There are many ways to design a clinical trial. For initial or basic trials an open-label or unblinded design may be used and is where both the investigator and participant know what treatment has been given. This design can bring up issues of bias. The potential for bias must be addressed when designing clinical trials because researchers and participants may unintentionally influence the interpretation of the results. To overcome bias there are a few techniques that can be used. One of these techniques is the use of a placebo or an active comparator. A placebo or control is a “fake” treatment that has no effect. An active comparator or active control is usually a currently approved treatment. Active controls are used as they are clearly better than doing nothing in the case of a placebo.

 

These controls allow researchers to isolate the effect of the study treatment. Participants with an illness or injury are desperate to get better and may perceive an improvement where there isn’t a significant difference. Spinal cord injury studies must be well designed due to issues of spontaneous recovery, where there is recovery of function to some extent after injury without treatment. The rate of spontaneous recovery is greatest in the first three months, but can continue for a year or even more. It is very difficult to work out if recovery is due to spontaneous recovery, or due to the effects of a treatment, particularly if the treatment is given soon after the injury.

 

Another technique to overcome bias is blinding. This is where participants are usually randomly assigned to the treatment or control group and the investigators and/or participants are unaware of who is in which group. It is optimal for both the investigators and participants to be blinded; however this is not always possible. A randomised controlled trial is considered to be the gold standard of clinical trial design. One or more intervention groups are compared to one or more control groups. The researchers randomly allocate participants into groups. Some groups receive the intervention or interventions of interest while the other groups do not.

 

Clinical trials are conducted in a series of steps called phases. These are important to answer questions in a way that obtains reliable results and protects the participants. Depending on the result of one phase, investigators determine whether to stop testing or move on to the next phase of the study. Phase I trials involve a small group of people (12-80 people) to evaluate the treatment’s safety and identify side effects. If the treatment is a drug other factors that are studied are a safe and effective dose range, how the treatment is given, how the body processes it, and how it works in the body. Phase I trials are usually the first step in testing a new treatment in people, often involving a group of healthy volunteers, however many potential spinal cord injury treatments are invasive and therefore a spinal cord injury trial may only include participants with spinal cord injury. These phase I trials may but more often do not include control subjects and are usually carried out in an open label (unblinded) design.

 

Phase II trials generally involve a larger group of people (20-300) and continue to test safety, as well as beginning to evaluate how well the treatment works. Most phase II trials include a control, where participants are randomly assigned to treatment and control groups, and investigators and participants are blinded to the treatment allocation. They involve relatively strict inclusion criteria to ensure uniformity and therefore reduce random variations and outcomes. It is not uncommon for investigators to undertake more than one phase II trial to explore different target populations that might get a benefit from the treatment.

 

Phase III trials involve even larger groups of people (300-3000) and are often international studies through multiple research centres. They are used to confirm effectiveness found in phase II studies, monitor side effects and compare the experimental treatment to commonly used treatments (active controls). Most phase III trials are randomised and blinded, studying a broader range of subjects. Once successfully completed, where a clear useful effect has been shown and no serious side effects have resulted, it will be approved by national regulatory agencies for availability to the general public.

 

Phase IV trials take place after the treatment has been approved for standard use and involve larger groups of people (1000s), over longer periods of time. The purpose of a phase IV trial is to establish interactions with other drugs or its actions in specific population groups such as pregnant women, as well as detecting any rare or long-term adverse effects. Investigators use many strategies to recruit participants including patient databases, newspaper and radio advertisements, flyers, posters in places patients might go (such as doctor’s offices), and personal recruitment by investigators. Patients may ask their doctor about available clinical trials, and there are various websites that list current and proposed clinical trials, for example the Spinal Cord Injury Network at www.anzscin.org/trials and the Australian New Zealand Clinical Trials Registry at www.anzctr.org.au/).