If you've ever participated in a clinical trialA clinical trial is a research study to answer specific questions about vaccines or new therapies or new ways of using known treatments. Clinical trials are used to determine whether new drugs or treatments are both safe and effective. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people. Trials are in four phases: Phase I tests a new drug or treatment in a small group; Phase II expands the study to a larger group of people; Phase III expands the study to an even larger group of people; and Phase IV takes place after the drug or treatment has been licensed and marketed. , or tried to make sense of scientific research reports, you may have found some of the specialised language confusing to say the least. This Backgrounder (from the Nov-Dec 2002 edition of Positive Living) looks at the vocabulary of clinicalPertaining to or founded on observation and treatment of participants, as distinguished from theoretical or basic science. 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 researcher use to describe their work.
Relax, it's just a phase
You've probably heard of Phase 1A clinical trial designed to establish whether an experimental drug is safe for humans to take. Phase I studies determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and look for early evidence of effectiveness; these studies may include either people with HIV, HIV-negative volunteers, or both, 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 preclinicalReferring to the testing of experimental drugs in the test tube or in animals – the testing that occurs before trials in humans may be carried out. studies. These include test-tube studies (often referred to by the Latin term ‘in vitro(Latin: within the glass) refers to the technique of performing a given experiment in a controlled environment outside of a living organism; for example in a test tube.,' 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(Of a drug or treatment). The maximum ability of a drug or treatment to produce a result regardless of dosage. A drug passes efficacy trials if it is effective at the dose tested and against the illness for which it is prescribed. In the standard procedure, Phase II clinical trials gauge efficacy, and Phase III trials confirm it.. The idea is just to get enough information about the safety and tolerability of a drug to design a good Phase 2A smaller clinical trial designed to establish whether a drug is effective. Phase II studies are conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks. If there is evidence that the drug is effective, a Phase III study is undertaken, with a larger number of participaants, to confirm this. 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 3A large clinical trial designed to establish whether a drug is effective and safe enough for widespread use. Phase III studies include expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling. 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 randomised, placeboA dummy medical treatment, designed to have no pharmacological effect, administered to the control group of a clinical trial.- controlled, double-blindA clinical trial design in which neither the participating individuals nor the study staff knows which participants are receiving the experimental drug and which are receiving a placebo (or another therapy). Double-blind trials are thought to produce objective results, since the expectations of the doctor and the participant about the experimental drug do not affect the outcome; also called double-masked study. studies (more on that later).
Just to make things confusing, there are also Phase 4Post-marketing studies to delineate additional information including the drug's risks, benefits, and optimal use. 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 antiretroviralA medication or other substance which is active against retroviruses such as HIV., 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-controlledA method of investigation of drugs in which an inactive substance (the placebo) is given to one group of participants, while the drug being tested is given to another group. The results obtained in the two groups are then compared to see if the investigational treatment is more effective in treating the condition. 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 randomisationA method based on chance by which study participants are assigned to a treatment group. Randomization minimizes the differences among groups by equally distributing people with particular characteristics among all the trial arms. The researchers do not know which treatment is better. From what is known at the time, any one of the treatments chosen could be of benefit to the participant 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 armA group of patients in a clinical trial who do not receive the drug or treatment being investigated, for the purpose of comparison with those who do. Participants in the control group of a clinical trial are either given standard treatment (excluding the drug being studied) or a placebo. 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 effectA physical or emotional change, occurring after a substance is taken or administered, that is not the result of any special property of the substance. The change may be beneficial, reflecting the expectations of the participant and, often, the expectations of the person giving the substance., some people experience real physical changes when they take a placebo. People on the placebo arms of clinical trials occasionally have CD4 increases, viral loadA measurement of the quantity of HIV RNA in the blood. Viral load blood test results are expressed as the number of copies (of HIV) per milliliter of blood plasma. 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 blindedA randomized trial is "Blind" if the participant is not told which arm of the trial he is on. A clinical trial is "Blind" if participants are unaware on whether they are in the experimental or control arm of the study; also called masked. 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.