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Step-by-step guide to setting up a clinical trial

Glossary

Analysis Plan

Once the data has been collected and entered onto the computer, statistical analyses of the data will be carried out. It is essential to pre-specify which statistical procedure will be used for each analysis, to avoid attempting various analytical techniques to identify a statistically significant difference. Staff in CEBU can help you further with this.

Clinical Trial

A well designed clinical trial provides the highest standard of evidence for assessing the impact of an intervention on a given outcome. The International Committee of Medical Journal Editors (ICMJE) defines a clinical trial as: "Any research project that prospectively assigns human subjects to intervention and comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. This definition includes drugs, surgical procedures, devices, behavioural treatments, process-of-care changes, and the like." http://content.nejm.org/cgi/content/full/351/12/1250

Collaborators

A group of experts that will form the core project management team and provide substantial contribution to the protocol. This usually consists of two or three clinical experts relevant to the major clinical fields under investigation, a senior statistician and a health economist if relevant.

Data Management

It is fundamental to any clinical trial that patient data is accurately recorded and processed. Incorrect data will result in incorrect conclusions. Efficient management of patient data thus becomes a priority. Please see CEBU's Data Services for further advice and information on data management.

Data Monitoring Committee (DSC)

This is a body of independent advisors who have access to the unblinded, comparative data and whose role it is to monitor these data for ethical and safety issues. Recommendations for continuing or stopping the trial can be communicated either to the chair of a Trial Steering Committee (where relevant) or to the Principal Investigator. Other names given to this group are Data Safety Monitoring Board (DSMB) or Data Monitoring and Ethics Committee (DMEC). Further advice and information on the role and procedures for setting up a DSMB can be sought from DAMOCLES Study Group: A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet - 2005; 365:711-722

Ethical approval

The purpose of ethical approval is to protect the welfare and rights of the participants in the research and to facilitate research that is or will be of benefit to the researchers' community or to human kind. In order for a study to be ethical it must have a clear aim, be clearly designed to achieve that aim, and give proper justification for all procedures and risks to which participants will be exposed.  All research conducted in humans must have ethical approval from a Human Research Ethics Committee constituted in accordance with the requirements of the NHMRC National Statement on Ethical Conduct in Research involving Humans (1999).  The RCH Ethics and Research Office staff are available to guide researchers through the ethics approval pathway.

Funding sources

Clinical Trials and Research Projects are regularly funded by Federal and State governments, industry and charitable foundations and trusts.  Information regarding possible funding sources for your project can be found on the MCRI Grants calendar or by discussion with MCRI Grant officers.

Grant proposal

Grant proposals may take the form of a 2-3 page request for financial support to major applications in excess of 30 pages required by government funding agencies.  Ideas on how to draft a grant submission can be found on the Grants Office website under Grants Writing Tips.  It is important to remember there are many experienced researchers on the RCH campus willing to share their expertise on how to write a grant proposal and the mechanisms of grant assessment and award.

Indemnity

Indemnity is giving an undertaking that compensation will be paid (whereas insurance is paying a premium for an insurance policy). All clinical trials conducted on the RCH campus must provide indemnity for the MCRI and the RCH. The Victorian Managed Insurance Authority (VMIA) provide indemnity for all RCH sponsored clinical trials that fulfil the minimum requirements described in the Guidelines for Clinical Trials for Victorian Public Hospitals (PDF)
(These guidelines ensure Hospitals/Institutions participating in the Clinical Trials Notification Scheme (CTN) do not jeopardise their entitlement to indemnity under the Medical Malpractice/Public Liability Policy).

For clinical trials that are commercially sponsored, indemnity must be provided by an Australian corporate entity on the standard Medicines Australia Form for Indemnity for Clinical Trials.
The RCH Ethics and Research office can provide assistance with meeting the requirements for clinical trial indemnity.

Legal & Regulatory requirements

Researchers need to be aware of a number of legal and regulatory requirements that MUST be adhered to when conducting a clinical trial at the RCH.
These are:

• Australian Government Exposure of Humans to Ionizing radiation for Research Purposes (May 2005)
• Australian Government Therapeutic Goods Administration Access to unapproved therapeutic goods - Clinical trials in Australia (Oct 2004)
• Australian Government Therapeutic Goods Administration Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) (July 2000)
• Guidelines approved under Section 95 of the Privacy Act 1988 (Commonwealth)
• Guidelines approved under Section 95A of the Privacy Act 1988 (Commonwealth)
• NHMRC National Statement on Ethical Conduct in Research involving Humans (1999)
• NHMRC Guidelines for ethical review of research proposals for Human Somatic Cell Gene Therapy and related therapies 
• Victorian Information Privacy Act 2000
• Victorian Health Records Act (containing the Health Privacy Principles)
• VMIA Guidelines for Clinical trials for Victorian Public Hospitals (Sept 2004)

The RCH Ethics and Research Office will provide assistance in ensuring your research study fulfils these requirements.

Literature search

It is important to undertake a systematic and exhaustive search for published material on a specific topic and this should be done with an aim to be comprehensive. It should enable you to acquire an understanding of your topic, with its key issues, and an awareness of relevant research that has already been conducted. The best single source of reliable evidence about the effects of health care can be found in The Cochrane Library (the entire set of Cochrane evidence-based medicine databases, including the Systematic Reviews and the Cochrane Central Register of Controlled Trials). Further tips for conducting a literature review can be found on the RCH library website Fact sheet no.1: Databases and planning a search 

Participant Information Statements (PIS) and Consent Forms

For the majority of clinical trials conducted at the RCH, researchers must obtain consent from the participants and/or their parent/guardian, before they can participate in the study. The ethical and legal requirements of consent have two aspects, the provision of information and the capacity to make voluntary choice.  The RCH Ethics and Research Office website have a number of templates for participant and parent/guardian information statements and consent forms for researchers to use. Further information on writing these documents can be obtained from Tips for Writing Parent/Guardian & Participant Information & Consent Forms (PDF)

PICOT

A standardized format for constructing clinical questions, PICOT is designed to help turn a research idea into an answerable research question. The initials stand for Patient population, Intervention under investigation, Comparator, Outcome and Time frame. The method provides a basis by which each element of the clinical question can be thoughtfully considered. See Teaching EBP: "Getting from Zero to One." for more detail.

Principal Investigator

The Principal Investigator is the person who initiates the trial and applies for support/funding. S/he has overall responsibility for the design and conduct of the trial. S/he must ensure that the trial is run in accordance with the guidelines set out in the protocol and that all investigators involved are aware and adhere to these guidelines. See Part 5 of MRC Guidelines for Good Clinical Practice in Clinical Trials (PDF) for further detail.

Randomisation

Randomisation is the name given to a method of assigning clinical trial participants to treatment groups so that each participant has a known (usually equal) chance of being assigned to the groups. There are many different ways of performing the randomisation and, if appropriately designed, then the group assignment cannot be predicted in advance. Randomisation minimises any systematic differences between groups (due to other factors apart from the intervention). CEBU can help with the design of the most appropriate randomisation process for your trial.

Recruitment

Clinical Trial success depends upon volunteers who agree to be part of the carefully controlled testing of medications, medical treatments, or devices. Recruiting and retaining trial volunteers is a major challenge for those conducting clinical trials. Trials involving children and adolescents can be particularly difficult. Particular issues worth considering are: where are your target audience?; how do you notify potential volunteers?; how will you retain volunteers; remember that volunteers and their families are doing you a favour - treat them as special.

Registering your trial

From 1 July 2005, the International Committee of Medical Journal Editors (ICMJE - which includes MJA, Lancet, New Engl J, and many others) will not publish the results of a clinical trial unless it is registered on an authorized registry. This is because there is a growing recognition internationally of the need to record the existence of clinical trials so that they can be publicly accessed. The RCH Ethics and Research Office suggest researchers use any of the following Public Trials Registers:

• Australian Clinical Trials Registry (ACTR) 
• The US National Library of Medicine 
• The International Standard Randomised Controlled Trial Number registry 
• The National (UK) Research Register 
• European Clinical Trials Database 

Sample size requirements

The number of patients required for you to attempt to answer your research question should be planned very carefully. Scientific and ethical considerations need to be made, and a balance between clinical and statistical considerations must be found. You can seek further help with this issue from CEBU.

Study design

This is the method used to collect trial participants, allocate them to one of the proposed interventions and collect the relevant data in order to answer your clinical question of interest. The study is designed in such a way so as to minimise all possible biases, so that the results can be generalised to a target population outside of your trial sample. Staff in CEBU can help you with the design of your study.

Study Protocol

A study protocol describes all aspects of the proposed study in a clear plan. This document is important for scientific reasons, to make sure there are clear aims and a clear plan for achieving those aims, and also for administrative reasons. In particular the protocol should contain all of the information that will be required for ethics approval, and forms an essential part of the application to the Ethics in Human Research Committee.

MCRI Theme director

There are six research themes within MCRI, each representing a broad area of research focus. Each theme is led by a Theme Director who is responsible for co-ordinating the overall strategy of the Theme. See the MCRI internet website for further information on the Themes.

Trial conduct

This is the stage of the study at which recruitment, randomisation, data collection, retention of participants and follow-up are carried out.  A trial co-ordinator is usually employed to oversee this stage of the project especially for large, multi-site studies.  It is important that the protocol is adhered to and that the trial is conducted according to the Declaration of Helsinki. See Declaration of Helsinki for the full text.

Trial Steering Committee

This is an independent body of experts and lay people which includes a majority of members who are not involved in running the trial. The Trial Steering Committee ultimately considers options and makes any major decisions about the trial recommended by the other committees. See Part 6 of MRC Guidelines for Good Clinical Practice in Clinical Trials (PDF) for further detail.