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.

1. W. Kuchinke (2012)
Legal and ethical issues regarding
international clinical trials
W. Kuchinke
University of Duesseldorf (Germany)
p-medicine project: 4th Progress Meeting
Working Task 5.5 – Legal and ethical issues in p-medicine
Aug 29-31, 2012 in Bonn, Germany

2. Del5.5: Legal and ethical issues
• Contributions
– Wolfgang Kuchinke (WK), UDUS
– Iheanyi Nwankwo (IN), LUH
– Nikolaus Forgo (NF), LUH
– Stefanie Hänold (SH), LUH
– Stephan Kiefer (SK), IAIS
– Fatima Schera (FS), IAIS
– Gordon McVie (GV), ecancer
– Norbert Graf (NG), USAAR
– Ali Haidar (AH), UCL (review)
Deliverable 5.5: Legal and ethical issues for p-
medicine tools used for international GCP trials
W. Kuchinke (2012)

3. Extension and consolidation of Del 9.1
• In Deliverable 9.1: Report of regulatory and
international aspects of the clinical trials
– all relevant regulatory requirements for the
conduct of international clinical trials have
been listed
– Del 5.5 deliverable builds on that report,
and its purpose is to extend on this topic by
discussing certain legal and ethical issues
that are of importance to p-medicine,
especially for these software tools that are
developed in p-medicine and that will be
used in clinical trials.
W. Kuchinke (2012)

4. Deliverable 9.1
• See:
http://p-medicine.eu/fileadmin/p-med
icine/public_website/downloads/p-med
icine_270089_D9-1_Report_on_regulato
ry_and_international_aspects_of_the_
clinical_trials_v1-0.pdf
http://p-medicine.eu/

5. Legal and ethical issues
• GCP requires that clinical trials are conducted ethically
– protection and the safety of clinical trial participants
– guarantee of the quality of clinical trials data
• GCP is not a single standard, but a set of guidelines that
cover design, conduct, monitoring, termination, audit,
analyses, reporting and documentation of clinical studies
• Analysis of the framework for the global regulatory
thinking that represents the interpretation of GCP
– These legal and ethical issues are the topic of expert groups,
advice groups and conferences
– regulatory authorities in Europe, USA and Japan cooperate and
harmonize initiatives, disseminate GCP knowledge and reach
out for innovative technologies
W. Kuchinke (2012)

6. The entrance for ethics into research

7. GCP – Good Clinical Practice
Ethical standard for clinical research

8. What are the 3 main principles of GCP ?
• Respect
• Beneficence
• Justice
• These principles ppermeate all other
GCP principles and guidelines

9. What is the purpose of GCP ?
• Good Clinical Practice (GCP) is an
international ethical and scientific
quality standard for the design,
conduct, performance, monitoring,
auditing, recording, analyses and
reporting of clinical trials
• It protects the rights, integrity and
confidentiality of trial subjects

10. Who needs GCP training?
• All investigators and staff who are
involved in the conduct, oversight or
management of clinical trials
• Completion of a training in Good
Clinical Practice (GCP) consistent with
principles of the International
Conference on Harmonisation (ICH)
E6 (R2)

11. The 13 GCP rules
1. Ethics originating in the Declaration of Helsinki
2. Assessment of trial risk vs trial benefit
3. Rights, safety, and well-being of the trial subjects
4. Information on the Medicinal Product
5. Need for good quality
6. Compliance with the study protocol
7. Medical decisions only by qualified physicians
8. Qualified and trained trial staff
9. Need for freely given informed consent
10.Accurate collection and reposting of clinical trial data
11.Protection of confidentiality
12.Good Manufacturing Practice
13.Quality assurance of every aspect of the trial

12. Legal issues for GCP trials
• Necessary roles and components of GCP
– Clinical Trial Investigator, Informed Consent, Independent Ethics Committees ,…
• Guiding documents on GCP
– ICH Topic E6 , ICH Topic E 2, EMEA Note for guidance on Good Clinical Practices
(2002), …
• International GCP framework
– Regulatory authorities in the GCP Areas: Japan, Europe and USA
• PMDA in Japan: Ministerial Ordinance on Good Clinical Practice for Drugs, administrative
notifications , Guidelines for Biologics, cell / tissue-based products, International Programs to
support the regulatory harmonization (e.g. PMDA International Strategic Plan) …
• FDA in USA: FDA Regulations and guidance for GCP , FDA regulations related to GCP, Standards for
Non-US Trials , Critical Path Initiative, Advancing Regulatory Science, Clinical Trials Transformation
Initiative , …
• EMA in Europe: Medicines and emerging science, Pharmacogenomics and personalised medine
(Reflection papers), International harmonization activities, GCP matters initiative, Pharmaceutical
Inspection Co-operation Scheme,…
– GCP principles are interpreted and applied to new areas, like
advanced therapies, paediatric trials and trials using genetic
information
W. Kuchinke (2012)

13. Global framework of regulatory thinking about
GCP compliant trials

14. Fragmentation of European regulatory frameworks for
clinical research
• ECRIN collected exhaustive information on national
legislation on clinical trials in Europe
• ECRIN played a major role in the discussion on the revision
of the 2001/20/EC Directive, and in proposals for a risk-
based approach to clinical research legislation
• Involvement in the Impact on Clinical Research of European
Legislation (ICREL) project
• ECRIN suggests to use
– a stratified approach for legislation purposes: three categories
depending on the status of the health product (non-marketed,
marketed exploring a new indication, or marketed within the
licensed indication) leading to risk-based adaptations for most of
the processes in clinical trial supervision
– a personalized approach for monitoring, with a decision tree for
risk assessment of each individual protocol
W. Kuchinke (2012)

15. National regulations for clinical trials
• ECRIN and TREAT-NMD (Translational Research in Europe
– Assessment & Treatment of Neuromuscular Diseases)
are cooperating to establish and maintain the TREAT-
NMD Regulatory Affairs Database
• The current version contains the contact addresses of
national authorities as well as national legislation on
clinical trials from 15 European countries
• Additionally, European regulations and other important
international documents and guidelines (e.g. from ICH
and EMEA)
• Detailed listing of national regulations applicable to the p-
medicine project:
– Austria, Germany, Switzerland, United Kingdom
W. Kuchinke (2012)

16. Application of ethical requirements to the
tools use in personalised medicine trials

17. Zone Model
• Allows analysis of data privacy and
confidentiality issues for research with patient
data in a structured way
• Provides a framework to specify a privacy
compliant data flow, to communicate privacy
requirements and to identify weak points for an
adequate implementation of data privacy in an
infrastructure connecting care, hospital, clinical
trials and research data
• Applied to the data flow in p-medicine, it allows
the identification of important points of transition
in need for special data protection measures

18. Different zones for compliant usage of patient data
In contrast to the physician or clinical trial investigator, the researcher is subject to
the least ethical and legal constraints and can therefore use only anonymous data

19. Reference of the Data Zone Model
Kuchinke W, Ohmann C, Verheij RA, van Veen EB, Arvanitis
TN, Taweel A, Delaney BC. A standardised graphic method
for describing data privacy frameworks in primary care
research using a flexible zone model. Int J Med Inform. 2014
Dec;83(12):941-57. doi: 10.1016/j.ijmedinf.2014.08.009. Epub
2014 Sep 3. PMID: 25241154.

20. p-medicine tools used in clinical trials
• ObTiMA (including Management SAEs/SUSARs)
• DoctorEye (including DICOM transfer)
• Biobanks access
• Portal function
• Patient Empowerment
W. Kuchinke (2012)

21. Example: ObTiMA based data management
Ontology-based clinical trial management: support clinicians in both
designing and conducting clinical trials; investigators can assemble
CRFs for their planned clinical trial (Trial Builder); treatment plans
for guiding clinicians through individual patient treatments, …

22. Ethical principles applied to international GCP trials
• On the one hand GCP compliance is built upon ethical principles;
on the other hand GCP rules have been concertized in laws,
regulations and guidelines
• Based on (examples):
– The Nuremberg Code (1947)
– Declaration of Helsinki (2008)
– CIOMS International Ethical Guidelines for Biomedical Research Involving
Human Subjects (2002)
• Four p-medcine deliverables dealing with ethical aspects:
– D5.1 Data protection and data security framework
– D5.2 Legal and ethical issues regarding data warehouse, data mining and IP
issues
– D5.3 Legal and ethical issues regarding access to biobanks
– D5.4 Legal and ethical issues regarding patient empowerment
W. Kuchinke (2012)

23. Core Ethical Principles in GCP Trials
• Ethics of Informed Consent
– Preconditions for a valid informed consent
– Protection of the research subjects and medical intervention
• Ethical issues concerning non-maleficence and justice in
clinical research
• The four Traditional Pillars of Medical Ethics and their relation
to clinical trial conduct
– ObTiMA, DrEye and Biobank Access (data management and transfer of
biosamples in clinical trials): area of beneficence/non-maleficence and
privacy/confidentiality
– Patient Empowerment and Portal (enabling patients to participate
more thoroughly in clinical trials): area of autonomy and justice
– Patient Empowerment tool can provide sufficient online information
for the patient, aided by a user-friendly GUI, influence of “therapeutic
misconception” should be avoided
W. Kuchinke (2012)

24. Relationship between ethical concepts, clinical trials
and p-medicine tools

25. Core Ethical Principles relevant for GCP trials in
personalised medicine
• Ethical issues for clinical trials with vulnerable populations
and children
• Ethical issues for cancer clinical trials (life threatening diseases)
– Risk/benefit-ratio
– Consequences for Informed Consent
• Ethical issues arising with personalized medicine clinical trials
– Privacy and Autonomy
– Pharmaceutical Industry
– Scientific racism and genetic determinism
• Ethical issues concerned with transparency in clinical trials
• Ethical issues regarding the necessity for Ethics Committees
• Ethical issues regarding the necessity for Data Safety Monitoring
Boards
W. Kuchinke (2012)

26. Evaluation of legal and ethical issues
• Legal and ethical GCP- requirements concerning the use of
p-medicine tools
– p-medicine tools are used mainly in connection with clinical data
management purposes
– GCP compliant data management is considerably hampered not only by the
problem of the heterogeneity of the software products, also proprietary rights
issues, deficits in the quality of data management caused by limited personal and
financial resources, underestimation of the complexity of data management, and
the lack of a general, specific and practicable standard for GCP compliant data
management have to be considered
• Ethical Consideration for the use of p-medicine tools
– Six clusters were assigned: informed consent, vulnerable populations, IRB/Ethics
Committee, data privacy, and investigator
– Two of these clusters: informed consent (patient decision, fine grained IC, IC for
biosamples, IC and life threatening disease, vulnerable populations) and data
privacy (complex tool integration, complex data flow, personal data, genetic data)
were discussed in detail
– The patient empowerment tool connects requirements for IC with the ones for
vulnerable populations; p-medicine contracts / agreements connect requirements
for personal data with investigator related requirements
W. Kuchinke (2012)

27. Summary of the ethical issues connected to the use
of p-medicine tools
Five requirements cluster (blue): informed consent, vulnerable populations,
IRB/Ethics Committee, data privacy, investigator), p-medicine tools (dark squares)

28. Summary of the ethical issues connected to the use
of p-medicine tools
Five requirements cluster (blue): informed consent, vulnerable populations,
IRB/Ethics Committee, data privacy, investigator), p-medicine tools (dark squares)
Ethical requirement
Cluster
Patient Empowerment
Ethical requirement
Cluster
Data protection
Ethical requirement
Cluster
Personal Medical
Research
Ethical requirement
Cluster
Contracts
Ethical requirement
Cluster
Tool / Portal

29. Considerations for using the personal medicine
tools
• Tools that have been completely developed and tested for use in
a medical environment and are GCP compliant
• all capture of patient data with p-medicine tools has to be
accurate, reliable and correctly
• Compliant clinical data management systems (CDMS) and system
validation
• The ethical environment for GCP compliance in data
management (audits, DSMB , Subject identification code,
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
– “Directly" or "indirectly" identifiable data
• Legal issues arising by deep integration of tools for clinical trials
• Issues caused by software that falls under the medical device law
W. Kuchinke (2012)

30. Discussion and Consequences
• Legal issues applicable to p-medicine tools that need
particular attention are:
– Clinical data management systems and system validation
(requirements for GCP, risk management, data integrity control,
quality system and audit information, etc.). The ECRIN GCP
standard has defined many requirements for high quality GCP
compliant data management in multinational clinical trials.
– Personal data used in clinical trials (pseudonymisation,
recruitment of patients, biosamples data, directly or indirectly
identifiable data)
– Legal issues arising by deep integration of tools for clinical trials
and a single point of access (portal, identifiability, personal data,
right not to know)
– Software that may fall under the medical device law. That
concerns p-medicine tools used for diagnostic and / or therapeutic
purposes (image based diagnosis, decision)
W. Kuchinke (2012)

31. Problem areas to address and assess
• Clinical trial sensitive patient data is involved: recruitment,
collection of biosamples, patient empowerment
• The sponsor should not have exclusive control of a source document
• dual nature of biobanking tools. Biobanks constitute a collection of
samples of human body substances (e.g. tissue, blood), which often
are linked to personal data and demographic information about the
donor
• multitude of regulations and guidelines exists that have to be
considered to use tools in a GCP compliant way. All software solutions
used in GCP clinical trials will have to undergo a comprehensive
system validation (according to GAMP and PIC/S)
• GCP compliance training / Validation simulation
• Ensuring patient’s autonomy during use of Patient Empowerment
– cover the use of the Empowerment GUI by patients with serious diseases, patients
in distress and users from vulnerable populations to ensure usability even under
special conditions (see above) to enable patients to freely make decisions
W. Kuchinke (2012)

32. W. Kuchinke (2012)
Thank you!
Wolfgang Kuchinke
Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
wolfgang.kuchinke@uni-duesseldorf.de
wokuchinke@outlook.de
Further information: www.ecrin.org
This presentation contains additional explanatory material for a workshop
and Q&A session.