Twenty years after the start of the AIDS epidemic we have 16 FDA-approved antiretroviral drugs in the U.S., and more drugs are in clinical development. So, how important are HIV clinical trials? As more people living with HIV are able to continue working and stay relatively healthy, and more women and people of color are becoming infected with HIV, it appears to be more difficult to enroll people into clinical trials. Is this a problem, or a reflection of the lack of significant questions still remaining unanswered in the treatment of HIV?

Unfortunately, there remain many critical unanswered questions about the treatment of HIV. From the beginning stages of HIV infection, through the initiation of therapy, selection of therapy, changing therapy, potential differences in treatment based on gender and ethnicity, the usefulness of measuring drug levels, and predicting and managing short and long-term side effects of HIV therapy, there remain many unanswered questions (to name only a few areas of needed research).

Early on in the AIDS epidemic, clinical trials often were the only way that many people could get access to the newest HIV drugs. In states like Washington, most people are able to get funding for HIV treatment, and they have many treatment options without enrolling in a clinical trial. Also, it is difficult to enroll representative numbers of women and people of color in clinical trials.

Compounding this problem has been some very adverse publicity about the conduct of clinical trials with two deaths of volunteers in non-HIV trials on the East Coast in the past couple of years, and the high-profile series of articles in the Seattle Times discussing possible institutional errors made in the conduct of cancer trials at the Fred Hutchinson Cancer Research Center.

Also, the federal government has temporarily halted clinical research at several major research centers in the past two years because of concerns about research oversight by local institutional review boards (IRB), the groups that oversee the conduct of research at local institutions. Pharmaceutical companies have been reluctant to cooperate with one another and conduct needed clinical trials after the FDA has approved their drug.

All of these factors are challenging the ability of researchers to successfully conduct HIV clinical research. The result of all of these factors is that many questions about the treatment and management of HIV infection remain unanswered.

Phases of Clinical Trials

There are four phases of testing of new drugs:

• Phase I: primarily performed to find the correct dose and evaluate side effects (toxicity).

• Phase II: a larger trial to evaluate safety and efficacy (i.e., does the drug work?).

• Phase III: a trial to compare the new drug to the standard treatment, to look for either equivalency, or superiority. Registrational trials are phase III trials specifically designed to lead to FDA drug approval.

• Phase IV: post-approval studies to learn more about the proper clinical use of a drug and long-term side effects after FDA approval.

Benefits and Risks of Participating in a Clinical Trial

Whenever someone is asked to participate in a trial, they are provided with information about the purpose of the trial, the risks and benefits, and an informed consent form explaining many of the details of the trial. Almost all informed consent forms state that there is no benefit to participating in the trial. Thus, the research community relies on the altruism of the trial participants.

The real benefit in participating in a trial is in contributing to the advancement in the knowledge of the field. However, a trial participant will almost always receive more monitoring and closer observation while participating in trial, compared to receiving the same treatment in a non-trial setting.

Many trials will provide investigation procedures at no cost to the participant, which may not be available outside of a clinical trial. Examples of such tests in HIV trials might include special tests to measure body fat changes, thickening of arteries, and bone density, resistance tests, or the measurement of drug levels in the blood. However, these tests and closer monitoring often require more frequent visits to the clinic.

Most trials pay some money to people for "invasive" procedures, such as lymph node biopsies, or spinal taps. Also, some trials will pay people some money to compensate them for their time or travel expenses.

The duration and complexity of HIV trials vary greatly. Some trials may be so simple as having a blood test and answering a questionnaire one time. At the other extreme, some studies require that you spend some time in the hospital, or require frequent visits over a long period of time. When considering participation in a trial, ask to see the schedule of evaluations. Most trials have a table that shows what tests are performed, and how often a person has to visit the clinic. Also, ask how many of the tests need to be done fasting. Many studies of the long-term metabolic complications of HIV treatment require fasting blood tests to get an accurate measurement of blood fats (cholesterol and triglycerides).

Ethics: Placebos and Randomization

There is a misconception that placebos (fake pills) are unethical. Some of these fears date back to trials done years ago that in fact are unethical by today's standards of research, or even by the standards at the time of the trial. The classic example is the Tuskegee trial, wherein the government enrolled African Americans in a trial to determine the natural history of syphilis infection. The participants were not offered treatment, even when effective treatment became available during the course of the study. Hopefully, with closer oversight of trials, such an experiment will never be conducted again.

Placebos are often used in trials to eliminate the possibility that the outcome of the trial will be influenced by either the researcher or the subject's bias if they knew which arm of the trial they are in. If the standard of care is that no treatment is available, then a trial may compare a placebo to a new compound.

A good example of this type of trial is an AIDS vaccine trial. Neither the subject nor the researcher knows which person is getting the vaccine and which person is receiving the placebo. There is nothing unethical about this type of trial, and it is the most scientifically sound way to evaluate a new treatment. However, if the standard of care is to treat the condition being studied, such as pneumocystis pneumonia (PCP), then the trial would compare the standard of care treatment to the new agent.

What has confused many people is that such a trial design might still use placebos, but all people would get an active drug. A typical design would compare the standard of care drug, agent A, to the new drug, agent B. So, one arm would be agent A plus placebo B, and the other arm would be agent B plus placebo A. Thus, neither the subject nor the researcher would know which arm they were in, but everyone in the trial would be receiving an active drug, even though the trial used placebos to eliminate possible bias.

Randomization is merely the process of assigning people to the different treatments being compared in the trial. This is done on a random basis so that neither the researcher nor the subject knows which arm they are going to be in when they agree to participate in a trial. Randomization is critical to achieve balance among the many variables, known and unknown, which may influence the outcome of a trial. Again, there is nothing inherently unethical about randomization.

How Is a Clinical Trial Monitored?

The local institutional review board (IRB) has the responsibility of monitoring the conduct of the trial. Researchers are required to report all problems ("adverse events") to the oversight board and the central group monitoring a trial. This is an area of current concern because many local IRBs in fact do not have adequate resources to closely monitor all trials ongoing at their institution.

Trials are required to have "interim monitoring" plans. There are also formal data safety monitoring boards (DSMBs) which are composed of independent members not on the trial team, and should include a community representative. The DSMB will look at the results of the ongoing trial, at pre-planned intervals, to determine if the trial should continue. The purpose of these monitoring plans is to determine if one of the treatments is performing much better or worse. In such a situation a trial may be stopped prematurely. Also, if it appears that is impossible for the trial to achieve its goals, the trial will be stopped for "futility." It is unethical to conduct a trial that has no chance of answering the question it is asking. A common scenario leading to stopping a study is if there are not enough "endpoints" occurring. This may occur in a trial studying a new drug for prevention of an opportunistic infection. If no new infections are occurring in either arm of the study, the study is not going to be able to determine which treatment is better.

Community Input and Oversight

The local HIV AIDS Clinical Trials Unit, Pediatric AIDS Clinical Trials Unit, the HIV Prevention Trials Unit, and the HIV Vaccine Trials Unit all have active community advisory boards which meet monthly. (You may call STEP if you would like meeting information.) Additionally, the national Adult and Pediatric AIDS Clinical Trials Group, and the international HIV Prevention and Vaccine Trials Groups all have community advisory boards. Community members provide input at all levels of operation, from scientific agenda development, to trial design and conduct, and assistance with recruitment and retention. Some other areas of medical research are now also incorporating community members in the design and conduct of trials, notably in the areas of breast cancer and hepatitis C research.

Conclusion

While participation in a clinical trial may not directly benefit the individual participant, critical questions in many areas of HIV research cannot be answered unless people enroll in research trials. It is always a good idea to ask the investigator if they would enroll in the trial they are discussing with you, if they were in your situation. It is also a good idea to ask for a copy of the consent form to take home and read, and review with your primary healthcare provider before enrolling in a research trial. All trials allow you to drop out from the trial at any time if you want to, although a trial can only be successful if almost all the people in the trial complete it. I have been a member of the national community advisory board of the Adult AIDS Clinical Trials Group for four years, and have been very impressed with the seriousness that researchers consider comments and concerns voiced by community representatives. Active community involvement in all levels of HIV research is essential both to focus the research and ensure that the trials proposed are ethical and of interest to the community.

One of the biggest challenges facing HIV research today is finding enough people to enroll in trials, and particularly finding adequate numbers of women and people of color to enroll in clinical trials. There is a lot of suspicion about medical research in the African-American community, in part because of the past history of research such as the Tuskegee Experiment. Also, many HIV-infected women are very busy taking care of their own children, who also may be HIV-infected, and lack the time to participate in trials. It is only through active cooperation between the community of HIV-infected people and researchers that these challenges can be overcome, so that the results of HIV research will provide answers to questions that apply to all people living with HIV.