experimental reproducibility, illustrated by examples of past experiences. I made the plee to move from 'Proudly invented here' to 'Proudly copyied from', to re-use each other's eperiences in successes and failures.
2023-11-09 HealthRI Biobanking day_Amsterdam_Alain van Gool.pdfAlain van Gool
Examples of lessons learned in Omics-based biomarker studies from myself and colleagues in X-omics and EATRIS, for an audience of biobankers, researchers and diagnostic/clinical chemistry experts.
Presentation on theme: "GCP (GOOD CLINICAL PRACTISE)"Nevin Francis
Creating a comprehensive 3000-word essay on Good Clinical Practice (GCP) would be quite extensive and may not fit within the scope of our conversation here. However, I can provide you with a detailed outline and key points that you could expand upon to reach the desired word count.
**Introduction to Good Clinical Practice (GCP)**
- Definition and importance of GCP in clinical research.
- Historical development and international harmonization efforts.
**Ethical Considerations in GCP**
- The role of ethics in clinical trials.
- Informed consent process and protection of participants' rights.
**Designing Clinical Trials under GCP Guidelines**
- Key elements in the design of a clinical trial.
- Considerations for protocol development.
**Conducting Clinical Trials According to GCP**
- Responsibilities of sponsors and investigators.
- Patient recruitment and data management strategies.
**Safety Monitoring and Adverse Event Reporting**
- Monitoring patient safety and reporting adverse events.
- The role of Data Safety Monitoring Boards (DSMBs).
**Quality Assurance in Clinical Trials**
- Audits, inspections, and ensuring compliance with GCP.
- The significance of documentation and record-keeping.
**Statistical Considerations in Clinical Trials**
- Importance of statistical methods in trial design and analysis.
- Interpreting results and determining clinical significance.
**The Future of GCP and Clinical Research**
- Innovations in clinical trial methodology.
- The impact of technology on GCP and patient engagement.
**Conclusion**
- The ongoing importance of GCP for the integrity of clinical research.
- The global impact of GCP on healthcare and medicine.
Each of these sections can be elaborated to create a full essay that discusses the principles and practices of GCP in depth. For the most current and detailed information, you can refer to the ICH E6 (R2) Good Clinical Practice guidelines¹, which are recognized internationally and provide a comprehensive framework for conducting clinical trials that involve human subjects. Additionally, the draft version of the ICH E6 (R3) principles provides updated guidance on ethical trial conduct, participant safety, and reliable results².
Remember, while expanding on these points, it's essential to cite relevant guidelines, regulations, and literature to support your discussion and provide a well-rounded view of GCP.
Source: Conversation with Bing, 19/02/2024
(1) ICH E6 (R2) Good clinical practice - Scientific guideline. https://www.ema.europa.eu/en/ich-e6-r2-good-clinical-practice-scientific-guideline.
(2) ICH-E6 Good Clinical Practice (GCP). https://database.ich.org/sites/default/files/ICH_E6-R3_GCP-Principles_Draft_2021_0419.pdf.
(3) ICH Guidance Documents | FDA. https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/ich-guidance-documents.
(4) Good Clinical Practice Guidelines (India) - Rajiv Gandhi Centre for .... https://www.rgcb.res.in/documents/Good-Clinical-Practice-Gu
Similar to Reverse Engineering of Clinical Trials to Improve Research (20)
Temporal relations in queries of ehr data for researchWolfgang Kuchinke
Temporal Relations in Queries of Electronic Patient Records. Our main scenario covers the patient identification and recruitment process for clinical trials. For this purpose an extension of the EHR4CR workbench to support patient recruitment was created. This workbench covers following requirements:
Need for built-in privacy protection.
Patient identification and recruitment tracking.
Availability at clinical sites in the form of a workbench with an user-friendly interface.
Each participating clinical site has its own installation only used locally.
Ability to generate queries with temporal relations and constraints for eligibility criteria to find candidate patients.
Our development is based on the fact that queries in EHRs often have a temporal component. But available user interfaces allow only the generation of simple queries with basic temporal relations. Time points and time intervals are therefore the main concepts that must be considered. Time points are related to instantaneous events (e.g. a single myocardial infarction), or to situations lasting for a span of time (e.g. a drug therapy for 2 weeks). Intervals can be represented using time points by their upper and lower temporal boundaries: the start and end. Temporal relations (e.g before, after) can be expressed via additional anchors. The dates of these anchor events can be retrieved and event dates relative to an anchor event can be calculated. EHR4CR decided to build its workbench upon a simple, time-stamp database concept. To each patient’s attribute a time-stamp, which corresponds to the time of the attribute’s occurrence was assigned. The processing of temporal intervals is necessary for EHR4CR since many questions dealing with inclusion / exclusion criteria often involve complex temporal periodes. A graphical interface to use boxes for querying with temporal relations was therefore created. The idea is that the easiest way to specify temporal operators is with an user interface based on the combination of boxes. Temporal operators based on Allen’s algebra were included. Expressions are displayed as graphic boxes and combined by
operators. Events are specified and a temporal operator selected from a predefined list.
Secure access to biomedical data sources for legal data sharing-kuchinkeWolfgang Kuchinke
Enabling Secure Access to Biomedical Data Sources. This is about a pilot installation of a data sharing system for legally compliant data access.
The first step was an analysis of ethical, legal and regulatory requirements for data access and of associated data security risks due to data sharing between Research Infrastructures. Analysis was followed by the development of a security framework to ensure that the data bridges of BioMedBridges project are compliant with regulations and consider privacy and data security requirements.
Elements of the security architecture and pilot implementation consist of the BioSamples Database from ELIXIR, BBMRI catalogue (BBMRI Hub) extended with a MIABIS layer and a data cube layer, Resource Entitlement Management System and add-on of Legal Assessment Tool. Central in the pilot was the role of the Resource Entitlement Management System (REMS), which manages policies for granting access to data providers (databases). For example: an application for granting access is required to get access to clinical data from a web application like BBMRI Hub. The approval is granted by a Data Access Committee (DAC). The process for access is managed by Shibboleth, a single sign-on login system. To get access, Identity providers (IdPs) supply user information, while service providers (SPs) use this information to give access. The Legal Assessment Tool (LAT) is an additional component to guide users through legal requirements for using data sharing of sensitive data with data bridges.
The Pilot workflow process: The Biosamples Database is the starting point. Using the linked LAT the researcher searching for specific data gets legal / ethical requirements to consider when accessing and sharing human data. The BBMRI Hub provides summary information of the requested datasets (makes it findable in the Biosamples Database). The Hub checks that the user has an associated Shibboleth session. If the user has no Shibboleth session, Shibboleth redirects the user to a sign-on page. After successful authentication the request is sent back to the Hub, where the user session is used to query REMS related attributes. Approved applications are notified by email including an link to the access site with data sets.
Computer System Validation with privacy zones, e-source and clinical trials b...Wolfgang Kuchinke
Clinical Trials in the Learning Health System: Computer System Validation of eSource and EHR Data. Basic question is how to make a clinical trial data management system that uses EHR data, Patient Reported Outcome (PRO) and eSource data as part of the Learning Health System compliant with regulations and with Good Clinical Practice (GCP)? Computer System Validation (CSV) is a requirement for all computer systems involved in clinical trials for drug submission. It consists of documented processes to produce evidence that a computerized system does exactly what it is designed to do in a consistent and reproducible manner. Validation begins with the system requirements definition and continues until system retirement. For example, the components of a clinical trials
framework used in our case are: Patient eligibility checks and enrolment, pre-population of eCRFs with data from EHRs, PROM data collection by patients, storing of a copy of study data in the EHR, and validation of the Study System that coordinates all study and data collection events.
eSource direct data entry in clinical trials and GCP requirements. It is the duty of physicians who are involved in medical research to protect the privacy and confidentiality of personal information of research subjects. Any eSource system should be fully compliant with the provisions of applicable data protection legislation. This creates the need to develop and implement processes that ensure the continuous control of the investigators over these data. This has to be the focus of CSV. Clinical Data drive the LHS. The results from randomized controlled trials are seen as the “gold standard” for medical evidence, but such trials are often performed outside the usual system of care and recruit highly selected populations. For this reason, the concept of using data gathered directly from the patient care environment has enormous potential for accelerating the rate at which useful knowledge is generated.
This leads to the requirement for validating electronic source data in clinical trials. This includes validation for clinical data that is either captured from the subject directly or from the subject’s medical records. The problem is the correct and appropriate system validation of electronic source data. The main componenets of CSV are the Validation Master Plan), User Requirements Specification, Hardware Requirements Specification, Design qualification, Installation qualification, Operational qualification, Performance qualification.
Any instrument used to capture source data should ensure that the data are captured as specified within the protocol. Source data should be accurate, legible, contemporaneous, original, attributable, complete and consistent. An audit trail should be maintained as part of the source documents for the original creation and subsequent modification of all source data.
Personalized medicine tools for clinical trials - kuchinkeWolfgang Kuchinke
Tools for personalised medicine in clinical trials. ---------
The implementation of clinical trials in personalized medicine is a different way of doing clinical research compared to the standard way of large clinical trials aiming for statistical significance. Personalized medicine uses a medical model that separates people into different groups with medical decisions, practices, drugs, interventions being tailored to the individual patient based on their predicted response. Basis for this approach is the progress of the study of the human genome and its variation over the last two decades. Especially advancement in automated DNA sequencing and PCR and the use of expressed sequence tags (ESTs), cDNAs, antisense molecules, small nterfering RNAs (siRNAs), full-length genes and their expression products and haplotypes.
But adoption of personalized medicine requires an active and flexible and highly integrated infrastructure, which allows joining of many different competences and technologies. We asked the question: can the tools developed for personalized medicine in the p-pedicine project be employed effectively in a clinical trials network to support personalised clinical trials. We conducted an analysis of tool integration and the evaluation tool usage requirements. Based on the survey results, the tendency for clinical trial network ECRIN is to use software as a service in the form as SaaS or ASP. ECRIN data centres will (probably) not install and employ p-medicine tools in one of their data centres. A robust business model for the provision of services and the implementation and employment of tools does not yet exist.
How can the personalized medicine infrastructure p-medicine and the clinical trials network ECRIN gain from each other to allow the conduct of personalized clinical trials?
We suggest a business model, in which personal medicine infrastructures and clinical trials networks exchange their services to gain jointly from each other. Therefore: an integration by reciprocal exchange of services may be the solution. Not only software as a service will be exchanged, but also knowledge, personnel and joint staff trainings.
Computer System Validation - privacy zones, eSource and EHR data in clinical ...Wolfgang Kuchinke
Clinical Trials in the Learning Health System (LHS): Computer System Validation of eSource and EHR Data.
The question that was addressed: How to make a clinical trial data management system that uses EHR data, Patient Reported Outcome (PRO) and eSource data as part of the Learning Health System compliant with regulations and with Good Clinical Practice (GCP)?
The Learning Health System (LHS) connects health care with translational and clinical research. It generates new medical knowledge as a by-product of the care process and its aim is to improve health and safety of patients. The LHS generates and applies knowledge. For this purpose, clinical research, which is research involving humans, must be part of the LHS. Two general types of research exists: observational studies and clinical trials.
Clinical data drive the LHS, because results from randomized controlled trials are seen as “gold standard” for medical evidence. For this reason the concept of using data gathered directly from the patient care environment has enormous potential for accelerating the rate at which useful knowledge is generated.
All computer systems involved in clinical trials must undergo Computer System Validation (CSV). For this process, a legal framework for the TRANSFoRm project was developed. It was used for data privacy analysis of the data flow in two research use cases: an epidemiological cohort study on Diabetes and a randomised clinical trial about different GORD treatment regimes.
Computerized system validation is the documented process to produce evidence that a computerized system does exactly what it is designed to do in a consistent and reproducible manner. The validation of electronic source data in clinical trials presents many challenges because of the blurring of the border between care and research. Here we present our approach for the validation of eSource data capture and the developed documentation for the CSV of the complete data flow in the LHS developed by the TRANSFoRm project. An important part hereby played the GORD Valuation Study.
Use of personalized medicine tools for clinical research networksWolfgang Kuchinke
Patient-centric clinical trials can gain enormously from the employment of personalised medicine tools. Here we address software tools created by the p-medicine network, which developed thr ObTiMA data management system, Patient Empowerment Tool, data mining, data warehousing, biobank access, decision support, image annotation (DrEye) and simulation (Oncosimulator). We evaluated of some of these tools for their suitablity to perform clinical trials. Is their usage conform with regulations and standards (GCP, GDPR, GAMP, computer system validation)? Can these tools be integrated into the existing systems (IT infrastructure / organisational framework) of an international clinical trials network (ECRIN)?
Kuchinke - Learning Health System (LHS) in Europe - Introduction and meeting ...Wolfgang Kuchinke
We present the results of the conference: The Learning Health System (LHS) in Europe. Two perspectives were compared, from the US by Charles Friedman; and from Europe by Federico Paoli. C. Friedman also introduced the concept of learning by virtious cycles. One advanced example for the implementation of the LHS in Europe is the TRANSFoRm project, which was presented in detail. It aims to develop and demonstrate methods, models, standards and a digital infrastructure for three specific components of the LHS: (1) Genotype-phenotype epidemiological studies using multiple existing primary care and ‘biobank’ genomic datasets; (2) Randomized Clinical Trials with both data and trial processes embedded within the functionality of EHRs and (3) Decision support for diagnosis, based on clinical prediction rules. Other topics discussed are: Sustainability and Business Development in the LHS. Knowledge Management & Data Standards in the LHS. Data privacy and security in the LHS. EHR4CR solutions for privacy protection, HIPAA, US experiences with privacy protection,
TRANSFoRm Zone Model for data privacy protection, IMI code of practice for the secondary use of health data, Knowledge Translation and Decision Support in the LHS, Decision support for interventions in the LHS, TRANSFoRm Decision support for diagnosis, TRANSFoRm Extensible model for diagnostic evidence, CareWell - A learning integrated care system
Improving quality of care with routine data: the perspective of a statutory health insurer - The impact on LHS, CDISC and clinical trial standards in the LHS, A pan-European platform for the re-use of EHR data, TRANSFoRm and CDISC standards,
Provenance and GCP for real world clinical trials, Using Health Data for Innovative Trial Designs, etc.
Regulations, privacy, security for data bridges - KuchinkeWolfgang Kuchinke
The presentation is addressing the complexity of data sharing from two view points: (1) Ethical, legal and regulatory challenges, (2) Data sharing between Research Infrastructures.
A comprehensive analysis of the regulatory landscape of data bridges is provided, including: Data Protection Directive, relevant national data protection acts, Good Clinical Practice (GCP), Animal protection laws, security rules for biosamples, data ownership regulations (intellectual ownership, database laws), and others.
Basis was the concepts of Open Data and Open Science, which aims to make scientific research output (publications, data, biosamples, and alogrithms) accessible to all levels of an inquiring including research bey citicen scientists. This includes transparent and accessible knowledge that is shared and developed through collaborative networks and practices such as publishing open research, campaigning for open access and data sharing. But several mechanisms restrict access to data or reuse of data: copyright, patents, database rights, time-limited access rules, political, commercial or legal rules and interests.
Researchers are confronted with the question, whether, on what basis and with what limitations, human data can be used freely and made available to support open research and open science. We conducted an analysis of the legal landscape for data sharing, employing concepts from requirements engineering, like the definition and collection of legal requirements for data bridges, which were based on access rules of many database providers. We defined “legal interoperability” of data sharing as interoperability that forms conditions where a combination of rules allows the exchange of data between different data providers. The basis was the creation of legal “requirement clusters” defining applicable rules, roles and policies used by database owners (data controllers). Such "requirement clusters” can act as a kind of „filter" between different data sources to allow for compliant data transfer. To create "requirement clusters” data sharing usage scenarios were built consisting of real-world examples of interaction between data providers during data sharing. Finally, the legal analysis based on five Usage Scenarios and the development of Requirements Clusters for data protection, data security, intellectual property, security of biosamples and animal protection providing constraints and recommendations for legally sound data bridges and the implementation of “legal filters“ for complinat data flow.
Agile Computer System Validation of software productsWolfgang Kuchinke
Personalized medicine seems to be a potential solution to the known challenges facing clinical research and drug development. To be employed in clinical research, software tools must undergo a process called Computer System Validation (CSV) for compliance with legal requirements and Good Clinical Practice (GCP). Four academic developer groups of the EU project p-medicine were surveyed to evaluate the readiness of their developed software products to be used for clinical research. The analysis of the survey showed that considerable gaps exist in tool maintenance, quality management and compliance documentation. Because all developer groups use agile development methods, recommendations for agile quality assurance were developed as well as for using agile methods to establish “compliance by design”. We show how agile validation can be established by small modifications of sprint processes.
Introduction to CTIM - the Clinical Trial Information MediatorWolfgang Kuchinke
A new tool was developed: Clinical Trial Information Mediator allows for easy, simoultaneous cross-domain searches through different databases. It is aimed at researchers interested in clinical trials, who want to design new studies and for this purpose need to find trial related information in different biomedical databases. CTIM supports researchers in their searches by linking clinical trials information to publications and information about biosamples / genes and thereby bridging the gap between different databases from different research domain.
The novel feature is that CTIM creates links between clinical trials and publications not through an ID or a key word (code item), but through information content that provides the
basis for queries. CTIM's knowledge base for clinical trials is based on the ClinicalTrials.gov database (CT.gov), the largest repository of clinical trials information. With CTIM one doesn’t have to search in CT.gov and PubMed separately.
Standard based Electronic Archiving for Clinical TrialsWolfgang Kuchinke
Content:
Requirements and challenges of electronic archiving on the way to an eArchive
Maintaining accessibility: the key challenge is the future use of materials when technological changes make original formats and operating environments obsolete
Transform materials to standard formats
Criteria for selecting file formats for long-term preservation
Methods of digital preservation Digital preservation
The archival properties of seven common formats
Archiving planing process
Archiving issues specific for clinical research
The Trial Master File (TMF) the central archival object
The Investigator Site File (ISF)
The trial master file contains the essential documents for a clinical trial that may be subject to regulatory agency oversight (audits)
An analysis of different TMFs was carried out for three representative studies
Electronic signatures may be created with increasing levels of security and validity
Qualified electronic signatures protect the authorship of a document (The signature is non-repudiable)
Joint archiving of data and documents
Digital archiving
Long-term preservation of appropriate materials should be based on “evidential, legal, contextual or information value”
GCP requirements also apply to digital archives
Data Life Cycle Management
Integrated Clinical Data Archive
Electronic Data Records Management and archiving
Persistence of Electronic Clinical Trial Data
Archive dichotomy - Two types of archiving: database and documents (TMF)
The three main components of a document record
Database archiving
Increased Ethical Demands for Patient Empowerment in Personalised MedicineWolfgang Kuchinke
A Patient Empowerment tool was developed by pmedicine project, with the aim to provide help for the patient to understand medical documentation, empower the patient to make informed choices and support patients with their decisions in personalised medicine treatments. To identify and evaluate ethical issues existing, ethical concepts were assigned to the use of the patient empowerment service. Concepts from IT requirements engineering were adapted to collect ethical requirements and five ethical requirements clusters were assigned: Informed Consent, Vulnerable populations, IRB/Ethics Committee, Data privacy, Investigator related ones. The identified areas of ethical concerns cover the ethical correct presentation of medical risks and probabilities, reactions to diagnosis, truth about the patient’s medical conditions, presentation of results of false positives and false negatives, inconsistent and incomplete medical results, understanding of clinical equipoise, confidentiality and data ownership issues, data falsification, proper and justified use of new technologies.
Complex ethical problems are created by combining cancer therapies, biosampling, genetic analysis and personalised medicine method. For example, such combinations create issues of data ownership, right to data deletion, right to forget, using care data for research purposes, suitable risk assessments, ... Based on this analysis we created demands for using the Patient Empowerment Service in a ethical way: enabling patient’s understanding of whole data set that the hospital has collected; patients must be able to understand medical statements, as well as legal and ethical considerations; the empowerment tool must represent data in a comprehensible format, but in case it confronts the patient to get unfavorable information and negative diagnoses it should provide help and guidance.
Ethical concerns caused by integrative patient empowerment servicesWolfgang Kuchinke
We conducted an ethical analysis of a Patient Empowerment Tool. The identified relevant ethical aspects were organized in ethical requirement clusters. These were further analysed for consequences for the structure of the tool and a suitable user interface of the Patient Empowerment Service. A central role that will be played by the Patient Empowerment Service is to guarantee patient autonomy and informed patient’s decisions. A User Interface Model that addresses our ethical concerns will allow user access channeled through a series of adaptable profiles that enable autonomy and present data in an understandable way with build-in support by help and guidance functions. In this way, it becomes possible to ensure patient autonomy even under adverse conditions, like access to unfavoable information, negative diagnoses, incomprehensible risk / benefit display, and other factors that impede the informed decision potential of the patient.
Regulations, privacy and security requirements - Legal interoperability for d...Wolfgang Kuchinke
We are addressing the complexity generated by different ethical, legal and regulatory requirements resulting from data sharing needs between Research Infrastructures. We conducted a comprehensive analysis of the regulatory landscape for creating data bridges: including GDPR (EU Data Protection Directive), relevant national data protection acts, Good Clinical Practice (GCP), animal protection laws, security rules for biosamples, intellectual property regulations. The legal analysis was based on five Usage Scenarios and used for the development of Legal Requirements Clusters for data protection, data security, intellectual property, security of biosamples and animal protection.
We intended to create conditions for legal interoperability for data sharing that may be used for the automation of data exchange processes.
Service Integration for Research Infrastructures by Reciprocal UsageWolfgang Kuchinke
Research infrastructures are building software tools and provide data services. Often these software solutions are to some degree redundant, for example, nearly each research infrastructure has developed its own data management system or data repository. Consequently, developers run into the problem of the sustainability of developed solutions. The academic research community needs better ways to collaborate and reuse and exchange developed software solutions. It is more important to foster the joint use of software tools or the exchange of existing solutions between projects than to develop new tools.
Here we present a concept of mutual exchange of services and a form of deep collaboration. We suggest a concept for the integration and use of software tools by the joint usage of tools and services between different research infrastructures. Including: increased interoperability of clinical data management, biobanking, genetic databases, Electronic Health Records (EHR), query systems, data warehouses and imaging systems. This reciprocal usage creates mutual benefits. Services and tools developed by research infrastructures can be shared and jointly used for mutual benefit.
Data repositories are the core components of an Open Data Ecosystem. To gain a comprehensive model of the data ecosystem supporting tools and services, FAIR principles, joint storage of open data and clinical data and the integration of analysis tools should be considered. The aim was to create a data ecosystem model suitable for the sharing of open data together with sensitive data. For this purpose several tools and services were included in our data ecosystem model: Research Data Marts, I2b2 / tranSMART, CKAN, Dataverse, figshare, OSF (Open Science Framework), ... This multitude of services supports research data repositories. Different types of repositories are connected and supplement each other in the storage, release and sharing of data with different degrees of protection and data ownership. Tools to analyze, browse and visualize data are integrated in the data flow between repositories. Results of our ecosystem analysis:
It doesn‘t matter where one stores data, because everything is connected for data sharing: institutional repositories with dataverses, data marts, general repositories, domain specific repositories, figshare etc. Data governance and privacy protection is integrated at the early stage of data generation.
Zone model for data privacy and confidentiality in medical researchWolfgang Kuchinke
There exist several privacy frameworks for cancer research or biobanking (e.g. ACGT, GenoMatch, caBIG). But most existing privacy frameworks apply the most stringent approach to their data flow and interpret “anonymisation” in a restrictive way. A more flexible approach is needed to guarantee privacy of patient data, but at the same time enable unhindered research. We developed an easy model to display policies and rules for data privacy; it employs the novel concept of "privacy zones for research data flows". The zone model can be used for all important research scenarios.
The Privacy Zone Model is built upon the concept of three zones (Care Zone, Non-care Zone and Research Zone) habouring databases, data transformation operators, such
as data linkers and privacy filters. Using our model, a risk gradient for moving data from a zone of high risk for patient identification to a zone of low risk can be created for each data flow.
CDISC Use Case: Study Migration and Archiving.
Use cases for the employment of CDISC standards for study migration and archiving were collected and discussed. Study archiving covers many issues: legal issues (Good Clinical Practice), reuse of study data, and the replay the study process in case of problems. CDISC ODM format is suitable for clinical study data, because it supports the turning away from proprietary formats and proprietary software solutions in research. In an survey of members of the TMF network, great importance was given to the ability to collect and exchange data together with metadata, and the sharing of complete eCRFs or individual domains of eCRFs. The collected use cases were divided into use cases for study migration, exchange of study data and study archiving, including:
Use case Data import into different EDC systems, Use case Exchange of eCRF, Use case Exchange of data plausibility checks, Use Case Implementation sub-studies, Use case Implementation of mobile data collection by EDC, Use case Archiving compliance with regulations, Use case Archiving of legacy systems, Use case Archiving and study simulation, Use case Archiving of cross-study views.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
What is greenhouse gasses and how many gasses are there to affect the Earth.moosaasad1975
What are greenhouse gasses how they affect the earth and its environment what is the future of the environment and earth how the weather and the climate effects.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
(May 29th, 2024) Advancements in Intravital Microscopy- Insights for Preclini...Scintica Instrumentation
Intravital microscopy (IVM) is a powerful tool utilized to study cellular behavior over time and space in vivo. Much of our understanding of cell biology has been accomplished using various in vitro and ex vivo methods; however, these studies do not necessarily reflect the natural dynamics of biological processes. Unlike traditional cell culture or fixed tissue imaging, IVM allows for the ultra-fast high-resolution imaging of cellular processes over time and space and were studied in its natural environment. Real-time visualization of biological processes in the context of an intact organism helps maintain physiological relevance and provide insights into the progression of disease, response to treatments or developmental processes.
In this webinar we give an overview of advanced applications of the IVM system in preclinical research. IVIM technology is a provider of all-in-one intravital microscopy systems and solutions optimized for in vivo imaging of live animal models at sub-micron resolution. The system’s unique features and user-friendly software enables researchers to probe fast dynamic biological processes such as immune cell tracking, cell-cell interaction as well as vascularization and tumor metastasis with exceptional detail. This webinar will also give an overview of IVM being utilized in drug development, offering a view into the intricate interaction between drugs/nanoparticles and tissues in vivo and allows for the evaluation of therapeutic intervention in a variety of tissues and organs. This interdisciplinary collaboration continues to drive the advancements of novel therapeutic strategies.
Reverse Engineering of Clinical Trials to Improve Research
1. 1
W. Kuchinke (2009)
Improve the transition from preclinical to
clinical research by reverse engineering of
clinical trials
WOLFGANG KUCHINKE
UNIVERSITY DUESSELDORF, DUESSELDORF, GERMANY
GMDS 2009, ESSEN, GERMANY
SEPTEMBER 7, 2009
2. 2
W. Kuchinke (2009)
Introduction
●
In clinical studies on regenerative therapy, combinations of stem
cells, genetically modified cells, modified genes, scaffolding
materials and growth factors have become common tools
●
A major bottleneck in the development of cell therapeutics is the
transition from preclinical research to clinical research on humans
●
Here two different ways of thinking collide:
–
Basic research with large numbers of animals
–
The area of highly regulated clinical studies with humans
●
The question arises how one can prepare researchers for the
requirements of clinical studies in a way that facilitates the transition
of knowledge between basic research and clinical studies
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W. Kuchinke (2009)
Introduction
●
All the requirements for clinical trials generally also
apply to clinical trials with biological medicinal products
●
There are also special aspects that must be taken into
account when planning and evaluating clinical studies or
study programs with these drugs
–
Manufacturing, analytical characterization, mechanisms of
drug action and questions of drug safety and toxicology,
questions of environmental safety
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W. Kuchinke (2009)
Clinical research vs. Translational research
●
Clinical research
–
Systematic study of human subjects and involving testing of new methods of
diagnosis, prevention and the treatment of diseases
–
Careful and pragmatic testing of mature hypotheses in a controlled environment
●
Translational research
–
Bridging science and practice
–
Linking laboratory science with patients and findings with the needs of the community
–
Possible human applications of scientific and clinical findings
–
Translation into strategies for improving healthcare, patient outcomes, and
community health
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Stakeholders in clinical research
Projects Proof-of-
Concept
Clinical
studies
GMP
production
GMP
production
FinancingFinancing
Industrial
partners
Industrial
partners
Pre-clinical
Research
Academic
partners
Academic
partners
Research
Organisations
Research
Organisations
GCP
oversight
GCP
oversight
Ideas
Theories
Questions
Ideas
Theories
Questions
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W. Kuchinke (2009)
Improving pre-clinical trials and translational
research
●
The requirements for successfully conducting clinical trials,
especially for cell therapy studies, are complex
–
Often stem cells, genetically modified cells and nanoparticles have to
be used together
●
The transition from preclinical to clinical testing in humans
represents a bottleneck for academic research
●
We asked ourselves how researchers can be prepared for an
easier entry into the requirements for clinical trials including the
need to work in a regulated area
●
We developed a "reverse engineering" approach that may be
helpful for researchers working at the transition between
translational and clinical research
7. 7
W. Kuchinke (2009)
The aim of “reverse engineering” approach
●
The “reverse engineering” approach can:
–
Familiarize basic researchers with the requirements and
characteristics of the clinical study culture
–
Prepare the basic researcher to create a more efficient
translational process
●
The goal is preclinical examinations
–
Optimize the regulatory requirements and adaption to the
requirements of GCP
–
Simplify cooperation with clinical study centres, especially with
ECRIN centers and logistics
–
Optimise pre-clinical output for translation in clinical trials
9. 9
W. Kuchinke (2009)
The TransVac-Project
●
TransVac Project is a Marie Curie Industry-Academic
Partnership covering:
●
Management of biomedical international research alliances in
Europe
●
Creating knowledge flow through knowledge management
●
Increases the level of research creativity between industrial
and academic biomedical research organizations
●
Creation of a project portfolio to generate knowledge and value
Marie Curie Industry-Academic Partnership
Theme: Trans-national life science value chain management
11. 11
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TransVac-Project: An overview
TransVac was founded in January 2007
●
FP6-MOBILITY - Human resources and Mobility in the specific programme
for research, technological development and demonstration
●
TransVac Management
–
Alliance Office: 4 managers, led by DANDO AND COLUCCI LLC (United
Kingdom)
●
Partners
–
Cambridge University Center for Brain Repair (Cambridge)
–
Ecole Polytechnique Fédérale de Lausanne (Lausanne)
–
ECRIN, Paris
–
Dando & Colucci (Management Company for Innovation Clusters)
–
Fondazione Parco Biomedico San Raffaele (Rome)
–
Coordination by FONDAZIONE PARCO BIOMEDICO SAN RAFFAELE
12. 12
W. Kuchinke (2009)
Management of the project
●
Project management (funds, funding and costs, go no-go decisions, and quality analysis)
●
Risk management
●
Change and communication management
–
Business managers are "on-site" for the research projects
–
Informal communication between managers based on short term needs
–
Formal communication through web conferences every 2 weeks
–
Monthly executive reports
●
Procedures and hands-on engagement
●
Financial control (collaboration with the administration of the research unit and training on
request)
●
●
●
●
Aim: Reverse engineering of the projects from the intended clinical phase back to the
current state-of-play
Adapted from: J. Dando: International portfolio development and alliances between academia and industry, 2007
14. 14
W. Kuchinke (2009)
Management focus on translational research
and interaction with biotechnology SMEs
●
Cooperation with ECRIN working groups in charge of defining tools,
guidelines and procedures to support clinical studies in the EU
●
Special reference to the comparison of national regulatory systems in EU
●
Participation in the development of services supporting phase
1-2 trials on biotechnology-derived products
●
Development of training documents on clinical trial issues in the
biotechnology field
●
Development of a strategy for center selection and fostering patient
recruitment
●
Development of model contracts for EU clinical studies between ECRIN
and biotechnology SMEs, design of a procedure for cost evaluation in EU
clinical studies
16. 16
W. Kuchinke (2009)
Method (Information collection)
●
●
Building on the portfolio of the Transvac project, an Europe-wide survey was carried
out within the framework of the ECRIN network
–
to record the requirements and legal regulations for clinical trials with cell products (biotherapy
studies), stem cells, organic products and genetically modified cells
●
Interviews with ECRIN clinical study centers, regulatory authorities, ethics committees
●
Additional surveys were carried out with regulatory authorities
–
Paul-Ehrlich Institute in Germany
–
ISS in Italy
–
AFSSAPS in France
●
Requirements for animal models and for animal experiments
●
Standard Operating Procedures and guidelines of various clinical trials centres were
analysed
●
A concept for the support of preclinical research and a guide for the transition from
preclinical to clinical studies were developed
17. 17
W. Kuchinke (2009)
Analysis method
Analysis of the use of animal models
–
Animal suppliers, animal husbandry at institutions, non-animal models
●
Analysis and registration of centers that have experience with phase I
studies
●
Collection and analysis of requirements and relevant legal regulations for
clinical trials
–
Focus on clinical trials with cell products, stem cells and genetically modified cells
–
Collecting requirements at meetings, with web conferences and surveys of
researchers and other stakeholders
●
Creation of a concept to support transition from preclinical research to
clinical studies
●
Reconditioning and modification of the analysed material about clinical
trials requirements to fit into the preclinical research environment
●
Development of requirement catalogs, guidelines and training courses
19. 19
W. Kuchinke (2009)
Specifics of the portfolio projects
●
The portfolio projects include research projects on tissue
regeneration for muscle, heart, bone and nerve cells
●
Genetically modified stem cells are used and partly
supported with the help of biomatrix scaffolds and
growth factors
●
The promotion of neuronal plasticity after spinal cord
injuries is achieved through the use of siRNA and the
introduction of pro-neural genes
20. 20
W. Kuchinke (2009)
Possibilities for the „reverse engineering“
approach
●
In the complex field of cell and gene therapy, a “reverse
engineering” approach can:
–
Familiarize the basic researcher with requirements and
characteristics of the clinical study culture
–
Considering special conditions for cell and gene therapy studies
–
Development of recommendations for suitable animal models
–
Identify suitable clinical study centers
–
Prepare for working in a regulated environment
●
The goal is preclinical analysis with regard to:
–
Optimizing the regulatory requirements and GCP rules
–
To simplify cooperation with ECRIN study centers and logistics
21. 21
W. Kuchinke (2009)
Reverse engineering process -
overview
Reverse engineering of the projects from the intended clinical phase
back to the current state-of-play
22. 22
W. Kuchinke (2009)
TransVac Management
Regularly communication Web conferences
Exchange of information newsletter
TransVac Central Management financing
Managers in the different centres Support of researchers
Exchange between managers
Collaboration with ECRIN Inclusion of EU correspondents
Meetings
23. 23
W. Kuchinke (2009)
Return of knowledge to basic researchers
Special populations Guidelines and catalogue of
regulations
Recruitment support by ECRIN
Non-animal tests consultation
Good Laboratory Practice (GLP) consultation
Phase I international studies support by ECRIN
Selection of study centers support by ECRIN
Good Manufactoring Practice support by ECRIN
Data protection consultation
25. 25
W. Kuchinke (2009)
Example Transvac 08
●
Clinical validation of mesoangioblasts from HLA-matched donors for
treatment of muscular dystrophy
–
Partners: Fondazione Parco Biomedico and ECRIN
–
Phase I clinical study with mesangioblasts from HLA-matched donors
–
Are transplanted into patients who have Duchenne muscle atrophy
–
Treatment was successful in pre-clinical animal models (mouse and dog)
–
Normal stem cells are supposed to fuse with regenerating dystrophin fibers
●
Intra-arterial transplantation tested in phase I study
–
Intra-arterial injections, restoring dystrophin production
Barriers to translational research
See: M Sampaolesi, S Blot, Cossu G, et al. Mesoangioblast stem cells ameliorate muscle function in dystrophic
dogs. Nature 2006; E-pub Nov 15, 2006
26. 26
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The art of working in a
regulated area
It is especially this requirement that
must be fed back to basic, pre-
clinically working researchers
27. 27
W. Kuchinke (2009)
Results
●
A lack of understanding was ascertained for the regulatory, ethical and
process management aspects for biotherapy projects
–
Requirements of ethics committees
–
The presentation of own results of research in the context of research state of
the art (i.e. the state of the art)
–
Ability to give a comprehensive and critical overview about research (traceability
by other research groups)
–
The possible toxicity of stem cells in general is underestimated
●
Creation of preclinical evaluation guide for animal models and
requirements for cell and gene therapy products prior to start of clinical
study:
–
Preclinical evaluation, drug safety concerns in phase I studies, EU guidelines for
phase I trials, EMEA guideline for phase I trials for cellular biotherapy and gene
therapy studies, country-specific requirements and regulations at the beginning
of biotherapy studies, overview of the animal models for cell therapy and
regeneration, problem areas of animal studies for clinical trials, animal studies
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W. Kuchinke (2009)
Results
●
A process description was developed (stages from preclinical research to phase I
transition process)
–
Analysis of the number of animals and important experimental data in selected cell and
gene therapy studies
–
Legal provisions and advice from the Paul-Ehrlich Institute in Germany and AFSSAPS in
France.
●
List of international requirements for animal models, costs of animals for studies,
special requirements for biotherapy studies, applicable guidelines for tires in
preclinical studies
●
Advice received from competent authorities
–
the national authorities in EU countries and the EMEA recommend attending advisory
meetings prior to the start of phase 1 studies
–
Questions in connection with the new investigational medicinal products, including the
relevance of the animal model
–
But authorities do not make recommendations for a model for any particular disease
–
A similar response in human and animal cells in vitro, does not guarantee that the in vivo
response is similar
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W. Kuchinke (2009)
Results of survey of Clinical Trials Centres
Clinical Study Centers (mostly ECRIN Clinical Trials Centres)
–
Little experience in phase I studies
–
Little experience with stem cells
–
No experience with clinical studies of nanotechnology products
–
Little contact and information of preclinical phase
●
Animal breeding and husbandry
–
Only a limited range of animal models at university clinics
–
Little experience with alternative testing methods
–
Use of commercial animal providers
●
Important topics for training preclinical researchers
–
Legal regulations, guidelines, GCP requirements, national differences in
regulation and practice
–
Requirements from authorities and ethics committee, clinical trials process
requirements
–
Data management / data privacy requirements
30. 30
W. Kuchinke (2009)
Results
●
The right animal model for preclinical research is essential
–
Analysis of the number of animals, characteristics, type of treatments for heart muscle
regeneration, skeletal muscle regeneration, bone development and neuroregeneration
–
Identification of problem areas in animal studies, international requirements for animal models,
costs of animals, measures for animal welfare, non-animal models
●
Collection of requirements for cell and gene therapy products prior to the start of a
clinical study
–
Preclinical evaluation, use of nanoparticles, drug safety concerns in phase I studies,
requirements of the EMEA guideline for phase I studies on cellular biotherapy and gene therapy
and country-specific conditions
●
There are no general rules for considering the number of animals in selected cell and
gene therapy studies
●
There are considerable country-specific differences in the field of:
–
Cell therapeutic requirements for animal models, study implementation, studies with stem cells,
studies with nanoparticles and active ingredients from animal or human products
–
Provision of animal models and the requirements for animal experiments
–
This makes it easier to carry out some aspects of preclinical research or clinical studies in some
countries than in others
31. 31
W. Kuchinke (2009)
Results
●
Improvements for basic researchers can be achieved
through:
–
Training of the important aspects of good clinical practice,
intensive dialogue with the authorities already during
development phase
–
Careful selection of animal models and non-animal models
–
Inclusion of centers with experience in phase I and / or stem cell
therapy
–
Comprehensive evidence of cellular safety (cell migration, cell
type, pre-neoplastic changes)
–
Complete presentation of published research data
–
Facilitate the conduct of international cell therapy studies in
ECRIN
32. 32
W. Kuchinke (2009)
Results
●
GCP training covering
–
Phase I-IV studies, differences between commercial and academic studies,
the different categories of clinical studies, the GCP directive, the various
actors (sponsor, study doctor, LKP, EK, authority, etc.), side effects, etc. Study
design, cross-over studies, controlled randomized studies, important terms
such as confounder (disruptive variable) process of informed consent, written
patient information, written patient information, revocation of consent,
declaration on data protection, data protection: personal data, sensitive data ,
transfer of study data, FIM (FIRST-IN-MEN) studies, data and risk
assessment, infrastructure for clinical research: centers and networks, clinical
study centers and clinical study units, clinical research costs
●
Overcome obstacles to the innovation of clinical research
–
Better dialogue with the authorities already during development
–
Increased acceptance of biomarkers and surrogate endpoints by authorities
–
Increased participation of other interest groups such as e.g. patients in the
regulatory review process
33. 33
W. Kuchinke (2009)
Results
●
Overcome difficulties conducting clinical trials
–
Lack of predictability in the operational environment, qualification
bottleneck
–
Lack of early support
–
Research of degenerative and chronic diseases is in general more
expensive (more complex patient treatment and monitoring is
necessary), long time to observe effects
–
Complex regulatory and ethical requirements
●
Very few centers have experience with phase I and even less
with FIM studies
●
Special features to consider: logistics, the availability of an
emergency rooms, etc.
34. 34
W. Kuchinke (2009)
Details of the employed Portfolio studies
●
Skeletal muscle
–
Muscle regeneration with either wild type of genetically modified cells
●
Cardiac muscle
–
Cardiac mesoangiobalsts are induced to differentiate into bio-matrix scaffolds and
implantted
●
Cardiovascular
–
Generation of cardiomyocytes from stem cell sources and gene delivery to such
cells
●
Bone formation
–
Skeletal stem cells used in combination with scaffolds and differentiation factors
●
Neurological
–
siRNA approach: reduction of expression of three target genes
–
Delivery pro-neural genes by the use of cationic oligopeptides and inhibition by
vector-driven siRNA
35. 35
W. Kuchinke (2009)
Portfolio studies: international requirements for tisssue studies
Requirements for specific populations, blood and tissue samples and genetic
studies by national authorities were collected and analysed. Example:
Country requirements for specific
populations
requirements regarding blood
and tissue samples, circulation
and storage
Specific requirements
regarding genetic
studies
Hungary no Yes, comprehensive listing of
investigations, specific IC for
DNA samples. DNA samples
max storage for n15 years
Yes, specific IC
UK Yes, COREC application form:
www.corec.org.uk
Yes: human tissue act.
www.opsi.gov.uk/acts
/acts2004/20040030.htm
no
France Yes: vulnerable pop (children,
pregnant, dementia,…) Art L
1121-5,-6,-7,-8,-9,-11,-14. L1122-
1,-2
Yes: Art L 1125-1. L 1243-3 Yes: CNIL, Comité
national d’éthique, Loi de
bioéthique
Italy Yes, vulnerable population
(children, unconscious, dementia)
article 3,4,5 legislation decree:
//oss-sper-clin.agenziafarmaco.it
/normative/dlgs_211_24-6-
03_Dir_UE_sper.pdf
yes Yes: specific IC, purpose
must be described in
advance
Spain no Yes: RD 478/1993:
www.agemed.es/actividad
/legislacion/espana/
especiales.htm
no
Ger Yes: vulnerable pop (children,
pregnant, unconcious,…) AMG
§41, MPG §20, §21, §88
StrlSchV, §28 RöV
37. 37
W. Kuchinke (2009)
Discussion
●
In the particularly complex area of stem cell-based cell therapy, a
“reverse engineering” approach can facilitate the transition from basic
research and preclinical studies to phase I / II clinical studies
●
By familiarizing basic researchers with the requirements and
peculiarities of the clinical study culture Approval for focused pre-
clinical research allowed
●
Reverse engineering generally refers to the process of extracting the
design elements and processes from an existing system by
examining the structures, states and behaviors
●
We have transfered this concept to clinical studies by examining and
comparing requirements and processes for conducting clinical studies
in 12 European countries in order to develop guidelines and
recommendations for preclinical research in the field of cell therapy
38. 38
W. Kuchinke (2009)
Discussion
●
Reverse engineering generally refers to the process of extracting elements and
processes from an existing, working system by examining its structures, states and
behavior
●
We transfered this concept to the clinical study area
●
With the new regulation on medicinal products for advanced therapies, the European
Union has created legal certainty in the approval of gene therapy, somatic cell therapy
and tissue engineering products
●
The products for novel therapies (gene therapy, somatic cell therapy and tissue
engineering ) are assigned to drugs area and must therefore pass the same approval
conditions as conventional drugs
●
But SMEs often lack required regulatory know-how for approval and licensing
●
Products from tissue engineering (human tissue engineering medicinal product) are
often developed at universities and research laboratories
●
By 2012 all hTEPs, including those currently in circulation, must undergo approval
procedures by the EMEA
●
Many SMEs fail to meet the requirements of the EMEA in the form of complex clinical
studies as part of the approval process.
39. 39
W. Kuchinke (2009)
Discussion
●
Suggestions for improvement
●
Training of basic researchers in Good Clinical Practice (GCP)
●
Improved dialogue with the authorities already during the development, e.g. by the
researcher's participation in advisory meetings before the start of the phase 1
studies
●
Verification of relevance of the animal model
●
Checking the migration of cells into the target organs (biodistribution) and cell
differentiation into the desired cell type, but also the absence of preneoplastic
changes
●
Model suitable to demonstrate virus and microbiological safety
●
Support for the comprehensive and complete data collection in support of clinical
studies
●
Consideration of the requirements of the ethics committees and authorities, in
particular with regard to the declaration of consent, data protection (personal data,
sensitive data, transfer of study data abroad) and the special regulations for
participation in clinical studies.
40. 40
W. Kuchinke (2009)
Contact
Wolfgang Kuchinke
Heinrich-Heine Universität Duesseldorf, Duesseldorf, Germany
wolfgang.kuchinke@uni-duesseldorf.de
wokuchinke@outlook.de
THANK YOU!
This is a translation of the presentation held in German; it contains additional
explanatory material for a workshop.