Human Research Ethics Office
Principles of Conducting Clinical Trials
Human Research Ethics Office
Principles of Conducting Clinical Trials
Version
Number
1.0
Date
29 September 2015
Summary of Revisions Made
Original document
Principles of Conducting Clinical Trials, Version 1.0, 29 September 2015
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Contents
Glossary ........................................................................................................................................... 2
Background ..................................................................................................................................... 4
2.1
Clinical trial definition ................................................................................................................. 4
2.2
Regulations.................................................................................................................................. 4
2.3
Key stakeholders ......................................................................................................................... 5
Conducting Clinical Trials ................................................................................................................ 7
3.1
Principles ..................................................................................................................................... 7
3.2
Governance ............................................................................................................................... 15
References .................................................................................................................................... 17
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Glossary
ARC
Australian Research Council
ARTG
Australian Register of Therapeutic Goods
CAPA
Corrective and Preventative Action
Code, the
Australian Code for the Responsible Conduct of Research
CTN
Clinical Trial Notification
CTX
Clinical Trial Exemption
EMA
European Medicines Agency
Ethics approval
Determination by an ethics review body that a research project satisfies
ethical standards and requirements including, but not limited to, the
National Statement
Ethics review
Process that explores the ethical implications of a proposed research
project
FDA
U.S. Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
Governance approval
See Site Authorisation
HREC
Human Research Ethics Committee
IEC
Independent Ethics Committee
Institution
Any public or private entity or agency (or group of agencies) that resources,
conducts or manages a clinical trial
Intervention
A manipulation of the clinical trial participants or their environment for the
purpose of modifying one or more of the study outcomes. The intervention
may be a drug, medical device, surgical procedure, diagnostic or screening
procedure, an health service change, or a psychological, educational or
behavioural strategy.
IRB
Institutional Review Board
Investigator
An individual responsible for the conduct of a clinical trial (or any aspect
thereof) at a trial site
National Statement
National Statement on Ethical Conduct in Human Research
NHMRC
National Health and Medical Research Council
Participant
See Research Participant
PDCA cycle
Plan-Do-Check-Act cycle
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PI
See Principal Investigator
Principal investigator
Individual accountable for a clinical trial and everything that happens on it
QA
Quality Assurance
QC
Quality Control
QMP
Quality Management Plan
Regulatory authority
Body responsible for the assessment, monitoring and regulation of
therapeutic goods in a particular country or region
Researcher
See Investigator
Research participant
An individual who participates in a clinical trial, whether as a recipient of an
intervention or as part of the control group
Risk
Potential for an adverse outcome to occur
Risk appetite
Amount and type of risk an organisation is prepared to tolerate in order to
achieve its objectives
Site
See Trial Site
Site assessment
Process used to assess whether a proposed clinical trial complies with
institutional requirements
Site authorisation
Determination by an institution that a proposed clinical trial satisfies
institutional requirements and may commence
Sponsor
An individual, company, institution or organisation that takes responsibility
for the initiation, management, and/or financing of research
Sub-I
See Sub-investigator
Sub-investigator
An individual member of a clinical trial team who is supervised by the
Principal Investigator and to whom the PI delegates critical trial-related
procedures and/or the ability to make important trial-related decisions
TGA
Therapeutic Goods Administration
Therapeutic good
Generally refers to a drug or medical device
Trial Site
An institution at which a clinical trial is conducted
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Background
2.1
Clinical trial definition
The Curtin University Ethics Office defines clinical trials as interventional studies that have a
biomedical or health-related outcome.
‘Interventional’ refers to manipulation of the trial participants or their environment for the purpose
of modifying one or more of the study outcomes. The intervention may be a drug, medical device,
surgical procedure, diagnostic or screening procedure, an health service change, or a psychological,
educational or behavioural strategy that could potentially result in the development of a new
standard of healthcare. Interventional studies characteristically involve comparison of one or more
interventional groups with a control group.
For a brief introduction to the clinical trials environment in Australia, refer to the National Health
and Medical Research Council’s (NHMRC) clinical trial eLearning modules. These modules consist of
three 45 minute videos providing an introduction to the clinical trials environment in Australia, a
discussion of ethical issues relating to clinical research and an overview of the clinical research
governance processes in Australia.
2.2
Regulations
Clinical trial regulations have both a legal and an ethical basis. The NHMRC has published tables of
National, State and Territory laws relating to the oversight and conduct of human research in
Australia. It is the responsibility of both institutions and researchers to be aware of and comply with
the general and specific legal requirements relating to the research they wish to carry out.
Researchers, however, are rarely expected to interpret legislation themselves. Instead, guidelines
are developed by research bodies and institutions that take both the law and established ethical
principles into account. It is these guidelines with which researchers are expected to comply.
Adherence with the following guidelines is required for the conduct of clinical trials in Australia.
Additional requirements may apply to specific types of research or to specific clinical trials.
Australian Code for the Responsible Conduct of Research
The Australian Code for the Responsible Conduct of Research (the Code) was jointly developed by
the NHMRC, the Australian Research Council (ARC) and Universities Australia.
The Code is a guide to responsible research practices. It examines the broad principles of
responsible and accountable research practice, and outlines what is expected of researchers and
institutions in the management of research data and associated materials, publication and
dissemination of research findings, peer review, authorship, conflict of interest, supervision of
students and research trainees, and collaboration. It also outlines a general process for identifying
and handling research misconduct and breaches of the Code.
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Compliance with the Code is a prerequisite for receipt of funding from the NHMRC, ARC or
Universities Australia.
National Statement on Ethical Conduct in Human Research
The National Statement on Ethical Conduct in Human Research (National Statement), like the Code,
was a jointly developed by the NHMRC, ARC and Universities Australia. It was developed in
accordance with international conventions in the ethical conduct of human research and with the
National Health and Medical Research Council Act 1992. It provides guidelines on the ethical design,
review and conduct of human research.
As with the Code, compliance with the National Statement is a prerequisite for receipt of funding
from the NHMRC, ARC or Universities Australia.
Good Clinical Practice
Good Clinical Practice (GCP) is an internationally recognised standard for the design, conduct,
performance, monitoring and auditing, recording, analysis and reporting of clinical trials.
GCP was originally developed for use by pharmaceutical companies seeking marketing approval for
their products, however, it has since been broadly adopted by research bodies around the world.
The GCP guidelines adopted in Australia, the Note for Guidance on Good Clinical Practice
(CPMP/ICH/135/95) – Annotated with TGA Comments, intercalate with the National Statement. Any
research to which Chapter 3.3 of the National Statement applies must also comply with GCP and
other applicable Therapeutic Goods Administration (TGA) requirements.
The equivalent good practice guideline for medical device trials is the ISO 14155 standard.
Curtin University Research Policies
All staff and students involved in the conduct of research at Curtin are obliged to comply with the
Curtin University Research Policies. Observance of the principles described in these policies ensures
that the research is conducted to an appropriate standard and in accordance with applicable
national and state legislation.
2.3
Key stakeholders
Sponsor
A sponsor is defined in the National Statement as an individual, company, institution or organisation
that takes responsibility for the initiation, management, and/or financing of research (p. 90). Largescale clinical trials are generally sponsored by either a pharmaceutical or medical device company.
In a university setting, however, it is not unusual to encounter what is known as a ‘sponsorinvestigator’, “an individual who both initiates and conducts, alone or with others, a clinical trial, and
under whose immediate direction the [intervention] is administered to, dispensed to, or used by a
subject” (Therapeutic Goods Administration 2000; p. 12). The sponsor-investigator responsibilities,
as defined in the regulations, encompass those of both the sponsor and the investigator.
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Regulatory Authority
In Australia, the regulatory authority is the Therapeutics Goods Administration, which is responsible
for the assessment, monitoring and regulation of therapeutic goods (drugs and medical devices) in
Australia. Overseas equivalents include the Food and Drug Administration (FDA) in the USA, and the
European Medicines Agency (EMA).
Research involving a drug or medical device that is registered, listed or entered on the Australian
Register of Therapeutic Goods (ARTG), and which will be used within the conditions of its marketing
approval, may be conducted without informing the TGA. However, where research involves a) a
product not listed on the ARTG or b) use of a drug or device beyond the conditions of its marketing
approval, the TGA must be informed prior to the commencement of the study. This may be
accomplished through either a Clinical Trial Notification (CTN) or via the Clinical Trial Exemption
(CTX) process.
Institution
‘Institution’ refers to any public or private entity or agency that resources, manages or conducts a
clinical trial. Institutions are responsible for carrying out governance and ethical review of clinical
trials. Their responsibilities are described in the Code and the National Statement.
Human Research Ethics Committee
Also referred to as an Institutional Review Board (IRB) or Independent Ethics Committee (IEC), the
Human Research Ethics Committee (HREC) is an independent body that reviews clinical trials prior to
their commencement to ensure that it meets relevant scholarly and scientific standards, fulfills
regulatory requirements and has sufficient measures in place to protect research participants from
harm.
Investigator
An investigator is an individual responsible for the conduct of a clinical trial (or any aspect thereof) at
a trial site. The terms ‘investigator’ and ‘researcher’ are interchangeable.
Where the trial is conducted by a team of individuals, one person must be accountable for the
clinical trial and everything that happens on it; this person is referred to as the principal investigator
(PI). The Curtin University Principal Investigator’s Pocket Guide to Research Projects describes the PI
responsibilities.
Individual members of a clinical trial team who are supervised by the PI and to whom the PI
delegates critical trial-related procedures and/or the ability to make important trial-related decisions
are referred to as sub-investigators (Sub-Is).
Participant
The term ‘participant’ refers to individuals who take part in clinical trials, whether as a recipient of
an intervention or as part of the control group.
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The rights, safety and well-being of research participants take precedence over all other
considerations, including the contribution of the trial to the scientific body of knowledge, and the
potential benefit of the trial to society as a whole (Therapeutic Goods Administration 2000; section
2.3, World Medical Association 2013; clause 8).
Conducting Clinical Trials
3.1
Principles
The principles of quality management, risk management and ethical conduct form the foundation of
all conventions and regulations relating to the conduct of clinical trials. These three principles are
inextricably interlinked (Figure 1), such that one concept cannot exist without the other. The 13
principles described in Chapter 2 of GCP each align with one or more of these principles.
Figure 1 – The principles underlying the regulation and conduct of clinical trials
Quality Management
Quality management is “the overall process of establishing and ensuring the quality of processes,
data and documentation associated with clinical research activities” (National Institute of Dental and
Craniofacial Research 2012; p. 1). It is necessary in clinical trials to protect the health, safety and
well-being research participants and to generate data that are accurate, reliable and fit for use
(Davis et al. 1999, Pfizer 2009). It is also a regulatory requirement, with a number of GCP principles
relating directly to quality management:
Principle 5: Clinical trials should be scientifically sound, and described in a clear, detailed
protocol
Principle 6: A trial should be conducted in compliance with the protocol that has received prior
institutional review board (IRB)/independent ethics committee (IEC) approval/favourable
opinion
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Principle 8: Each individual involved in conducting a trial should be qualified by education,
training, and experience to perform his or her respective task(s).
Principle 10: All clinical trial information should be recorded, handled, and stored in a way that
allows its accurate reporting, interpretation and verification.
Principle 12: Investigational products should be manufactured, handled, and stored in
accordance with applicable good manufacturing practice (GMP). They should be used in
accordance with the approved protocol.
Principle 13: Systems with procedures that assure the quality of every aspect of the trial should
be implemented.
It is not possible to implement quality retrospectively, therefore, quality management necessarily
begins when the trial is first conceived. A good quality management system will take into
consideration all variables that may affect the trial, including its organisational structure,
responsibilities, processes, procedures and resources for implementing quality management
(Manghani 2011).
Quality management processes may be divided into quality planning, quality control (QC), quality
assurance (QA) and quality improvement procedures.
Quality Planning
Quality outcomes will only be achieved when the clinical trial as a whole is properly designed and
conducted. Careful consideration must be given to the selection of a suitable research question and
development of an appropriate trial design, which is then be described in a clear, detailed protocol
(see GCP Principle 5 above). While the protocol is being developed so too should the other study
management tools, including a Quality Management Plan (QMP).
The QMP is a written document that details the responsibility, scope and frequency of quality
management activities on a clinical trial (National Institute of Dental and Craniofacial Research
2012). It defines quality standards and details the quality control, quality assurance and quality
improvement processes that will be used to ensure those standards are met. This includes the
generation of procedural documents, such as policies and Standard Operating Procedures (SOPs),
that help standardise the way in which these procedures are carried out. It will also define and
document the responsibilities, authorities and interrelation of key personnel involved in quality
management. Those staff must be qualified by education, training and experience for their role (see
GCP Principle 8 above).
Care needs to be taken that sufficient resources are available for the implementation and
maintenance of the quality management processes described in the QMP.
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Quality Control
Quality control activities carried out on clinical trials are often called monitoring. It refers to a set of
operational (day-to-day) activities intended to ensure that the planned requirements for data quality
and participant protection are met. In other words, QC is a quality management activity that occurs
on a regular basis (it is often carried out every time a particular process occurs). Examples of quality
control measures include:
 Completing a checklist for each participant to ensure that all steps in the consent
process have been carried out
 Source data verification (checking that the data entered into the database match their
source)
 Ongoing review of the regulatory documents file to ensure it is complete and up-to-date
 Completing and documenting the training given to new staff members
 Maintaining temperature logs on specimen storage freezers (National Institute of
Dental and Craniofacial Research 2012)
Quality Assurance
Quality assurance most often occurs in the form of an audit. It is an intermittent activity that is
carried out to ensure that quality processes and procedures are being followed, and that those
processes are resulting in outcomes that meet the planned quality requirements. Examples of QA
activities include:
 Reviewing trial documentation to assess whether trial staff are complying with the
required policies, procedures and regulations
 Reviewing training logs to ensure that staff have received sufficient and relevant
training for their role on the study, and that the training has been appropriately
completed and documented (National Institute of Dental and Craniofacial Research
2012)
Quality Improvement
Quality improvement occurs when the outcomes on a clinical trial do not meet planned quality
requirements, or when an issue is identified that has the potential to adversely affect quality. After
an issue has been identified, a common model for implementing change is the Deming-Shewhart
cycle, otherwise known as a Plan-Do-Check-Act (PDCA) cycle (Figure 2).
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Figure 2 – Deming-Shewhart cycle
The four phases in the Deming-Shewhart cycle involve:
 Plan: perform a thorough investigation to establish the root cause of the problem and
identify an appropriate corrective or preventative action
 Do: develop and test the action
 Check: verify that the action produces the required outcome and check whether it can
be improved in some way
 Act: implement the improvement
Use of tools such as the Deming-Shewhart cycle encourages a methodical approach to problem
solving and implementing change.
Risk Management
Risk management goes hand in hand with quality management, as anything that could adversely
affect the quality of a clinical trial is considered a risk. When managing risk in clinical trials there is
particular emphasis on participant safety, data integrity, regulatory and protocol compliance, and
project scope (budget and timelines) (Macri and Merrifield 2014).
Risk management refers to an overall process, the main elements of which are (Figure 3):
 establishing the context
 risk assessment, consisting of:
- risk identification
- risk analysis
- risk evaluation
 risk treatment
 monitoring and review
 communication and consultation
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Figure 3 – Risk management process (Standards Australia 1999)
Establishing the context
The first step in the risk management process is to stablish the strategic and organisational context
in which the rest of the risk management process will occur. This ensures that the objectives of the
research to be undertaken are clearly articulated, that the internal and external stakeholders and
environment in which the risk management process will take place is defined, to determine the
purpose, scope and circumstances of the risk management strategy and to define the risk criteria for
the rest risk management process (Standards Australia 2013).
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Curtin’s Risk Management Framework provides information on the University’s risk management
environment, policy and procedures. The University’s risk appetite is detailed in the Risk Reference
Tables.
Risk assessment
Risk assessment is the overall process of risk identification, risk analysis and risk evaluation.
Risk identification requires information to be gathered at both the system and project level in order
to identify risks (Table 1), their sources, areas of impact, events (including changes in circumstances),
and their causes and potential consequences (Standards Australia 2009).
Table 1 – Information gathering at the system and project level for risk identification in clinical trials
(adapted from European Medicines Agency 2013)
Organisation structures and responsibilities
Quality systems and processes (e.g. standardised procedures)
Facilities and computerised systems (e.g. information technology infrastructure,
data management system)
System Level
Human resources including staff qualifications and training (e.g. job descriptions,
training plans, performance management)
Compliance metrics, performance measurements, quality audit and / or
inspection outcomes
Regulatory and ethical framework
Intervention related risk: any available information about the properties and risks
associated with the intervention
Trial design related risk: complexity of trial design, trial population (e.g.
vulnerability, morbidity), therapeutic area (e.g. difficult recruitment associated
with rare disease), sample size calculation, suitability of eligibility criteria, risks of
protocol-specified procedures not related to the intervention
Project Level
Operational risk: study budget (e.g. inadequate resourcing for trial activities),
development deadlines, staff resource level and study-specific training (e.g. lack
of GCP experience at trial sites), study management team and responsibilities
(e.g. lack of revision of study documents), site selection and management,
contract research organisation involvement, clinical trial supply processes and
management, clinical site set-up and infrastructure, laboratory set-up, set-up of
trial databases, trial monitoring, clinical data monitoring including safety
monitoring, reporting and / or communication channels
Risk analysis is used to develop an understanding of the risks identified in the previous step and to
prioritise them to determine the most appropriate treatment strategies and methods (Standards
Australia 2013). It involves consideration of the causes and sources of risk, their consequences and
the likelihood that those consequences will occur (Standards Australia 2009). The likelihoods and
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consequences are ranked and the risks analysed to determine the overall level of risk. The result of
this process is commonly depicted on a risk rating matrix (Table 2).
Table 2 – Example of a risk rating matrix where the Level of Risk = Consequence x Likelihood
Risk evaluation uses the outcomes of the risk analysis to assist in making decisions about the risks
that need treatment and the priorities for treatment implementation. It involves comparison of the
risk level found during the analysis process with risk criteria established when the context was
considered in order to determine the need for treatment (Standards Australia 2009). Decisions must
be made in accordance with legal, regulatory and other requirements.
Risk treatment
Once risks have been evaluated and ranked, they may either be accepted or treated. Risk treatment
involves selecting and implementing one or more options for modifying risks including:
 avoiding the risk (not starting or discontinuing the activity giving rise to the risk)
 taking or increasing the risk in order to pursue an opportunity
 removing the source of the risk
 changing the likelihood
 changing the consequences
 sharing the risk with another party or parties (including contracts and risk financing)
 retaining the risk by informed decision (Standards Australia 2009).
Treatment options may be applied either individually or in combination, however, they should be
articulated in a treatment plan that clearly identifies the priority order in which individual risk
treatments will be implemented (Standards Australia 2009).
Monitoring and review
Monitoring and review are distinct techniques that are used to detect change and determine the
ongoing validity of assumptions made during the risk management process (Standards Australia
2013). The purpose of this is to:
 ensure that controls are effective and efficient in both design and operation
 obtain further information to improve risk assessment
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 analyse and learn lessons from events (including near-misses), changes, trends,
successes and failures
 detect changes in internal and external context including changes to risk criteria and the
risk itself which may require revision of risk treatments and priorities
 identify emerging risks (Standards Australia 2009).
Communication and consultation
Effective communication and consultation with internal and external stakeholders should occur
throughout the risk management process. Plans for communication and consultation should be
developed early and should address issues relating to the risk itself, its causes, its consequences (if
known) and the measures taken to treat it.
For more information on risk management process refer to the AS/NZS ISO 31000:2009 Risk
Management - Principles and Guidelines and SA/SNZ HB 436:2013 Risk Management Guidelines Companion to AS/NZS ISO 31000:2009 standards, available from the Curtin University library. For
more detail of how these processes are implemented in a clinical trials context refer to the EMA’s
Reflection Paper on Risk Based Quality Management in Clinical Trials and this article by Stansbury
and Perrin.
Ethical Conduct
Well-known guidelines describing the principles of ethical conduct in human research include the
World Medical Association’s Declaration of Helsinki and the Belmont Report. In the Australian
context, the National Statement articulates four values to provide a framework for the design,
review and conduct of research in humans: research merit and integrity, respect for human beings,
justice and beneficence.
Research merit and integrity
Involving human participants in research is only ethically justifiable where the proposed research has
merit and is conducted with integrity (National Health and Medical Research Council 2007). Ethically
justifiable research must offer a means of generating information that would otherwise not be
obtainable; the information generated must be relevant in some way to the community from which
the participants will be selected (i.e. it must not exploit participants or the community); the research
must be scientifically valid (i.e. sound methodology and protocol design), such that the data
generated are fit-for-purpose; and the investigators and other research personnel must be qualified
by education, training and experience to competently perform their roles (Council for International
Organizations of Medical Sciences and Organization 2002, Training and Resources in Research Ethics
Evaluation 2014).
Respect
Respect for human beings is a recognition that all people possess intrinsic worth and that research
must be conducted with “a due regard for the welfare, beliefs, perceptions, customs and cultural
heritage, both individual or collective, of those involved in research” (National Health and Medical
Research Council 2007; p. 11). This engenders two fundamental ethical principles, namely:
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 respect for autonomy, where those who are capable of making their own decisions are
able to do so
 people who have a diminished capacity to make decisions are empowered, where
possible, and are protected against harm or abuse (Council for International
Organizations of Medical Sciences and Organization 2002, National Health and Medical
Research Council 2007).
Respect also means that participants’ identifiable personal information must be kept confidential.
Justice
Justice refers to the fair distribution of the risks and potential benefits of participation in research
(Training and Resources in Research Ethics Evaluation 2014), which requires that:
 the process of recruiting participants is fair
 the burden of research does not fall unfairly on any particular group of participants
 fair distribution and access to the benefits of research
 research participants are not exploited (National Health and Medical Research Council
2007).
Research outcomes should also be made available to participants in a manner that is timely and fair.
Beneficence
Beneficence refers to the ethical obligation to maximise the benefits of research and minimise harm
to participants and the community. This means that the potential benefits of the research must
outweigh the risk of harm.
3.2
Governance
Research governance is defined in the NHMRC’s Good Practice Process for Site Assessment and
Authorisation Phases of Clinical Trial Research Governance as (pp. 5-6):
[A] process used by an [institution] for the oversight, assessment, authorisation and
monitoring of research conducted at one or more of its sites or under its auspices. A research
governance framework includes good research culture and practice, organisational strategy,
role definition and accountabilities, risk, resources and financial assessment and management,
compliance with legal, regulatory and contractual requirements, competencies and training of
personnel, site assessment, scientific review, ethical review and approval, site authorisation,
monitoring of research, and management of conflicts of interest, complaints and allegations of
research misconduct.
The aims of this governance review process are to ensure the safety of research participants, the
integrity of the clinical trial, the effective use of research funds, and the responsible conduct of
research (National Health and Medical Research Council 2015). The review itself consists of a) a site
assessment to determine whether a proposed clinical trial complies with institutional requirements,
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and b) ethics review, in which the science and methodology of the trial is reviewed, as well as
exploring any ethical issues presented by the trial. Institutional requirements relate to budget and
finance, risk management, insurance and indemnity, contracts, occupational safety and health, and
regulatory compliance.
Both a site authorisation (also known as governance approval) and ethics approval must be obtained
prior to a clinical trial commencing at a particular site.
Curtin University governance and ethics requirements may be found on the key compliance
requirements, conducting research and research ethics and integrity webpages.
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References
Council for International Organizations of Medical Sciences and W. H. Organization (2002).
International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva
Davis, J. R., V. P. Nolan and J. Woodcock (1999). Assuring Data Quality and Validity in Clinical Trials
for Regulatory Decision Making: Workshop Report. Washington, DC, USA, National Academies Press.
European Medicines Agency (2013). Reflection Paper on Risk Based Quality Management in Clinical
Trials.
London.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/11/WC50015
5491.pdf. 25 September 2015.
Macri, M. and S. Merrifield (2014). Managing Clinical Trial Risk: It's a Tough Job, but One Person Has
To Do It, inVentive Health Clinical. http://www.inventivhealthclinical.com/resource-library-whitepapers.htm. 24 September 2015.
Manghani, K. (2011). "Quality assurance: Importance of systems and standard operating
procedures." Perspectives in Clinical Research 2(1): 34-37.
National Health and Medical Research Council (2007). National Statement on Ethical Conduct in
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