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.

"If you are not doing well on the currently available treatments, clinical trials are a way of gaining access to new drugs that might help you. Sometimes these experimental treatments are available outside of clinical trials, and you may want to explore this option after you have discussed the matter with your care-providers."

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:

• If you are not doing well on the currently available treatments, clinical trials are a way of gaining access to new drugs that might help you. Sometimes these experimental treatments are available outside of clinical trials, and you may want to explore this option after you have discussed the matter with your care-providers. The F.D.A. has permitted some pharmaceutical companies to set up "early release" programs for promising new drugs, programs that give people with HIV direct access to experimental drugs if they meet the criteria of the program. In most cases, however, a clinical trial is the only way to get an unapproved drug.

• If you agree to participate in a clinical trial you often receive extra medical care, and it is usually free or offered at very low cost. Keep in mind that the care you are being given by researchers should not replace regular visits to your primary care-provider. Think of this extra care as a bonus, not a substitute. Some patients with little or no health insurance can get better medical care by participating in clinical trials.

• Since drugs that are already approved are sometimes studied in clinical trials, participation can be a way to gain access to a treatment that you otherwise could not afford, if your insurance does not cover prescriptions for the drugs being used in the study.

• Some people feel a sense of heightened power, and of closer control over their clinical condition, when they seek out the latest treatments. For these individuals, participation is a way of ensuring that they have left no stone unturned in their efforts to achieve clinical stability and maintain their health.

• Participating in a trial "helps the cause." It is no exaggeration to say that a large share of the credit for current treatment successes belongs to the people who participated in the clinical trials conducted over the last decade. Still, it is important that you do not lose sight of the fact that your first responsibility is to yourself and to your own health.

• Some primary care-providers participate in clinical trials, and they may be able to give you the study drugs in their own offices. This eliminates the need to go to someone else's office, or to a clinic or hospital, for testing and treatment.

Now, let's consider the possible disadvantages of participation in a clinical trial:

• If it is a controlled trial, you may not get the experimental drug. Indeed, if it is a placebo-controlled trial, you may not get any drug at all.

• There is no guarantee that an experimental treatment will help. In fact, it might even hurt you -- despite whatever evidence has been gathered from test-tube studies that the experimental treatment is beneficial.

• Some trials require that you stop current treatments. If you are stable on your current regimen, changing it is probably unwise.

• Even if a drug has proven to be safe when taken in short-term Phase I trials, this does not guarantee that side effects won't develop with long-term use. On rare occasions these unanticipated side effects can be serious, and on very rare occasions they can even be life-threatening.

• Some trials require you (or your insurance carrier) to bear some of the costs of the study. Clinical trials that entail significant costs to participants should generally be avoided.

• Trials can be inconvenient. They usually require extra visits to the doctor's office or to a clinic or hospital. Some may even require you to be admitted to the hospital for a time. Transportation and/or child-care may be a problem for some patients. Ask if any of these costs are covered by the trial.

• Trials can be unpleasant. They may require that you undergo a lot of tests, and these tests may be uncomfortable or even painful. It is not uncommon for such studies to require that you have blood samples taken on a regular basis, and some trials may also require stool samples, sputum samples, bone-marrow testing, and other laboratory tests.

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.

"Clinical trials can be inconvenient. They usually require extra visits to the doctor's office or to a clinic or hospital. Some may even require you to be admitted to the hospital for a time. Transportation and/or child-care may be a problem for some patients. Be sure to ask if any of these costs are covered by the trial."

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.

The Terms You Need to Know

Arm: all of the study subjects taking a particular drug or drug dose are said to be in that "arm" (or "cohort") of the study Bioavailability: how much of the drug is absorbed into the bloodstream Blinded: participants do not know which arm of the study they are in (i.e. they do not know what drug or drug dose they are getting) Control group: the trial participants who do not receive the experimental treatment Crossover: a trial in which the experimental and control groups switch treatments Data Safety Monitoring Board (DSMB): a group of independent researchers who review the data while the trial is going on, to determine if one drug or drug dose is markedly safer or more effective than another Double-blinded: neither the trial participants nor the researchers know who is receiving which drug or drug dose Exclusion criteria: list of reasons why some prospective participants should not be included in the study (e.g. a trial may not want people with CD4 counts above 500, or pregnant women, or patients who have previously used the drug being studied) Experimental group: the trial participants who do receive the experimental treatment Half-life: the time it takes for the body to eliminate half of the drug that reaches the bloodstream Inclusion criteria: list of things (clinical state, blood values, etc.) that are required of every participant in a clinical trial at time of entry Open-label: a trial in which everyone gets the experimental treatment Pharmacokinetics: the study of how the body metabolizes a drug, which tissues the drug penetrates, its half-life, and other variables Placebo: a pill that looks like the experimental drug but does not contain any active ingredients Protocol: the overall design, or blueprint, of the study Randomized: distributed by chance

The Questions You Need to Ask

Here are some of the issues to consider when you meet with the study coordinators: Will you need to alter -- or stop -- your current treatment? (Be sure to bring to your first meeting with the study organizers a list of all drugs you are taking.) What is the evidence that this treatment might work against HIV? What are the potential risks? How long will the study last? How often do you need to come in for visits, and how many blood samples and/or other specimens will be needed? Are evening/weekend appointments available? Are there any costs to you? Can you be reimbursed for travel expenses or child care? Who will take care of you if you have side effects? Will you have 24-hour access to a doctor involved in the study, in case you have an emergency that could be related to the experimental drug? Will you have access to the drug after the study is over, and will you be eligible for future studies of the drug?