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Should You Enroll in a Clinical Trial?

September/October 2002

Photo by Paul Antico
Photo by Paul Antico
With 16 anti-HIV medications approved by the Food and Drug Administration and more than 15 years of antiretroviral treatment, you might think the medical community has optimized HIV treatment.

This is not the case. While clinical trials have answered many questions about patient treatment, even more remain. When is the best time to start therapy? Which regimens work best for treatment-naive patients? Which regimens should be saved for salvage options? How can treatment complications be minimized? What are long-term effects of receiving intermittent treatment or stopping treatment altogether?

Clinical trials are studies designed to test treatment safety and efficacy in patients. Researchers rely on volunteer patients to fill these trials. Some studies require only a handful of patients and a short period of time, while others follow hundreds of patients over a number of years.

Some studies look at the effects of new medications, others look at older medications, and still others do not investigate medications at all. A clinical trial might follow patients' diets, or a holistic therapy or a vaccine. Some HIV trials even need non-infected volunteers. In short, for every patient, there is probably a clinical trial being conducted that could use him or her.

Clinical research depends on patients wanting to get involved in the system. However, before a patient rushes to enroll, he or she should know the facts.


The Four Phases of Clinical Trials
  1. Phase I clinical trials are the first step in human testing. Prior to Phase I, treatments are tested in the lab and on animals. If a treatment is safe in the lab and in animals, safety testing is conducted with a small number of human volunteers. In Phase I trials, patients are usually given very short doses of the trial treatment to see the effects. Accordingly, patients are heavily monitored. Phase I clinical trials tend to require a large amount of patient interaction, but not for a very long period.

  2. If a treatment is deemed safe, it moves on to Phase II trials. These follow a larger number of patients for a longer period of time. Phase II trials look for treatment efficacy. Does the new treatment work? As the treatment is still relatively new to human patients, Phase II studies also require a large amount of patient time.

  3. Phase III begins after the treatment is found to be safe and effective for smaller numbers of patients in the first two phases. Phase III trials need to be conducted prior to FDA approval. These trials follow a large number of patients over a long period of time. The do not require as much patient time as phase I and II trials, but the duration of treatment is longer. If the Phase III trial is successful, the FDA may choose to approve the experimental therapy.

  4. After a treatment has been approved by the FDA, the testing does not stop. Phase IV trials are post-marketing trials. They may compare different approved regimens or they may look at side effects of the treatments. They often run for very long periods. Phase IV trials are designed to help optimize already available treatments. As these trials generally look at standard of care treatments, the involvement from the patient is not much different from non-research treatment.



UCLA's Steven Miles, M.D., examines a representation of resistant HIV protease (photo by Paul Antico).
UCLA's Steven Miles, M.D., examines a representation of resistant HIV protease (photo by Paul Antico).

The Benefits

Clinical trials are the primary method for patients to legally receive medications that have not yet been approved by the Food and Drug Administration.

Prior to widespread release, medications must face a series of tests (see "The Four Phases of Clinical Trials" above). For patients who have had difficulty with approved antiretrovirals, access to these medications may represent an attractive option. This includes patients who have drug-resistant HIV strains and patients who experience adverse events related to anti-HIV treatment.

Clinical trials may offer the best method to get the latest medications, which may be more potent or more tolerable than currently available anti-HIV medications. Patients should always keep in mind that these drugs haven not been tested thoroughly. Risk is always involved when taking untested treatments.

Even when a medication has been approved by the FDA, it may be costly. Clinical trials offer the opportunity for some patients to receive these medications free of charge. Additionally, patients may receive other benefits, such as compensation for time off from work, or for transportation costs.

Patients in clinical trials also often receive additional attention from health-care providers. Clinical trials often require more intensive monitoring, which may equate to more frequent appointments, viral genotyping or phenotyping, and monitoring of patient characteristics (such as blood levels of certain chemicals).

Increased monitoring may also mean increased time demands on the patient, however. Furthermore, entering a clinical trial does not guarantee increased attention for the patient. Control arms of many clinical trial control arms may not offer much benefit to the patient beyond the standard of care or conventional treatment.

"We try not to encourage patients to join [clinical trials] just to try and get better treatment," said Deon Claiborne, outreach coordinator for the Center for Clinical AIDS Research and Education at UCLA.


Suzette Chafey, a nurse practitioner at UCLA, records data from blood specimens. (Photo by Paul Antico.)
Suzette Chafey, a nurse practitioner at UCLA, records data from blood specimens (photo by Paul Antico).

The Risks

Patients should not lose sight of the fact that clinical trials are investigations.

While there is a risk for any treatment undertaken -- whether or not it is FDA-approved -- very little may be known about a clinically unproven medication or treatment. Clinical trial outcomes are not assured to be superior to the standard of care.

Clinical trial safeguards protect patients; still, there are risks. On rare occasions, clinical trials must be closed early due to unforeseen and unacceptable adverse events or poor anti-HIV effect.

Patients in clinical trials may not know what medication they receive. In double-blinded trials, neither patients nor their treating physicians knows the medication that the patients receive. This is an attempt to eliminate bias from the study.

In certain circumstances, the blind in a double-blinded trial may be "broken." This happens rarely, however, and is usually done in response to a serious adverse event.

Not all trials are blinded. Patients will be informed prior to agreeing to enter a trial whether or not it is blinded. If a patient is uncomfortable not knowing which medications are being dispensed, he or she can choose not to enter a trial.

Patients enrolling in clinical trials do not choose the arm they enter. Patients seeking investigational treatment may end up randomized to the control arm, thereby receiving conventional therapy.

One trial conducted at Cedars-Sinai Medical Center is investigating the treatment of depression among AIDS patients through massage therapy. While patients entering the trial may have visions of receiving free massages, the study has three arms -- two of which do not involve patient massage. Thus, two-thirds of the patients in the trial will not receive massages (although all patients receive vouchers for massages at the end of the study).

Clinical trials require an investment of time and commitment. The increased treatment that patients may get as a clinical trial volunteer can be problematic. For one former clinical trial patient, participating in a trial was "inconvenient for work because there were so many clinic visits."


Staff at the Center for Clinical AIDS Research and Education at UCLA work with patients and perform research for clinical trials. From left, Michael Marcial; Ann Johiro, F.N.P.; Judy Carden, R.N.; Steven Miles, M.D.; Margrit Carlson, M.D. and Stevon Washington (photo by Paul Antico).
Staff at the Center for Clinical AIDS Research and Education at UCLA work with patients and perform research for clinical trials. From left, Michael Marcial; Ann Johiro, F.N.P.; Judy Carden, R.N.; Steven Miles, M.D.; Margrit Carlson, M.D. and Stevon Washington (photo by Paul Antico).

Protections From Risk

"Do no harm to the patient" is one of the primary rules of medicine. Numerous safeguards have been developed to ensure that clinical trials are safe for patients.

The first measures designed to ensure patient safety come in the trial design. Clinical trials must be approved by both the FDA and an Institutional Review Board (IRB). These agencies make sure that patients do not undergo unnecessary or unsafe treatment.

HIV clinical trials also have the benefit of the AIDS Clinical Trials Group (ACTG), a large system composed of researchers, industry and patient advocates. The ACTG was created to develop clinical trials that are of importance to both care providers and patients. Thus, the proper design of a useful clinical trial is the first patient safeguard.

Informed consent forms are another safeguard. Once a patient has expressed interest in participating in a clinical trial, he or she is informed of the details of the trial, including the risks involved and what will be expected of the patient. Prior to entering the study, the patient must sign the informed consent forms. Often, patients are encouraged to take the forms home and give the trial serious thought before to enrolling. This is a good time for patients to discuss trials with family members, research the treatments being investigated, and generate questions for their treating physician.

Following enrollment, patients are heavily monitored in order to make sure that the treatment is both safe and efficacious. Periodically, a Data Monitoring Committee (DMC) will review the data from the trial to determine if the trial is worth continuing. If one arm is performing poorly compared with another arm, patients in the under-achieving arm are often offered the choice of receiving the more robust therapy.

Patients can leave a trial whenever they want. While it is important for each patient to stay committed to the trials he or she enrolls in, the option to leave is always available. The informed consent form is not a contract and does not bind a patient to participate in the trial.


Why Volunteer?

The amount of knowledge gained about HIV over the past 20 years has been nothing short of astounding.

Life expectancies for people with HIV have increased dramatically. The list of antiretrovirals available to patients receiving antiretrovirals has expanded from only zidovudine (AZT) in 1987 to 16 today, with more medications in the pipeline. Without the use of clinical trials and volunteers who enroll in them, these advances could not have been achieved.

Researchers continue to examine the best ways to treat HIV disease. With the continuance of clinical trials, our scientific and medical knowledge advances. This translates into more and better options for patients with HIV, increased management of treatment side effects, and, hopefully, into HIV vaccines -- both therapeutic and preventative.

One particular problem with HIV clinical trials is that the majority of volunteers have traditionally been white males. The New England Journal of Medicine recently reported that minority groups were less likely to receive experimental procedures for HIV infection. Women also have been traditionally underrepresented.

As the face of HIV changes, the need to study these groups increases. Sex, sociodemographic background, race and other patient characteristics may affect disease course or treatment response. Therefore, getting underrepresented populations involved in clinical research is of utmost importance.


Getting Involved

The first thing any patient should do is ask his or her care provider for information.

Some physicians will inform you of prospective clinical trials at the outset of treatment. Dr. Kathleen Squires, Associate Professor of Medicine at the University of Southern California's Keck School of Medicine and Medical Director at the Rand-Schrader Clinic of the LAC+USC Medical Center, states that she offers clinical trials as a viable treatment option for patients, if they are interested, when treatments are first being discussed.

Not all physicians and clinics participate in clinical trials; not all physicians feel comfortable working in the research setting. Therefore, it may be necessary for interested patients to look at other sources of information. As Dr. Squires states, "patients must be proactive about their treatment."

The AIDS Clinical Trials Information Service (www.actis.org) offers a list of clinical trials. The ACTG websites (adults: http://aactg.s-3.com; pediatric: http://pactg.s-3.com) provide numerous links to sites of interest, both nationally and locally. The HIV InSite (http://hivinsite.ucsf.edu) has a clinical trial database search. Locally, UCLA (www.medsch.ucla.edu/aidsinst) has a list of trials being conducted there.

Another method is through treatment advocates; treatment advocates are valuable resources and will help patients decide whether they want to get involved in clinical studies. There are many advocacy groups that can steer prospective patients to the proper gateway. Clinical trials are also sometimes advertised on message boards aimed at people living with HIV.

Even when patients find trials they want to participate in, they must be screened prior to admission. Rejection from one trial, however, does not mean that the patient is not fit for all clinical trials. Many studies are being conducted and all types of patients are needed.


Steven Miles, M.D., of the UCLA CARE Center (photo by Paul Antico).
Steven Miles, M.D., of the UCLA CARE Center (photo by Paul Antico).

What to Ask

The key to knowing which questions to ask is doing background research on the trial and medication studied.

One former clinical trial patient advises volunteers to "learn as much as you can about the drugs in the clinical trials on your own. Don't be afraid to ask questions." Study operators will be able to answer questions about treatment side effects, the demands the study will make on the patient, and the study design. Patients should find out what will happen to them at the end of the study, such as, if he or she be allowed to continue on the medication.

Patients will want to find out how often they will have to go to the clinic and for how long. While most studies will pay for the cost of medication, it is important to find out if all medication expenses are covered by the treatment site. Also, patients should inquire about any potential compensation for participating in the study. Some studies will not offer any compensation, but might be able to help with transportation to the clinic.

Other questions include: Does the study require hospitalization at any point? What is the study trying to find out? What sorts of patients are being enrolled?

Most importantly, patients should ask what other options are available. Making an informed choice to join a clinical trial is difficult if other options are unexplored. Patients should ask the same questions about standard treatment options, so they may compare options and make the right decisions.

There is only one way to find out if a clinical trial is the right decision for you: Get informed. The more you find out about what it takes to be involved, the easier it will be to decide on the right course of action. Clinical trials are not for everyone. By informing yourself and talking with your healthcare provider and treatment advocate you can determine if you are ready to volunteer.


Glossary of Terms Commonly Used in Clinical Trials
Article: Should You Enroll in a Clinical Trial?

Adverse Event: A side effect that results from the use of a treatment. Life-threatening side effects are called "serious adverse events."

Arm: A branch of the study. Most studies are divided into groups, or arms, designed to compare one treatment arm with another.

Bias: A flaw in the study design that could skew the results in favor of a particular conclusion. Researchers try to eliminate bias in clinical trials to get an impartial and scientific result; however, it is very hard to eliminate all bias from a study.

Control: The standard that is compared against. In order to determine if a new treatment is beneficial, it must be compared against a standard. Almost all clinical trials have a control arm.

Data Monitoring Committee (DMC): An independent panel that monitors the study results. The DMC is used to help eliminate study bias. The DMC may also intervene to stop a trial if one arm is found to be unsafe or sub-standard.

Double-Blind: When neither the patient nor the health care providers know which medications are being dispensed to trial participants. Double-blind studies are used to get impartial results and eliminate study bias.

Informed Consent: The process of educating a potential clinical trials participant so he or she can make an educated decision as to whether to join a clinical trial. All patients must be informed of their rights as a participant, the safety hazards they might face, the study aims, and what is to be expected of him or her. Patients must sign an informed consent form to attest that they have received this information.

Institutional Review Board (IRB): A panel created to look at and approve or reject clinical trial study proposals. An IRB is mandated by the FDA and is composed of many different types of people, including researchers, ethicists, lay people, treatment advocates, lawyers, clergy, and others. Clinical trials must be approved by an IRB before they can begin. IRBs are used to help ensure that patients are not exposed to unreasonable or unnecessary risks or unethical treatments.

Phase: The stage if the trial. Clinical trials are divided into phases I, II, III and IV. The lower the phase number, the earlier the treatment is in the development pipeline.

Placebo: An inactive medication given as a control in some clinical trials.

Randomization: The process of randomly assigning clinical trial volunteers into separate arms. This is done to make sure that the arms are evenly balanced by patient characteristics and that bias is not introduced by the assignment of patients.

Standard of Care: The conventionally given treatment. It is unethical to knowingly assign patients to treatments that do not meet the standard of care.


Michael LindeMichael Linde is a graduate student at the University of Southern California. He previously worked as an HIV writer in New York City and Washington, D.C. He can be reached by e-mail at linde@usc.edu.


Back to the September/October 2002 issue of Positive Living.


This article has been reprinted at The Body with the permission of AIDS Project Los Angeles (APLA).



  
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This article was provided by AIDS Project Los Angeles. It is a part of the publication Positive Living.
 
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