About Clinical Trials
Clinical trials are an important method for discovering and providing the evidence for treatments as well as identifying new ways to detect, diagnose, prevent or reduce the risk of diseases. Clinical trials provide a ‘bridge’ between laboratory research and patient care.
Participating in clinical trials can give doctors and their patients early access to new and emerging treatments. Clinical trials provide the basis for the development of guidelines and standards so patients receive optimal care. Clinical trials can provide important information about the cost-effectiveness of specific treatments, and for treatments to be compared.
Data from clinical trials help doctors to discuss and make evidence-based decisions with their patients about appropriate treatment options and care. For a doctor to confidently prescribe a medicine, they need to know the medicine is safe and effective, that it won’t interact in harmful ways with other medicines and that it won’t produce serious side effects in their patient. High quality clinical trials can deliver information in these crucial areas.
Ultimately, sufficient evidence from high quality clinical trials can lead to registration of a cannabis medicine by the Therapeutic Goods Administration (TGA), listing on the Pharmaceutical Benefits Scheme (PBS) and, potentially, patient access at a subsidised price.
- What is a clinical trial?
A clinical trial is a research study where interventions in human subjects are tested. These interventions could include a new medicine, biological product, procedure, process or device; or a new application of an existing medicine, process or device.
Clinical trials provide evidence about whether a new intervention works, how people respond to it (positively and negatively), if it is safe and if it is better than standard treatments. In Australia, clinical trials must be scientifically and ethically assessed before they can begin, in line with national- and state-specific research ethics and governance policies outlined here.
The World Health Organisation defines a clinical trial as ‘any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes’.
- How does a clinical trial add to the evidence base?
At the end of a clinical trial, the lead clinician and any collaborating academics may author a scientific paper outlining the trial’s aims, results and findings. The paper will be reviewed by academic peers and submitted for publication in one of a number of influential scientific journals.
Publishing clinical trial results, either positive or negative, gives regulators and clinicians evidence to examine when considering the use of any medicine.
A meta-analysis is an assessment made of all published research for a particular clinical field; in medicine, this can be for a symptom or condition. These provide a particularly powerful analysis of the existing evidence to inform both clinicians and policy makers. An example is the Commonwealth Therapeutic Goods Administration’s national evidence review, which has examined research evaluating the use cannabinoids in five conditions. Information about the review can be found here.
- How does a randomised controlled trial work?
The highest quality evidence comes from the ‘gold standard’ of clinical research – the randomised, double-blind controlled trial (RCT). An RCT is a study designed to remove or minimise sources of bias that can affect the study and its reported results.
As part of the recruitment process for an RCT, the patient will receive either the active medicine or a comparison product called the control. Often the control used is a placebo, which is a substance with no therapeutic effect.
To prevent any trial participant, whether patient, clinical team or assessor, knowing which of these products the patient is receiving, RCTs employ two techniques, randomising and blinding.
Randomising is where patients are randomly assigned to receive either the active medicine or the control.
Blinding conceals the identity of the assigned treatment from both the patients being treated and the clinical team treating them, hence the term ‘double blind’.
At the end of the trial, the assessors analyse the findings before ‘unblinding’ (revealing the identity of) the treatments to establish whether the medicine has proven effective.
By concealing the identity of the trial medicine from those taking part, an RCT delivers the most accurate result possible, by greatly reducing any chance of bias.
Human nature plays a role here. The patient is more likely to report an improvement in their symptoms if they know they are receiving the trial medicine, as they are hopeful it will provide a cure. Likewise, they are more likely to report no change or a worsening of symptoms if they know they are receiving the placebo. The impartiality of clinicians and assessors is similarly compromised if they know the identity of the trial medicine.
- Why are the inclusion and exclusion criteria important for a clinical trial?
Successful recruitment is a vital part of any successful clinical trial. ‘Inclusion criteria’ are the conditions that have to be met for someone to take part in the trial; ‘exclusion criteria’ rule them out. The criteria can be based on a number of elements: age, gender, disease type and its stage of progression, other current medical conditions and treatments. Inclusion and exclusion criteria for each of the NSW Government-funded clinical trials can be found on this website.
The inclusion and exclusion criteria are designed to ensure that the participants selected give the trial the best chance of arriving at a clear, reliable result while prioritising safety.
- The importance of safety and reporting of serious adverse events
Clinical trials evaluating the potential of unregistered or experimental medicines may have little or no information about the quality, safety and efficacy of the product. In each case it is necessary that the trial doctors closely observe the participants for side effects or any reaction between the experimental medicine and other currently prescribed medicines.
There are detailed regulations around reporting different types of adverse events and reactions.
Any undesirable effect experienced by the clinical trial subject is known as an adverse event, whether it is directly related to the treatment medicine or not. It is the responsibility of the trial leader to report any such event to the trial’s Human Research Ethics Committee (HREC).
A serious adverse event is any medical occurrence during the trial with more serious implications such as hospitalisation, threat to life, or death. In this case, as well as reporting back to the HREC, the trial leader must inform the Therapeutic Goods Administration (TGA).
Reporting allows the TGA to develop a better understanding of therapeutic goods and their possible adverse effects when they are used outside the controlled conditions of clinical trials.
- What are the different stages of a clinical trial?
There are several stages or phases of a clinical trial. While these are defined separately, in some studies these phases are combined.
Phase 0, also known as a ‘microdosing’ study, is an early phase trial set up to establish several critical factors:
- that the medicine behaves in humans as it did in animal studies
- to gather early data on the medicine’s pharmacokinetic properties (PK; how it changes as is absorbed, distributed, metabolised and excreted) and pharmacodynamic properties (PD; how and by how much the medicine changes the body, both in therapeutic and adverse ways)
- to select promising trial candidates
- to track where the medicine travels in the body of the experimental subject.
This early phase work is designed to filter out ineffective medicines early in the development process, with the aim of speeding up the development of potentially effective medicines.
Phase I, sometimes referred to as the pilot study, this early stage of a clinical trial, allows researchers to evaluate the safety of a new treatment for the first time in a small group of people, often in healthy individuals (e.g. 20-80). Phase I of a trial is used to determine the safe dosage range, how well the medicine is tolerated by patients, any positive or negative effects, and any notable side effects.
Phase II aims to evaluate the effectiveness of this new treatment in a larger group of people (several hundred) with the symptom or condition, fine-tune dosage requirements and further assess its safety.
Phase III studies the effectiveness of the treatment in large groups of trial participants (from several hundred to several thousand) by comparing the treatment to other standard or experimental treatments. This stage determines whether there is clinical benefit from the treatment for a particular symptom or condition.
Phase IV is carried out after the treatment has been approved by a medicines regulator. This study is designed to monitor the effectiveness of the approved treatment in the general population and to collect information about any adverse effects associated with its widespread use over longer periods of time. A Phase IV trial may also be used to investigate the potential use of the treatment for different conditions or in combination with other therapies. The goal is to assess the real-world effectiveness of the treatment outside of clinical conditions.
- that the medicine behaves in humans as it did in animal studies
- Conducting a clinical trial in Australia
A clinical trial has to have an Australian sponsor, which can be an individual (e.g. a doctor), an organisation (e.g. a hospital or area health service) or a company (e.g. a pharmaceutical company).
Clinical trials in Australia are governed by the National Health and Medical Research Council’s (NHMRC) National Statement on Ethical Conduct in Human Research, which can be found here. Human Research Ethics Committee (HREC) approval is the first step for all research involving humans.
Conducting a clinical trial in a NSW Public Health Organisation must be first authorised by the Chief Executive or their delegate. Information about research ethics and governance can be found on the NSW Office for Health and Medical Research website.
Clinical trials in Australia can be carried out under two schemes regulated by the TGA: Clinical Trial Notification (CTN) or Clinical Trial Exemption (CTX).
CTN is a notification scheme, where the HREC is responsible for assessing the trial design, safety and efficacy of the medicine, ethics of the trial process and approval of its protocol. Following advice from the HREC, the institution where the trial will be held gives final approval and the TGA is notified.
CTX is an approval process, where the TGA directly reviews the proposed trial program and must give an approval for the trial to proceed. An HREC review is still required.
- Human Research Ethics Committee (HREC) approval
An HREC reviews the research proposal to ensure that it is ethically acceptable and planned in accordance with relevant standards and guidelines. The committee considers a variety of issues, including the trial’s potential to help in the treatment of an illness, that the risk to its participants is minimised and that they are treated with integrity and sensitivity, how the research will add to the overall scientific understanding, and how the trial might help in the improved delivery of health services.
Typically, an HREC contains a variety of members including a lay person, a lawyer, a minister of religion and one or more individuals experienced in research and professional medical care.
- Site approval
Approval is also required from the site (or sites) where the trial is to be held. The research governance officer from each site considers the legal, financial and resource requirements, medical record access and the accountability and risk management considerations involved in conducting the clinical trial at that location.
- The path to registration and the Pharmaceutical Benefits Scheme (PBS)
If, at a clinical trial’s conclusion, the medicine is assessed to be safe and effective, this research may be included in an application by the developer of the medicine to have it approved for use in Australia. The research will crucially inform a decision by the regulator, the Commonwealth Therapeutic Goods Administration (TGA), to weigh up its benefits and harms.
A favourable assessment leads to the medicine being registered on the Australian Register of Therapeutic Goods (ARTG), at which point it can legally be prescribed in Australia.
A manufacturer of a registered medicine can apply for the Pharmaceutical Benefits Assessment Committee (PBAC) to assess whether the medicine can be included in the Pharmaceutical Benefits Scheme. The PBAC considers the efficacy and cost of the medicine compared to existing treatment options for the condition. Medicines on the PBS are subsidised by the Commonwealth Government, passing on a considerable cost saving to the patient.
Ultimately, clinical trials are an important step on the path to registration, which will allow a doctor to prescribe the new medicine with confidence and will assure the patient that what they are receiving has been scientifically established as a safe and effective treatment for their symptom or condition.
- Research requirements
All research undertaken in Australia is subject of legislation, policy and ethical oversight. The following links provide further information in these areas as well as links to Commonwealth and state funding bodies.
- The National Health and Medical Research Council provide guidelines and policies about health and research ethics, found here.
- All human and animal research conducted within or supported by NSW Health must comply with the Human and Animal Research and the National Health & Medical Research Council Act 1992.
- Additional NSW Health research ethics and governance policies can be found here.
- Any research on animals must be approved by an Animal Ethics Committee (AEC) required by the NSW Animal Research Act 1985.
- Each university and research institution will also have specific research ethics policies and guidelines that researchers must comply with.
Undertaking research, analysis or instruction using cannabis (other than clinical trials) requires an authority from NSW Health. Information about applying for an authority for research from NSW Health can be found here.
- Research funding
For information about funding and grants, please visit: