Guide to clinical trials

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Post by Paul Kidd03 Jun 2014

If you've ever participated in a clinical trial, or tried to make sense of scientific research reports, you may have found some of the specialised language confusing to say the least. Let's look at the vocabulary of clinical trials.

Clinical trials are research studies in which new therapies for HIV are tested in humans. There are many different types of clinical trials and not all trials are designed to find out the same kinds of information. Whether you're considering entering a clinical trial or trying to make sense of the results of a trial , it's important to understand the way that trials operate and the language that researchers use to describe their work.

Relax, it's just a phase

You've probably heard of Phase 1, 2 and 3 (or Phase I, II and III) clinical trials. When new drugs are being tested, they usually follow the same process. Even before Phase 1 trials, new drugs go through a series of preclinical studies. These include test-tube studies (often referred to by the Latin term ‘in vitro', which means ‘in glass') to determine whether the drug has anti-HIV activity, and animal studies, which are helpful in determining whether the drug is likely to be safe and effective in humans.

If a drug passes these early tests, it can move on to be tested in humans.

Phase 1 trials are designed to determine whether a drug is safe for humans to take. These trials are generally conducted in just a few dozen people, who may have HIV or may be ‘healthy' volunteers. Phase 1 trials, which are usually open- label (see below), look at the safety of a drug, its pharmacologic action, side-effects with increasing doses and, sometimes, early evidence of effectiveness. The idea is just to get enough information about the safety and tolerability of a drug to design a good Phase 2 trial .

Phase 2 trials measure a drug's clinical effectiveness (whether it works or not) and to collect further information about the drug's safety, tolerability and side-effects. These trials usually involve a few hundred people.

The most critical stage in getting a new drug to market is the Phase 3 trial . Most of the trials which enrol people from Australia are Phase 3 trials, although some trials from other phases are conducted here too. The objective of a Phase 3 clinical trial is to determine whether a drug is effective enough, safe enough, and has few enough serious side-effects to be used in the general population. Phase 3 trials are sometimes combined with Phase 2 trials (Phase 2/3 trials) and can include anything from several hundred to several thousand people. The end result of Phase 3 trials (and there may be several Phase 3 trials conducted for a particular drug) is getting the drug approved by the government.

Phase 3 trials are usually randomisedplacebo- controlled, double-blind studies (more on that later).

Just to make things confusing, there are also Phase 4 trials, also called ‘Post-marketing Studies', too. These are studies carried out after the drug has been approved to confirm the results of earlier studies and look in more detail at long-term effects. Phase 4 studies can be especially important in HIV/AIDS when drugs are given accelerated approval.

The blind leading the blind 

Unlike lab rats, which are carefully bred to be identical, humans are variable creatures. People with HIV know all too well that just because your best friend is on some new antiretroviral, has no side-effects and gets great results from it, doesn't mean that for you that drug won't be a miserable choice. Scientists know this too.

In order to guarantee that the results of human trials are as scientifically valid as they can be, scientists follow the rather arcane method of randomised  double-blind placebo -controlled trials.

These trials have several arms (there must be at least two, but, like a Hindu god, sometimes more arms are better). In a randomised trial people who join the trial are randomly assigned to one of these arms. The process is not quite random, however: most trials adjust the randomisation so that the participants in each arm have more or less the same characteristics (similar numbers of men and women, a similar range of ages, etc.) Again, this not-quite-random process helps to ensure that the results of the trial are scientifically valid by avoiding over-representing any type of patient in any arm 

The participants in each arm receive a different treatment regimen. In some cases, people in one arm may receive a placebo .‘Placebo' is a Latin word that means ‘I shall please', probably the opposite of what it means to people who enrol in placebo -controlled trials in the hope of getting access to a promising new treatment.

Originally, a placebo was a fake treatment given by doctors to patients who either had nothing wrong with them or for whom there was no treatment, to keep them happy, thus the name. These days no doctor would give you a sugar pill to shut you up, so a placebo is an inactive substance (usually designed to look exactly like the real thing) given to the control or placebo arm  of a clinical trial .

The control arm  is there to answer an important scientific question: if the people we gave this treatment to responded in this way, how does that compare with people we did not give this treatment to? Because of the placebo effect, some people experience real physical changes when they take a placebo . People on the placebo arms of clinical trials occasionally have CD4 increases, viral load reductions, and debilitating side-effects just like the people taking the real drug. Having a control arm helps iron out these results in a scientifically valid way.

Not all clinical trials have a placebo arm . Some trials are designed to compare one treatment with another treatment (rather than one treatment with no treatment) and so these trials may have all active treatment arms.

Usually, but not always, the patients in a clinical trial are not told which arm of the trial they have been assigned to. This means that trial participants don't usually know which drug, or placebo ,they are getting. Trials like this are called blind or blinded studies.

Because scientists are humans just like patients, it's important to take account of the kind of expectations, reactions and prejudices people may have when administering a new drug and observing the results. That's where double-blind  studies come in. Double-blind  means that neither the patients nor the doctors and other scientists running a clinical trial know who is getting what. This approach helps to maintain objectivity on the part of the study staff.

At the end of the study (sometimes sooner) after the trial participants have taken the drug (or placebo )for a long enough period of time, the study is unblinded and the scientists can compare the results and side-effects from the various arms, and from that determine whether the drug is effective.