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Clinical trials: why are they important?

Clinical trials are essential in contemporary evidence-based medicine. They help us to evaluate new drugs, therapies, devices, interventions, systems, methods and tests (let’s call them all ‘interventions’ from here on). In this article, we describe the main aspects of clinical trials, why they are important and the benefits of participation.

We’ve relied heavily on material from the Australian Clinical Trials initiative, which provides information for consumers, health care providers, industry and sponsors and researchers – the website is well worth a visit if you’d like more information on any topics discussed here.

Definition of a clinical trial

The World Health Organization’s definition of a clinical trial is ‘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’.

This means that people are invited to take part in study in which they (might) receive the new intervention, and are followed over time to determine whether it works.

Why do we need clinical trials?

Clinical trials are essential to the development of new interventions that help people to live longer and with less pain or disability. Computer simulation and animal testing are important, but are limited in their ability to determine how a new intervention will work in the human body.

Clinical trials allow us to test whether a new intervention:

  • is effective or safe
  • works properly in the clinical setting
  • works better with one group of people than another
  • is acceptable to a larger proportion of patients than the existing intervention.

Most recent medical interventions are a direct result of clinical research. New interventions for most diseases and conditions — including cancer, heart diseases, hepatitis, high blood pressure and asthma — were developed in this way.


Clinical trials can be used to test:

  • experimental drugs
  • medical devices
  • surgical and other medical treatments and procedures
  • diagnostic or screening tests
  • psychotherapeutic and behavioural therapies
  • health service changes
  • cells and other biological products
  • vaccines
  • dietary changes
  • preventive care strategies
  • educational interventions.

Evaluating trial outcomes

Clinical trials are designed to test whether a new intervention is effective. A new intervention found to be effective might:

  • cure a higher proportion of treated people than an existing intervention
  • work significantly better than a placebo (see below)
  • result in greater improvement in (or better management of) a health condition than another intervention
  • perform at least as well as another intervention, and:
    • have fewer or less-severe side effects
    • be safer
    • be easier to administer or promote better patient adherence or compliance
    • be significantly cheaper.

Clinical trials measure the effects of interventions in large numbers of people, ensuring that improvement is a real outcome for many people (e.g. in 800 of 1000 people treated) rather than a randomly occurring effect for a few (e.g. in 8 of 10). Although the proportions cited here are identical (8/10 = 80 per cent), larger sample sizes give greater statistical confidence in the result.

What is a placebo?

Placebos are dummy interventions that are indistinguishable from real interventions. Placebos are usually substances containing no medication, but surgical placebos are also possible. Despite involving no active ingredient or therapy, a placebo can have real effects in some patients due solely to the psychological benefit of being treated – this is known as the ‘placebo effect’.

The inverse to the placebo effect is the ‘nocebo effect’, in which patients experience adverse effects of a dummy intervention – or placebo – due to their negative expectations. The placebo and nocebo effects are the subjects of considerable research. Recent discoveries include a possible genetic basis for the propensity to respond to placebos. Click here for a summary of current knowledge about placebos.

Types of trials

A clinical trial can involve testing the effect of an intervention on its own, or in comparison to a previously tested intervention or a placebo, or both.

In a randomised controlled trial (RCT), participants are assigned to a treatment group through a scientific process of random selection. The group assigned to the treatment receives the intervention being trialled while the control group receives a different intervention or a placebo.

In trials that are ‘single-blind’, participants are unaware of which group they are in; this eliminates the placebo effect, making the true effect of the intervention easier to detect.
In a ‘double-blind’ RCT, neither the participants nor the clinicians (initially) know which individuals are in the treatment and control groups. This helps to eliminate bias that might arise from clinicians treating the groups differently.

RCTs are the most powerful type of clinical trial because they generate the best evidence, but, for practical or ethical reasons, are not always feasible. For example, it is impossible for students to be blinded so that they are unaware of the content of the educational interventions they receive.

With respect to ethics, in the 1990s, the drug Zidovudine was shown to prevent mother-to-child transmission of HIV infection but was too expensive for developing countries. Placebo-controlled trials of cheaper medicines were deemed unethical, as the babies of mothers given the placebo would have contracted HIV. An equivalence study, in which control group mothers were given the cheaper medicines and the treatment group the Zidovudine, was run instead.


Safety is the primary concern of any clinical trial. Clinical trials go through well-defined phases that allow safety to be assessed in stages. The three main phases are Phase I to Phase III, but there are earlier and later phases too.

In pharmaceutical studies, the phases start with drug design and drug discovery, before proceeding to animal testing.

Pre-clinical studies are required before any clinical trial in humans can be started. Data are collected regarding the feasibility and safety of proceeding to Phase I clinical trials.

Phase 0 clinical trials are a recent additional phase designed to speed up the development of promising interventions. These trials test microscopic doses of new drugs (typically in about 10 patients) to gather preliminary data, such as what the body does to the drug.

This phase is often skipped in favour of Phase I clinical trials, primarily because the doses are so small they are likely to show little effect. For example, in a Phase 0 cancer trial the dose may be too small to benefit the patient (though there are also less likely to be side effects).

A Phase I clinical trial tests a new intervention in a small group of people (e.g. 20–80 participants) to evaluate safety – for example, to determine a safe dosage range and identify side-effects.

Phase I trials, sometimes known as ‘first-in-human’ studies, can further be split into additional phases:

  • Phase Ia, or single-ascending dose, studies – a small group (e.g. 3 participants) is given a single dose of the intervention and observed for a time to confirm its safety. If no adverse effects occur a higher dose is given to a second small group, and so on until the drug is said to have reached the maximum tolerated dose.
  • Phase Ib, or multiple-ascending dose – a group of participants is given multiple low doses of the drug while blood and other fluid samples are collected at various time points and analysed to investigate how the drug is processed within the body. The dose may then be escalated to a predetermined level for further groups of participants.
  • Food effect – a short trial to study the absorption of the drug when the participant eats prior to taking it; participants may be given two identical doses while fasting and after eating, to compare effects.

Phase II clinical trials assess an intervention in a larger group of people (several hundred participants) to determine whether it works as intended (efficacy), and to further evaluate its safety.

Some Phase II trials are divided into:

  • Phase IIa – to assess how much of the drug should be given
  • Phase IIb – to assess how well the drug works at the prescribed dose.

Phase III trials examine the efficacy of an intervention in hundreds or thousands of participants by comparing it to other interventions or a placebo, as described above. They are also used to monitor adverse effects and to collect information that allows the intervention to be used safely.

Phase IV clinical trials, also known as ‘post-marketing surveillance’, can provide further information about the safety and side effects of an intervention, its long-term risks and benefits and how well it works in a broad range of participant groups. It may be a requirement of the regulatory authority, and the minimum time period is two years.

Harmful effects discovered in Phase IV trials can result in a drug being no longer sold, or being restricted to certain uses. One recent such example is Cerivastatin: used to lower cholesterol and prevent cardiovascular disease, the drug was voluntarily withdrawn from the market worldwide by Bayer A.G. in 2001, due to reports of fatal rhabdomyolysis (rapid muscle breakdown).

Most clinical trials cover just one phase, but some cover multiple phases – typically Phases I and II, or Phases II and III. Multi-arm, multi-stage (MAMS) trials compare several interventions: multi-arm trials randomise participants to one of three or more treatment groups, while multi-stage trials are designed to stop recruiting participants from a particular group if early results show more side effects or that the intervention is less effective.

Ethical issues

In Australia, clinical trials are governed by national guidelines for ethical conduct of research that aim to protect trial participants and the integrity of the research (the National Statement on Ethical Conduct in Human Research and the Australian Code for Responsible Conduct of Research). Clinical trials of substances and devices also must comply with the requirements of the Therapeutic Goods Administration (TGA).

All clinical research undertaken in Australia must be approved by a Human Research Ethics Committee, which checks that the research proposed is ethical, conforms with the requirements of the National Statement on Ethical Conduct in Human Research and is completed according to those guidelines.

Anyone taking part in a clinical trial must be fully informed about the aims and objectives of the research, what is expected of them if they should decide to participate, and any risks and inconveniences that might be experienced during and after the trial. Potential trial participants must be given a participant information and consent form (PICF) that explains the nature of the trial and participation in it, and seeks informed consent. The PICF must also include information about withdrawing participation and what to do if the participant wishes to withdraw from a study.

Trials must follow a carefully controlled protocol, which is a plan that describes how the research will be conducted. As a clinical trial progresses, researchers may report the results of the trial at scientific meetings, in medical journals and to government agencies. The names and personal details of trial participants are kept confidential.

Health service participation in trials

Generating the evidence needed to reliably inform clinical practice requires clinical trials to involve multiple centres and the collaboration of hundreds or thousands of participants, health care practitioners and researchers.

Clinical trials networks worldwide bring together clinical researchers and health practitioners with a common interest in advancing the evidence in their particular areas of practice. In Australia, trial networks focus on specific areas of interest, including, for example, emergency medicine, breast cancer, melanoma, epilepsy, paediatrics, primary care, palliative care, sleep, diabetes and vaccines.

Multidisciplinary collaborations link and promote clinical research leadership, expertise and capacity across the health care system. Clinical trials networks are extensively integrated with acute and sub-acute hospitals as well as primary and community care facilities across all jurisdictions and in regional and rural areas of Australia.

Costs and benefits of clinical trials

The process of developing a drug from preclinical trial stage to market can take a long time (typically 12–18 years) and can cost well over $1 billion. In 2010 the Institute of Medicine estimated that 20 per cent of 7776 adult Phase II and Phase III clinical trials in the United States might never be completed. These factors contribute to the rising costs of drugs and the slowing of progress in drug development.

Participation in clinical trials has benefits for participants, researchers and health service providers.

Participants can benefit in the short term from the intervention being trialled, and in the long term they and the entire community benefit from the knowledge they help to generate.

Clinical researchers involved in clinical trials learn whether their interventions are effective, or whether they need to refine their work or rethink it completely. They also benefit from interaction with people at the health ‘coal face’, gaining insights into the practicalities of clinical and other service provision that then influence their thinking and planning.

Health service providers gain new perspectives from research collaborations, and the knowledge they help to generate can often be applied directly in their work.

Clinical trials in Australia

Australian clinical trials have made a substantial contribution to global knowledge. The Australian Clinical Trials Alliance’s Report on the Activities and Achievements of Clinical Trials Networks in Australia 2004–2014 identifies more than 100 high-profile studies that have directly influenced clinical practice and/or healthcare policy within Australia and internationally.

An example is the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial, designed to test the hypothesis that intensive glucose control reduces mortality in acutely ill people at 90 days. This RCT involved adult medical and surgical patients admitted to the intensive care units of 42 hospitals in Australia, New Zealand and Canada.

It found that a blood glucose target of 180mg per decilitre or less resulted in significantly lower mortality than a target of 81–108 mg. This result reversed international practice, changed major sets of international guidelines, and saved countless lives.

Clinical trials participation in western Victoria

Western Alliance is working to increase collaboration and integration in health research, clinical services, and research education and training in the western region of Victoria. Although integration needs to be improved overall, numerous clinical trials are already underway.

In 2015 we wrote about Dr Gemma Strickland and her colleagues at Barwon Rheumatology Service (BRS), who are currently involved in several major studies, including a clinical trial of treatments for rheumatoid arthritis that will involve 50 patients at BRS’s Geelong clinic. BRS has been running clinical trials since 2008.

Barwon Health (Geelong), South West Healthcare (Warrnambool), Wimmera Health Care Group (Horsham), Stawell Regional Health and East Grampians Health Service (Ararat) are currently involved in an RCT of online versus telephone-based information and support for lung cancer patients.

Funded by the National Health and Medical Research Council and led by researchers from the University of Newcastle, the findings of this study will have national and international relevance for decisions about community-based information and support.