Should You Participate in Clinical Trials?
Once there was only AZT. Now there are a dozen drugs that can be used to combat HIV, and new drugs are being developed, tested, and approved at an unprecedented rate. Last October the Food and Drug Administration approved Combivir®, the first two-in-one pill for antiretroviral therapy. As its name suggests, Combivir combines two widely prescribed antiretroviral agents, AZT and 3TC, in a single tablet. These two drugs are routinely prescribed together because the addition of 3TC to an AZT-containing regimen results in the reversal of high-level resistance to AZT and leads to more durable suppression of viral load.
The particular advantage of Combivir, which is now on pharmacy shelves, is that it allows patients to take fewer pills -- two tablets a day, instead of the four to eight pills per day that patients assigned AZT and 3TC must take. This simplified dosing will make it easier for people with HIV who are taking these two drugs to remain compliant with their daily pill-taking schedule.
Last month the F.D.A. approved a new formulation of the protease inhibitor Invirase®. This version, a soft-gel capsule, has eight or nine times the bioavailability of the old formulation. Low bioavailability has been the chief limitation of this otherwise well-tolerated protease inhibitor, and the new formulation has compared favorably with Crixivan® in head-to-head studies.
With the wealth of new anti-HIV drugs now on pharmacy shelves, it is easy to forget that a relatively short time ago AZT was the only therapeutic option for people with HIV. Our current good fortune is the direct result of years of hard and often frustrating effort on the part of physicians, pharmaceutical companies, and their partners in the healthcare profession. These partners include unnamed and uncounted thousands of people with HIV who volunteered to participate in so-called clinical trials of new AIDS drugs. Some of these drugs were found to be highly effective in combating HIV infection, especially when used in combination with other agents. Others, like suramin, were found to be not only ineffective but highly, even fatally, toxic.
All of these experimental drugs -- the good, the bad, and the ugly -- were tested on human subjects before they were approved by the F.D.A. Those human subjects, the often unsung heroes of the AIDS epidemic, participated in the clinical trials of these drugs knowing the risks involved. You owe it to yourself to know the risks -- and the potential benefits -- of such trials before you consent to participate in one or more of them.
Despite the dramatic advances that have been made in treating HIV, the need for solid clinical research -- and for volunteers to participate in that research -- is as strong as ever. Researchers have not yet hit upon a combination of drugs that works for everyone. Indeed, the plain truth is that we have only learned how to slow the spread of HIV in the body. We still don't know how to eradicate it. And until we do, clinical trials of anti-HIV drugs are essential in the war against this cunning and persistent enemy.
What is a clinical trial?
Clinical trials are not for everyone. Sometimes a particular clinical trial is not in a particular patient's best interests. Sometimes a given clinical trial is a given patient's best treatment option. How do you know the difference? To help you decide, this article will explain what clinical trials are, and it will explore some of the issues that people should consider before joining a trial. Because the language of clinical trials is highly technical -- and most of it is unfamiliar to those who are not members of the healthcare profession -- we have defined some of the terms that are commonly used to describe clinical trials (see "The Terms You Need to Know," below). These terms also appear in the Pull Out and Save section of this issue, "From AZT to ZDV, a Glossary for People with HIV."
You might start by asking: What is meant by the phrase "clinical trial"? Basically, that means a drug trial that involves people. "Pre-clinical trials" are those conducted in test tubes and in animals. Test-tube studies are done to see if a potential anti-HIV drug kills the virus or, failing that, dramatically slows its growth. Animal studies provide all-important information about the toxicity and safety of an experimental compound. (Because few laboratory animals become infected when they are exposed to HIV, it has been difficult to determine how safe new anti-HIV drugs are before they are tested in human beings.) If the results from pre-clinical studies are encouraging, a drug is next tested in clinical studies.
There are four phases to all clinical studies, but when we are dealing with anti-HIV drugs we are mainly concerned with the first two. Phase I clinical trials focus primarily on safety and on what is called the "pharmacokinetics" of the drug in question -- that is, on how the drug is distributed throughout the body and how the body metabolizes the drug. These studies help researchers determine where the drug becomes concentrated after it is taken and how long it lasts in the blood stream.
Usually, only a few patients are recruited for Phase I trials, and such trials last a short period of time -- typically from a few weeks to a few months. Phase II trials are larger and longer. They provide additional information about a drug's safety and new information about its efficacy -- that is, how well the drug works. Some anti-HIV drugs have been approved or made available through large early-release programs after successful Phase II trials. However, the norm is for drugs to go on to still larger and longer Phase III trials before they are licensed. In the United States, a drug can only be licensed by the Food and Drug Administration, which also defines the specific medical conditions for which a drug may be prescribed.
Let's focus a little more on Phase II trials. Usually, they compare two or more groups of participants. The idea is to make the groups as similar as possible, so that the only variable is the experimental drug; this way, researchers can be reasonably sure that differences between the groups are due to the drug. For instance, the organizers of a trial might set up two groups of 50 HIV-positive patients who have roughly the same CD4 counts and are in about the same state of health. Typically, one group receives the experimental drug and the other gets either a placebo (a dummy pill that looks like the trial drug but contains no active ingredients) or another standard medication (like AZT or ddI).
The group that receives the placebo or the standard treatment is called the "control" group. Not all Phase II trials are controlled; some are designed so that everyone receives the experimental treatment. These trials are called "open-label" studies. Today, of course, very few trials look at only one drug; most test several combinations of several drugs in several groups -- which makes conducting the trials, and analyzing their results, exceedingly complicated.
Objectivity is extremely important in clinical research. For this reason, controlled trials are often "blinded." This means that patients do not know which drug (or drug dose) they are receiving. If a study is described as "double-blind," this means that no one -- not even the researchers who are conducting the trial -- knows who is getting what drug until the end of the trial. Long clinical trials have a mechanism built into their design, however, to ensure the safety of the participants. Halfway through the study an independent group of researchers "unblinds" the results, to see if there is a real advantage to the experimental drug. If a significant difference is found, the trial may be stopped and the new drug offered to everyone.
Should you participate in a clinical trial?
What do you have to gain -- or lose -- by entering a clinical trial? For some people with HIV, there are real advantages to participation. For others, the benefits are not so clear. Let's start with the potential advantages:
Now, let's consider the possible disadvantages of participation in a clinical trial:
Although the list of disadvantages is longer than the list of advantages, this does not mean that the scales usually tip against joining a trial. What this does mean is that entering a clinical trial is not a decision that should be taken lightly. Don't sign up on the spur of the moment. Talk your options over with your regular healthcare providers, and listen carefully to their advice. Discuss these options with your friends and with fellow patients -- especially those who have had experience participating in clinical trials.
Next, you should discuss the pros and cons of participation with the researchers who are conducting the trial. Until they have allayed any anxieties you may have -- and have answered whatever questions you have about the risks and benefits of participation -- don't agree to enroll. To help you reach a decision, we have prepared a list of questions that you may want to ask the organizers of the study (see "The Questions You Need to Ask," below). Last but certainly not least, ask yourself if you are absolutely certain that you are willing and able to fulfill the requirements of participation before you sign up.
At the time of your formal enrollment in the trial, you will be asked to sign an "informed consent" form. By signing it, you affirm that the organizers of the trial have explained all of the potential risks to you and outlined all of your responsibilities as a participant. Do not join a trial that does not require an informed-consent form, and keep in mind that informed consent is not a contract. You have the right to leave a trial for any reason whatsoever at any time you choose.
It is appropriate to become suspicious of the objectives of a clinical trial if its organizers seem to be pulling you away from your regular care-providers or the type of medical care you have been receiving. Their "trial" may be a money-making scheme rather than serious science.
Ideally, a clinical trial should be beneficial to researchers who conduct it, to patients who participate in it, and to the patients, the healthcare professionals, and the pharmaceutical companies who later benefit from the information it generates. To maximize their utility, clinical trials need to be carefully designed, so that they both accommodate the needs of participants and yield useful data.
Over the last fifteen years, AIDS activists have become intimately involved in the planning and execution of clinical trials in a way that has enhanced the state of AIDS research. Today, many well-designed trials are available to patients at all stages of HIV disease. If the idea of participating in one or more of these trials appeals to you, talk the matter over with your primary care-providers and investigate all of your options. You can get information about clinical trials -- anywhere in the country -- by calling the National Clinical Trials Hotline at 1-800-TRIALS-A.
Back to the December 1997 AIDS Care contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication AIDS Care.